WO2025090870A1

WO2025090870A1 - Infigratinib and metabolites thereof for use in methods of treating skeletal disorders

Info

Publication number: WO2025090870A1
Application number: PCT/US2024/052968
Authority: WO
Inventors: Xue Ge; David Martin; Maribel REYES
Original assignee: QED Therapeutics Inc
Current assignee: QED Therapeutics Inc
Priority date: 2023-10-27
Filing date: 2024-10-25
Publication date: 2025-05-01
Anticipated expiration: 2026-04-27

Abstract

Provided herein are methods of delivering effective amounts of active metabolites of infigratinib to a patient in need of treatment for a skeletal disorder (e.g., achondroplasia or hypochondroplasia).

Description

INFIGRATINIB AND METABOLITES THEREOF FOR USE IN METHODS OF TREATING SKELETAL DISORDERS

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63/546,133, filed October 27, 2023, the contents of which are incorporated by reference herein in their entirety.

BACKGROUND

[0002] Skeletal dysplasias can affect bone development, cartilage growth, and neurological functioning. Certain skeletal dysplasias, including achondroplasia (ACH) and hypochondroplasia (HCH), are forms of dwarfism. ACH is the most common nonlethal form of skeletal dysplasia, affecting between 1 in 15,000 to 1 in 30,000 individuals (Horton WA, Hall JG, Hecht JT., Achondroplasia. Lancet., 2007, 370, 162-72; Waller DK, Correa A, Vo TM, Wang Y, Hobbs C, Langlois PH, et al., US. Am. J. Med. Genet. A., 2008, 146A(18), 2385- 2389). People with ACH have short stature, on average growth to approximately 4 feet (-125 cm) in height, and are prone to significant co-morbidities including sleep apnea, chronic otitis media with conductive hearing loss, spinal stenosis, obesity, and in some cases, narrowing of the foramen magnum that can require urgent surgical intervention. HCH is similar to ACH and is characterized by less pronounced physical signs; however, HCH patients may also be impacted by greater neurological challenges including mild to moderate intellectual disabilities or learning problems.

[0003] ACH is characterized by defective endochondral ossification resulting from gain of function mutations in the fibroblast growth factor receptor (FGFR) 3 gene. These mutations, of which 99% are G380R mutations (Bellus GA, Hefferon TW, Ortiz de Luna RI, Hecht JT, Horton WA, Machado M, et al., Am. J. Hu. Genet., 56, 368-373, 1995), cause the receptor to be in a constitutively active state, disrupting the chondrocyte proliferation and differentiation in the growth plate and thereby inhibiting linear bone growth (Unger S, Bonafe L, Gouze D., Curr. Osteoporos. Rep., 2017, 15, 53-60). The key phenotype of ACH is disproportionate short stature with rhizomelia (shortened proximal limbs). [0004] Approximately 80% of cases result from de novo mutations (Omitz DM, Legeai-Mallet L., Dev. Dyn., 2017, 246, 291-309). Diagnosis typically occurs at birth, although it may be suspected on the basis of a late prenatal ultrasound.

[0005] There are limited therapeutic interventions for ACH and HCH in North America, Europe, and Australia, and no widely accepted consensus about treatment (Unger). The majority of treatment options are nontargeted, ineffective, or painful interventions aimed at preventing or treating complications of ACH (FDA Background Document. Joint meeting of the Pediatric Advisory Committee and Endocrinologic and Metabolic Drugs Advisory Committee. 11 May 2018. Available at: https://www.fda.gov/downloads/AdvisoryCommittees/; Unger). While a peptide therapy, vosoritide, is approved in at least the US, Europe, Japan, and Australia, it requires daily subcutaneous injection, which is undesirable for the pediatric patient population, and provides limited therapeutic benefits.

[0006] Recombinant human growth hormone (r-hGH) has also been explored for use as an ACH or HCH intervention; however, while an increase in growth velocity was noted after treatment with r-hGH (height increase from -5.0 to -4.0 standard deviations over 5 years), no clear longterm growth effects have been shown . and no clear benefit has been established for long-term treatment (Miccoli M, Bertelloni S, Massart F., Horm. Res. Paediatr., 2016, 86, 27-34). Accordingly, rhGH has not emerged as a recommended treatment option for ACH (Horton;

FDA) or HCH (Cetin T., §iklar Z., Kocaay P., Berberoglu M., J. Clin. Res. Pediatr. Endocrinol., 2018 Dec, 10(4), 373-376).

[0007] Limb-lengthening procedures can provide 15-30 cm of additional height (-20% increased length of bone segment), but the procedures are painful, often require repeat procedures, and have high complication rates (Horton). Furthermore, the growth rate of the growth plate can be disturbed by these procedures, and the cosmetic effect of long legs and short arms may not be suitable for some patients (FDA). Clinicians who consider limb lengthening now typically require psychological evaluations and require that children be old enough to provide assent for the procedure (Wright MJ, Irving MD., Arch. Dis. Child., 2012, 97(2), 129-134).

[0008] Therefore, there remains an unmet need to develop novel therapeutic strategies for treating subjects with ACH or HCH. SUMMARY

[0009] The present disclosure provides methods of treating skeletal dysplasias, such as achondroplasia (ACH) and hypochondroplasia (HCH). The methods disclosed herein may comprise administration of an FGFR inhibitor, namely infigratinib, and/or provision of a compound of formula (II), a compound of formula (III), and a compound of formula (IV). [0010] In an aspect, the present disclosure provides a method of delivering or providing a compound of formula (II) to a subject in need of treatment for a skeletal dysplasia, comprising administering infigratinib, or a pharmaceutically acceptable salt thereof, to the subject in an amount sufficient to deliver an effective amount of a compound of formula (II) to the subject, wherein the compound of formula (II) has the structure:

[0011] In another aspect, the present disclosure provides a method of treating a skeletal dysplasia in a subject in need thereof, comprising administering infigratinib, or a pharmaceutically acceptable salt thereof, to the subject in an amount sufficient to deliver an effective amount of a compound of formula (II) to the subject, wherein the compound of formula (II) has the structure:

[0012] In another aspect, the present disclosure provides a method of delivering or providing a compound of formula (III) to a subject in need of treatment for a skeletal dysplasia, comprising administering infigratinib, or a pharmaceutically acceptable salt thereof, to the subject in an amount sufficient to deliver an effective amount of a compound of formula (III) to the subject, wherein the compound of formula (III) has the structure:

[0013] In another aspect, the present disclosure provides a method of treating a skeletal dysplasia in a subject in need thereof, comprising administering infigratinib, or a pharmaceutically acceptable salt thereof, to the subject in an amount sufficient to deliver an effective amount of a compound of formula (III) to the subject, wherein the compound of formula (III) has the structure:

[0014] In another aspect, the present disclosure provides a method of delivering or providing a compound of formula (IV) to a subject in need of treatment for a skeletal dysplasia, comprising administering infigratinib, or a pharmaceutically acceptable salt thereof, to the subject in an amount sufficient to deliver an effective amount of a compound of formula (IV) to the subject, wherein the compound of formula (IV) has the structure:

[0015] In some embodiments, the subject is in need of FGFR3 modulation.

[0016] In another aspect, the present disclosure provides a method of treating a condition, disease, or disorder requiring FGFR3 modulation in a subject in need thereof, comprising administering infigratinib, or a pharmaceutically acceptable salt thereof, to the subject in an amount sufficient to modulate the pharmaceutical activity of a compound of formula (II) on FGFR3, wherein the compound of formula (II) has the structure:

[0017] In another aspect, the present disclosure provides a method of treating a condition, disease, or disorder requiring FGFR3 modulation in a subject in need thereof, comprising administering infigratinib, or a pharmaceutically acceptable salt thereof, to the subject in an amount sufficient to modulate the pharmaceutical activity of a compound of formula (III) on FGFR3, wherein the compound of formula (III) has the structure:

[0018] In another aspect, the present disclosure provides a method of treating a condition, disease, or disorder requiring FGFR3 modulation in a subject in need thereof, comprising administering infigratinib, or a pharmaceutically acceptable salt thereof, to the subject in an amount sufficient to modulate the pharmaceutical activity of a compound of formula (IV) on FGFR3, wherein the compound of formula (IV) has the structure:

[0019] In some embodiments, the condition, disease, or disorder is a skeletal dysplasia.

[0020] In some embodiments, the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia (e.g., thanatophoric dysplasia type I or thanatophoric dysplasia type II), osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, Crouzon syndrome (e.g., Crouzon syndrome acanthosis nigricans), craniosynostosis, Kallmann syndrome, hypogonadotropic hypogonadism, cleft palate and other craniofacial defects, scoliosis, Type 1 or classic Pfeiffer syndrome, osteoglophonic dysplasia, craniosynostosis, mandibular progmathism, hypertelorism, brachydactyly, inter- phalangeal joint fusion, Jackson-Weiss syndrome, Antley-Bixler syndrome, Apert syndrome, Crouzon syndrome, X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, and trigonocephaly. In some embodiments, the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia (e.g., thanatophoric dysplasia type I or thanatophoric dysplasia type II), osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, and Crouzon syndrome (e.g., Crouzon syndrome acanthosis nigricans). In some embodiments, the skeletal disorder is achondroplasia. In some embodiments, the skeletal disorder is hypochondroplasia.

[0021] In some embodiments, administering infigratinib, or a pharmaceutically acceptable salt thereof, comprises administering a daily dose of about 0. 1 mg to about 50.0 mg of infigratinib, or a pharmaceutically acceptable salt thereof, to the subject.

[0022] In some embodiments, administering the daily dose of about 0.1 mg to about 50 mg of infigratinib, or a pharmaceutically acceptable salt thereof, results in an increased Cmax ratio of the compound of formula (II) to infigratinib in the subject, as compared to administering a daily dose of 125 mg of infigratinib, or a pharmaceutically acceptable salt thereof. In some embodiments, administering the daily dose of about 0. 1 mg to about 50 mg of infigratinib, or a pharmaceutically acceptable salt thereof, results in an increased Cmax ratio of the compound of formula (II) to infigratinib in the subject about 4 hours after administration, as compared to administering a daily dose of 125 mg of infigratinib, or a pharmaceutically acceptable salt thereof. In some embodiments, administering the daily dose of about 0. 1 mg to about 50 mg of infigratinib, or a pharmaceutically acceptable salt thereof, results in a Cmax of the compound of formula (II) in a range of about 0.1 ng/mL to about 21 ng/mL in the subject about 4 hours after administration. In some embodiments, the Cmax is determined on Day 1 of administration. In some embodiments, the Cmax is determined on Day 21 of administration.

[0023] In some embodiments, administering infigratinib, or a pharmaceutically acceptable salt thereof, comprises administering a daily dose of about 0. 1 mg to about 40.0 mg of infigratinib, or a pharmaceutically acceptable salt thereof, to the subject.

[0024] In some embodiments, administering infigratinib, or a pharmaceutically acceptable salt thereof, comprises administering a daily dose of about 1.0 mg to about 20.0 mg of infigratinib, or a pharmaceutically acceptable salt thereof, to the subject. [0025] In some embodiments, administering infigratinib, or a pharmaceutically acceptable salt thereof, comprises administering a daily dose of about 1.0 mg to about 10.0 mg of infigratinib, or a pharmaceutically acceptable salt thereof, to the subject.

[0026] In some embodiments, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, 3.5 mg, about 4.0 mg, about 5.0 mg, about 6.0 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg, about 16.0 mg, about 17.0 mg, about 18.0 mg, about 19.0 mg, about 20.0 mg, about 21.0 mg, about 22.0 mg, about 23.0 mg, about 24.0 mg, about 25.0 mg, about 26.0 mg, about 27.0 mg, about 28.0 mg, about 29.0 mg, about 30.0 mg, about 31.0 mg, about 32.0 mg, about 33.0 mg, about 34.0 mg, about 35.0 mg, about 36.0 mg, about 37.0 mg, about 38.0 mg, about 39.0 mg, or about 40.0 mg of infigratinib, or a pharmaceutically acceptable salt thereof, is administered daily to the subject.

[0027] In some embodiments, about 1.5 mg, about 2.5 mg, 3.5 mg, about 5.0 mg, about 7.0 mg, about 10.0 mg, about 14.0 mg, or about 20.0 mg of infigratinib, or a pharmaceutically acceptable salt thereof, is administered daily to the subject.

[0028] In some embodiments, administering infigratinib, or a pharmaceutically acceptable salt thereof, comprises administering a daily dose of about 0.01 milligrams per kilogram (mg/kg) to about 0.60 mg/kg of infigratinib, or a pharmaceutically acceptable salt thereof, to the subject. [0029] In some embodiments, administering infigratinib, or a pharmaceutically acceptable salt thereof, comprises administering a daily dose of about 0. 1 mg/kg to about 0.50 mg/kg of infigratinib, or a pharmaceutically acceptable salt thereof, to the subject.

[0030] In some embodiments, administering infigratinib, or a pharmaceutically acceptable salt thereof, comprises administering a daily dose of about 0.15 mg/kg to about 0.50 mg/kg of infigratinib, or a pharmaceutically acceptable salt thereof, to the subject.

[0031] In some embodiments, administering infigratinib, or a pharmaceutically acceptable salt thereof, comprises administering a daily dose of about 0.25 mg/kg of infigratinib, or a pharmaceutically acceptable salt thereof, to the subject.

[0032] In some embodiments, infigratinib is administered as infigratinib monophosphate. In some embodiments, the infigratinib monophosphate is present as an anhydrous crystalline form. In some embodiments, the anhydrous crystalline form of infigratinib monophosphate is characterized by an X-ray powder diffraction (XRPD) peak (2 theta) at 15.0° ± 0.2°. [0033] In some embodiments, infigratinib, or the pharmaceutically acceptable salt thereof, is administered in a solid dosage form. In some embodiments, infigratinib, or the pharmaceutically acceptable salt thereof, is administered in a tablet or capsule. In some embodiments, infigratinib, or the pharmaceutically acceptable salt thereof, is administered in a mini-tablet or sprinkle capsule.

[0034] In some embodiments, infigratinib, or the pharmaceutically acceptable salt thereof, is administered orally.

[0035] In some embodiments, the subject has an FGFR3 mutation. In some embodiments, the FGFR3 mutation is a G380R or N540K mutation.

[0036] In some embodiments, the subject is less than 18 years of age. In some embodiments, the subject is 0 to 4 months old, 0 to 6 months old, 0 to 1 year of age, 0 to 2 years of age, 0 to 3 years of age, 0 to 5 years of age, 1 to 2 years of age, 1 to 3 years of age, 1 to 5 years of age, 2 to 3 years of age, 2 to 5 years of age, 2 to 8 years of age, 2 to 11 years of age, 2 to 17 years of age, 3 to 5 years of age, 3 to 8 years of age, 3 to 11 years of age, 3 to 17 years of age, 5 to 8 years of age, 5 to 11 years of age, 5 to 17 years of age, 8 to 11 years of age, 8 to 17 years of age, 11 to 17 years of age, or 12 to 17 years of age. In some embodiments, the subject is less than 2 years of age. In some embodiments, the subject is less than 3 years of age. In some embodiments, the subject is less than 5 years of age. In some embodiments, the subject is less than 12 years of age. In some embodiments, the subject has open epiphyses.

[0037] In another aspect, the present disclosure provides a method of modulating FGFR3, comprising contacting FGFR3 with a compound of formula (II), wherein the compound of formula (II) has the structure:

[0038] In another aspect, the present disclosure provides a method of modulating FGFR3, comprising contacting FGFR3 with a compound of formula (III), wherein the compound of formula (III) has the structure:

[0039] In some embodiments, the FGFR3 is disposed within a cell. In some embodiments, the cell is located within a subject. In some embodiments, the subject has a skeletal dysplasia. [0040] In some embodiments, the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia (e.g., thanatophoric dysplasia type I or thanatophoric dysplasia type II), osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, Crouzon syndrome (e.g., Crouzon syndrome acanthosis nigricans), craniosynostosis, Kallmann syndrome, hypogonadotropic hypogonadism, cleft palate and other craniofacial defects, scoliosis, Type 1 or classic Pfeiffer syndrome, osteoglophonic dysplasia, craniosynostosis, mandibular progmathism, hypertelorism, brachydactyly, inter- phalangeal joint fusion, Jackson-Weiss syndrome, Antley-Bixler syndrome, Apert syndrome, Crouzon syndrome, X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, and trigonocephaly. In some embodiments, the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia (e.g., thanatophoric dysplasia type I or thanatophoric dysplasia type II), osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, and Crouzon syndrome (e.g., Crouzon syndrome acanthosis nigricans). In some embodiments, the skeletal dysplasia is achondroplasia. In some embodiments, the skeletal dysplasia is hypochondroplasia.

[0041] In some embodiments, the subject has an FGFR3 mutation. In some embodiments, the FGFR3 mutation is a G380R or N540K mutation.

[0042] In some embodiments, the subject is less than 18 years of age. In some embodiments, the subject is 0 to 4 months old, 0 to 6 months old, 0 to 1 year of age, 0 to 2 years of age, 0 to 3 years of age, 0 to 5 years of age, 1 to 2 years of age, 1 to 3 years of age, 1 to 5 years of age, 2 to

3 years of age, 2 to 5 years of age, 2 to 8 years of age, 2 to 11 years of age, 2 to 17 years of age, 3 to 5 years of age, 3 to 8 years of age, 3 to 11 years of age, 3 to 17 years of age, 5 to 8 years of age, 5 to 11 years of age, 5 to 17 years of age, 8 to 11 years of age, 8 to 17 years of age, 11 to 17 years of age, or 12 to 17 years of age. In some embodiments, the subject is less than 2 years of age. In some embodiments, the subject is less than 3 years of age. In some embodiments, the subject is less than 5 years of age. In some embodiments, the subject is less than 12 years of age. In some embodiments, the subject has open epiphyses.

[0043] In another aspect, the present disclosure provides a method of treating a skeletal dysplasia in a subject in need thereof, comprising providing an effective amount of a compound of formula (II), or a pharmaceutically acceptable salt or N-oxide thereof, to the subject, wherein the compound of formula (II) has the structure:

[0044] In another aspect, the present disclosure provides a method of treating a skeletal dysplasia in a subject in need thereof, comprising admininstering an effective amount of a compound of formula (II), or a pharmaceutically acceptable salt or N-oxide thereof, to the subject, wherein the compound of formula (II) has the structure:

[0045] In another aspect, the present disclosure provides a method of treating a skeletal dysplasia in a subject in need thereof, comprising providing an effective amount of a compound of formula (III), or a pharmaceutically acceptable salt or N-oxide thereof, to the subject, wherein the compound of formula (III) has the structure:

[0046] In another aspect, the present disclosure provides a method of treating a skeletal dysplasia in a subject in need thereof, comprising admininstering an effective amount of a compound of formula (III), or a pharmaceutically acceptable salt or N-oxide thereof, to the subject, wherein the compound of formula (III) has the structure:

[0047] In some embodiments, the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia (e.g., thanatophoric dysplasia type I or thanatophoric dysplasia type II), osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, Crouzon syndrome (e.g., Crouzon syndrome acanthosis nigricans), craniosynostosis, Kallmann syndrome, hypogonadotropic hypogonadism, cleft palate and other craniofacial defects, scoliosis, Type 1 or classic Pfeiffer syndrome, osteoglophonic dysplasia, craniosynostosis, mandibular progmathism, hypertelorism, brachydactyly, inter- phalangeal joint fusion, Jackson-Weiss syndrome, Antley-Bixler syndrome, Apert syndrome, Crouzon syndrome, X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, and trigonocephaly. In some embodiments, the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia (e.g., thanatophoric dysplasia type I or thanatophoric dysplasia type II), osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, and Crouzon syndrome (e.g., Crouzon syndrome acanthosis nigricans). In some embodiments, the skeletal disorder is achondroplasia. In some embodiments, the skeletal disorder is hypochondroplasia.

[0048] In some embodiments, the subject has an FGFR3 mutation. In some embodiments, the FGFR3 mutation is a G380R or N540K mutation.

[0049] In some embodiments, the subject is less than 18 years of age. In some embodiments, the subject is 0 to 4 months old, 0 to 6 months old, 0 to 1 year of age, 0 to 2 years of age, 0 to 3 years of age, 0 to 5 years of age, 1 to 2 years of age, 1 to 3 years of age, 1 to 5 years of age, 2 to 3 years of age, 2 to 5 years of age, 2 to 8 years of age, 2 to 11 years of age, 2 to 17 years of age, 3 to 5 years of age, 3 to 8 years of age, 3 to 11 years of age, 3 to 17 years of age, 5 to 8 years of age, 5 to 11 years of age, 5 to 17 years of age, 8 to 11 years of age, 8 to 17 years of age, 11 to 17 years of age, or 12 to 17 years of age. In some embodiments, the subject is less than 2 years of age. In some embodiments, the subject is less than 3 years of age. In some embodiments, the subject is less than 5 years of age. In some embodiments, the subject is less than 12 years of age. In some embodiments, the subject has open epiphyses.

BRIEF DESCRIPTION OF THE DRAWINGS

[0050] FIG. 1 A shows a comparison of the intense mean concentration in plasma of (i) infigratinib (BGJ398), (ii) the compound of formula (IV), (iii) the compound of formula (II), and (iv) the compound of formula (III) in pediatric patients with achondroplasia receiving a daily dose of 0.128 mg/kg infigratinib on Day 1 of treatment, as described in Example 4.

[0051] FIG. IB shows a comparison of the sparse mean concentration in plasma of (i) infigratinib (BGJ398), (ii) the compound of formula (IV), (iii) the compound of formula (II), and (iv) the compound of formula (III) in pediatric patients with achondroplasia receiving a daily dose of 0.128 mg/kg infigratinib on Day 1 of treatment, as described in Example 4. [0052] FIG. 1C shows a comparison of the intense mean concentration in plasma of (i) infigratinib (BGJ398), (ii) the compound of formula (IV), (iii) the compound of formula (II), and (iv) the compound of formula (III) in pediatric patients with achondroplasia receiving a daily dose of 0.128 mg/kg infigratinib on Day 21 of treatment, as described in Example 4.

[0053] FIG. ID shows a comparison of the sparse mean concentration in plasma of (i) infigratinib (BGJ398), (ii) the compound of formula (IV), (iii) the compound of formula (II), and (iv) the compound of formula (III) in pediatric patients with achondroplasia receiving a daily dose of 0.128 mg/kg infigratinib on Day 21 of treatment, as described in Example 4.

[0054] FIG. 2A shows a comparison of the intense mean concentration in plasma of (i) infigratinib (BGJ398), (ii) the compound of formula (IV), (iii) the compound of formula (II), and (iv) the compound of formula (III) in pediatric patients with achondroplasia receiving a daily dose of 0.250 mg/kg infigratinib on Day 1 of treatment, as described in Example 4.

[0055] FIG. 2B shows a comparison of the sparse mean concentration in plasma of (i) infigratinib (BGJ398), (ii) the compound of formula (IV), (iii) the compound of formula (II), and (iv) the compound of formula (III) in pediatric patients with achondroplasia receiving a daily dose of 0.250 mg/kg infigratinib on Day 1 of treatment, as described in Example 4.

[0056] FIG. 2C shows a comparison of the intense mean concentration in plasma of (i) infigratinib (BGJ398), (ii) the compound of formula (IV), (iii) the compound of formula (II), and (iv) the compound of formula (III) in pediatric patients with achondroplasia receiving a daily dose of 0.250 mg/kg infigratinib on Day 21 of treatment, as described in Example 4.

[0057] FIG. 2D shows a comparison of the sparse mean concentration in plasma of (i) infigratinib (BGJ398), (ii) the compound of formula (IV), (iii) the compound of formula (II), and (iv) the compound of formula (III) in pediatric patients with achondroplasia receiving a daily dose of 0.250 mg/kg infigratinib on Day 21 of treatment, as described in Example 4.

[0058] FIGS. 3A-3D show the intense and sparse mean concentrations in plasma of (i) infigratinib (BGJ398), (ii) the compound of formula (IV), (iii) the compound of formula (II), and (iv) the compound of formula (III) in subjects enrolled in cohort 5 (i.e., 0.064 mg/kg) on days 1 and 21 of treatment.

[0059] FIG. 4A shows an ICso plot comparing infigratinib inhibition against various FGFR3c variants (N540K, N540S, N540T, K650Q, K650N, K650T, R223C, T264M, S351F, and G380R), as described in Example 6. [0060] FIG. 4B shows an ICso plot comparing the compound of formula (II) inhibition against various FGFR3c variants (N540K, N540S, N540T, K650Q, K650N, K650T, R223C, T264M, S351F, and G380R), as described in Example 6.

[0061] FIG. 4C shows an ICso plot comparing the compound of formula (III) inhibition against various FGFR3c variants (N540K, N540S, N540T, K650Q, K650N, K650T, R223C, T264M, S351F, and G380R), as described in Example 6.

[0062] FIG. 4D shows an ICso plot comparing the compound of formula (IV) inhibition against various FGFR3c variants (N540K, N540S, N540T, K650Q, K650N, K650T, R223C, T264M, S351F, and G380R), as described in Example 6.

DETAILED DESCRIPTION

[0063] As generally described herein, the present disclosure provides methods of treating a condition, disease, or disorder requiring FGFR3 modulation (e.g., a skeletal dysplasia) in a subject in need thereof. The methods generally comprise administering infigratinib, or a pharmaceutically acceptable salt thereof, to the subject in a daily dose (e.g., 0. 1 mg to about 50 mg) sufficient to deliver an effective amount of a compound of formula (II) and/or formula (III) and/or formula (IV) to the subject. In addition, methods for treating a skeletal dysplasia in a subject in need thereof comprising administering/providing an effective amount of a compound of formula (II) and/or (III) are provided. Skeletal dysplasias for which the methods described herein are contemplated to be useful in treating include, but are not limited to, achondroplasia, hypochondroplasia, thanatophoric dysplasia (e.g., thanatophoric dysplasia type I or thanatophoric dysplasia type II), osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, Crouzon syndrome (e.g., Crouzon syndrome acanthosis nigricans), craniosynostosis, Kallmann syndrome, hypogonadotropic hypogonadism, cleft palate and other craniofacial defects, scoliosis, Type 1 or classic Pfeiffer syndrome, osteoglophonic dysplasia, craniosynostosis, mandibular progmathism, hypertelorism, brachydactyly, inter- phalangeal joint fusion, Jackson-Weiss syndrome, Antley-Bixler syndrome, Apert syndrome, Crouzon syndrome, X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, and trigonocephaly. Definitions

[0064] To facilitate an understanding of the present disclosure, a number of terms and phrases are defined below.

[0065] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0066] Throughout the description, where compositions and kits are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present disclosure that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present disclosure that consist essentially of, or consist of, the recited processing steps.

[0067] In the application, where an element or component is said to be included in and/or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components.

[0068] Further, it should be understood that elements and/or features of a composition or a method described herein can be combined in a variety of ways without departing from the spirit and scope of the present disclosure, whether explicit or implicit herein. For example, where reference is made to a particular compound, that compound can be used in various embodiments of compositions of the present disclosure and/or in methods of the present disclosure, unless otherwise understood from the context. In other words, within this application, embodiments have been described and depicted in a way that enables a clear and concise application to be written and drawn, but it is intended and will be appreciated that embodiments may be variously combined or separated without parting from the present teachings and disclosure(s). For example, it will be appreciated that all features described and depicted herein can be applicable to all aspects of the disclosure(s) described and depicted herein. [0069] The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article, unless the context is inappropriate. By way of example, “an element” means one element or more than one element.

[0070] The term “and/or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise.

[0071] It should be understood that the expression “at least one of’ includes individually each of the recited objects after the expression and the various combinations of two or more of the recited objects unless otherwise understood from the context and use. The expression “and/or” in connection with three or more recited objects should be understood to have the same meaning unless otherwise understood from the context.

[0072] The use of the term “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context. [0073] Where the use of the term “about” is before a quantitative value, the present disclosure also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a ±10% variation from the nominal value unless otherwise indicated or inferred from the context.

[0074] At various places in the present specification, variable or parameters are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, an integer in the range of 0 to 40 is specifically intended to individually disclose 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, and 40, and an integer in the range of 1 to 20 is specifically intended to individually disclose 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

[0075] The use of any and all examples, or exemplary language herein, for example, “such as” or “including,” is intended merely to illustrate better the present disclosure and does not pose a limitation on the scope of the disclosure unless claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the present invention. [0076] As a general mater, compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.

[0077] As used herein, “pharmaceutical composition” or “pharmaceutical formulation” refers to the combination of an active agent with an excipient, inert or active, making the composition or formulation especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0078] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0079] As used herein, “pharmaceutically acceptable salt” refers to any salt of an acidic or a basic group that may be present in a compound of the present invention (e.g., infigratinib or a compound of formula (II)), which salt is compatible with pharmaceutical administration.

[0080] As is known to those of skill in the art, “salts” of compounds may be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acid. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts.

[0081] Examples of bases include, but are not limited to, alkali metal (e.g., sodium and potassium) hydroxides, alkaline earth metal (e.g., magnesium and calcium) hydroxides, ammonia, and compounds of formula NW-i . wherein W is Ci-4 alkyl, and the like.

[0082] Examples of salts include, but are not limited, to acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like. Other examples of salts include anions of the compounds of the present disclosure compounded with a suitable cation such as Na⁺, K⁺, Ca²⁺, NH4⁺, and NW4⁺ (where W can be a Ci-4 alkyl group), and the like.

[0083] For therapeutic use, salts of the compound of the present disclosure are pharmaceutically acceptable. However, salts of acids and bases that are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0084] As used herein, “pharmaceutically acceptable excipient” refers to a substance that aids the administration of an active agent to and/or absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable excipients, which include pharmaceutically acceptable carriers, include water, NaCl, normal saline solutions, such as a phosphate buffered saline solution, emulsions (e.g., such as an oil/water or water/oil emulsions), lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethylcellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the disclosure. For examples of excipients, see Martin, Remington’s Pharmaceutical Sciences, 15^th Ed., Mack Publ. Co., Easton, PA (1975).

[0085] The term “AUC” refers to the area under the time/plasma concentration curve after administration of the pharmaceutical composition. AUCo-infinity denotes the area under the plasma concentration versus time curve from time 0 to infinity; AUCo-t denotes the area under the plasma concentration versus time curve from time 0 to time t. It should be appreciated that AUC values can be determined by known methods in the art.

[0086] The terms “subject” and “patient” are used interchangeably herein. In certain embodiments, the subject is a pediatric patient. As used herein, “pediatric patient” may refer to a patient whose growth plates remain open.

[0087] A “subject” or “patient” to which administration is contemplated includes, but is not limited to, humans (e.g., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[0088] the term Cmax refers to the maximum concentration of a therapeutic agent (e.g., infigratinib) in plasma following administration of the pharmaceutical composition.

[0089] The term “tmax” refers to the time in hours when Cmax is achieved following administration of the pharmaceutical composition comprising a therapeutic agent (e.g., infigratinib).

[0090] As used herein, “solid dosage form” means a pharmaceutical dose(s) in solid form, e.g., tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers and chewable s.

[0091] As used herein, “administering” means oral administration, administration as a suppository, topical contact, intravenous administration, parenteral administration, intraperitoneal administration, intramuscular administration, intralesional administration, intrathecal administration, intracranial administration, intranasal administration or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini-osmotic pump, to a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, e.g., intravenous, intramuscular, intra-arterial, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. By “co-administer” it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies (e.g., anti -cancer agent, chemotherapeutic, or treatment for a neurodegenerative disease). Infigratinib, or a pharmaceutically acceptable salt thereof, can be administered alone or can be co-administered to the patient. A compound of formula (II), or a pharmaceutically acceptable salt thereof, can be administered alone or can be co-administered to the patient. Co-administration is meant to include simultaneous or sequential administration of the compound individually or in combination (more than one compound or agent). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation).

[0092] The terms “disease,” “disorder,” and “condition” are used interchangeably herein. [0093] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which ameliorates the symptoms of the disease, disorder, or condition, or reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (e.g., “therapeutic treatment”).

[0094] In general, an “effective amount” of a compound (e.g., infigratinib or a compound of formula (II)) refers to an amount sufficient to elicit the desired biological response, e.g., to treat a skeletal disorder (e.g., achondroplasia). As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the disclosure (e.g., infigratinib or a compound of formula (II)) may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, and the age, weight, health, and condition of the subject.

[0095] The term “proportional increase” with respect to head circumference may refer to an increase in head circumference that brings a subject’s head circumference into proportion with their body. For example, without treatment (e.g., treatment with infigratinib monophosphate) a subject (e.g., a child or adult) with achondroplasia exhibits macrocephaly (i.e., the circumference of the subject’s head is more than two standard deviations above the average for their age). In certain embodiments, administration of infigratinib monophosphate treats macrocephaly in a subject suffering with achondroplasia.

[0096] The term “normalization” with respect to a body proportion measurement ratio may refer to a rate of limb growth (i.e., rate of arm growth and/or rate of leg growth) in a subject that results in limb size that is more proportionate to the subject’s trunk (i.e., torso). For example, without treatment (e.g., treatment with infigratinib monophosphate) a subject (e.g., a child or adult) with achondroplasia exhibits disproportionately short limbs compared to the trunk. In certain embodiments, administration of infigratinib monophosphate results in a subject growing limbs of proportionate size to their trunk.

Compounds

Infigratinib

[0097] Infigratinib, as depicted in formula (I), is a selective and ATP-competitive pan-fibroblast growth factor receptor (FGFR) kinase inhibitor, also known as 3-(2,6-dichloro-3,5- dimethoxyphenyl)- 1 - { 6- [4-(4-ethyl- 1 -piperazin- 1 -yljphenylamino] -pyrimidinyl-4-yl } - 1 - methylurea. Infigratinib potently and selectively inhibits the kinase activity of FGFR1, FGFR2, and FGFR3.

[0098] A method of chemically synthesizing infigratinib (including Example 1 provided herein), several crystalline and amorphous forms of infigratinib (including the anhydrous crystalline monophosphate salt described herein) and methods of preparing said forms (including Example 2 provided herein) were described in U.S. Patent No. 9,067,896, which is incorporated by reference in its entirety herein.

[0099] In one aspect, provided herein is infigratinib, or a pharmaceutically acceptable salt thereof, for the treatment of a skeletal dysplasia described herein (e.g., achondroplasia or hypochondroplasia) in a subject in need thereof.

[0100] In some embodiments, provided herein is a pharmaceutically acceptable salt of infigratinib for the treatment of a skeletal dysplasia in a subject in need thereof. In some embodiments, the pharmaceutically acceptable salt of infigratinib is a phosphate salt. In some embodiments, the pharmaceutically acceptable salt of infigratinib is a monophosphate salt. The monophosphate salt of infigratinib may also be referred to as BGJ398, infigratinib phosphate, and infigratinib monophosphate.

[0101] In some embodiments, the monophosphate salt of infigratinib is an anhydrous crystalline monophosphate salt. In some embodiments, the anhydrous crystalline monophosphate salt has an X-ray powder diffraction (XRPD) pattern comprising a characteristic peak, in terms of 20, at about 15.0° or 15.0° ± 0.2°. In some embodiments, the X-ray powder diffraction pattern of the anhydrous crystalline monophosphate salt further comprises one or more characteristic peaks, in terms of 20, selected from peaks at about 13.7° ± 0.2°, about 16.8° ± 0.2°, about 21.3° ± 0.2° and about 22.4°± 0.2°. In some embodiments, the X-ray powder diffraction pattern of the anhydrous crystalline monophosphate salt further comprises one or more characteristic peaks, in terms of 20, selected from peaks at about 9.2°, about 9.6°, about 18.7°, about 20.0°, about 22.9°, and about 27.2°. In some embodiment, the anhydrous crystalline monophosphate salt has an XRPD pattern comprising at least three characteristic peaks, in terms of 20, selected from the peaks at about 13.7°, about 15°, about 16.8, about 21.3° and about 22.4°. In some embodiments, the X- ray powder diffraction pattern for the anhydrous crystalline monophosphate salt may comprise one, two, three, four, five, six, seven, eight, nine, ten or eleven characteristic peaks, in terms of 20, selected from the peaks at about 9.2°, about 9.6°, about 13.7°, about 15°, about 16.8°, about 18.7°, about 20.0°, about 21.3° and about 22.4°, about 22.9°, and about 27.2. Metabolites of Infigratinib

[0102] Infigratinib metabolizes in vivo to produce a number of active metabolites. The compounds of formula (II), formula (III), and formula (IV), as depicted below, are active metabolites of infigratinib and FGFR inhibitors. In some embodiments, the compound of formula (II), the compound of formula (III), and/or the compound of formula (IV) is an inhibitor of FGFR1, FGFR2, and/or FGFR3. In some embodiments, the compound of formula (II), the compound of formula (III), and/or the compound of formula (IV) is an inhibitor of FGFR3.

[0103] In one aspect, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt or N-oxide thereof. In another aspect, provided herein is a compound of formula

(II).

[0104] In another aspect, provided herein is a compound of formula (III), or a pharmaceutically acceptable salt or N-oxide thereof. In another aspect, provided herein is a compound of formula

(III).

[0105] In another aspect, provided herein is a compound of formula (IV), or a pharmaceutically acceptable salt or N-oxide thereof. In another aspect, provided herein is a compound of formula

(IV). [0106] A synthetic scheme describing the synthesis of the compounds of formula (II) and (III) is shown below:

[0107] A synthetic scheme for synthesizing the compound of formula (IV) is included in International Patent Publication No. W02007071752, which is herein included by reference in its entirety. Pharmaceutical Compositions

[0108] The present disclosure provides pharmaceutical compositions comprising a compound provided herein (e.g., infigratinib, or a pharmaceutically acceptable salt thereof; a compound of formula (II), or a pharmaceutically acceptable salt orN-oxide thereof; a compound of formula (III), or a pharmaceutically acceptable salt or N-oxide thereof, or a compound of formula (IV), or a pharmaceutically acceptable salt or N-oxide thereof); and a pharmaceutically acceptable excipient.

[0109] In an aspect, provided herein is a pharmaceutical composition comprising infigratinib, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises about 0. 1 mg to about 50 mg of infigratinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient.

[0110] In an aspect, provided herein is a pharmaceutical composition comprising a compound of formula (II), or a pharmaceutically acceptable salt or N-oxide thereof. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient.

[oni] In another aspect, provided herein is a pharmaceutical composition comprising a compound of formula (III), or a pharmaceutically acceptable salt or N-oxide thereof. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient.

[0112] In an aspect, provided herein is a pharmaceutical composition comprising a compound of formula (IV), or a pharmaceutically acceptable salt or N-oxide thereof. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient.

[0113] In some embodiments, a pharmaceutical composition provided herein is configured for use in the treatment of a skeletal dysplasia described herein in a subject in need thereof.

[0114] In an aspect, provided herein are pharmaceutical compositions comprising about 0.1 mg to about 50 mg infigratinib, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient, for the treatment of a skeletal disorder described herein in a subject in need thereof.

[0115] In an aspect, provided herein are pharmaceutical compositions comprising a compound of formula (II), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient, for the treatment of a skeletal dysplasia described herein in a subject in need thereof. [0116] In an aspect, provided herein are pharmaceutical compositions comprising a compound of formula (III), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient, for the treatment of a skeletal dysplasia described herein in a subject in need thereof. [0117] In an aspect, provided herein are pharmaceutical compositions comprising a compound of formula (IV), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient, for the treatment of a skeletal dysplasia described herein in a subject in need thereof. [0118] In certain embodiments, the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia (e.g., thanatophoric dysplasia type I or thanatophoric dysplasia type II), osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, Crouzon syndrome (e.g., Crouzon syndrome acanthosis nigricans), craniosynostosis, Kallmann syndrome, hypogonadotropic hypogonadism, cleft palate and other craniofacial defects, scoliosis, Type 1 or classic Pfeiffer syndrome, osteoglophonic dysplasia, craniosynostosis, mandibular progmathism, hypertelorism, brachydactyly, inter- phalangeal joint fusion, Jackson-Weiss syndrome, Antley-Bixler syndrome, Apert syndrome, Crouzon syndrome, X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, and trigonocephaly. In certain embodiments, the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia (e.g., thanatophoric dysplasia type I or thanatophoric dysplasia type II), osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, and Crouzon syndrome (e.g., Crouzon syndrome acanthosis nigricans).

[0119] In certain embodiments, the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia, osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, Crouzon syndrome, craniosynostosis, Kallmann syndrome, hypogonadotropic hypogonadism, cleft palate and other craniofacial defects, scoliosis, Type 1 or classic Pfeiffer syndrome, osteoglophonic dysplasia, craniosynostosis, mandibular progmathism, hypertelorism, brachydactyly, inter-phalangeal joint fusion, Jackson-Weiss syndrome, Antley-Bixler syndrome, Apert syndrome, Crouzon syndrome, X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, and trigonocephaly. In certain embodiments, the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia, osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, and Crouzon syndrome. In certain embodiments, the thanatophoric dysplasia is thanatophoric dysplasia type I or thanatophoric dysplasia type II. In certain embodiments, the Crouzon syndrome is Crouzon syndrome acanthosis nigricans.

[0120] In certain embodiments, the skeletal dysplasia is achondroplasia. In certain embodiments, the skeletal dysplasia is hypochondroplasia.

[0121] In certain embodiments, a pharmaceutical composition described herein comprises about 0.1 mg to about 50 mg, about 0.2 mg to about 50 mg, about 0.3 mg to about 50 mg, about 0.4 mg to about 50 mg, about 0.5 mg to about 50 mg, about 0.6 mg to about 50 mg, about 0.7 mg to about 50 mg, about 0.8 mg to about 50 mg, about 0.9 mg to about 50 mg, about 1 mg to about 50 mg, about 2 mg to about 50 mg, about 3 mg to about 50 mg, about 4 mg to about 50 mg, about 5 mg to about 50 mg, about 6 mg to about 50 mg, about 7 mg to about 50 mg, about 8 mg to about 50 mg, about 9 mg to about 50 mg, about 10 mg to about 50 mg, about 15 mg to about 50 mg, about 20 mg to about 50 mg, about 25 mg to about 50 mg, about 30 mg to about 50 mg, about 35 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 0.1 mg to about 45 mg, about 0.1 mg to about 40 mg, about 0.1 mg to about 35 mg, about 0.1 mg to about 30 mg, about 0. 1 mg to about 25 mg, about 0. 1 mg to about 20 mg, about 0. 1 mg to about 15 mg, about 0. 1 mg to about 10 mg, about 0. 1 mg to about 9 mg, about 0. 1 mg to about 8 mg, about 0.1 mg to about 7 mg, about 0. 1 mg to about 6 mg, about 0. 1 mg to about 5 mg, about 0.1 mg to about 4 mg, about 0.1 mg to about 3 mg, about 0.1 mg to about 2 mg, about 0. 1 mg to about 1 mg, about 0. 1 mg to about 0.9 mg, about 0. 1 mg to about 0.8 mg, about 0.1 mg to about 0.7 mg, about 0.1 mg to about 0.6 mg, about 0. 1 mg to about 0.5 mg, about 0.1 mg to about 0.4 mg, about 0.1 mg to about 0.3 mg, about 0. 1 mg to about 0.2 mg, about 0.2 mg to about 45 mg, about 0.2 mg to about 40 mg, about 0.2 mg to about 35 mg, about 0.2 mg to about 30 mg, about 0.2 mg to about 25 mg, about 0.2 mg to about 20 mg, about 0.2 mg to about 15 mg, about 0.2 mg to about 10 mg, about 0.2 mg to about 9 mg, about 0.2 mg to about 8 mg, about 0.2 mg to about 7 mg, about 0.2 mg to about 6 mg, about 0.2 mg to about 5 mg, about 0.2 mg to about 4 mg, about 0.2 mg to about 3 mg, about 0.2 mg to about 2 mg, about 0.2 mg to about 1 mg, about 0.2 mg to about 0.9 mg, about 0.2 mg to about 0.8 mg, about 0.2 mg to about 0.7 mg, about 0.2 mg to about 0.6 mg, about 0.2 mg to about 0.5 mg, about 0.2 mg to about 0.4 mg, about 0.2 mg to about 0.3 mg, about 0.3 mg to about 45 mg, about 0.3 mg to about 40 mg, about 0.3 mg to about 35 mg, about 0.3 mg to about 30 mg, about 0.3 mg to about 25 mg, about 0.3 mg to about 20 mg, about 0.3 mg to about 15 mg, about 0.3 mg to about 10 mg, about 0.3 mg to about 9 mg, about 0.3 mg to about 8 mg, about 0.3 mg to about 7 mg, about 0.3 mg to about 6 mg, about 0.3 mg to about 5 mg, about 0.3 mg to about 4 mg, about 0.3 mg to about 3 mg, about 0.3 mg to about 2 mg, about 0.3 mg to about 1 mg, about 0.3 mg to about 0.9 mg, about 0.3 mg to about 0.8 mg, about 0.3 mg to about 0.7 mg, about 0.3 mg to about 0.6 mg, about 0.3 mg to about 0.5 mg, about 0.3 mg to about 0.4 mg, about 0.4 mg to about 45 mg, about 0.4 mg to about 40 mg, about 0.4 mg to about 35 mg, about 0.4 mg to about 30 mg, about 0.4 mg to about 25 mg, about 0.4 mg to about 20 mg, about 0.4 mg to about 15 mg, about 0.4 mg to about 10 mg, about 0.4 mg to about 9 mg, about 0.4 mg to about 8 mg, about 0.4 mg to about 7 mg, about 0.4 mg to about 6 mg, about 0.4 mg to about 5 mg, about 0.4 mg to about 4 mg, about 0.4 mg to about 3 mg, about 0.4 mg to about 2 mg, about 0.4 mg to about 1 mg, about 0.4 mg to about 0.9 mg, about 0.4 mg to about 0.8 mg, about 0.4 mg to about 0.7 mg, about 0.4 mg to about 0.6 mg, about 0.4 mg to about 0.5 mg, about 0.5 mg to about 45 mg, about 0.5 mg to about 40 mg, about 0.5 mg to about 35 mg, about 0.5 mg to about 30 mg, about 0.5 mg to about 25 mg, about 0.5 mg to about 20 mg, about 0.5 mg to about 15 mg, about 0.5 mg to about 10 mg, about 0.5 mg to about 0.9 mg, about 0.5 mg to about 0.8 mg, about 0.5 mg to about 0.7 mg, about 0.5 mg to about 0.6 mg, about 0.6 mg to about 45 mg, about 0.6 mg to about 40 mg, about 0.6 mg to about 35 mg, about 0.6 mg to about 30 mg, about 0.6 mg to about 25 mg, about 0.6 mg to about 20 mg, about 0.6 mg to about 15 mg, about 0.6 mg to about 10 mg, about 0.6 mg to about 9 mg, about 0.6 mg to about 8 mg, about 0.6 mg to about 7 mg, about 0.6 mg to about 6 mg, about 0.6 mg to about 5 mg, about 0.6 mg to about 4 mg, about 0.6 mg to about 3 mg, about 0.6 mg to about 2 mg, about 0.6 mg to about 1 mg, about 0.6 mg to about 0.9 mg, about 0.6 mg to about 0.8 mg, about 0.6 mg to about 0.7 mg, about 0.7 mg to about 45 mg, about 0.7 mg to about 40 mg, about 0.7 mg to about 35 mg, about 0.7 mg to about 30 mg, about 0.7 mg to about 25 mg, about 0.7 mg to about 20 mg, about 0.7 mg to about 15 mg, about 0.7 mg to about 10 mg, about 0.7 mg to about 9 mg, about 0.7 mg to about 8 mg, about 0.7 mg to about 7 mg, about 0.7 mg to about 6 mg, about 0.7 mg to about 5 mg, about 0.7 mg to about 4 mg, about 0.7 mg to about 3 mg, about 0.7 mg to about 2 mg, about 0.7 mg to about 1 mg, about 0.7 mg to about 0.9 mg, about 0.7 mg to about 0.8 mg, about 0.8 mg to about 45 mg, about 0.8 mg to about 40 mg, about 0.8 mg to about 35 mg, about 0.8 mg to about 30 mg, about 0.8 mg to about 25 mg, about 0.8 mg to about 20 mg, about 0.8 mg to about 15 mg, about 0.8 mg to about 10 mg, about 0.8 mg to about 9 mg, about 0.8 mg to about

8 mg, about 0.8 mg to about 7 mg, about 0.8 mg to about 6 mg, about 0.8 mg to about 5 mg, about 0.8 mg to about 4 mg, about 0.8 mg to about 3 mg, about 0.8 mg to about 2 mg, about 0.8 mg to about 1 mg, about 0.8 mg to about 0.9 mg, about 0.9 mg to about 45 mg, about 0.9 mg to about 40 mg, about 0.9 mg to about 35 mg, about 0.9 mg to about 30 mg, about 0.9 mg to about 25 mg, about 0.9 mg to about 20 mg, about 0.9 mg to about 15 mg, about 0.9 mg to about 10 mg, about 0.9 mg to about 9 mg, about 0.9 mg to about 8 mg, about 0.9 mg to about 7 mg, about 0.9 mg to about 6 mg, about 0.9 mg to about 5 mg, about 0.9 mg to about 4 mg, about 0.9 mg to about 3 mg, about 0.9 mg to about 2 mg, about 0.9 mg to about 1 mg, about 1 mg to about 45 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 1 mg to about 15 mg, about 1 mg to about 10 mg, about 1 mg to about 9 mg, about 1 mg to about 8 mg, about 1 mg to about 7 mg, about 1 mg to about 6 mg, about 1 mg to about 5 mg, about 1 mg to about 4 mg, about 1 mg to about 3 mg, about 1 mg to about 2 mg, about 2 mg to about 45 mg, about 2 mg to about 40 mg, about 2 mg to about 35 mg, about 2 mg to about 30 mg, about 2 mg to about 25 mg, about 2 mg to about 20 mg, about 2 mg to about 15 mg, about 2 mg to about 10 mg, about 2 mg to about 9 mg, about 2 mg to about 8 mg, about 2 mg to about 7 mg, about 2 mg to about 6 mg, about 2 mg to about 5 mg, about 2 mg to about 4 mg, about 2 mg to about 3 mg, about 3 mg to about 45 mg, about 3 mg to about 40 mg, about 3 mg to about 35 mg, about 3 mg to about 30 mg, about 3 mg to about 25 mg, about 3 mg to about 20 mg, about 3 mg to about 15 mg, about 3 mg to about 10 mg, about 3 mg to about 9 mg, about 3 mg to about 8 mg, about 3 mg to about 7 mg, about 3 mg to about 6 mg, about 3 mg to about 5 mg, about 3 mg to about 4 mg, about 4 mg to about 45 mg, about 4 mg to about 40 mg, about 4 mg to about 35 mg, about 4 mg to about 30 mg, about 4 mg to about 25 mg, about 4 mg to about 20 mg, about 4 mg to about 15 mg, about 4 mg to about 10 mg, about 4 mg to about 9 mg, about 4 mg to about 8 mg, about 4 mg to about 7 mg, about 4 mg to about 6 mg, about 4 mg to about 5 mg, about 5 mg to about 45 mg, about 5 mg to about 40 mg, about 5 mg to about 35 mg, about 5 mg to about 30 mg, about 5 mg to about 25 mg, about 5 mg to about 20 mg, about 5 mg to about 15 mg, about 5 mg to about 10 mg, about 5 mg to about

9 mg, about 5 mg to about 8 mg, about 5 mg to about 7 mg, about 5 mg to about 6 mg, about 6 mg to about 45 mg, about 6 mg to about 40 mg, about 6 mg to about 35 mg, about 6 mg to about 30 mg, about 6 mg to about 25 mg, about 6 mg to about 20 mg, about 6 mg to about 15 mg, about 6 mg to about 10 mg, about 6 mg to about 9 mg, about 6 mg to about 8 mg, about 6 mg to about 7 mg, about 7 mg to about 45 mg, about 7 mg to about 40 mg, about 7 mg to about 35 mg, about 7 mg to about 30 mg, about 7 mg to about 25 mg, about 7 mg to about 20 mg, about 7 mg to about 15 mg, about 7 mg to about 10 mg, about 7 mg to about 9 mg, about 7 mg to about 8 mg, about 8 mg to about 45 mg, about 8 mg to about 40 mg, about 8 mg to about 35 mg, about 8 mg to about 30 mg, about 8 mg to about 25 mg, about 8 mg to about 20 mg, about 8 mg to about 15 mg, about 8 mg to about 10 mg, about 8 mg to about 9 mg, about 9 mg to about 45 mg, about 9 mg to about 40 mg, about 9 mg to about 35 mg, about 9 mg to about 30 mg, about 9 mg to about 25 mg, about 9 mg to about 20 mg, about 9 mg to about 15 mg, about 9 mg to about 10 mg, about 10 mg to about 45 mg, about 10 mg to about 40 mg, about 10 mg to about 35 mg, about 10 mg to about 30 mg, about 10 mg to about 25 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 15 mg to about 45 mg, about 15 mg to about 40 mg, about 15 mg to about 35 mg, about 15 mg to about 30 mg, about 15 mg to about 25 mg, about 15 mg to about 20 mg, about 20 mg to about 45 mg, about 20 mg to about 40 mg, about 20 mg to about 35 mg, about 20 mg to about 30 mg, about 20 mg to about 25 mg, about 25 mg to about 45 mg, about 25 mg to about 40 mg, about 25 mg to about 35 mg, about 25 mg to about 30 mg, about 30 mg to about 45 mg, about 30 mg to about 40 mg, about 30 mg to about 35 mg, about 35 mg to about 45 mg, about 35 mg to about 40 mg, or about 35 mg to about 45 mg infigratinib, or a pharmaceutically acceptable salt thereof. In certain embodiments, a pharmaceutical composition described herein comprises about 0. 1 mg to about 20 mg infigratinib, or a pharmaceutically acceptable salt thereof. In certain embodiments, a pharmaceutical composition described herein comprises about 0. 1 mg to about 8 mg infigratinib, or a pharmaceutically acceptable salt thereof. [0122] In certain embodiments, a pharmaceutical composition described herein comprises about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, or about 50 mg infigratinib, or a pharmaceutically acceptable salt thereof. [0123] In certain embodiments, the pharmaceutically acceptable salt of infigratinib is infigratinib monophosphate.

[0124] In certain embodiments, the infigratinib monophosphate is present as an anhydrous crystalline form. In certain embodiments, the anhydrous crystalline form of infigratinib monophosphate is characterized by an XRPD peak (2 theta) at 15.0° ± 0.2°.

[0125] The pharmaceutical compositions provided herein can be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, intracranial administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration. In some embodiments, the pharmaceutical compositions disclosed herein are administered orally.

[0126] The pharmaceutical compositions provided herein may also be administered chronically (“chronic administration”). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may be continued indefinitely, for example, for the rest of the subject’s life. In certain embodiments, the chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time.

[0127] The pharmaceutical compositions provided herein may be presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include, but are not limited to, prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, minitablets, capsules or the like in the case of solid compositions.

[0128] In certain embodiments, the pharmaceutical compositions provided herein are administered to the patient as a solid dosage form. In some embodiments, the solid dosage form is a capsule. In some embodiments, the solid dosage form is a sprinkle capsule. In some embodiments, the solid dosage form is a tablet. In some embodiments, the solid dosage form is a minitablet. [0129] In certain embodiments, the compounds provided herein can be administered as the sole active agent, or they can be administered in combination with other active agents.

[0130] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. General considerations in the formulation and/or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21^st ed., Lippincott Williams & Wilkins, 2005.

Methods of Use and Treatment

[0131] The present disclosure provides methods of delivering or providing compounds of formulas (II), (III), and/or (IV), which methods may comprise administration of infigratinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds are delivered or provided to a subject in need of treatment for a skeletal dysplasias such as achondroplasia or hypochondroplasia.

[0132] In an aspect, provided herein is a method of delivering or providing a compound of formula (II) to a subject in need of treatment for a skeletal dysplasia described herein (e.g., achondroplasia or hypochondroplasia), wherein the compound of formula (II) has the structure:

[0133] In another aspect, provided herein is a method of delivering or providing a compound of formula (III) to a subject in need of treatment for a skeletal dysplasia described herein (e.g., achondroplasia or hypochondroplasia), wherein the compound of formula (III) has the structure:

[0134] In another aspect, provided herein is a method of delivering or providing a compound of formula (IV) to a subject in need of treatment for a skeletal dysplasia described herein (e.g., achondroplasia or hypochondroplasia), wherein the compound of formula (IV) has the structure:

[0135] In some embodiments, a method of delivering or providing a compound of formula (II),

(III), or (IV) comprises administering infigratinib, or a pharmaceutically acceptable salt thereof, in an amount sufficient to deliver/provide an effective amount of the compound of formula (II), the compound of formula (III), or a compound of formula (IV) to the subject.

[0136] The present disclosure also provides methods of treating skeletal dysplasias such as achondroplasia and hypochondroplasia. The methods may comprise administering infigratinib, or a pharmaceutically acceptable salt thereof, to deliver a compound of formula (II), (III), and/or

(IV).

[0137] In an aspect, provided herein is a method of treating a skeletal dysplasia in a subject in need thereof, comprising administering infigratinib, or a pharmaceutically acceptable salt thereof, to the subject to deliver an effective amount of a compound of formula (II), wherein the compound of formula (II) has the structure:

[0138] In another aspect, provided herein is a method of treating a skeletal dysplasia in a subject in need thereof, comprising administering infigratinib, or a pharmaceutically acceptable salt thereof, to the subject to deliver an effective amount of a compound of formula (III), wherein the compound of formula (III) has the structure:

[0139] In another aspect, provided herein is a method of treating a skeletal dysplasia in a subject in need thereof, comprising administering infigratinib, or a pharmaceutically acceptable salt thereof, to the subject to deliver an effective amount of a compound of formula (IV), wherein the compound of formula (IV) has the structure:

[0140] In some embodiments of any of the preceding aspects, the subject is in need of FGFR3 modulation.

[0141] The present disclosure also provides methods of treating a condition, disease, or disorder requiring FGFR3 modulation, such as a skeletal dysplasia such as achondroplasia or hypochondroplasia. The methods may comprise administering infigratinib, or a pharmaceutically acceptable salt thereof, in an amount sufficient to modulate the pharmaceutical activity of a compound of formula (II), (III), and/or (IV) on FGFR3.

[0142] In an aspect, provided herein is a method of treating a condition, disease, or disorder requiring FGFR3 modulation in a subject in need thereof, comprising administering infigratinib, or a pharmaceutically acceptable salt thereof, to the subject in an amount sufficient to modulate the pharmaceutical activity of a compound of formula (II) on FGFR3, wherein the compound of formula (II) has the structure:

[0143] In another aspect, provided herein is a method of treating a condition, disease, or disorder requiring FGFR3 modulation in a subject in need thereof, comprising administering infigratinib, or a pharmaceutically acceptable salt thereof, to the subject in an amount sufficient to modulate the pharmaceutical activity of a compound of formula (III) on FGFR3, wherein the compound of formula (III) has the structure:

[0144] In another aspect, provided herein is a method of treating a condition, disease, or disorder requiring FGFR3 modulation in a subject in need thereof, comprising administering infigratinib, or a pharmaceutically acceptable salt thereof, to the subject in an amount sufficient to modulate the pharmaceutical activity of a compound of formula (IV) on FGFR3, wherein the compound of formula (IV) has the structure:

[0145] In some embodiments of the preceding aspects, the condition, disease, or disorder is a skeletal dysplasia, such as achondroplasia or hypochondroplasia.

[0146] In some embodiments of any of the preceding aspects, administering infigratinib, or a pharmaceutically acceptable salt thereof, comprises administering a daily dose of about 0. 1 mg to about 50.0 mg of infigratinib, or a pharmaceutically acceptable salt thereof.

[0147] In some embodiments of any of the preceding aspects, administering the daily dose of about 0. 1 mg to about 50 mg of infigratinib, or a pharmaceutically acceptable salt thereof, results in a Cmax ratio of the compound of formula (II) to infigratinib of about 5 : 1 to about 1: 1.5, about 4: 1 to about 1: 1.5, about 3 : 1 to about 1: 1.5, about 2: 1 to about 1: 1.5, about 1 : 1 to about 1: 1.5, about 5: 1 to about 1: 1, about 5: 1 to about 2: 1, about 5: 1 to about 3: 1, about 5: 1 to about 4: 1, about 4: 1 to about 1: 1, about 4: 1 to about 2: 1, about 4: 1 to about 3: 1, about 3: 1 to about 1: 1, about 3 : 1 to about 2: 1, or about 2: 1 to about 1 : 1 in the subject.

[0148] In some embodiments of any of the preceding aspects, administering the daily dose of about 0. 1 mg to about 50 mg of infigratinib, or a pharmaceutically acceptable salt thereof, results in a Cmax ratio of the compound of formula (II) to infigratinib of about 1 : 1.5, about 1: 1, about 1.5: 1, about 2: 1, about 2.5: 1, about 3: 1, about 3.5: 1, about 4: 1, about 4.5: 1, about 5: 1, about 5.5: 1, or about 6: 1 in the subject.

[0149] In some embodiments of any of the preceding aspects, administering the daily dose of about 0. 1 mg to about 50 mg of infigratinib, or a pharmaceutically acceptable salt thereof, results in a Cmax ratio of the compound of formula (II) to infigratinib of greater than about 1: 1.75, greater than about 1: 1.5, greater than about 1: 1.25, greaterthan about 1: 1, greaterthan about 1.5 : 1 , greater than about 2 : 1 , greater than about 2.5: 1, greater than about 3: 1, greater than about 4.5: 1, or greater than about 5: 1 in the subject.

[0150] In some embodiments of any of the preceding aspects, administering the daily dose of about 0. 1 mg to about 50 mg of infigratinib, or a pharmaceutically acceptable salt thereof, results in a Cmax of the compound of formula (II) in a range of about 0.1 ng/mL to about 21 ng/mL, in the subject about 4 hours after administration.

[0151] In some embodiments of any of the preceding aspects, the Cmax is determined on Day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 of administration. In certain embodiments, Cmax is determined on Day 21 of continuous administration.

[0152] In some embodiments of any of the preceding aspects, admininstering infigratinib, or a pharmaceutically acceptable salt thereof comprises administering a daily dose of about 0. 1 mg to about 50 mg, about 0.2 mg to about 50 mg, about 0.3 mg to about 50 mg, about 0.4 mg to about 50 mg, about 0.5 mg to about 50 mg, about 0.6 mg to about 50 mg, about 0.7 mg to about 50 mg, about 0.8 mg to about 50 mg, about 0.9 mg to about 50 mg, about 1 mg to about 50 mg, about 2 mg to about 50 mg, about 3 mg to about 50 mg, about 4 mg to about 50 mg, about 5 mg to about 50 mg, about 6 mg to about 50 mg, about 7 mg to about 50 mg, about 8 mg to about 50 mg, about 9 mg to about 50 mg, about 10 mg to about 50 mg, about 15 mg to about 50 mg, about 20 mg to about 50 mg, about 25 mg to about 50 mg, about 30 mg to about 50 mg, about 35 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 0. 1 mg to about 45 mg, about 0. 1 mg to about 40 mg, about 0. 1 mg to about 35 mg, about 0.1 mg to about 30 mg, about 0.1 mg to about 25 mg, about 0.1 mg to about 20 mg, about 0.1 mg to about 15 mg, about 0.1 mg to about 10 mg, about 0.1 mg to about 9 mg, about 0.1 mg to about 8 mg, about 0. 1 mg to about 7 mg, about 0.1 mg to about 6 mg, about 0.1 mg to about 5 mg, about 0. 1 mg to about 4 mg, about 0. 1 mg to about 3 mg, about 0. 1 mg to about 2 mg, about 0.1 mg to about 1 mg, about 0.1 mg to about 0.9 mg, about 0. 1 mg to about 0.8 mg, about 0.1 mg to about 0.7 mg, about 0.1 mg to about 0.6 mg, about 0.1 mg to about 0.5 mg, about 0. 1 mg to about 0.4 mg, about 0. 1 mg to about 0.3 mg, about 0.1 mg to about 0.2 mg, about 0.2 mg to about 45 mg, about 0.2 mg to about 40 mg, about 0.2 mg to about 35 mg, about 0.2 mg to about 30 mg, about 0.2 mg to about 25 mg, about 0.2 mg to about 20 mg, about 0.2 mg to about 15 mg, about 0.2 mg to about 10 mg, about 0.2 mg to about 9 mg, about 0.2 mg to about 8 mg, about 0.2 mg to about 7 mg, about 0.2 mg to about 6 mg, about 0.2 mg to about 5 mg, about 0.2 mg to about 4 mg, about 0.2 mg to about 3 mg, about 0.2 mg to about 2 mg, about 0.2 mg to about 1 mg, about 0.2 mg to about 0.9 mg, about 0.2 mg to about 0.8 mg, about 0.2 mg to about 0.7 mg, about 0.2 mg to about 0.6 mg, about 0.2 mg to about 0.5 mg, about 0.2 mg to about 0.4 mg, about 0.2 mg to about 0.3 mg, about 0.3 mg to about 45 mg, about 0.3 mg to about 40 mg, about 0.3 mg to about 35 mg, about 0.3 mg to about 30 mg, about 0.3 mg to about 25 mg, about 0.3 mg to about 20 mg, about 0.3 mg to about 15 mg, about 0.3 mg to about 10 mg, about 0.3 mg to about 9 mg, about 0.3 mg to about 8 mg, about 0.3 mg to about 7 mg, about 0.3 mg to about 6 mg, about 0.3 mg to about 5 mg, about 0.3 mg to about 4 mg, about 0.3 mg to about 3 mg, about 0.3 mg to about 2 mg, about 0.3 mg to about 1 mg, about 0.3 mg to about 0.9 mg, about 0.3 mg to about 0.8 mg, about 0.3 mg to about 0.7 mg, about 0.3 mg to about 0.6 mg, about 0.3 mg to about 0.5 mg, about 0.3 mg to about 0.4 mg, about 0.4 mg to about 45 mg, about 0.4 mg to about 40 mg, about 0.4 mg to about 35 mg, about 0.4 mg to about 30 mg, about 0.4 mg to about 25 mg, about 0.4 mg to about 20 mg, about 0.4 mg to about 15 mg, about 0.4 mg to about 10 mg, about 0.4 mg to about 9 mg, about 0.4 mg to about 8 mg, about 0.4 mg to about 7 mg, about 0.4 mg to about 6 mg, about 0.4 mg to about 5 mg, about 0.4 mg to about 4 mg, about 0.4 mg to about 3 mg, about 0.4 mg to about 2 mg, about 0.4 mg to about 1 mg, about 0.4 mg to about 0.9 mg, about 0.4 mg to about 0.8 mg, about 0.4 mg to about 0.7 mg, about 0.4 mg to about 0.6 mg, about 0.4 mg to about 0.5 mg, about 0.5 mg to about 45 mg, about 0.5 mg to about 40 mg, about 0.5 mg to about 35 mg, about 0.5 mg to about 30 mg, about 0.5 mg to about 25 mg, about 0.5 mg to about 20 mg, about 0.5 mg to about 15 mg, about 0.5 mg to about 10 mg, about 0.5 mg to about 0.9 mg, about 0.5 mg to about 0.8 mg, about 0.5 mg to about 0.7 mg, about 0.5 mg to about 0.6 mg, about 0.6 mg to about 45 mg, about 0.6 mg to about 40 mg, about 0.6 mg to about 35 mg, about 0.6 mg to about 30 mg, about 0.6 mg to about 25 mg, about 0.6 mg to about 20 mg, about 0.6 mg to about 15 mg, about 0.6 mg to about 10 mg, about 0.6 mg to about 9 mg, about 0.6 mg to about 8 mg, about 0.6 mg to about 7 mg, about 0.6 mg to about 6 mg, about 0.6 mg to about 5 mg, about 0.6 mg to about 4 mg, about 0.6 mg to about 3 mg, about 0.6 mg to about 2 mg, about 0.6 mg to about 1 mg, about 0.6 mg to about 0.9 mg, about 0.6 mg to about 0.8 mg, about 0.6 mg to about 0.7 mg, about 0.7 mg to about 45 mg, about 0.7 mg to about 40 mg, about 0.7 mg to about 35 mg, about 0.7 mg to about 30 mg, about 0.7 mg to about 25 mg, about 0.7 mg to about 20 mg, about 0.7 mg to about 15 mg, about 0.7 mg to about 10 mg, about 0.7 mg to about 9 mg, about 0.7 mg to about 8 mg, about 0.7 mg to about 7 mg, about 0.7 mg to about 6 mg, about 0.7 mg to about 5 mg, about 0.7 mg to about 4 mg, about 0.7 mg to about 3 mg, about 0.7 mg to about 2 mg, about 0.7 mg to about 1 mg, about 0.7 mg to about 0.9 mg, about 0.7 mg to about 0.8 mg, about 0.8 mg to about 45 mg, about 0.8 mg to about 40 mg, about 0.8 mg to about 35 mg, about 0.8 mg to about 30 mg, about 0.8 mg to about 25 mg, about 0.8 mg to about 20 mg, about 0.8 mg to about 15 mg, about 0.8 mg to about 10 mg, about 0.8 mg to about 9 mg, about 0.8 mg to about 8 mg, about 0.8 mg to about 7 mg, about 0.8 mg to about 6 mg, about 0.8 mg to about 5 mg, about 0.8 mg to about 4 mg, about 0.8 mg to about 3 mg, about 0.8 mg to about 2 mg, about 0.8 mg to about 1 mg, about 0.8 mg to about 0.9 mg, about 0.9 mg to about 45 mg, about 0.9 mg to about 40 mg, about 0.9 mg to about 35 mg, about 0.9 mg to about 30 mg, about 0.9 mg to about 25 mg, about 0.9 mg to about 20 mg, about 0.9 mg to about 15 mg, about 0.9 mg to about 10 mg, about 0.9 mg to about 9 mg, about 0.9 mg to about 8 mg, about 0.9 mg to about 7 mg, about 0.9 mg to about 6 mg, about 0.9 mg to about 5 mg, about 0.9 mg to about 4 mg, about 0.9 mg to about 3 mg, about 0.9 mg to about 2 mg, about 0.9 mg to about 1 mg, about 1 mg to about 45 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 1 mg to about 15 mg, about 1 mg to about 10 mg, about 1 mg to about 9 mg, about 1 mg to about 8 mg, about 1 mg to about 7 mg, about 1 mg to about 6 mg, about 1 mg to about 5 mg, about 1 mg to about 4 mg, about 1 mg to about 3 mg, about 1 mg to about 2 mg, about 2 mg to about 45 mg, about 2 mg to about 40 mg, about 2 mg to about 35 mg, about 2 mg to about 30 mg, about 2 mg to about 25 mg, about 2 mg to about 20 mg, about 2 mg to about 15 mg, about 2 mg to about 10 mg, about 2 mg to about 9 mg, about 2 mg to about 8 mg, about 2 mg to about 7 mg, about 2 mg to about 6 mg, about 2 mg to about 5 mg, about 2 mg to about 4 mg, about 2 mg to about 3 mg, about 3 mg to about 45 mg, about 3 mg to about 40 mg, about 3 mg to about 35 mg, about 3 mg to about 30 mg, about 3 mg to about 25 mg, about 3 mg to about 20 mg, about 3 mg to about 15 mg, about 3 mg to about 10 mg, about 3 mg to about

9 mg, about 3 mg to about 8 mg, about 3 mg to about 7 mg, about 3 mg to about 6 mg, about 3 mg to about 5 mg, about 3 mg to about 4 mg, about 4 mg to about 45 mg, about 4 mg to about 40 mg, about 4 mg to about 35 mg, about 4 mg to about 30 mg, about 4 mg to about 25 mg, about 4 mg to about 20 mg, about 4 mg to about 15 mg, about 4 mg to about 10 mg, about 4 mg to about 9 mg, about 4 mg to about 8 mg, about 4 mg to about 7 mg, about 4 mg to about 6 mg, about 4 mg to about 5 mg, about 5 mg to about 45 mg, about 5 mg to about 40 mg, about 5 mg to about 35 mg, about 5 mg to about 30 mg, about 5 mg to about 25 mg, about 5 mg to about 20 mg, about 5 mg to about 15 mg, about 5 mg to about 10 mg, about 5 mg to about 9 mg, about 5 mg to about 8 mg, about 5 mg to about 7 mg, about 5 mg to about 6 mg, about 6 mg to about 45 mg, about 6 mg to about 40 mg, about 6 mg to about 35 mg, about 6 mg to about 30 mg, about 6 mg to about 25 mg, about 6 mg to about 20 mg, about 6 mg to about 15 mg, about 6 mg to about 10 mg, about 6 mg to about 9 mg, about 6 mg to about 8 mg, about 6 mg to about 7 mg, about 7 mg to about 45 mg, about 7 mg to about 40 mg, about 7 mg to about 35 mg, about 7 mg to about 30 mg, about 7 mg to about 25 mg, about 7 mg to about 20 mg, about 7 mg to about 15 mg, about 7 mg to about 10 mg, about 7 mg to about 9 mg, about 7 mg to about 8 mg, about 8 mg to about 45 mg, about 8 mg to about 40 mg, about 8 mg to about 35 mg, about 8 mg to about 30 mg, about 8 mg to about 25 mg, about 8 mg to about 20 mg, about 8 mg to about 15 mg, about 8 mg to about 10 mg, about 8 mg to about 9 mg, about 9 mg to about 45 mg, about 9 mg to about 40 mg, about 9 mg to about 35 mg, about 9 mg to about 30 mg, about 9 mg to about 25 mg, about 9 mg to about 20 mg, about 9 mg to about 15 mg, about 9 mg to about 10 mg, about 10 mg to about 45 mg, about 10 mg to about 40 mg, about 10 mg to about 35 mg, about 10 mg to about 30 mg, about 10 mg to about 25 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 15 mg to about 45 mg, about 15 mg to about 40 mg, about 15 mg to about 35 mg, about 15 mg to about 30 mg, about 15 mg to about 25 mg, about 15 mg to about 20 mg, about 20 mg to about 45 mg, about 20 mg to about 40 mg, about 20 mg to about 35 mg, about 20 mg to about 30 mg, about 20 mg to about 25 mg, about 25 mg to about 45 mg, about 25 mg to about 40 mg, about 25 mg to about 35 mg, about 25 mg to about 30 mg, about 30 mg to about 45 mg, about 30 mg to about 40 mg, about 30 mg to about 35 mg, about 35 mg to about 45 mg, about 35 mg to about 40 mg, or about 35 mg to about 45 mg of infigratinib, or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, administering infigratinib, or a pharmaceutically acceptable salt thereof, comprises administering a daily dose of about 0.1 mg to about 20 mg of infigratinib, or a pharmaceutically acceptable salt thereof. In some embodiments, administering infigratinib, or a pharmaceutically acceptable salt thereof, comprises administering to a daily dose about 1 mg to about 10 mg of infigratinib, or a pharmaceutically acceptable salt thereof. In some embodiments, administering infigratinib, or a pharmaceutically acceptable salt thereof, comprises administering to a daily dose about 1 mg to about 8 mg of infigratinib, or a pharmaceutically acceptable salt thereof.

[0153] In some embodiments of any of the preceding aspects, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, 3.5 mg, about 4.0 mg, about 5.0 mg, about 6.0 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg, about 16.0 mg, about 17.0 mg, about 18.0 mg, about 19.0 mg, or about 20.0 mg of infigratinib, or a pharmaceutically acceptable salt thereof, is administered daily. In certain embodiments, about 1.5 mg, about 2.5 mg, 3.5 mg, about 5.0 mg, about 7.0 mg, about 10.0 mg, about 14.0 mg, or about 20.0 mg of infigratinib, or a pharmaceutically acceptable salt thereof, is administered daily.

[0154] In some embodiments of any of the preceding aspects, the amount of infigratinib, or the pharmaceutically acceptable salt thereof, administered to the subject (e.g., pediatric patient) is determined based on the subject’s body weight. In some embodiments, the amount of infigratinib, or the pharmaceutically acceptable salt thereof, administered to the subject is determined according to Table 1.

Table 1. Infigratinib dosing of subject by weight.

[0155] In some embodiments of any of the preceding aspects, administering infigratinib, or a pharmaceutically acceptable salt thereof, comprises administering a daily dose of about 0.01 mg/kg to about 0.6 mg/kg, about 0.015 mg/kg to about 0.6 mg/kg, about 0.02 mg/kg to about 0.6 mg/kg, about 0.025 mg/kg to about 0.6 mg/kg, about 0.03 mg/kg to about 0.6 mg/kg, about 0.05 mg/kg to about 0.6 mg/kg, about 0.07 mg/kg to about 0.6 mg/kg, about 0.09 mg/kg to about 0.6 mg/kg, about 0.11 mg/kg to about 0.6 mg/kg, about 0.13 mg/kg to about 0.6 mg/kg, about 0.15 mg/kg to about 0.6 mg/kg, about 0.17 mg/kg to about 0.6 mg/kg, about 0.19 mg/kg to about 0.6 mg/kg, about 0.21 mg/kg to about 0.6 mg/kg, about 0.23 mg/kg to about 0.6 mg/kg, about 0.25 mg/kg to about 0.6 mg/kg, about 0.27 mg/kg to about 0.6 mg/kg, about 0.29 mg/kg to about 0.6 mg/kg, about 0.3 mg/kg to about 0.6 mg/kg, about 0.4 mg/kg to about 0.6 mg/kg, about 0.5 mg/kg to about 0.6 mg/kg, about 0.01 mg/kg to about 0.5 mg/kg, about 0.01 mg/kg to about 0.4 mg/kg, about 0.01 mg/kg to about 0.3 mg/kg, about 0.01 mg/kg to about 0.29 mg/kg, about 0.01 mg/kg to about 0.27 mg/kg, about 0.01 mg/kg to about 0.25 mg/kg, about 0.01 mg/kg to about 0.23 mg/kg, about 0.01 mg/kg to about 0.21 mg/kg, about 0.01 mg/kg to about 0.19 mg/kg, about 0.01 mg/kg to about 0.17 mg/kg, about 0.01 mg/kg to about 0.15 mg/kg, about 0.01 mg/kg to about 0.13 mg/kg, about 0.01 mg/kg to about 0.11 mg/kg, about 0.01 mg/kg to about 0.09 mg/kg, about 0.01 mg/kg to about 0.07 mg/kg, about 0.01 mg/kg to about 0.05 mg/kg, about 0.01 mg/kg to about 0.03 mg/kg, about 0.01 mg/kg to about 0.025 mg/kg, about 0.01 mg/kg to about 0.02 mg/kg, about 0.01 mg/kg to about 0.015 mg/kg, about 0.015 mg/kg to about 0.5 mg/kg, about 0.015 mg/kg to about 0.4 mg/kg, about 0.015 mg/kg to about 0.3 mg/kg, about 0.015 mg/kg to about 0.29 mg/kg, about 0.015 mg/kg to about 0.27 mg/kg, about 0.015 mg/kg to about 0.25 mg/kg, about 0.015 mg/kg to about 0.23 mg/kg, about 0.015 mg/kg to about 0.21 mg/kg, about 0.015 mg/kg to about 0.19 mg/kg, about 0.015 mg/kg to about 0.17 mg/kg, about 0.015 mg/kg to about 0.15 mg/kg, about 0.015 mg/kg to about 0.13 mg/kg, about 0.015 mg/kg to about 0.11 mg/kg, about 0.015 mg/kg to about 0.09 mg/kg, about 0.015 mg/kg to about 0.07 mg/kg, about 0.015 mg/kg to about 0.05 mg/kg, about 0.015 mg/kg to about 0.03 mg/kg, about 0.015 mg/kg to about 0.025 mg/kg, about 0.015 mg/kg to about 0.02 mg/kg, about 0.02 mg/kg to about 0.5 mg/kg, about 0.02 mg/kg to about 0.4 mg/kg, about 0.02 mg/kg to about 0.3 mg/kg, about 0.02 mg/kg to about 0.29 mg/kg, about 0.02 mg/kg to about 0.27 mg/kg, about 0.02 mg/kg to about 0.25 mg/kg, about 0.02 mg/kg to about 0.23 mg/kg, about 0.02 mg/kg to about 0.21 mg/kg, about 0.02 mg/kg to about 0.19 mg/kg, about 0.02 mg/kg to about 0.17 mg/kg, about 0.02 mg/kg to about 0.15 mg/kg, about 0.02 mg/kg to about 0.13 mg/kg, about 0.02 mg/kg to about 0.11 mg/kg, about 0.02 mg/kg to about 0.09 mg/kg, about 0.02 mg/kg to about 0.07 mg/kg, about 0.02 mg/kg to about 0.05 mg/kg, about 0.02 mg/kg to about 0.03 mg/kg, about 0.02 mg/kg to about 0.025 mg/kg, about 0.025 mg/kg to about 0.5 mg/kg, about 0.025 mg/kg to about 0.4 mg/kg, about 0.025 mg/kg to about 0.3 mg/kg, about 0.025 mg/kg to about 0.29 mg/kg, about 0.025 mg/kg to about 0.27 mg/kg, about 0.025 mg/kg to about 0.25 mg/kg, about 0.025 mg/kg to about 0.23 mg/kg, about 0.025 mg/kg to about 0.21 mg/kg, about 0.025 mg/kg to about 0.19 mg/kg, about 0.025 mg/kg to about 0.17 mg/kg, about 0.025 mg/kg to about 0.15 mg/kg, about 0.025 mg/kg to about 0.13 mg/kg, about 0.025 mg/kg to about 0.11 mg/kg, about 0.025 mg/kg to about 0.09 mg/kg, about 0.025 mg/kg to about 0.07 mg/kg, about 0.025 mg/kg to about 0.05 mg/kg, about 0.025 mg/kg to about 0.03 mg/kg, about 0.03 mg/kg to about 0.5 mg/kg, about 0.03 mg/kg to about 0.4 mg/kg, about 0.03 mg/kg to about 0.3 mg/kg, about 0.03 mg/kg to about 0.29 mg/kg, about 0.03 mg/kg to about 0.27 mg/kg, about 0.03 mg/kg to about 0.25 mg/kg, about 0.03 mg/kg to about 0.23 mg/kg, about 0.03 mg/kg to about 0.21 mg/kg, about 0.03 mg/kg to about 0.19 mg/kg, about 0.03 mg/kg to about 0.17 mg/kg, about 0.03 mg/kg to about 0.15 mg/kg, about 0.03 mg/kg to about 0.13 mg/kg, about 0.03 mg/kg to about 0.11 mg/kg, about 0.03 mg/kg to about 0.09 mg/kg, about 0.03 mg/kg to about 0.07 mg/kg, about 0.03 mg/kg to about 0.05 mg/kg, about 0.05 mg/kg to about 0.5 mg/kg, about 0.05 mg/kg to about 0.4 mg/kg, about 0.05 mg/kg to about 0.3 mg/kg, about 0.05 mg/kg to about 0.29 mg/kg, about 0.05 mg/kg to about 0.27 mg/kg, about 0.05 mg/kg to about 0.25 mg/kg, about 0.05 mg/kg to about 0.23 mg/kg, about 0.05 mg/kg to about 0.21 mg/kg, about 0.05 mg/kg to about 0.19 mg/kg, about 0.05 mg/kg to about 0.17 mg/kg, about 0.05 mg/kg to about 0.15 mg/kg, about 0.05 mg/kg to about 0.13 mg/kg, about 0.05 mg/kg to about 0.11 mg/kg, about 0.05 mg/kg to about 0.09 mg/kg, about 0.05 mg/kg to about 0.07 mg/kg, about 0.07 mg/kg to about 0.5 mg/kg, about 0.07 mg/kg to about 0.4 mg/kg, about 0.07 mg/kg to about 0.3 mg/kg, about 0.07 mg/kg to about 0.29 mg/kg, about 0.07 mg/kg to about 0.27 mg/kg, about 0.07 mg/kg to about 0.25 mg/kg, about 0.07 mg/kg to about 0.23 mg/kg, about 0.07 mg/kg to about 0.21 mg/kg, about 0.07 mg/kg to about 0.19 mg/kg, about 0.07 mg/kg to about 0.17 mg/kg, about 0.07 mg/kg to about 0.15 mg/kg, about 0.07 mg/kg to about 0.13 mg/kg, about 0.07 mg/kg to about 0.11 mg/kg, about 0.07 mg/kg to about 0.09 mg/kg, about 0.09 mg/kg to about 0.5 mg/kg, about 0.09 mg/kg to about 0.4 mg/kg, about 0.09 mg/kg to about 0.3 mg/kg, about 0.09 mg/kg to about 0.29 mg/kg, about 0.09 mg/kg to about 0.27 mg/kg, about 0.09 mg/kg to about 0.25 mg/kg, about 0.09 mg/kg to about 0.23 mg/kg, about 0.09 mg/kg to about 0.21 mg/kg, about 0.09 mg/kg to about 0.19 mg/kg, about 0.09 mg/kg to about 0.17 mg/kg, about 0.09 mg/kg to about 0.15 mg/kg, about 0.09 mg/kg to about 0.13 mg/kg, about 0.09 mg/kg to about 0.11 mg/kg, about 0.11 mg/kg to about 0.5 mg/kg, about 0.11 mg/kg to about 0.4 mg/kg, about 0.11 mg/kg to about 0.3 mg/kg, about 0.11 mg/kg to about 0.29 mg/kg, about 0.11 mg/kg to about 0.27 mg/kg, about 0.11 mg/kg to about 0.25 mg/kg, about 0.11 mg/kg to about 0.23 mg/kg, about 0.11 mg/kg to about 0.21 mg/kg, about 0.11 mg/kg to about 0.19 mg/kg, about 0.11 mg/kg to about 0.17 mg/kg, about 0.11 mg/kg to about 0.15 mg/kg, about 0.11 mg/kg to about 0.13 mg/kg, about 0.13 mg/kg to about 0.5 mg/kg, about 0.13 mg/kg to about 0.4 mg/kg, about 0.13 mg/kg to about 0.3 mg/kg, about 0.13 mg/kg to about 0.29 mg/kg, about 0.13 mg/kg to about 0.27 mg/kg, about 0.13 mg/kg to about 0.25 mg/kg, about 0.13 mg/kg to about 0.23 mg/kg, about 0.13 mg/kg to about 0.21 mg/kg, about 0.13 mg/kg to about 0.19 mg/kg, about 0.13 mg/kg to about 0.17 mg/kg, about 0.13 mg/kg to about 0.15 mg/kg, about 0.15 mg/kg to about 0.5 mg/kg, about 0.15 mg/kg to about 0.4 mg/kg, about 0.15 mg/kg to about 0.3 mg/kg, about 0.15 mg/kg to about 0.29 mg/kg, about 0.15 mg/kg to about 0.27 mg/kg, about 0.15 mg/kg to about 0.25 mg/kg, about 0.15 mg/kg to about 0.23 mg/kg, about 0.15 mg/kg to about 0.21 mg/kg, about 0.15 mg/kg to about 0.19 mg/kg, about 0.15 mg/kg to about 0.17 mg/kg, about 0.17 mg/kg to about 0.5 mg/kg, about 0.17 mg/kg to about 0.4 mg/kg, about 0.17 mg/kg to about 0.3 mg/kg, about 0.17 mg/kg to about 0.29 mg/kg, about 0.17 mg/kg to about 0.27 mg/kg, about 0.17 mg/kg to about 0.25 mg/kg, about 0.17 mg/kg to about 0.23 mg/kg, about 0.17 mg/kg to about 0.21 mg/kg, about 0.17 mg/kg to about 0.19 mg/kg, about 0.19 mg/kg to about 0.5 mg/kg, about 0.19 mg/kg to about 0.4 mg/kg, about 0.19 mg/kg to about 0.3 mg/kg, about 0.19 mg/kg to about 0.27 mg/kg, about 0.19 mg/kg to about 0.25 mg/kg, about 0.19 mg/kg to about 0.23 mg/kg, about 0.19 mg/kg to about 0.21 mg/kg, about 0.21 mg/kg to about 0.5 mg/kg, about 0.21 mg/kg to about 0.4 mg/kg, about 0.21 mg/kg to about 0.3 mg/kg, about 0.21 mg/kg to about 0.29 mg/kg, about 0.21 mg/kg to about 0.27 mg/kg, about 0.21 mg/kg to about 0.25 mg/kg, about 0.21 mg/kg to about 0.23 mg/kg, about 0.23 mg/kg to about 0.5 mg/kg, about 0.23 mg/kg to about 0.4 mg/kg, about 0.23 mg/kg to about 0.3 mg/kg, about 0.23 mg/kg to about 0.29 mg/kg, about 0.23 mg/kg to about 0.27 mg/kg, about 0.23 mg/kg to about 0.25 mg/kg, about 0.25 mg/kg to about 0.5 mg/kg, about 0.25 mg/kg to about 0.4 mg/kg, about 0.25 mg/kg to about 0.3 mg/kg, about 0.25 mg/kg to about 0.29 mg/kg, about 0.25 mg/kg to about 0.27 mg/kg, about 0.27 mg/kg to about 0.5 mg/kg, about 0.27 mg/kg to about 0.4 mg/kg, about 0.27 mg/kg to about 0.3 mg/kg, about 0.27 mg/kg to about 0.29 mg/kg, about 0.29 mg/kg to about 0.5 mg/kg, about 0.29 mg/kg to about 0.4 mg/kg, about 0.29 mg/kg to about 0.3 mg/kg, about 0.3 mg/kg to about 0.5 mg/kg, about 0.3 mg/kg to about 0.4 mg/kg, or about 0.4 mg/kg to about 0.5 mg/kg of infigratinib, or a pharmaceutically acceptable salt thereof. In certain embodiments, administering infigratinib, or a pharmaceutically acceptable salt thereof, comprises administering a daily dose of about 0.01 mg/kg to about 0.6 mg/kg of infigratinib, or a pharmaceutically acceptable salt thereof. In certain embodiments, administering infigratinib, or a pharmaceutically acceptable salt thereof, comprises administering a daily dose of about 0.15 mg/kg to about 0.5 mg/kg of infigratinib, or a pharmaceutically acceptable salt thereof.

[0156] In some embodiments of any of the preceding aspects, administering infigratinib, or a pharmaceutically acceptable salt thereof, comprises administering a daily dose of about 0.01 mg/kg, about 0.011 mg/kg, about 0.012 mg/kg, about 0.013 mg/kg, about 0.014 mg/kg, about 0.015 mg/kg, about 0.016 mg/kg, about 0.018 mg/kg, about 0.02 mg/kg, about 0.022 mg/kg, about 0.024 mg/kg, about 0.026 mg/kg, about 0.028 mg/kg, about 0.03 mg/kg, about 0.032 mg/kg, about 0.036 mg/kg, about 0.04 mg/kg, about 0.044 mg/kg, about 0.048 mg/kg, about 0.052 mg/kg, about 0.056 mg/kg, about 0.06 mg/kg, about 0.064 mg/kg, about 0.072 mg/kg, about 0.08 mg/kg, about 0.088 mg/kg, about 0.096 mg/kg, about 0.104 mg/kg, about 0.112 mg/kg, about 0.12 mg/kg, about 0.128 mg/kg, about 0.13 mg/kg, about 0.14 mg/kg, about 0.15 mg/kg, about 0.16 mg/kg, about 0.17 mg/kg, about 0.18 mg/kg, about 0.19 mg/kg, about 0.2 mg/kg, about 0.21 mg/kg, about 0.22 mg/kg, about 0.23 mg/kg, about 0.24 mg/kg, about 0.25 mg/kg, about 0.26 mg/kg, about 0.27 mg/kg, about 0.28 mg/kg, about 0.29 mg/kg, about 0.3 mg/kg, about 0.31 mg/kg, about 0.32 mg/kg, about 0.33 mg/kg, about 0.34 mg/kg, about 0.35 mg/kg, about 0.36 mg/kg, about 0.37 mg/kg, about 0.38 mg/kg, about 0.39 mg/kg, about 0.4 mg/kg, about 0.41 mg/kg, about 0.42 mg/kg, about 0.43 mg/kg, about 0.44 mg/kg, about 0.45 mg/kg, about 0.46 mg/kg, about 0.47 mg/kg, about 0.48 mg/kg, about 0.49 mg/kg, about 0.5 mg/kg, about 0.51 mg/kg, about 0.52 mg/kg, about 0.53 mg/kg, about 0.54 mg/kg, about 0.55 mg/kg, about 0.56 mg/kg, about 0.57 mg/kg, about 0.58 mg/kg, about 0.59 mg/kg, or about 0.6 mg/kg of infigratinib, or a pharmaceutically acceptable salt thereof. In certain embodiments, administering infigratinib, or a pharmaceutically acceptable salt thereof, comprises administering a daily dose of about 0.25 mg/kg of infigratinib, or a pharmaceutically acceptable salt thereof. In certain embodiments, administering infigratinib, or a pharmaceutically acceptable salt thereof, comprises administering a daily dose of about 0.5 mg/kg of infigratinib, or a pharmaceutically acceptable salt thereof.

[0157] In some embodiments of any of the preceding aspects, infigratinib is administered as a phosphate salt. In certain embodiments, infigratinib is administered as infigratinib monophosphate. In certain embodiments, the infigratinib monophosphate is present as an anhydrous crystalline form. In certain embodiments, the anhydrous crystalline form of infigratinib monophosphate is characterized by an X-ray powder diffraction (XRPD) peak (2 theta) at 15.0° ± 0.2°.

[0158] In some embodiments of any of the preceding aspects, infigratinib, or the pharmaceutically acceptable salt thereof, is administered in a solid dosage form. In some embodiments, infigratinib, or the pharmaceutically acceptable salt thereof, is administered in a tablet. In some embodiments, infigratinib, or the pharmaceutically acceptable salt thereof, is administered in a minitablet. In some embodiments, infigratinib, or the pharmaceutically acceptable salt thereof, is administered in a capsule. In some embodiments, infigratinib, or the pharmaceutically acceptable salt thereof, is administered in a sprinkle capsule. In some embodiments, infigratinib, or the pharmaceutically acceptable salt thereof, is administered orally.

[0159] In some embodiments of any of the preceding aspects, the dose of infigratinib, or a pharmaceutically acceptable salt thereof, is administered to the subject daily, every other day, two days a week, three days a week, four days a week, five days a week, or six days a week. In certain embodiments, the dose of infigratinib, or a pharmaceutically acceptable salt thereof, is administered to the subject daily.

[0160] In some embodiments of any of the preceding aspects, the dose of infigratinib, or a pharmaceutically acceptable salt thereof, is administered to the subject once daily, twice daily, three times daily, four times daily, five times daily, or six times daily. [0161] In some embodiments, the compound of formula (II) and/or the compound of formula (III) is administered directly to the subject.

[0162] In some embodiments of any of the preceding aspects, the subject is a pediatric patient. In some embodiments, the subject is less than 18 years of age. In some embodiments, the subject is 0 to 4 months old, 0 to 6 months old, 0 to 1 year of age, 0 to 2 years of age, 0 to 3 years of age, 0 to 5 years of age, 1 to 2 years of age, 1 to 3 years of age, 1 to 5 years of age, 2 to 3 years of age, 2 to 5 years of age, 2 to 8 years of age, 2 to 11 years of age, 2 to 17 years of age, 3 to 5 years of age, 3 to 8 years of age, 3 to 11 years of age, 3 to 17 years of age, 5 to 8 years of age, 5 to 11 years of age, 5 to 17 years of age, 8 to 11 years of age, 8 to 17 years of age, 11 to 17 years of age, or 12 to 17 years of age. In some embodiments, the subject is 0 to 4 months old. In some embodiments, the subject is 0 to 6 months old. In some embodiments, the subject is 0 to 1 year of age. In some embodiments, the subject is 0 to 2 years of age. In some embodiments, the subject is 0 to 3 years of age. In some embodiments, the subject is 0 to 5 years of age. In some embodiments, the subject is 1 to 2 years of age. In some embodiments, the subject is 1 to 3 years of age. In some embodiments, the subject is 1 to 5 years of age. In some embodiments, the subject is 2 to 3 years of age. In some embodiments, the subject is 2 to 5 years of age. In some embodiments, the subject is 2 to 8 years of age. In some embodiments, the subject is 2 to 11 years of age. In some embodiments, the subject is 2 to 17 years of age. In some embodiments, the subject is 3 to 5 years of age. In some embodiments, the subject is 3 to 8 years of age. In some embodiments, the subject is 3 to 11 years of age. In some embodiments, the subject is 3 to 17 years of age. In some embodiments, the subject is 5 to 8 years of age. In some embodiments, the subject is 5 to 11 years of age. In some embodiments, the subject is 5 to 17 years of age. In some embodiments, the subject is 8 to 11 years of age. In some embodiments, the subject is 8 to 17 years of age. In some embodiments, the subject is 11 to 17 years of age. In some embodiments, the subject is 12 to 17 years of age. In some embodiments, the subject is less than 2 years of age. In some embodiments, the subject is less than 3 years of age. In some embodiments, the subject is less than 5 years of age. In some embodiments, the subject is less

than 8 years of age. In some embodiments, the subject is less than 11 years of age. In some embodiments, the subject is less than 12 years of age.

[0163] In some embodiments of any of the preceding aspects, the subject has open epiphyses (growth plates).

[0164] In some embodiments of any of the preceding aspects, the subject has an FGFR3 mutation. In some embodiments, the FGFR3 mutation is a G380R or N540K mutation.

[0165] In some embodiments of any of the preceding aspects, the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia (e.g., thanatophoric dysplasia type I or thanatophoric dysplasia type II), osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, Crouzon syndrome (e.g., Crouzon syndrome acanthosis nigricans), craniosynostosis, Kallmann syndrome, hypogonadotropic hypogonadism, cleft palate and other craniofacial defects, scoliosis, Type 1 or classic Pfeiffer syndrome, osteoglophonic dysplasia, craniosynostosis, mandibular progmathism, hypertelorism, brachydactyly, inter-phalangeal joint fusion, Jackson-Weiss syndrome, Antley-Bixler syndrome, Apert syndrome, Crouzon syndrome, X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, and trigonocephaly. In some embodiments, the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia (e.g., thanatophoric dysplasia type I or thanatophoric dysplasia type II), osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, and Crouzon syndrome (e.g., Crouzon syndrome acanthosis nigricans). In some embodiments, the skeletal disorder is achondroplasia. In some embodiments, the skeletal disorder is hypochondroplasia.

[0166] The present disclosure also provides provided herein are methods of modulating FGFR3. The methods generally comprise contacting FGFR3 with a compound of formula (II) and/or a compound of formula (III).

[0167] In an aspect, provided herein is a method of modulating FGFR3, comprising contacting FGFR3 with a compound of formula (II), wherein the compound of formula (II) has the structure:

[0168] In another aspect, provided herein is a method of modulating FGFR3, comprising contacting FGFR3 with a compound of formula (III), wherein the compound of formula (III) has the structure:

[0169] In another aspect, provided herein is a method of modulating FGFR3, comprising contacting FGFR3 with a compound of formula (IV), wherein the compound of formula (IV) has the structure:

[0170] In some embodiments of the preceding aspects, the FGFR3 is disposed within a cell. In some embodiments, the cell is located within a subject. In some embodiments, the subject has a skeletal dysplasia. In some embodiments, the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia (e.g., thanatophoric dysplasia type I or thanatophoric dysplasia type II), osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, Crouzon syndrome (e.g., Crouzon syndrome acanthosis nigricans), craniosynostosis, Kallmann syndrome, hypogonadotropic hypogonadism, cleft palate and other craniofacial defects, scoliosis, Type 1 or classic Pfeiffer syndrome, osteoglophonic dysplasia, craniosynostosis, mandibular progmathism, hypertelorism, brachydactyly, inter-phalangeal joint fusion, Jackson-Weiss syndrome, Antley-Bixler syndrome, Apert syndrome, Crouzon syndrome, X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, and trigonocephaly. In some embodiments, the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia (e.g., thanatophoric dysplasia type I or thanatophoric dysplasia type II), osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, and Crouzon syndrome (e.g., Crouzon syndrome acanthosis nigricans). In some embodiments, the skeletal dysplasia is achondroplasia. In some embodiments, the skeletal dysplasia is hypochondroplasia.

[0171] In some embodiments of any of the preceding aspects, the subject is a pediatric patient. In some embodiments, the subject is less than 18 years of age. In some embodiments, the subject is 0 to 4 months old, 0 to 6 months old, 0 to 1 year of age, 0 to 2 years of age, 0 to 3 years of age, 0 to 5 years of age, 1 to 2 years of age, 1 to 3 years of age, 1 to 5 years of age, 2 to 3 years of age, 2 to 5 years of age, 2 to 8 years of age, 2 to 11 years of age, 2 to 17 years of age, 3 to 5 years of age, 3 to 8 years of age, 3 to 11 years of age, 3 to 17 years of age, 5 to 8 years of age, 5 to 11 years of age, 5 to 17 years of age, 8 to 11 years of age, 8 to 17 years of age, 11 to 17 years of age, or 12 to 17 years of age. In some embodiments, the subject is 0 to 4 months old. In some embodiments, the subject is 0 to 6 months old. In some embodiments, the subject is 0 to 1 year of age. In some embodiments, the subject is 0 to 2 years of age. In some embodiments, the subject is 0 to 3 years of age. In some embodiments, the subject is 0 to 5 years of age. In some embodiments, the subject is 1 to 2 years of age. In some embodiments, the subject is 1 to 3 years of age. In some embodiments, the subject is 1 to 5 years of age. In some embodiments, the subject is 2 to 3 years of age. In some embodiments, the subject is 2 to 5 years of age. In some embodiments, the subject is 2 to 8 years of age. In some embodiments, the subject is 2 to 11 years of age. In some embodiments, the subject is 2 to 17 years of age. In some embodiments, the subject is 3 to 5 years of age. In some embodiments, the subject is 3 to 8 years of age. In some embodiments, the subject is 3 to 11 years of age. In some embodiments, the subject is 3 to 17 years of age. In some embodiments, the subject is 5 to 8 years of age. In some embodiments, the subject is 5 to 11 years of age. In some embodiments, the subject is 5 to 17 years of age. In some embodiments, the subject is 8 to 11 years of age. In some embodiments, the subject is 8 to 17 years of age. In some embodiments, the subject is 11 to 17 years of age. In some embodiments, the subject is 12 to 17 years of age. In some embodiments, the subject is less than 2 years of age. In some embodiments, the subject is less than 3 years of age. In some embodiments, the subject is less than 5 years of age. In some embodiments, the subject is less than 8 years of age. In some embodiments, the subject is less than 11 years of age. In some embodiments, the subject is less than 12 years of age.

[0172] In some embodiments of any of the preceding aspects, the subject has open epiphyses (growth plates).

[0173] In some embodiments of any of the preceding aspects, the subject has an FGFR3 mutation. In some embodiments, the FGFR3 mutation is a G380R or N540K mutation.

[0174] In some embodiments of the preceding aspects, contacting FGFR3 with a compound of formula (II), (III), or (IV) in a subject comprises administering infigratinib, or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the dosage amount of infigratinib, or a pharmaceutically acceptable salt thereof, to thereby significantly modulate pharmaceutical activity on FGFR3 by the compound of formula (II), (III), or (IV) is about 0.1 mg to about 50 mg, about 0.2 mg to about 50 mg, about 0.3 mg to about 50 mg, about 0.4 mg to about 50 mg, about 0.5 mg to about 50 mg, about 0.6 mg to about 50 mg, about 0.7 mg to about 50 mg, about 0.8 mg to about 50 mg, about 0.9 mg to about 50 mg, about 1 mg to about 50 mg, about 2 mg to about 50 mg, about 3 mg to about 50 mg, about 4 mg to about 50 mg, about 5 mg to about 50 mg, about 6 mg to about 50 mg, about 7 mg to about 50 mg, about 8 mg to about 50 mg, about 9 mg to about 50 mg, about 10 mg to about 50 mg, about 15 mg to about 50 mg, about 20 mg to about 50 mg, about 25 mg to about 50 mg, about 30 mg to about 50 mg, about 35 mg to about 50 mg, about 40 mg to about 50 mg, about 45 mg to about 50 mg, about 0.1 mg to about 45 mg, about 0.1 mg to about 40 mg, about 0.1 mg to about 35 mg, about 0.1 mg to about 30 mg, about 0.1 mg to about 25 mg, about 0.1 mg to about 20 mg, about 0.1 mg to about 15 mg, about 0.1 mg to about 10 mg, about 0. 1 mg to about 9 mg, about 0.1 mg to about 8 mg, about 0. 1 mg to about 7 mg, about 0. 1 mg to about 6 mg, about 0. 1 mg to about 5 mg, about 0.1 mg to about 4 mg, about 0. 1 mg to about 3 mg, about 0. 1 mg to about 2 mg, about 0.1 mg to about 1 mg, about 0.1 mg to about 0.9 mg, about 0. 1 mg to about 0.8 mg, about 0.1 mg to about 0.7 mg, about 0.1 mg to about 0.6 mg, about 0. 1 mg to about 0.5 mg, about 0. 1 mg to about 0.4 mg, about 0. 1 mg to about 0.3 mg, about 0.1 mg to about 0.2 mg, about 0.2 mg to about 45 mg, about 0.2 mg to about 40 mg, about 0.2 mg to about 35 mg, about 0.2 mg to about 30 mg, about 0.2 mg to about 25 mg, about 0.2 mg to about 20 mg, about 0.2 mg to about 15 mg, about 0.2 mg to about 10 mg, about 0.2 mg to about 9 mg, about 0.2 mg to about 8 mg, about 0.2 mg to about 7 mg, about 0.2 mg to about 6 mg, about 0.2 mg to about 5 mg, about 0.2 mg to about 4 mg, about 0.2 mg to about 3 mg, about 0.2 mg to about 2 mg, about 0.2 mg to about 1 mg, about 0.2 mg to about 0.9 mg, about 0.2 mg to about 0.8 mg, about 0.2 mg to about 0.7 mg, about 0.2 mg to about 0.6 mg, about 0.2 mg to about 0.5 mg, about 0.2 mg to about 0.4 mg, about 0.2 mg to about 0.3 mg, about 0.3 mg to about 45 mg, about 0.3 mg to about 40 mg, about 0.3 mg to about 35 mg, about 0.3 mg to about 30 mg, about 0.3 mg to about 25 mg, about 0.3 mg to about 20 mg, about 0.3 mg to about 15 mg, about 0.3 mg to about 10 mg, about 0.3 mg to about 9 mg, about 0.3 mg to about 8 mg, about 0.3 mg to about 7 mg, about 0.3 mg to about 6 mg, about 0.3 mg to about 5 mg, about 0.3 mg to about 4 mg, about 0.3 mg to about 3 mg, about 0.3 mg to about 2 mg, about 0.3 mg to about 1 mg, about 0.3 mg to about 0.9 mg, about 0.3 mg to about 0.8 mg, about 0.3 mg to about 0.7 mg, about 0.3 mg to about 0.6 mg, about 0.3 mg to about 0.5 mg, about 0.3 mg to about 0.4 mg, about 0.4 mg to about 45 mg, about 0.4 mg to about 40 mg, about 0.4 mg to about 35 mg, about 0.4 mg to about 30 mg, about 0.4 mg to about 25 mg, about 0.4 mg to about 20 mg, about 0.4 mg to about 15 mg, about 0.4 mg to about 10 mg, about 0.4 mg to about 9 mg, about 0.4 mg to about 8 mg, about 0.4 mg to about 7 mg, about 0.4 mg to about 6 mg, about 0.4 mg to about 5 mg, about 0.4 mg to about 4 mg, about 0.4 mg to about 3 mg, about 0.4 mg to about 2 mg, about 0.4 mg to about 1 mg, about 0.4 mg to about 0.9 mg, about 0.4 mg to about 0.8 mg, about 0.4 mg to about 0.7 mg, about 0.4 mg to about 0.6 mg, about 0.4 mg to about 0.5 mg, about 0.5 mg to about 45 mg, about 0.5 mg to about 40 mg, about 0.5 mg to about 35 mg, about 0.5 mg to about 30 mg, about 0.5 mg to about 25 mg, about 0.5 mg to about 20 mg, about 0.5 mg to about 15 mg, about 0.5 mg to about 10 mg, about 0.5 mg to about 0.9 mg, about 0.5 mg to about 0.8 mg, about 0.5 mg to about 0.7 mg, about 0.5 mg to about 0.6 mg, about 0.6 mg to about 45 mg, about 0.6 mg to about 40 mg, about 0.6 mg to about 35 mg, about 0.6 mg to about 30 mg, about 0.6 mg to about 25 mg, about 0.6 mg to about 20 mg, about 0.6 mg to about 15 mg, about 0.6 mg to about 10 mg, about 0.6 mg to about 9 mg, about 0.6 mg to about 8 mg, about 0.6 mg to about 7 mg, about 0.6 mg to about 6 mg, about 0.6 mg to about 5 mg, about 0.6 mg to about 4 mg, about 0.6 mg to about 3 mg, about 0.6 mg to about 2 mg, about 0.6 mg to about 1 mg, about 0.6 mg to about 0.9 mg, about 0.6 mg to about 0.8 mg, about 0.6 mg to about 0.7 mg, about 0.7 mg to about 45 mg, about 0.7 mg to about 40 mg, about 0.7 mg to about 35 mg, about 0.7 mg to about 30 mg, about 0.7 mg to about 25 mg, about 0.7 mg to about 20 mg, about 0.7 mg to about 15 mg, about 0.7 mg to about 10 mg, about 0.7 mg to about 9 mg, about 0.7 mg to about 8 mg, about 0.7 mg to about 7 mg, about 0.7 mg to about 6 mg, about 0.7 mg to about 5 mg, about 0.7 mg to about 4 mg, about 0.7 mg to about 3 mg, about 0.7 mg to about 2 mg, about 0.7 mg to about 1 mg, about 0.7 mg to about 0.9 mg, about 0.7 mg to about 0.8 mg, about 0.8 mg to about 45 mg, about 0.8 mg to about 40 mg, about 0.8 mg to about 35 mg, about 0.8 mg to about 30 mg, about 0.8 mg to about 25 mg, about 0.8 mg to about 20 mg, about 0.8 mg to about 15 mg, about 0.8 mg to about 10 mg, about 0.8 mg to about 9 mg, about 0.8 mg to about 8 mg, about 0.8 mg to about 7 mg, about 0.8 mg to about 6 mg, about 0.8 mg to about 5 mg, about 0.8 mg to about 4 mg, about 0.8 mg to about 3 mg, about 0.8 mg to about 2 mg, about 0.8 mg to about 1 mg, about 0.8 mg to about 0.9 mg, about 0.9 mg to about 45 mg, about 0.9 mg to about 40 mg, about 0.9 mg to about 35 mg, about 0.9 mg to about 30 mg, about 0.9 mg to about 25 mg, about 0.9 mg to about 20 mg, about 0.9 mg to about 15 mg, about 0.9 mg to about 10 mg, about 0.9 mg to about 9 mg, about 0.9 mg to about 8 mg, about 0.9 mg to about 7 mg, about 0.9 mg to about 6 mg, about 0.9 mg to about 5 mg, about 0.9 mg to about 4 mg, about 0.9 mg to about 3 mg, about 0.9 mg to about 2 mg, about 0.9 mg to about 1 mg, about 1 mg to about 45 mg, about 1 mg to about 40 mg, about 1 mg to about 35 mg, about 1 mg to about 30 mg, about 1 mg to about 25 mg, about 1 mg to about 20 mg, about 1 mg to about 15 mg, about 1 mg to about 10 mg, about 1 mg to about 9 mg, about 1 mg to about 8 mg, about 1 mg to about 7 mg, about 1 mg to about 6 mg, about 1 mg to about 5 mg, about 1 mg to about 4 mg, about 1 mg to about 3 mg, about 1 mg to about 2 mg, about 2 mg to about 45 mg, about 2 mg to about 40 mg, about 2 mg to about 35 mg, about 2 mg to about 30 mg, about 2 mg to about 25 mg, about 2 mg to about 20 mg, about 2 mg to about 15 mg, about 2 mg to about 10 mg, about 2 mg to about 9 mg, about 2 mg to about 8 mg, about 2 mg to about 7 mg, about 2 mg to about 6 mg, about 2 mg to about 5 mg, about 2 mg to about 4 mg, about 2 mg to about 3 mg, about 3 mg to about 45 mg, about 3 mg to about 40 mg, about 3 mg to about 35 mg, about 3 mg to about 30 mg, about 3 mg to about 25 mg, about 3 mg to about 20 mg, about 3 mg to about 15 mg, about 3 mg to about 10 mg, about 3 mg to about 9 mg, about 3 mg to about 8 mg, about 3 mg to about 7 mg, about 3 mg to about 6 mg, about 3 mg to about 5 mg, about 3 mg to about 4 mg, about 4 mg to about 45 mg, about 4 mg to about 40 mg, about 4 mg to about 35 mg, about 4 mg to about 30 mg, about 4 mg to about 25 mg, about 4 mg to about 20 mg, about 4 mg to about 15 mg, about 4 mg to about 10 mg, about 4 mg to about 9 mg, about 4 mg to about 8 mg, about 4 mg to about 7 mg, about 4 mg to about 6 mg, about 4 mg to about 5 mg, about 5 mg to about 45 mg, about 5 mg to about 40 mg, about 5 mg to about 35 mg, about 5 mg to about 30 mg, about 5 mg to about 25 mg, about 5 mg to about 20 mg, about 5 mg to about 15 mg, about 5 mg to about 10 mg, about 5 mg to about 9 mg, about 5 mg to about 8 mg, about 5 mg to about 7 mg, about 5 mg to about 6 mg, about 6 mg to about 45 mg, about 6 mg to about 40 mg, about 6 mg to about 35 mg, about 6 mg to about 30 mg, about 6 mg to about 25 mg, about 6 mg to about 20 mg, about 6 mg to about 15 mg, about 6 mg to about 10 mg, about 6 mg to about 9 mg, about 6 mg to about 8 mg, about 6 mg to about 7 mg, about 7 mg to about 45 mg, about 7 mg to about 40 mg, about 7 mg to about 35 mg, about 7 mg to about 30 mg, about 7 mg to about 25 mg, about 7 mg to about 20 mg, about 7 mg to about 15 mg, about 7 mg to about 10 mg, about 7 mg to about 9 mg, about 7 mg to about 8 mg, about 8 mg to about 45 mg, about 8 mg to about 40 mg, about 8 mg to about 35 mg, about 8 mg to about 30 mg, about 8 mg to about 25 mg, about 8 mg to about 20 mg, about 8 mg to about 15 mg, about 8 mg to about 10 mg, about 8 mg to about 9 mg, about 9 mg to about 45 mg, about 9 mg to about 40 mg, about 9 mg to about 35 mg, about 9 mg to about 30 mg, about 9 mg to about 25 mg, about 9 mg to about 20 mg, about 9 mg to about 15 mg, about 9 mg to about 10 mg, about 10 mg to about 45 mg, about 10 mg to about 40 mg, about 10 mg to about 35 mg, about 10 mg to about 30 mg, about 10 mg to about 25 mg, about 10 mg to about 20 mg, about 10 mg to about 15 mg, about 15 mg to about 45 mg, about 15 mg to about 40 mg, about 15 mg to about 35 mg, about 15 mg to about 30 mg, about 15 mg to about 25 mg, about 15 mg to about 20 mg, about 20 mg to about 45 mg, about 20 mg to about 40 mg, about 20 mg to about 35 mg, about 20 mg to about 30 mg, about 20 mg to about 25 mg, about 25 mg to about 45 mg, about 25 mg to about 40 mg, about 25 mg to about 35 mg, about 25 mg to about 30 mg, about 30 mg to about 45 mg, about 30 mg to about 40 mg, about 30 mg to about 35 mg, about 35 mg to about 45 mg, about 35 mg to about 40 mg, or about 35 mg to about 45 mg. In certain embodiments, the dosage amount of infigratinib, or a pharmaceutically acceptable salt thereof, to thereby significantly modulate pharmaceutical activity on FGFR3 by the compound of formula (II), (III), or (IV) is about 0.1 mg to about 50 mg. In certain embodiments, the dosage amount of infigratinib, or a pharmaceutically acceptable salt thereof, to thereby significantly modulate pharmaceutical activity on FGFR3 by the compound of formula (II), (III), or (IV) is about 0.1 mg to about 20 mg. In certain embodiments, the dosage amount of infigratinib, or a pharmaceutically acceptable salt thereof, to thereby significantly modulate pharmaceutical activity on FGFR3 by the compound of formula (II), (III), or (IV) is about 0.1 mg to about 8 mg. In some embodiments, the dosage amount of infigratinib, or a pharmaceutically acceptable salt thereof, to thereby significantly modulate pharmaceutical activity on FGFR3 by the compound of formula (II), (III), or (IV) is about 0.01 mg/kg to about 0.6 mg/kg, about 0.015 mg/kg to about 0.6 mg/kg, about 0.02 mg/kg to about 0.6 mg/kg, about 0.025 mg/kg to about 0.6 mg/kg, about 0.03 mg/kg to about 0.6 mg/kg, about 0.05 mg/kg to about 0.6 mg/kg, about 0.07 mg/kg to about 0.6 mg/kg, about 0.09 mg/kg to about 0.6 mg/kg, about 0.11 mg/kg to about 0.6 mg/kg, about 0.13 mg/kg to about 0.6 mg/kg, about 0.15 mg/kg to about 0.6 mg/kg, about 0.17 mg/kg to about 0.6 mg/kg, about 0.19 mg/kg to about 0.6 mg/kg, about 0.21 mg/kg to about 0.6 mg/kg, about 0.23 mg/kg to about 0.6 mg/kg, about 0.25 mg/kg to about 0.6 mg/kg, about 0.27 mg/kg to about 0.6 mg/kg, about 0.29 mg/kg to about 0.6 mg/kg, about 0.3 mg/kg to about 0.6 mg/kg, about 0.4 mg/kg to about 0.6 mg/kg, about 0.5 mg/kg to about 0.6 mg/kg, about 0.01 mg/kg to about 0.5 mg/kg, about 0.01 mg/kg to about 0.4 mg/kg, about 0.01 mg/kg to about 0.3 mg/kg, about 0.01 mg/kg to about 0.29 mg/kg, about 0.01 mg/kg to about 0.27 mg/kg, about 0.01 mg/kg to about 0.25 mg/kg, about 0.01 mg/kg to about 0.23 mg/kg, about 0.01 mg/kg to about 0.21 mg/kg, about 0.01 mg/kg to about 0.19 mg/kg, about 0.01 mg/kg to about 0.17 mg/kg, about 0.01 mg/kg to about 0.15 mg/kg, about 0.01 mg/kg to about 0.13 mg/kg, about 0.01 mg/kg to about 0.11 mg/kg, about 0.01 mg/kg to about 0.09 mg/kg, about 0.01 mg/kg to about 0.07 mg/kg, about 0.01 mg/kg to about 0.05 mg/kg, about 0.01 mg/kg to about 0.03 mg/kg, about 0.01 mg/kg to about 0.025 mg/kg, about 0.01 mg/kg to about 0.02 mg/kg, about 0.01 mg/kg to about 0.015 mg/kg, about 0.015 mg/kg to about 0.5 mg/kg, about 0.015 mg/kg to about 0.4 mg/kg, about 0.015 mg/kg to about 0.3 mg/kg, about 0.015 mg/kg to about 0.29 mg/kg, about 0.015 mg/kg to about 0.27 mg/kg, about 0.015 mg/kg to about 0.25 mg/kg, about 0.015 mg/kg to about 0.23 mg/kg, about 0.015 mg/kg to about 0.21 mg/kg, about 0.015 mg/kg to about 0.19 mg/kg, about 0.015 mg/kg to about 0.17 mg/kg, about 0.015 mg/kg to about 0.15 mg/kg, about 0.015 mg/kg to about 0.13 mg/kg, about 0.015 mg/kg to about 0.11 mg/kg, about 0.015 mg/kg to about 0.09 mg/kg, about 0.015 mg/kg to about 0.07 mg/kg, about 0.015 mg/kg to about 0.05 mg/kg, about 0.015 mg/kg to about 0.03 mg/kg, about 0.015 mg/kg to about 0.025 mg/kg, about 0.015 mg/kg to about 0.02 mg/kg, about 0.02 mg/kg to about 0.5 mg/kg, about 0.02 mg/kg to about 0.4 mg/kg, about 0.02 mg/kg to about 0.3 mg/kg, about 0.02 mg/kg to about 0.29 mg/kg, about 0.02 mg/kg to about 0.27 mg/kg, about 0.02 mg/kg to about 0.25 mg/kg, about 0.02 mg/kg to about 0.23 mg/kg, about 0.02 mg/kg to about 0.21 mg/kg, about 0.02 mg/kg to about 0.19 mg/kg, about 0.02 mg/kg to about 0.17 mg/kg, about 0.02 mg/kg to about 0.15 mg/kg, about 0.02 mg/kg to about 0.13 mg/kg, about 0.02 mg/kg to about 0.11 mg/kg, about 0.02 mg/kg to about 0.09 mg/kg, about 0.02 mg/kg to about 0.07 mg/kg, about 0.02 mg/kg to about 0.05 mg/kg, about 0.02 mg/kg to about 0.03 mg/kg, about 0.02 mg/kg to about 0.025 mg/kg, about 0.025 mg/kg to about 0.5 mg/kg, about 0.025 mg/kg to about 0.4 mg/kg, about 0.025 mg/kg to about 0.3 mg/kg, about 0.025 mg/kg to about 0.29 mg/kg, about 0.025 mg/kg to about 0.27 mg/kg, about 0.025 mg/kg to about 0.25 mg/kg, about 0.025 mg/kg to about 0.23 mg/kg, about 0.025 mg/kg to about 0.21 mg/kg, about 0.025 mg/kg to about 0.19 mg/kg, about 0.025 mg/kg to about 0.17 mg/kg, about 0.025 mg/kg to about 0.15 mg/kg, about 0.025 mg/kg to about 0.13 mg/kg, about 0.025 mg/kg to about 0.11 mg/kg, about 0.025 mg/kg to about 0.09 mg/kg, about 0.025 mg/kg to about 0.07 mg/kg, about 0.025 mg/kg to about 0.05 mg/kg, about 0.025 mg/kg to about 0.03 mg/kg, about 0.03 mg/kg to about 0.5 mg/kg, about 0.03 mg/kg to about 0.4 mg/kg, about 0.03 mg/kg to about 0.3 mg/kg, about 0.03 mg/kg to about 0.29 mg/kg, about 0.03 mg/kg to about 0.27 mg/kg, about 0.03 mg/kg to about 0.25 mg/kg, about 0.03 mg/kg to about 0.23 mg/kg, about 0.03 mg/kg to about 0.21 mg/kg, about 0.03 mg/kg to about 0.19 mg/kg, about 0.03 mg/kg to about 0.17 mg/kg, about 0.03 mg/kg to about 0.15 mg/kg, about 0.03 mg/kg to about 0.13 mg/kg, about 0.03 mg/kg to about 0.11 mg/kg, about 0.03 mg/kg to about 0.09 mg/kg, about 0.03 mg/kg to about 0.07 mg/kg, about 0.03 mg/kg to about 0.05 mg/kg, about 0.05 mg/kg to about 0.5 mg/kg, about 0.05 mg/kg to about 0.4 mg/kg, about 0.05 mg/kg to about 0.3 mg/kg, about 0.05 mg/kg to about 0.29 mg/kg, about 0.05 mg/kg to about 0.27 mg/kg, about 0.05 mg/kg to about 0.25 mg/kg, about 0.05 mg/kg to about 0.23 mg/kg, about 0.05 mg/kg to about 0.21 mg/kg, about 0.05 mg/kg to about 0.19 mg/kg, about 0.05 mg/kg to about 0.17 mg/kg, about 0.05 mg/kg to about 0.15 mg/kg, about 0.05 mg/kg to about 0.13 mg/kg, about 0.05 mg/kg to about 0.11 mg/kg, about 0.05 mg/kg to about 0.09 mg/kg, about 0.05 mg/kg to about 0.07 mg/kg, about 0.07 mg/kg to about 0.5 mg/kg, about 0.07 mg/kg to about 0.4 mg/kg, about 0.07 mg/kg to about 0.3 mg/kg, about 0.07 mg/kg to about 0.29 mg/kg, about 0.07 mg/kg to about 0.27 mg/kg, about 0.07 mg/kg to about 0.25 mg/kg, about 0.07 mg/kg to about 0.23 mg/kg, about 0.07 mg/kg to about 0.21 mg/kg, about 0.07 mg/kg to about 0.19 mg/kg, about 0.07 mg/kg to about 0.17 mg/kg, about 0.07 mg/kg to about 0.15 mg/kg, about 0.07 mg/kg to about 0.13 mg/kg, about 0.07 mg/kg to about 0.11 mg/kg, about 0.07 mg/kg to about 0.09 mg/kg, about 0.09 mg/kg to about 0.5 mg/kg, about 0.09 mg/kg to about 0.4 mg/kg, about 0.09 mg/kg to about 0.3 mg/kg, about 0.09 mg/kg to about 0.29 mg/kg, about 0.09 mg/kg to about 0.27 mg/kg, about 0.09 mg/kg to about 0.25 mg/kg, about 0.09 mg/kg to about 0.23 mg/kg, about 0.09 mg/kg to about 0.21 mg/kg, about 0.09 mg/kg to about 0.19 mg/kg, about 0.09 mg/kg to about 0.17 mg/kg, about 0.09 mg/kg to about 0.15 mg/kg, about 0.09 mg/kg to about 0.13 mg/kg, about 0.09 mg/kg to about 0.11 mg/kg, about 0.11 mg/kg to about 0.5 mg/kg, about 0.11 mg/kg to about 0.4 mg/kg, about 0.11 mg/kg to about 0.3 mg/kg, about 0.11 mg/kg to about 0.29 mg/kg, about 0.11 mg/kg to about 0.27 mg/kg, about 0.11 mg/kg to about 0.25 mg/kg, about 0.11 mg/kg to about 0.23 mg/kg, about 0.11 mg/kg to about 0.21 mg/kg, about 0.11 mg/kg to about 0.19 mg/kg, about 0.11 mg/kg to about 0.17 mg/kg, about 0.11 mg/kg to about 0.15 mg/kg, about 0.11 mg/kg to about 0.13 mg/kg, about 0.13 mg/kg to about 0.5 mg/kg, about 0.13 mg/kg to about 0.4 mg/kg, about 0.13 mg/kg to about 0.3 mg/kg, about 0.13 mg/kg to about 0.29 mg/kg, about 0.13 mg/kg to about 0.27 mg/kg, about 0.13 mg/kg to about 0.25 mg/kg, about 0.13 mg/kg to about 0.23 mg/kg, about 0.13 mg/kg to about 0.21 mg/kg, about 0.13 mg/kg to about 0.19 mg/kg, about 0.13 mg/kg to about 0.17 mg/kg, about 0.13 mg/kg to about 0.15 mg/kg, about 0.15 mg/kg to about 0.5 mg/kg, about 0.15 mg/kg to about 0.4 mg/kg, about 0.15 mg/kg to about 0.3 mg/kg, about 0.15 mg/kg to about 0.29 mg/kg, about 0.15 mg/kg to about 0.27 mg/kg, about 0.15 mg/kg to about 0.25 mg/kg, about 0.15 mg/kg to about 0.23 mg/kg, about 0.15 mg/kg to about 0.21 mg/kg, about 0.15 mg/kg to about 0.19 mg/kg, about 0.15 mg/kg to about 0.17 mg/kg, about 0.17 mg/kg to about 0.5 mg/kg, about 0.17 mg/kg to about 0.4 mg/kg, about 0.17 mg/kg to about 0.3 mg/kg, about 0.17 mg/kg to about 0.29 mg/kg, about 0.17 mg/kg to about 0.27 mg/kg, about 0.17 mg/kg to about 0.25 mg/kg, about 0.17 mg/kg to about 0.23 mg/kg, about 0.17 mg/kg to about 0.21 mg/kg, about 0.17 mg/kg to about 0.19 mg/kg, about 0.19 mg/kg to about 0.5 mg/kg, about 0.19 mg/kg to about 0.4 mg/kg, about 0.19 mg/kg to about 0.3 mg/kg, about 0.19 mg/kg to about 0.27 mg/kg, about 0.19 mg/kg to about 0.25 mg/kg, about 0.19 mg/kg to about 0.23 mg/kg, about 0.19 mg/kg to about 0.21 mg/kg, about 0.21 mg/kg to about 0.5 mg/kg, about 0.21 mg/kg to about 0.4 mg/kg, about 0.21 mg/kg to about 0.3 mg/kg, about 0.21 mg/kg to about 0.29 mg/kg, about 0.21 mg/kg to about 0.27 mg/kg, about 0.21 mg/kg to about 0.25 mg/kg, about 0.21 mg/kg to about 0.23 mg/kg, about 0.23 mg/kg to about 0.5 mg/kg, about 0.23 mg/kg to about 0.4 mg/kg, about 0.23 mg/kg to about 0.3 mg/kg, about 0.23 mg/kg to about 0.29 mg/kg, about 0.23 mg/kg to about 0.27 mg/kg, about 0.23 mg/kg to about 0.25 mg/kg, about 0.25 mg/kg to about 0.5 mg/kg, about 0.25 mg/kg to about 0.4 mg/kg, about 0.25 mg/kg to about 0.3 mg/kg, about 0.25 mg/kg to about 0.29 mg/kg, about 0.25 mg/kg to about 0.27 mg/kg, about 0.27 mg/kg to about 0.5 mg/kg, about 0.27 mg/kg to about 0.4 mg/kg, about 0.27 mg/kg to about 0.3 mg/kg, about 0.27 mg/kg to about 0.29 mg/kg, about 0.29 mg/kg to about 0.5 mg/kg, about 0.29 mg/kg to about 0.4 mg/kg, about 0.29 mg/kg to about 0.3 mg/kg, about 0.3 mg/kg to about 0.5 mg/kg, about 0.3 mg/kg to about 0.4 mg/kg, or about 0.4 mg/kg to about 0.5 mg/kg. In certain embodiments, the dosage amount of infigratinib, or a pharmaceutically acceptable salt thereof, to thereby significantly modulate pharmaceutical activity on FGFR3 by the compound of formula (II), (III), or (IV) is about 0.01 mg/kg to about 0.6 mg/kg. In certain embodiments, the dosage amount of infigratinib, or a pharmaceutically acceptable salt thereof, to thereby significantly modulate pharmaceutical activity on FGFR3 by the compound of formula (II), (III), or (IV) is about 0. 1 mg/kg to about 0. 5 mg/kg. In certain embodiments, the dosage amount of infigratinib, or a pharmaceutically acceptable salt thereof, to thereby significantly modulate pharmaceutical activity on FGFR3 by the compound of formula (II), (III), or (IV) is about 0. 15 mg/kg to about 0.5 mg/kg. In certain embodiments, the dosage amount of infigratinib, or a pharmaceutically acceptable salt thereof, to thereby significantly modulate pharmaceutical activity on FGFR3 by the compound of formula (II), (III), or (IV) is about 0.01 mg/kg, about 0.011 mg/kg, about 0.012 mg/kg, about 0.013 mg/kg, about 0.014 mg/kg, about 0.015 mg/kg, about 0.016 mg/kg, about 0.018 mg/kg, about 0.02 mg/kg, about 0.022 mg/kg, about 0.024 mg/kg, about 0.026 mg/kg, about 0.028 mg/kg, about 0.03 mg/kg, about 0.032 mg/kg, about 0.036 mg/kg, about 0.04 mg/kg, about 0.044 mg/kg, about 0.048 mg/kg, about 0.052 mg/kg, about 0.056 mg/kg, about 0.06 mg/kg, about 0.064 mg/kg, about 0.072 mg/kg, about 0.08 mg/kg, about 0.088 mg/kg, about 0.096 mg/kg, about 0.104 mg/kg, about 0.112 mg/kg, about 0.12 mg/kg, about 0.128 mg/kg, about 0.13 mg/kg, about 0.14 mg/kg, about 0.15 mg/kg, about 0.16 mg/kg, about 0.17 mg/kg, about 0.18 mg/kg, about 0.19 mg/kg, about 0.2 mg/kg, about 0.21 mg/kg, about 0.22 mg/kg, about 0.23 mg/kg, about 0.24 mg/kg, about 0.25 mg/kg, about 0.26 mg/kg, about 0.27 mg/kg, about 0.28 mg/kg, about 0.29 mg/kg, about 0.3 mg/kg, about 0.31 mg/kg, about 0.32 mg/kg, about 0.33 mg/kg, about 0.34 mg/kg, about 0.35 mg/kg, about 0.36 mg/kg, about 0.37 mg/kg, about 0.38 mg/kg, about 0.39 mg/kg, about 0.4 mg/kg, about 0.41 mg/kg, about 0.42 mg/kg, about 0.43 mg/kg, about 0.44 mg/kg, about 0.45 mg/kg, about 0.46 mg/kg, about 0.47 mg/kg, about 0.48 mg/kg, about 0.49 mg/kg, about 0.5 mg/kg, about 0.51 mg/kg, about 0.52 mg/kg, about 0.53 mg/kg, about 0.54 mg/kg, about 0.55 mg/kg, about 0.56 mg/kg, about 0.57 mg/kg, about 0.58 mg/kg, about 0.59 mg/kg, or about 0.6 mg/kg. In certain embodiments, the dosage amount of infigratinib, or a pharmaceutically acceptable salt thereof, to thereby significantly modulate pharmaceutical activity on FGFR3 by the compound of formula (II), (III), or (IV) is about 0.25 mg/kg. In certain embodiments, the dosage amount of infigratinib, or a pharmaceutically acceptable salt thereof, to thereby significantly modulate pharmaceutical activity on FGFR3 by the compound of formula (II), (III), or (IV) is about 0.5 mg/kg.

[0175] In some embodiments of any of the preceding aspects, infigratinib, or a pharmaceutically acceptable salt thereof, is administered to the subject daily, every other day, two days a week, three days a week, four days a week, five days a week, or six days a week. In certain embodiments, infigratinib, or a pharmaceutically acceptable salt thereof, is administered to the subject daily.

[0176] In some embodiments of any of the preceding aspects, infigratinib, or a pharmaceutically acceptable salt thereof, is administered to the subject once daily, twice daily, three times daily, four times daily, five times daily, or six times daily.

[0177] In some embodiments of any of the preceding aspects, the pharmaceutically acceptable salt of infigratinib is infigratinib monophosphate. In certain embodiments, the infigratinib monophosphate is present as an anhydrous crystalline form. In certain embodiments, the anhydrous crystalline form of infigratinib monophosphate is characterized by an XRPD peak (2 theta) at 15.0° ± 0.2°.

[0178] The present disclosure also provides methods of treating a skeletal dysplasia such as achondroplasia or hypochondroplasia in a subject in need thereof. The methods generally comprise administering/providing an effective amount of a compound of formula (II), or a pharmaceutically acceptable salt or N-oxide thereof; a compound of formula (III), or a pharmaceutically acceptable salt or N-oxide thereof; or a compound of formula (IV), or a pharmaceutically acceptable salt or N-oxide thereof, to the subject.

[0179] In an aspect, provided herein is a method of treating a skeletal dysplasia in a subject in need thereof, comprising providing an effective amount of a compound of formula (II), or a pharmaceutically acceptable salt or N-oxide thereof, to the subject, wherein the compound of formula (II) has the structure:

[0180] In another aspect, provided herein is a method of treating a skeletal dysplasia in a subject in need thereof, comprising providing an effective amount of a compound of formula (III), or a pharmaceutically acceptable salt or N-oxide thereof, to the subject, wherein the compound of formula (III) has the structure:

[0181] In another aspect, provided herein is a method of treating a skeletal dysplasia in a subject in need thereof, comprising providing an effective amount of a compound of formula (IV), or a pharmaceutically acceptable salt or N-oxide thereof, to the subject, wherein the compound of formula (IV) has the structure:

[0182] In some embodiments of the preceding aspects, the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia (e.g., thanatophoric dysplasia type I or thanatophoric dysplasia type II), osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, Crouzon syndrome (e.g., Crouzon syndrome acanthosis nigricans), craniosynostosis, Kallmann syndrome, hypogonadotropic hypogonadism, cleft palate and other craniofacial defects, scoliosis, Type 1 or classic Pfeiffer syndrome, osteoglophonic dysplasia, craniosynostosis, mandibular progmathism, hypertelorism, brachydactyly, inter-phalangeal joint fusion, Jackson-Weiss syndrome, Antley-Bixler syndrome, Apert syndrome, Crouzon syndrome, X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, and trigonocephaly. In certain embodiments, the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia (e.g., thanatophoric dysplasia type I or thanatophoric dysplasia type II), osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, and Crouzon syndrome (e.g., Crouzon syndrome acanthosis nigricans).

[0183] In some embodiments of the preceding aspects, the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia, osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, Crouzon syndrome, craniosynostosis, Kallmann syndrome, hypogonadotropic hypogonadism, cleft palate and other craniofacial defects, scoliosis, Type 1 or classic Pfeiffer syndrome, osteoglophonic dysplasia, craniosynostosis, mandibular progmathism, hypertelorism, brachydactyly, inter-phalangeal joint fusion, Jackson-Weiss syndrome, Antley-Bixler syndrome, Apert syndrome, Crouzon syndrome, X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, and trigonocephaly. In some embodiments, the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia, osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, and Crouzon syndrome. In certain embodiments, thanatophoric dysplasia is thanatophoric dysplasia type I or thanatophoric dysplasia type II. In some embodiments, the Crouzon syndrome is Crouzon syndrome acanthosis nigricans.

[0184] In some embodiments of the preceding aspects, the skeletal disorder is achondroplasia. In some embodiments, the skeletal disorder is hypochondroplasia.

[0185] In some embodiments of any of the preceding aspects, the subject is a pediatric patient. In some embodiments, the subject is less than 18 years of age. In some embodiments, the subject is 0 to 4 months old, 0 to 6 months old, 0 to 1 year of age, 0 to 2 years of age, 0 to 3 years of age, 0 to 5 years of age, 1 to 2 years of age, 1 to 3 years of age, 1 to 5 years of age, 2 to 3 years of age, 2 to 5 years of age, 2 to 8 years of age, 2 to 11 years of age, 2 to 17 years of age, 3 to 5 years of age, 3 to 8 years of age, 3 to 11 years of age, 3 to 17 years of age, 5 to 8 years of age, 5 to 11 years of age, 5 to 17 years of age, 8 to 11 years of age, 8 to 17 years of age, 11 to 17 years of age, or 12 to 17 years of age. In some embodiments, the subject is 0 to 4 months old. In some embodiments, the subject is 0 to 6 months old. In some embodiments, the subject is 0 to 1 year of age. In some embodiments, the subject is 0 to 2 years of age. In some embodiments, the subject is 0 to 3 years of age. In some embodiments, the subject is 0 to 5 years of age. In some embodiments, the subject is 1 to 2 years of age. In some embodiments, the subject is 1 to 3 years of age. In some embodiments, the subject is 1 to 5 years of age. In some embodiments, the subject is 2 to 3 years of age. In some embodiments, the subject is 2 to 5 years of age. In some embodiments, the subject is 2 to 8 years of age. In some embodiments, the subject is 2 to 11 years of age. In some embodiments, the subject is 2 to 17 years of age. In some embodiments, the subject is 3 to 5 years of age. In some embodiments, the subject is 3 to 8 years of age. In some embodiments, the subject is 3 to 11 years of age. In some embodiments, the subject is 3 to 17 years of age. In some embodiments, the subject is 5 to 8 years of age. In some embodiments, the subject is 5 to 11 years of age. In some embodiments, the subject is 5 to 17 years of age. In some embodiments, the subject is 8 to 11 years of age. In some embodiments, the subject is 8 to 17 years of age. In some embodiments, the subject is 11 to 17 years of age. In some embodiments, the subject is 12 to 17 years of age. In some embodiments, the subject is less than 2 years of age. In some embodiments, the subject is less than 3 years of age. In some embodiments, the subject is less than 5 years of age. In some embodiments, the subject is less than 8 years of age. In some embodiments, the subject is less than 11 years of age. In some embodiments, the subject is less than 12 years of age.

[0186] In some embodiments of any of the preceding aspects, the subject has open epiphyses (growth plates).

[0187] In some embodiments of any of the preceding aspects, the subject has an FGFR3 mutation. In some embodiments, the FGFR3 mutation is a G380R or N540K mutation.

[0188] The present disclosure also provides methods of treating a subject in need of treatment for a condition, disease, or disorder requiring FGFR3 modulation. The methods generally comprise administering/providing an effective amount of a compound of formula (II), or a pharmaceutically acceptable salt or N-oxide thereof; a compound of formula (III), or a pharmaceutically acceptable salt or N-oxide thereof; or a compound of formula (IV), or a pharmaceutically acceptable salt or N-oxide thereof, to the subject.

[0189] In an aspect, provided herein is a method of treating a subject in need of treatment for a condition, disease, or disorder requiring FGFR3 modulation, comprising administering to the subject an effective amount of a compound of formula (II):

or a pharmaceutically acceptable salt or an N-oxide thereof.

[0190] In another aspect, provided herein is a method of treating a subject in need of treatment for a condition, disease, or disorder requiring FGFR3 modulation, comprising administering to the subject an effective amount of a compound of formula (III):

or a pharmaceutically acceptable salt or an N-oxide thereof.

[0191] In a further aspect, provided herein is a method of treating a subject in need of treatment for a condition, disease, or disorder requiring FGFR3 modulation, comprising administering to the subject an effective amount of a compound of formula (IV):

or a pharmaceutically acceptable salt or an N-oxide thereof.

[0192] In some embodiments of the preceding aspects, the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia (e.g., thanatophoric dysplasia type I or thanatophoric dysplasia type II), osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, Crouzon syndrome (e.g., Crouzon syndrome acanthosis nigricans), craniosynostosis, Kallmann syndrome, hypogonadotropic hypogonadism, cleft palate and other craniofacial defects, scoliosis, Type 1 or classic Pfeiffer syndrome, osteoglophonic dysplasia, craniosynostosis, mandibular progmathism, hypertelorism, brachydactyly, inter-phalangeal joint fusion, Jackson-Weiss syndrome, Antley-Bixler syndrome, Apert syndrome, Crouzon syndrome, X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, and trigonocephaly. In certain embodiments, the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia (e.g., thanatophoric dysplasia type I or thanatophoric dysplasia type II), osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, and Crouzon syndrome (e.g., Crouzon syndrome acanthosis nigricans).

[0193] In some embodiments of the preceding aspects, the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia, osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, Crouzon syndrome, craniosynostosis, Kallmann syndrome, hypogonadotropic hypogonadism, cleft palate and other craniofacial defects, scoliosis, Type 1 or classic Pfeiffer syndrome, osteoglophonic dysplasia, craniosynostosis, mandibular progmathism, hypertelorism, brachydactyly, inter-phalangeal joint fusion, Jackson-Weiss syndrome, Antley-Bixler syndrome, Apert syndrome, Crouzon syndrome, X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, and trigonocephaly. In some embodiments, the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia, osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, and Crouzon syndrome. In certain embodiments, thanatophoric dysplasia is thanatophoric dysplasia type I or thanatophoric dysplasia type II. In some embodiments, the Crouzon syndrome is Crouzon syndrome acanthosis nigricans.

[0194] In some embodiments of the preceding aspects, the skeletal disorder is achondroplasia. In some embodiments, the skeletal disorder is hypochondroplasia.

[0195] In some embodiments of any of the preceding aspects, the subject is a pediatric patient. In some embodiments, the subject is less than 18 years of age. In some embodiments, the subject is 0 to 4 months old, 0 to 6 months old, 0 to 1 year of age, 0 to 2 years of age, 0 to 3 years of age, 0 to 5 years of age, 1 to 2 years of age, 1 to 3 years of age, 1 to 5 years of age, 2 to 3 years of age, 2 to 5 years of age, 2 to 8 years of age, 2 to 11 years of age, 2 to 17 years of age, 3 to 5 years of age, 3 to 8 years of age, 3 to 11 years of age, 3 to 17 years of age, 5 to 8 years of age, 5 to 11 years of age, 5 to 17 years of age, 8 to 11 years of age, 8 to 17 years of age, 11 to 17 years of age, or 12 to 17 years of age. In some embodiments, the subject is 0 to 4 months old. In some embodiments, the subject is 0 to 6 months old. In some embodiments, the subject is 0 to 1 year of age. In some embodiments, the subject is 0 to 2 years of age. In some embodiments, the subject is 0 to 3 years of age. In some embodiments, the subject is 0 to 5 years of age. In some embodiments, the subject is 1 to 2 years of age. In some embodiments, the subject is 1 to 3 years of age. In some embodiments, the subject is 1 to 5 years of age. In some embodiments, the subject is 2 to 3 years of age. In some embodiments, the subject is 2 to 5 years of age. In some embodiments, the subject is 2 to 8 years of age. In some embodiments, the subject is 2 to 11 years of age. In some embodiments, the subject is 2 to 17 years of age. In some embodiments, the subject is 3 to 5 years of age. In some embodiments, the subject is 3 to 8 years of age. In some embodiments, the subject is 3 to 11 years of age. In some embodiments, the subject is 3 to 17 years of age. In some embodiments, the subject is 5 to 8 years of age. In some embodiments, the subject is 5 to 11 years of age. In some embodiments, the subject is 5 to 17 years of age. In some embodiments, the subject is 8 to 11 years of age. In some embodiments, the subject is 8 to 17 years of age. In some embodiments, the subject is 11 to 17 years of age. In some embodiments, the subject is 12 to 17 years of age. In some embodiments, the subject is less than 2 years of age. In some embodiments, the subject is less than 3 years of age. In some embodiments, the subject is less than 5 years of age. In some embodiments, the subject is less than 8 years of age. In some embodiments, the subject is less than 11 years of age. In some embodiments, the subject is less than 12 years of age.

[0196] In some embodiments of any of the preceding aspects, the subject has open epiphyses (growth plates).

[0197] In some embodiments of any of the preceding aspects, the subject has an FGFR3 mutation. In some embodiments, the FGFR3 mutation is a G380R or N540K mutation.

[0198] In an aspect, provided herein is a method of treating a subject in need of treatment for achondroplasia and in need of FGFR3 modulation, comprising administering to the subject an effective amount of a compound of formula (II):

or a pharmaceutically acceptable salt or an N-oxide thereof.

[0199] In an aspect, provided herein is a method of treating a subject in need of treatment for hypochondroplasia and in need of FGFR3 modulation, comprising administering to the subject an effective amount of a compound of formula (II):

or a pharmaceutically acceptable salt or an N-oxide thereof.

[0200] In certain embodiments, administration of the effective amount of the compound of formula (II), as described herein, reduces the activity of FGFR3. In certain embodiments, administration of the effective amount of the compound of formula (II), as described herein, inhibits the activity of FGFR3.

[0201] In an aspect, provided herein is a method of treating a subject in need of treatment for achondroplasia and in need of FGFR3 modulation, comprising administering to the subject an effective amount of a compound of formula (III):

or a pharmaceutically acceptable salt or an N-oxide thereof.

[0202] In an aspect, provided herein is a method of treating a subject in need of treatment for hypochondroplasia and in need of FGFR3 modulation, comprising administering to the subject an effective amount of a compound of formula (III):

or a pharmaceutically acceptable salt or an N-oxide thereof.

[0203] In certain embodiments, administration of the effective amount of the compound of formula (III), as described herein, reduces the activity of FGFR3. In certain embodiments, administration of the effective amount of the compound of formula (III), as described herein, inhibits the activity of FGFR3.

[0204] In an aspect, provided herein is a method of treating a subject in need of treatment for achondroplasia and in need of FGFR3 modulation, comprising administering to the subject an effective amount of a compound of formula (IV):

or a pharmaceutically acceptable salt or an N-oxide thereof.

[0205] In an aspect, provided herein is a method of treating a subject in need of treatment for hypochondroplasia and in need of FGFR3 modulation, comprising administering to the subject an effective amount of a compound of formula (IV):

or a pharmaceutically acceptable salt or an N-oxide thereof.

[0206] In certain embodiments, administration of the effective amount of the compound of formula (IV), as described herein, reduces the activity of FGFR3. In certain embodiments, administration of the effective amount of the compound of formula (IV), as described herein, inhibits the activity of FGFR3.

[0207] In an aspect, provided herein is a method of treating a subject in need of treatment for achondroplasia, comprising administering to the subject an effective amount of a compound of formula (II):

or a pharmaceutically acceptable salt or an N-oxide thereof.

[0208] In an aspect, provided herein is a method of treating a subject in need of treatment for hypochondroplasia, comprising administering to the subject an effective amount of a compound of formula (II):

or a pharmaceutically acceptable salt or an N-oxide thereof.

[0209] In an aspect, provided herein is a method of treating a subject in need of treatment for achondroplasia, comprising administering to the subject an effective amount of a compound of formula (III):

or a pharmaceutically acceptable salt or an N-oxide thereof. [0210] In an aspect, provided herein is a method of treating a subject in need of treatment for hypochondroplasia, comprising administering to the subject an effective amount of a compound of formula (III):

or a pharmaceutically acceptable salt or an N-oxide thereof.

[0211] In an aspect, provided herein is a method of treating a subject in need of treatment for achondroplasia, comprising administering to the subject an effective amount of a compound of formula (IV):

or a pharmaceutically acceptable salt or an N-oxide thereof.

[0212] In an aspect, provided herein is a method of treating a subject in need of treatment for hypochondroplasia, comprising administering to the subject an effective amount of a compound of formula (IV):

or a pharmaceutically acceptable salt or an N-oxide thereof.

[0213] In another aspect, provided herein is a method of delivering a compound of formula (II) to a subject in need of treatment for a skeletal disorder selected from the group consisting of achondroplasia, severe achondroplasia with development delay and acanthosis nigricans, X- linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, hypochondroplasia, craniosynostosis, thanatophoric dysplasia type I, and thanatophoric dysplasia type II, comprising administering to the subject a pharmaceutical composition described herein, thereby delivering an effective amount of a compound of formula (II) to the subject, wherein the compound of formula (II) has the structure:

or a pharmaceutically acceptable salt or an N-oxide thereof.

[0214] In another aspect, provided herein is a method of treating a subject in need of treatment for achondroplasia, comprising administering to the subject a pharmaceutical composition described herein, thereby delivering an effective amount of a compound of formula (II) to the patient, wherein the compound of formula (II) has the structure:

or a pharmaceutically acceptable salt or an N-oxide thereof.

[0215] In another aspect, provided herein is a method of treating a subject in need of treatment for hypochondroplasia, comprising administering to the subject a pharmaceutical composition described herein, thereby delivering an effective amount of a compound of formula (II) to the patient, wherein the compound of formula (II) has the structure:

or a pharmaceutically acceptable salt or an N-oxide thereof.

[0216] In another aspect, provided herein is a method of delivering a compound of formula (III) to a subject in need of treatment for a skeletal disorder selected from the group consisting of achondroplasia, severe achondroplasia with development delay and acanthosis nigricans, X- linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, hypochondroplasia, craniosynostosis, thanatophoric dysplasia type I, and thanatophoric dysplasia type II, comprising administering to the subject a pharmaceutical composition described herein, thereby delivering an effective amount of a compound of formula (III) to the subject, wherein the compound of formula (III) has the structure:

or a pharmaceutically acceptable salt or an N-oxide thereof.

[0217] In another aspect, provided herein is a method of treating a subject in need of treatment for achondroplasia, comprising administering to the subject a pharmaceutical composition described herein, thereby delivering an effective amount of a compound of formula (III) to the patient, wherein the compound of formula (III) has the structure:

or a pharmaceutically acceptable salt or an N-oxide thereof.

[0218] In another aspect, provided herein is a method of treating a subject in need of treatment for hypochondroplasia, comprising administering to the subject a pharmaceutical composition described herein, thereby delivering an effective amount of a compound of formula (III) to the patient, wherein the compound of formula (III) has the structure:

or a pharmaceutically acceptable salt or an N-oxide thereof.

[0219] In another aspect, provided herein is a method of delivering a compound of formula (IV) to a subject in need of treatment for a skeletal disorder selected from the group consisting of achondroplasia, severe achondroplasia with development delay and acanthosis nigricans, X- linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, hypochondroplasia, craniosynostosis, thanatophoric dysplasia type I, and thanatophoric dysplasia type II, comprising administering to the subject a pharmaceutical composition described herein, thereby delivering an effective amount of a compound of formula (IV) to the subject, wherein the compound of formula (IV) has the structure:

or a pharmaceutically acceptable salt or an N-oxide thereof.

[0220] In another aspect, provided herein is a method of treating a subject in need of treatment for achondroplasia, comprising administering to the subject a pharmaceutical composition described herein, thereby delivering an effective amount of a compound of formula (IV) to the patient, wherein the compound of formula (IV) has the structure:

or a pharmaceutically acceptable salt or an N-oxide thereof.

[0221] In another aspect, provided herein is a method of treating a subject in need of treatment for hypochondroplasia, comprising administering to the subject a pharmaceutical composition described herein, thereby delivering an effective amount of a compound of formula (IV) to the patient, wherein the compound of formula (IV) has the structure:

or a pharmaceutically acceptable salt or an N-oxide thereof.

[0222] In another aspect, provided herein is a method of treating a subject in need of treatment for a skeletal disorder selected from the group consisting of achondroplasia, severe achondroplasia with development delay and acanthosis nigricans, X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, hypochondroplasia, craniosynostosis, thanatophoric dysplasia type I, and thanatophoric dysplasia type II, comprising administering to the patient an effective amount of a pharmaceutical composition described herein.

[0223] In certain embodiments of any of the preceding aspects, the methods provided herein further comprise administering an effective amount of a second therapeutic agent to the subject. [0224] In some embodiments of any of the preceding aspects, the subject’s weight is less than about 12 kg. In certain embodiments, the subject’s weight is between about 12 kg and about 15 kg. In certain embodiments, the subject’s weight is between about 16 kg and about 22 kg. In certain embodiments, the subject’s weight is between about 23 kg and about 31 kg. In certain embodiments, the subject’s weight is between about 32 kg and about 43 kg. In certain embodiments, the subject’s weight is between about 44 kg and about 70 kg. In certain embodiments, the subject’s weight is at least about 70 kg.

[0225] In some embodiments of any of the preceding aspects, the subject’s weight is between about 10 kg and about 80 kg, about 15 kg and about 80 kg, about 20 kg and about 80 kg, about 25 kg and about 80 kg, about 30 kg and about 80 kg, about 35 kg and about 80 kg, about 40 kg and about 80 kg, about 45 kg and about 80 kg, about 50 kg and about 80 kg, about 55 kg and about 80 kg, about 60 kg and about 80 kg, about 65 kg and about 80 kg, about 70 kg and about 80 kg, about 75 kg and about 80 kg, about 10 kg and about 75 kg, about 10 kg and about 70 kg, about 10 kg and about 65 kg, about 10 kg and about 60 kg, about 10 kg and about 55 kg, about 10 kg and about 50 kg, about 10 kg and about 45 kg, about 10 kg and about 40 kg, about 10 kg and about 35 kg, about 10 kg and about 30 kg, about 10 kg and about 25 kg, about 10 kg and about 20 kg, about 10 kg and about 15 kg, about 15 kg and about 75 kg, about 15 kg and about 70 kg, about 15 kg and about 65 kg, about 15 kg and about 60 kg, about 15 kg and about 55 kg, about 15 kg and about 50 kg, about 15 kg and about 45 kg, about 15 kg and about 40 kg, about 15 kg and about 35 kg, about 15 kg and about 30 kg, about 15 kg and about 25 kg, about 15 kg and about 20 kg, about 20 kg and about 75 kg, about 20 kg and about 70 kg, about 20 kg and about 65 kg, about 20 kg and about 60 kg, about 20 kg and about 55 kg, about 20 kg and about 50 kg, about 20 kg and about 45 kg, about 20 kg and about 40 kg, about 20 kg and about 35 kg, about 20 kg and about 30 kg, about 20 kg and about 25 kg, about 20 kg and about 25 kg, about 25 kg and about 75 kg, about 25 kg and about 70 kg, about 25 kg and about 65 kg, about 25 kg and about 60 kg, about 25 kg and about 55 kg, about 25 kg and about 50 kg, about 25 kg and about 45 kg, about 25 kg and about 40 kg, about 25 kg and about 35 kg, about 25 kg and about 30 kg, about 30 kg and about 75 kg, about 30 kg and about 70 kg, about 30 kg and about 65 kg, about 30 kg and about 60 kg, about 30 kg and about 55 kg, about 30 kg and about 50 kg, about 30 kg and about 45 kg, about 30 kg and about 40 kg, about 30 kg and about 35 kg, about 35 kg and about 75 kg, about 35 kg and about 70 kg, about 35 kg and about 65 kg, about 35 kg and about 60 kg, about 35 kg and about 55 kg, about 35 kg and about 50 kg, about 35 kg and about 45 kg, about 35 kg and about 40 kg, about 40 kg and about 75 kg, about 40 kg and about 70 kg, about 40 kg and about 65 kg, about 40 kg and about 60 kg, about 40 kg and about 55 kg, about 40 kg and about 50 kg, about 40 kg and about 45 kg, about 45 kg and about 75 kg, about 45 kg and about 70 kg, about 45 kg and about 65 kg, about 45 kg and about 60 kg, about 45 kg and about 55 kg, about 45 kg and about 50 kg, about 50 kg and about 75 kg, about 50 kg and about 70 kg, about 50 kg and about 65 kg, about 50 kg and about 60 kg, about 50 kg and about 55 kg, about 55 kg and about 75 kg, about 55 kg and about 70 kg, about 55 kg and about 65 kg, about 55 kg and about 60 kg, about 60 kg and about 75 kg, about 60 kg and about 70 kg, about 60 kg and about 65 kg, about 65 kg and about 75 kg, about 65 kg and about 70 kg, or about 70 kg and about 75 kg.

[0226] In some embodiments of any of the preceding aspects, the subject’s weight is about 10 kg, about 15 kg, about 20 kg, about 25 kg, about 30 kg, about 35 kg, about 40 kg, about 45 kg, about 50 kg, about 55 kg, about 60 kg, about 65 kg, about 70 kg, about 75 kg, or about 80 kg. [0227] In some embodiments of any of the preceding aspects, administration of the dose of infigratinib, or a pharmaceutically acceptable salt thereof reduces the activity of FGFR3. In certain embodiments, administration of the dose of infigratinib, or a pharmaceutically acceptable salt thereof, as described herein, inhibits the activity of FGFR3.

[0228] In some embodiments of any of the preceding aspects, administration of a dosage amount of infigratinib, or a pharmaceutically acceptable salt thereof, as described herein, reduces the activity of FGFR3. In certain embodiments, administration of a dosage amount of infigratinib, or a pharmaceutically acceptable salt thereof, as described herein, inhibits the activity of FGFR3. [0229] In some embodiments of any of the preceding aspects, the subject has a FGFR3 mutation. In certain embodiments, the FGFR3 mutation is selected from the group consisting of N540K, N540S, N540T, K650Q, K650N, K650T, R223C, T264M, S351F, R200C, G268C, N328I, I538V, Y278C, P449S, N262H, S84L, V381E, S384C, G380K, E360K, G65R, Q115L, and S269C. In certain embodiments, the FGFR3 mutation is selected from the group consisting of N540K, N540S, N540T, K650Q, K650N, K650T, R223C, T264M, and S351F. In certain embodiments, the FGFR3 mutation is a G380R mutation. In certain embodiments, the FGFR3 mutation is selected from the group consisting of G380R, N540K, N540S, N540T, K650Q, K650N, K650T, R223C, T264M, and S351F.

[0230] In some embodiments of any of the preceding aspects, the subject is no more than 2 years of age, no more than 3 years of age, no more than 4 years of age, no more than 5 years of age, no more than 6 years of age, no more than 7 years of age, no more than 8 years of age, no more than 9 years of age, no more than 10 years of age, no more than 11 years of age, no more than 12 years of age, no more than 13 years of age, no more than 14 years of age, no more than 15 years of age, no more than 16 years of age, no more than 17 years of age, no more than 18 years of age, no more than 19 years of age, no more than 20 years of age, or no more than 21 years of age. In certain embodiments, the subject is no more than 12 years of age.

[0231] In some embodiments of any of the preceding aspects, the subject is 2 to 21 years of age,

3 to 21 years of age, 4 to 21 years of age, 5 to 21 years of age, 6 to 21 years of age, 7 to 21 years of age, 8 to 21 years of age, 9 to 21 years of age, 10 to 21 years of age, 11 to 21 years of age, 12 to 21 years of age, 13 to 21 years of age, 14 to 21 years of age, 15 to 21 years of age, 16 to 21 years of age, 17 to 21 years of age, 18 to 21 years of age, 19 to 21 years of age, 20 to 21 years of age, 2 to 20 years of age, 2 to 19 years of age, 2 to 18 years of age, 2 to 17 years of age, 2 to 16 years of age, 2 to 15 years of age, 2 to 14 years of age, 2 to 13 years of age, 2 to 12 years of age, 2 to 11 years of age, 2 to 10 years of age, 2 to 9 years of age, 2 to 8 years of age, 2 to 7 years of age, 2 to 6 years of age, 2 to 5 years of age, 2 to 4 years of age, 2 to 3 years of age, 3 to 20 years of age, 3 to 19 years of age, 3 to 18 years of age, 3 to 17 years of age, 3 to 16 years of age, 3 to 15 years of age, 3 to 14 years of age, 3 to 13 years of age, 3 to 12 years of age, 3 to 11 years of age, 3 to 10 years of age, 3 to 9 years of age, 3 to 8 years of age, 3 to 7 years of age, 3 to 6 years of age, 3 to 5 years of age, 3 to 4 years of age, 4 to 20 years of age, 4 to 19 years of age, 4 to 18 years of age, 4 to 17 years of age, 4 to 16 years of age, 4 to 15 years of age, 4 to 14 years of age,

4 to 13 years of age, 4 to 12 years of age, 4 to 11 years of age, 4 to 10 years of age, 4 to 9 years of age, 4 to 8 years of age, 4 to 7 years of age, 4 to 6 years of age, 4 to 5 years of age, 5 to 20 years of age, 5 to 19 years of age, 5 to 18 years of age, 5 to 17 years of age, 5 to 16 years of age,

5 to 15 years of age, 5 to 14 years of age, 5 to 13 years of age, 5 to 12 years of age, 5 to 11 years of age, 5 to 10 years of age, 5 to 9 years of age, 5 to 8 years of age, 5 to 7 years of age, 5 to 6 years of age, 6 to 20 years of age, 6 to 19 years of age, 6 to 18 years of age, 6 to 17 years of age,

6 to 16 years of age, 6 to 15 years of age, 6 to 14 years of age, 6 to 13 years of age, 6 to 12 years of age, 6 to 11 years of age, 6 to 10 years of age, 6 to 9 years of age, 6 to 8 years of age, 6 to 7 years of age, 7 to 20 years of age, 7 to 19 years of age, 7 to 18 years of age, 7 to 17 years of age,

7 to 16 years of age, 7 to 15 years of age, 7 to 14 years of age, 7 to 13 years of age, 7 to 12 years of age, 7 to 11 years of age, 7 to 10 years of age, 7 to 9 years of age, 7 to 8 years of age, 8 to 20 years of age, 8 to 19 years of age, 8 to 18 years of age, 8 to 17 years of age, 8 to 16 years of age, 8 to 15 years of age, 8 to 14 years of age, 8 to 13 years of age, 8 to 12 years of age, 8 to 11 years of age, 8 to 10 years of age, 8 to 9 years of age, 9 to 20 years of age, 9 to 19 years of age, 9 to 18 years of age, 9 to 17 years of age, 9 to 16 years of age, 9 to 15 years of age, 9 to 14 years of age,

9 to 13 years of age, 9 to 12 years of age, 9 to 11 years of age, 9 to 10 years of age, 10 to 20 years of age, 10 to 19 years of age, 10 to 18 years of age, 10 to 17 years of age, 10 to 16 years of age, 10 to 15 years of age, 10 to 14 years of age, 10 to 13 years of age, 10 to 12 years of age, 10 to 11 years of age, 11 to 20 years of age, 11 to 19 years of age, 11 to 18 years of age, 11 to 17 years of age, 11 to 16 years of age, 11 to 15 years of age, 11 to 14 years of age, 11 to 13 years of age, 11 to 12 years of age, 12 to 20 years of age, 12 to 19 years of age, 12 to 18 years of age, 12 to 17 years of age, 12 to 16 years of age, 12 to 15 years of age, 12 to 14 years of age, 12 to 13 years of age, 13 to 20 years of age, 13 to 19 years of age, 13 to 18 years of age, 13 to 17 years of age, 13 to 16 years of age, 13 to 15 years of age, 13 to 14 years of age, 14 to 20 years of age, 14 to 19 years of age, 14 to 18 years of age, 14 to 17 years of age, 14 to 16 years of age, 14 to 15 years of age, 15 to 20 years of age, 15 to 19 years of age, 15 to 18 years of age, 15 to 17 years of age, 15 to 16 years of age, 16 to 20 years of age, 16 to 19 years of age, 16 to 18 years of age, 16 to 17 years of age, 17 to 20 years of age, 17 to 19 years of age, 17 to 18 years of age, 18 to 20 years of age, 18 to 19 years of age, or 19 to 20 years of age. In certain embodiments, the subject is 12 to 17 years of age. In certain embodiments, the subject is 3 to 11 years of age. In certain embodiments, the subject is 3 to 18 years of age. In certain embodiments, the subject is 5 to 8 years of age. In certain embodiments, the subject is 8 to 11 years of age.

[0232] In some embodiments of any of the preceding aspects, the subject is less than 3 years of age, less than 4 years of age, less than 5 years of age, less than 6 years of age, less than 7 years of age, less than 8 years of age, less than 9 years of age, less than 10 years of age, less than 11 years of age, less than 12 years of age, less than 13 years of age, less than 14 years of age, less than 15 years of age, less than 16 years of age, less than 17 years of age, less than 18 years of age, less than 19 years of age, less than 20 years of age, or less than 21 years of age. In certain embodiments, the subject is less than 18 years of age. In certain embodiments, the subject is less than 12 years of age. In certain embodiments, the subject is less than 5 years of age.

[0233] In some embodiments of any of the preceding aspects, the subject is 2 years of age or older, 3 years of age or older, 4 years of age or older, 5 years of age or older, 6 years of age or older, 7 years of age or older, 8 years of age or older, 9 years of age or older, 10 years of age or older, 11 years of age or older, 12 years of age or older, 13 years of age or older, 14 years of age or older, 15 years of age or older, 16 years of age or older, 17 years of age or older, 18 years of age or older, 19 years of age or older, or 20 years of age or older. In certain embodiments, the subject is 3 years of age or older.

[0234] In some embodiments of any of the preceding aspects, the epiphyses (growth plates) of the subject are still open.

[0235] In some embodiments of any of the preceding aspects, the subject is an adult patient. In certain embodiments, the subject is a pediatric patient.

[0236] In some embodiments of any of the preceding aspects, the pediatric patient is no more than 2 years of age, no more than 3 years of age, no more than 4 years of age, no more than 5 years of age, no more than 6 years of age, no more than 7 years of age, no more than 8 years of age, no more than 9 years of age, no more than 10 years of age, no more than 11 years of age, no more than 12 years of age, no more than 13 years of age, no more than 14 years of age, no more than 15 years of age, no more than 16 years of age, no more than 17 years of age, no more than 18 years of age, no more than 19 years of age, no more than 20 years of age, or no more than 21 years of age. In certain embodiments, the pediatric patient is no more than 12 years of age.

[0237] In some embodiments of any of the preceding aspects, the pediatric patient is 2 to 21 years of age, 3 to 21 years of age, 4 to 21 years of age, 5 to 21 years of age, 6 to 21 years of age, 7 to 21 years of age, 8 to 21 years of age, 9 to 21 years of age, 10 to 21 years of age, 11 to 21 years of age, 12 to 21 years of age, 13 to 21 years of age, 14 to 21 years of age, 15 to 21 years of age, 16 to 21 years of age, 17 to 21 years of age, 18 to 21 years of age, 19 to 21 years of age, 20 to 21 years of age, 2 to 20 years of age, 2 to 19 years of age, 2 to 18 years of age, 2 to 17 years of age, 2 to 16 years of age, 2 to 15 years of age, 2 to 14 years of age, 2 to 13 years of age, 2 to 12 years of age, 2 to 11 years of age, 2 to 10 years of age, 2 to 9 years of age, 2 to 8 years of age, 2 to 7 years of age, 2 to 6 years of age, 2 to 5 years of age, 2 to 4 years of age, 2 to 3 years of age, 3 to 20 years of age, 3 to 19 years of age, 3 to 18 years of age, 3 to 17 years of age, 3 to 16 years of age, 3 to 15 years of age, 3 to 14 years of age, 3 to 13 years of age, 3 to 12 years of age, 3 to 11 years of age, 3 to 10 years of age, 3 to 9 years of age, 3 to 8 years of age, 3 to 7 years of age,

3 to 6 years of age, 3 to 5 years of age, 3 to 4 years of age, 4 to 20 years of age, 4 to 19 years of age, 4 to 18 years of age, 4 to 17 years of age, 4 to 16 years of age, 4 to 15 years of age, 4 to 14 years of age, 4 to 13 years of age, 4 to 12 years of age, 4 to 11 years of age, 4 to 10 years of age,

4 to 9 years of age, 4 to 8 years of age, 4 to 7 years of age, 4 to 6 years of age, 4 to 5 years of age, 5 to 20 years of age, 5 to 19 years of age, 5 to 18 years of age, 5 to 17 years of age, 5 to 16 years of age, 5 to 15 years of age, 5 to 14 years of age, 5 to 13 years of age, 5 to 12 years of age,

5 to 11 years of age, 5 to 10 years of age, 5 to 9 years of age, 5 to 8 years of age, 5 to 7 years of age, 5 to 6 years of age, 6 to 20 years of age, 6 to 19 years of age, 6 to 18 years of age, 6 to 17 years of age, 6 to 16 years of age, 6 to 15 years of age, 6 to 14 years of age, 6 to 13 years of age,

6 to 12 years of age, 6 to 11 years of age, 6 to 10 years of age, 6 to 9 years of age, 6 to 8 years of age, 6 to 7 years of age, 7 to 20 years of age, 7 to 19 years of age, 7 to 18 years of age, 7 to 17 years of age, 7 to 16 years of age, 7 to 15 years of age, 7 to 14 years of age, 7 to 13 years of age,

7 to 12 years of age, 7 to 11 years of age, 7 to 10 years of age, 7 to 9 years of age, 7 to 8 years of age, 8 to 20 years of age, 8 to 19 years of age, 8 to 18 years of age, 8 to 17 years of age, 8 to 16 years of age, 8 to 15 years of age, 8 to 14 years of age, 8 to 13 years of age, 8 to 12 years of age,

8 to 11 years of age, 8 to 10 years of age, 8 to 9 years of age, 9 to 20 years of age, 9 to 19 years of age, 9 to 18 years of age, 9 to 17 years of age, 9 to 16 years of age, 9 to 15 years of age, 9 to 14 years of age, 9 to 13 years of age, 9 to 12 years of age, 9 to 11 years of age, 9 to 10 years of age, 10 to 20 years of age, 10 to 19 years of age, 10 to 18 years of age, 10 to 17 years of age, 10 to 16 years of age, 10 to 15 years of age, 10 to 14 years of age, 10 to 13 years of age, 10 to 12 years of age, 10 to 11 years of age, 11 to 20 years of age, 11 to 19 years of age, 11 to 18 years of age, 11 to 17 years of age, 11 to 16 years of age, 11 to 15 years of age, 11 to 14 years of age, 11 to 13 years of age, 11 to 12 years of age, 12 to 20 years of age, 12 to 19 years of age, 12 to 18 years of age, 12 to 17 years of age, 12 to 16 years of age, 12 to 15 years of age, 12 to 14 years of age, 12 to 13 years of age, 13 to 20 years of age, 13 to 19 years of age, 13 to 18 years of age, 13 to 17 years of age, 13 to 16 years of age, 13 to 15 years of age, 13 to 14 years of age, 14 to 20 years of age, 14 to 19 years of age, 14 to 18 years of age, 14 to 17 years of age, 14 to 16 years of age, 14 to 15 years of age, 15 to 20 years of age, 15 to 19 years of age, 15 to 18 years of age, 15 to 17 years of age, 15 to 16 years of age, 16 to 20 years of age, 16 to 19 years of age, 16 to 18 years of age, 16 to 17 years of age, 17 to 20 years of age, 17 to 19 years of age, 17 to 18 years of age, 18 to 20 years of age, 18 to 19 years of age, or 19 to 20 years of age. In certain embodiments, the pediatric patient is 12 to 17 years of age. In certain embodiments, the pediatric patient is 3 to 11 years of age. In certain embodiments, the pediatric patient is 3 to 18 years of age. In certain embodiments, the pedatric patient is 5 to 8 years of age. In certain embodiments, the pediatric patient is 8 to 11 years of age.

[0238] In some embodiments of any of the preceding aspects, the pediatric patient is less than 3 years of age, less than 4 years of age, less than 5 years of age, less than 6 years of age, less than 7 years of age, less than 8 years of age, less than 9 years of age, less than 10 years of age, less than 11 years of age, less than 12 years of age, less than 13 years of age, less than 14 years of age, less than 15 years of age, less than 16 years of age, less than 17 years of age, less than 18 years of age, less than 19 years of age, less than 20 years of age, or less than 21 years of age. In certain embodiments, the pediatric patient is less than 18 years of age. In certain embodiments, the pediatric patient is less than 12 years of age. In certain embodiments, the pediatric patient is less than 5 years of age.

[0239] In some embodiments of any of the preceding aspects, the pediatric patient is 2 years of age or older, 3 years of age or older, 4 years of age or older, 5 years of age or older, 6 years of age or older, 7 years of age or older, 8 years of age or older, 9 years of age or older, 10 years of age or older, 11 years of age or older, 12 years of age or older, 13 years of age or older, 14 years of age or older, 15 years of age or older, 16 years of age or older, 17 years of age or older, 18 years of age or older, 19 years of age or older, or 20 years of age or older. In certain embodiments, the pediatric patient is 3 years of age or older.

[0240] In some embodiments of any of the preceding aspects, the epiphyses (growth plates) of the pediatric patient are still open.

[0241] In some embodiments of any of the preceding aspects, the daily dose is in a solid dosage form. In certain embodiments, the solid dosage form is a capsule. In some embodiments, the solid dosage form is a sprinkle capsule. In some embodiments, the solid dosage form is a tablet. In certain embodiments, the solid dosage form is a minitablet.

[0242] In some embodiments of any of the preceding aspects, the methods described herein result in the subject (e.g., the pediatric patient) exhibiting increased height velocity relative to baseline. In certain embodiments, the methods described herein result in the subject (e.g., the pediatric patient) exhibiting a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, or 100% increase in height velocity relative to baseline.

[0243] In certain embodiments, during or after treatment using the methods described herein, the subject (e.g., the pediatric patient) exhibits a mean change from baseline in annualized height velocity (AHV) of at least about 1.0 centimeters per year (cm/yr), at least about 1.1 cm/yr, at least about 1.2 cm/yr, at least about 1.3 cm/yr, at least about 1.4 cm/yr, at least about 1.5 cm/yr, at least about 1.6 cm/yr, at least about 1.7 cm/yr, at least about 1.8 cm/yr, at least about 1.9 cm/yr, at least about 2.0 cm/yr, at least about 2. 1 cm/yr, at least about 2.2 cm/yr, at least about 2.3 cm/yr, at least about 2.4 cm/yr, at least about 2.5 cm/yr, at least about 2.6 cm/yr, at least about 2.7 cm/yr, at least about 2.8 cm/yr, at least about 2.9 cm/yr, at least about 3.0 cm/yr, at least about 3.1 cm/yr, at least about 3.2 cm/yr, at least about 3.3 cm/yr, at least about 3.4 cm/yr, at least about 3.5 cm/yr, at least about 3.6 cm/yr, at least about 3.7 cm/yr, at least about 3.8 cm/yr, at least about 3.9 cm/yr, or at least about 4.0 cm/yr. In some embodiments, during or after treatment using the methods described herein, the subject (e.g., the pediatric patient) exhibits a mean change from baseline in AHV of at least about 2.0 cm/yr.

[0244] In some embodiments of any of the preceding aspects, during or after treatment using the methods described herein, the subject exhibits a change from baseline in AHV of between about 1.0 cm/yr and about 14 cm/yr, about 1.0 cm/yr and about 13.0 cm/yr, about 1.0 cm/yr and about 12.0 cm/yr, about 1.0 cm/yr and about 11.0 cm/yr, about 1.0 cm/yr and about 10.0 cm/yr, about 1.0 cm/yr and about 9.0 cm/yr, about 1.0 cm/yr and about 8.0 cm/yr, about 1.0 cm/yr and about 7.0 cm/yr, about 1.0 cm/yr and about 6.0 cm/yr, about 1.0 cm/yr and about 5.0 cm/yr, about 1.0 cm/yr and about 4.5 cm/yr, about 1.0 cm/yr and about 4.0 cm/yr, about 1.0 cm/yr and about 3.5 cm/yr, about 1.0 cm/yr and about 3.0 cm/yr, about 1.0 cm/yr and about 2.5 cm/yr, about 1.0 cm/yr and about 2.0 cm/yr, about 1.0 cm/yr and about 1.5 cm/yr, about 1.5 cm/yr and about 14.0 cm/yr, about 1.5 cm/yr and about 13.0 cm/yr, about 1.5 cm/yr and about 12.0 cm/yr, about 1.5 cm/yr and about 11.0 cm/yr, about 1.5 cm/yr and about 10.0 cm/yr, about 1.5 cm/yr and about 9.0 cm/yr, about 1.5 cm/yr and about 8.0 cm/yr, about 1.5 cm/yr and about 7.0 cm/yr, about 1.5 cm/yr and about 6.0 cm/yr, about 1.5 cm/yr and about 5.0 cm/yr, about 1.5 cm/yr and about 4.5 cm/yr, about 1.5 cm/yr and about 4.0 cm/yr, about 1.5 cm/yr and about 3.5 cm/yr, about 1.5 cm/yr and about 3.0 cm/yr, about 1.5 cm/yr and about 2.5 cm/yr, about 1.5 cm/yr and about 2.0 cm/yr, about 2.0 cm/yr and about 14 cm/yr, about 2.0 cm/yr and about 13.0 cm/yr, about 2.0 cm/yr and about 12.0 cm/yr, about 2.0 cm/yr and about 11.0 cm/yr, about 2.0 cm/yr and about 10.0 cm/yr, about 2.0 cm/yr and about 9.0 cm/yr, about 2.0 cm/yr and about 8.0 cm/yr, about 2.0 cm/yr and about 7.0 cm/yr, about 2.0 cm/yr and about 6.0 cm/yr, about 2.0 cm/yr and about 5.0 cm/yr, about 2.0 cm/yr and about 4.5 cm/yr, about 2.0 cm/yr and about 4.0 cm/yr, about 2.0 cm/yr and about 3.5 cm/yr, about 2.0 cm/yr and about 3.0 cm/yr, about 2.0 cm/yr and about 2.5 cm/yr, about 2.5 cm/yr and about 14 cm/yr, about 2.5 cm/yr and about 13.0 cm/yr, about 2.5 cm/yr and about 12.0 cm/yr, about 2.5 cm/yr and about 11.0 cm/yr, about 2.5 cm/yr and about 10.0 cm/yr, about 2.5 cm/yr and about 9.0 cm/yr, about 2.5 cm/yr and about 8.0 cm/yr, about 2.5 cm/yr and about 7.0 cm/yr, about 2.5 cm/yr and about 6.0 cm/yr, about 2.5 cm/yr and about 5.0 cm/yr, about 2.5 cm/yr and about 4.5 cm/yr, about 2.5 cm/yr and about 4.0 cm/yr, about 2.5 cm/yr and about 3.5 cm/yr, about 2.5 cm/yr and about 3.0 cm/yr, about 3.0 cm/yr and about 14 cm/yr, about 3.0 cm/yr and about 13.0 cm/yr, about 3.0 cm/yr and about 12.0 cm/yr, about 3.0 cm/yr and about 11.0 cm/yr, about 3.0 cm/yr and about 10.0 cm/yr, about 3.0 cm/yr and about 9.0 cm/yr, about 3.0 cm/yr and about 8.0 cm/yr, about 3.0 cm/yr and about 7.0 cm/yr, about 3.0 cm/yr and about 6.0 cm/yr, about 3.0 cm/yr and about 5.0 cm/yr, about 3.0 cm/yr and about 4.5 cm/yr, about 3.0 cm/yr and about 4.0 cm/yr, about 3.0 cm/yr and about 3.5 cm/yr, about 3.5 cm/yr and about 14 cm/yr, about 3.5 cm/yr and about 13.0 cm/yr, about 3.5 cm/yr and about 12.0 cm/yr, about 3.5 cm/yr and about 11.0 cm/yr, about 3.5 cm/yr and about 10.0 cm/yr, about 3.5 cm/yr and about 9.0 cm/yr, about 3.5 cm/yr and about 8.0 cm/yr, about 3.5 cm/yr and about 7.0 cm/yr, about 3.5 cm/yr and about 6.0 cm/yr, about 3.5 cm/yr and about 5.0 cm/yr, about 3.5 cm/yr and about 4.5 cm/yr, about 3.5 cm/yr and about 4.0 cm/yr, about 4.0 cm/yr and about 14 cm/yr, about 4.0 cm/yr and about 13.0 cm/yr, about 4.0 cm/yr and about 12.0 cm/yr, about 4.0 cm/yr and about 11.0 cm/yr, about 4.0 cm/yr and about 10.0 cm/yr, about 4.0 cm/yr and about 9.0 cm/yr, about 4.0 cm/yr and about 8.0 cm/yr, about 4.0 cm/yr and about 7.0 cm/yr, about 4.0 cm/yr and about 6.0 cm/yr, about 4.0 cm/yr and about 5.0 cm/yr, about 4.0 cm/yr and about 4.5 cm/yr, about 4.5 cm/yr and about 14 cm/yr, about 4.5 cm/yr and about 13.0 cm/yr, about 4.5 cm/yr and about 12.0 cm/yr, about 4.5 cm/yr and about 11.0 cm/yr, about 4.5 cm/yr and about 10.0 cm/yr, about 4.5 cm/yr and about 9.0 cm/yr, about 4.5 cm/yr and about 8.0 cm/yr, about 4.5 cm/yr and about 7.0 cm/yr, about 4.5 cm/yr and about 6.0 cm/yr, about 4.5 cm/yr and about 5.0 cm/yr, about 5.0 cm/yr and about 14 cm/yr, about 5.0 cm/yr and about 13.0 cm/yr, about 5.0 cm/yr and about 12.0 cm/yr, about 5.0 cm/yr and about 11.0 cm/yr, about 5.0 cm/yr and about 10.0 cm/yr, about 5.0 cm/yr and about 9.0 cm/yr, about 5.0 cm/yr and about 8.0 cm/yr, about 5.0 cm/yr and about 7.0 cm/yr, or about 5.0 cm/yr and about 6.0 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a change from baseline in AHV of between about 1.0 cm/yr and about 14 cm/yr.

[0245] In some embodiments of any of the preceding aspects, during or after treatment using the methods described herein, the subject exhibits a change from baseline in 86AVE of about 1.0 cm/yr, about 1.1 cm/yr, about 1.2 cm/yr, about 1.3 cm/yr, about 1.4 cm/yr, about 1.5 cm/yr, about 1.6 cm/yr, about 1.7 cm/yr, about 1.8 cm/yr, about 1.9 cm/yr, about 2.0 cm/yr, about 2.1 cm/yr, about 2.2 cm/yr, about 2.3 cm/yr, about 2.4 cm/yr, about 2.5 cm/yr, about 2.6 cm/yr, about 2.7 cm/yr, about 2.8 cm/yr, about 2.9 cm/yr, about 3.0 cm/yr, about 3.1 cm/yr, about 3.2 cm/yr, about 3.3 cm/yr, about 3.4 cm/yr, about 3.5 cm/yr, about 3.6 cm/yr, about 3.7 cm/yr, about 3.8 cm/yr, about 3.9 cm/yr, about 4.0 cm/yr, about 4. 1 cm/yr, about 4.2 cm/yr, about 4.3 cm/yr, about 4.4 cm/yr, about 4.5 cm/yr, about 4.6 cm/yr, about 4.7 cm/yr, about 4.8 cm/yr, about 4.9 cm/yr, about 5.0 cm/yr, about 5.1 cm/yr, about 5.2 cm/yr, about 5.3 cm/yr, about 5.4 cm/yr, about 5.5 cm/yr, about 5.6 cm/yr, about 5.7 cm/yr, about 5.8 cm/yr, about 5.9 cm/yr, about 6.0 cm/yr, about 6.1 cm/yr, about 6.2 cm/yr, about 6.3 cm/yr, about 6.4 cm/yr, about 6.5 cm/yr, about 6.6 cm/yr, about 6.7 cm/yr, about 6.8 cm/yr, about 6.9 cm/yr, about 7.0 cm/yr, about 7.1 cm/yr, about 7.2 cm/yr, about 7.3 cm/yr, about 7.4 cm/yr, about 7.5 cm/yr, about 7.6 cm/yr, about 7.7 cm/yr, about 7.8 cm/yr, about 7.9 cm/yr, about 8.0 cm/yr, about 8.1 cm/yr, about 8.2 cm/yr, about 8.3 cm/yr, about 8.4 cm/yr, about 8.5 cm/yr, about 8.6 cm/yr, about 8.7 cm/yr, about 8.8 cm/yr, about 8.9 cm/yr, about 9.0 cm/yr, about 9.1 cm/yr, about 9.2 cm/yr, about 9.3 cm/yr, about 9.4 cm/yr, about 9.5 cm/yr, about 9.6 cm/yr, about 9.7 cm/yr, about 9.8 cm/yr, about 9.9 cm/yr, about 10.0 cm/yr, about 10.1 cm/yr, about 10.2 cm/yr, about 10.3 cm/yr, about 10.4 cm/yr, about 10.5 cm/yr, about 10.6 cm/yr, about 10.7 cm/yr, about 10.8 cm/yr, about 10.9 cm/yr, about 11.0 cm/yr, about 11.1 cm/yr, about 11.2 cm/yr, about 11.3 cm/yr, about 11.4 cm/yr, about 11.5 cm/yr, about 11.6 cm/yr, about 11.7 cm/yr, about 11.8 cm/yr, about 11.9 cm/yr, about 12.0 cm/yr, about 12.1 cm/yr, about 12.2 cm/yr, about 12.3 cm/yr, about 12.4 cm/yr, about 12.5 cm/yr, about 12.6 cm/yr, about 12.7 cm/yr, about 12.8 cm/yr, about 12.9 cm/yr, about 13.0 cm/yr, about 13.1 cm/yr, about 13.2 cm/yr, about 13.3 cm/yr, about 13.4 cm/yr, about 13.5 cm/yr, about 13.6 cm/yr, about 13.7 cm/yr, about 13.8 cm/yr, about 13.9 cm/yr, or about 14.0 cm/yr.

[0246] In some embodiments of any of the preceding aspects, during or after treatment using the methods describe herein, the subject exhibits a mean change from baseline in AHV of about 2.0 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change from baseline in AHV of about 2. 1 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change from baseline in AHV of about 2.2 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change from baseline in AHV of about 2.3 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change from baseline in AHV of about 2.4 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change from baseline in AHV of about 2.5 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change from baseline in AHV of about 2.6 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change from baseline in AHV of about 2.7 cm/yr. In certain embodiments, during or after treatment using a method described herein, the subject exhibits a mean change from baseline in AHV of about 2.8 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change from baseline in AHV of about 2.9 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change from baseline in AHV of about 3.0 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change from baseline in AHV of about 3. 1 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change from baseline in AHV of about 3.2 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change from baseline in AHV of about 3.3 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change from baseline in AHV of about 3.4 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change from baseline in AHV of about 3.5 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change from baseline in AHV of about 3.6 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change from baseline in AHV of about 3.7 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change from baseline in AHV of about 3.8 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change from baseline in AHV of about 3.9 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change from baseline in AHV of about 4.0 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change from baseline in AHV of about 4. 1 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change from baseline in AHV of about 4.2 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change from baseline in AHV of about 4.3 cm/yr. In certain embodiments, during or after treatment using the methodes described herein, the subject exhibits a mean change from baseline in AHV of about 4.4 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change from baseline in AHV of about 4.5 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change from baseline in AHV of about 4.6 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change from baseline in AHV of about 4.7 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change from baseline in AHV of about 4.8 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change from baseline in AHV of about 4.9 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change from baseline in AHV of about 5.0 cm/yr.

[0247] In some embodiments of any of the preceding aspects, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of at least about 2.0 cm/yr, at least about 2.1 cm/yr, at least about 2.2 cm/yr, at least about 2.3 cm/yr, at least about 2.4 cm/yr, at least about 2.5 cm/yr, at least about 2.6 cm/yr, at least about 2.7 cm/yr, at least about 2.8 cm/yr, at least about 2.9 cm/yr, at least about 3.0 cm/yr, at least about 3.1 cm/yr, at least about 3.2 cm/yr, at least about 3.3 cm/yr, at least about 3.4 cm/yr, at least about 3.5 cm/yr, at least about 3.6 cm/yr, at least about 3.7 cm/yr, at least about 3.8 cm/yr, at least about 3.9 cm/yr, at least about 4.0 cm/yr, at least about 4.1 cm/yr, at least about 4.2 cm/yr, at least about 4.3 cm/yr, at least about 4.4 cm/yr, at least about 4.5 cm/yr, at least about 4.6 cm/yr, at least about 4.7 cm/yr, at least about 4.8 cm/yr, at least about 4.9 cm/yr, at least about 5.0 cm/yr, at least about 5.1 cm/yr, at least about 5.2 cm/yr, at least about 5.3 cm/yr, at least about 5.4 cm/yr, at least about 5.5 cm/yr, at least about 5.6 cm/yr, at least about 5.7 cm/yr, at least about 5.8 cm/yr, at least about 5.9 cm/yr, at least about 6.0 cm/yr, at least about 6.1 cm/yr, at least about 6.2 cm/yr, at least about 6.3 cm/yr, at least about 6.4 cm/yr, at least about 6.5 cm/yr, at least about 6.6 cm/yr, at least about 6.7 cm/yr, at least about 6.8 cm/yr, at least about 6.9 cm/yr, at least about 7.0 cm/yr, at least about 7.1 cm/yr, at least about 7.2 cm/yr, at least about 7.3 cm/yr, at least about 7.4 cm/yr, at least about 7.5 cm/yr, at least about 7.6 cm/yr, at least about 7.7 cm/yr, at least about 7.8 cm/yr, at least about 7.9 cm/yr, at least about 8.0 cm/yr, at least about 8.1 cm/yr, at least about 8.2 cm/yr, at least about 8.3 cm/yr, at least about 8.4 cm/yr, at least about 8.5 cm/yr, at least about 8.6 cm/yr, at least about 8.7 cm/yr, at least about 8.8 cm/yr, at least about 8.9 cm/yr, at least about 9.0 cm/yr, at least about 9. 1 cm/yr, at least about 9.2 cm/yr, at least about 9.3 cm/yr, at least about 9.4 cm/yr, at least about 9.5 cm/yr, at least about 9.6 cm/yr, at least about 9.7 cm/yr, at least about 9.8 cm/yr, at least about 9.9 cm/yr, at least about 10.0 cm/yr, at least about 10.1 cm/yr, at least about 10.2 cm/yr, at least about 10.3 cm/yr, at least about 10.4 cm/yr, at least about 10.5 cm/yr, at least about 10.6 cm/yr, at least about 10.7 cm/yr, at least about 10.8 cm/yr, at least about 10.9 cm/yr, at least about 11.0 cm/yr, at least about 11.1 cm/yr, at least about 11.2 cm/yr, at least about 11.3 cm/yr, at least about 11.4 cm/yr, at least about 11.5 cm/yr, at least about 11.6 cm/yr, at least about 11.7 cm/yr, at least about 11.8 cm/yr, at least about 11.9 cm/yr, at least about 12.0 cm/yr, at least about 12.1 cm/yr, at least about 12.2 cm/yr, at least about 12.3 cm/yr, at least about 12.4 cm/yr, at least about 12.5 cm/yr, at least about 12.6 cm/yr, at least about 12.7 cm/yr, at least about 12.8 cm/yr, at least about 12.9 cm/yr, at least about 13.0 cm/yr, at least about 13.1 cm/yr, at least about 13.2 cm/yr, at least about 13.3 cm/yr, at least about 13.4 cm/yr, at least about 13.5 cm/yr, at least about 13.6 cm/yr, at least about 13.7 cm/yr, at least about 13.8 cm/yr, at least about 13.9 cm/yr, or at least about 14.0 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of at least about 4.0 cm/yr, at least about 4. 1 cm/yr, at least about 4.2 cm/yr, at least about 4.3 cm/yr, at least about 4.4 cm/yr, at least about 4.5 cm/yr, at least about 4.6 cm/yr, at least about 4.7 cm/yr, at least about 4.8 cm/yr, at least about 4.9 cm/yr, at least about 5.0 cm/yr, at least about 5.1 cm/yr, at least about 5.2 cm/yr, at least about 5.3 cm/yr, at least about 5.4 cm/yr, at least about 5.5 cm/yr, at least about 5.6 cm/yr, at least about 5.7 cm/yr, at least about 5.8 cm/yr, at least about 5.9 cm/yr, at least about 6.0 cm/yr, at least about 6.1 cm/yr, at least about 6.2 cm/yr, at least about 6.3 cm/yr, at least about 6.4 cm/yr, at least about 6.5 cm/yr, at least about 6.6 cm/yr, at least about 6.7 cm/yr, at least about 6.8 cm/yr, at least about 6.9 cm/yr, at least about 7.0 cm/yr, at least about 7.1 cm/yr, at least about 7.2 cm/yr, at least about 7.3 cm/yr, at least about 7.4 cm/yr, at least about 7.5 cm/yr, at least about 7.6 cm/yr, at least about 7.7 cm/yr, at least about 7.8 cm/yr, at least about 7.9 cm/yr, at least about 8.0 cm/yr, at least about 8.1 cm/yr, at least about 8.2 cm/yr, at least about 8.3 cm/yr, at least about 8.4 cm/yr, at least about 8.5 cm/yr, at least about 8.6 cm/yr, at least about 8.7 cm/yr, at least about 8.8 cm/yr, at least about 8.9 cm/yr, at least about 9.0 cm/yr, at least about 9.1 cm/yr, at least about 9.2 cm/yr, at least about 9.3 cm/yr, at least about 9.4 cm/yr, at least about 9.5 cm/yr, at least about 9.6 cm/yr, at least about 9.7 cm/yr, at least about 9.8 cm/yr, at least about 9.9 cm/yr, at least about 10.0 cm/yr, at least about 10.1 cm/yr, at least about 10.2 cm/yr, at least about 10.3 cm/yr, at least about 10.4 cm/yr, at least about 10.5 cm/yr, at least about 10.6 cm/yr, at least about 10.7 cm/yr, at least about 10.8 cm/yr, at least about 10.9 cm/yr, at least about 11.0 cm/yr, at least about 11.1 cm/yr, at least about 11.2 cm/yr, at least about 11.3 cm/yr, at least about 11.4 cm/yr, at least about 11.5 cm/yr, at least about 11.6 cm/yr, at least about 11.7 cm/yr, at least about 11.8 cm/yr, at least about 11.9 cm/yr, at least about 12.0 cm/yr, at least about 12.1 cm/yr, at least about 12.2 cm/yr, at least about 12.3 cm/yr, at least about 12.4 cm/yr, at least about 12.5 cm/yr, at least about 12.6 cm/yr, at least about 12.7 cm/yr, at least about 12.8 cm/yr, at least about 12.9 cm/yr, at least about 13.0 cm/yr, at least about 13.1 cm/yr, at least about 13.2 cm/yr, at least about 13.3 cm/yr, at least about 13.4 cm/yr, at least about 13.5 cm/yr, at least about 13.6 cm/yr, at least about 13.7 cm/yr, at least about 13.8 cm/yr, at least about 13.9 cm/yr, or at least about 14.0 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of at least about 7.0 cm/yr, at least about 7.1 cm/yr, at least about 7.2 cm/yr, at least about 7.3 cm/yr, at least about 7.4 cm/yr, at least about 7.5 cm/yr, at least about 7.6 cm/yr, at least about 7.7 cm/yr, at least about 7.8 cm/yr, at least about 7.9 cm/yr, at least about 8.0 cm/yr, at least about 8.1 cm/yr, at least about 8.2 cm/yr, at least about 8.3 cm/yr, at least about 8.4 cm/yr, at least about 8.5 cm/yr, at least about 8.6 cm/yr, at least about 8.7 cm/yr, at least about 8.8 cm/yr, at least about 8.9 cm/yr, at least about 9.0 cm/yr, at least about 9.1 cm/yr, at least about 9.2 cm/yr, at least about 9.3 cm/yr, at least about 9.4 cm/yr, at least about 9.5 cm/yr, at least about 9.6 cm/yr, at least about 9.7 cm/yr, at least about 9.8 cm/yr, at least about 9.9 cm/yr, at least about 10.0 cm/yr, at least about 10.1 cm/yr, at least about 10.2 cm/yr, at least about 10.3 cm/yr, at least about 10.4 cm/yr, at least about 10.5 cm/yr, at least about 10.6 cm/yr, at least about 10.7 cm/yr, at least about 10.8 cm/yr, at least about 10.9 cm/yr, at least about 11.0 cm/yr, at least about 11.1 cm/yr, at least about 11.2 cm/yr, at least about 11.3 cm/yr, at least about 11.4 cm/yr, at least about 11.5 cm/yr, at least about 11.6 cm/yr, at least about 11.7 cm/yr, at least about 11.8 cm/yr, at least about 11.9 cm/yr, at least about 12.0 cm/yr, at least about 12.1 cm/yr, at least about 12.2 cm/yr, at least about 12.3 cm/yr, at least about 12.4 cm/yr, at least about 12.5 cm/yr, at least about 12.6 cm/yr, at least about 12.7 cm/yr, at least about 12.8 cm/yr, at least about 12.9 cm/yr, at least about 13.0 cm/yr, at least about 13.1 cm/yr, at least about 13.2 cm/yr, at least about 13.3 cm/yr, at least about 13.4 cm/yr, at least about 13.5 cm/yr, at least about 13.6 cm/yr, at least about 13.7 cm/yr, at least about 13.8 cm/yr, at least about 13.9 cm/yr, or at least about 14.0 cm/yr. [0248] In some embodiments of any of the preceding aspects, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of between about 1.0 cm/yr and about 14 cm/yr, about 1.0 cm/yr and about 13.0 cm/yr, about 1.0 cm/yr and about 12.0 cm/yr, about 1.0 cm/yr and about 11.0 cm/yr, about 1.0 cm/yr and about 10.0 cm/yr, about 1.0 cm/yr and about 9.0 cm/yr, about 1.0 cm/yr and about 8.0 cm/yr, about 1.0 cm/yr and about 7.0 cm/yr, about 1.0 cm/yr and about 6.0 cm/yr, about 1.0 cm/yr and about 5.0 cm/yr, about 1.0 cm/yr and about 4.5 cm/yr, about 1.0 cm/yr and about 4.0 cm/yr, about 1.0 cm/yr and about 3.5 cm/yr, about 1.0 cm/yr and about 3.0 cm/yr, about 1.0 cm/yr and about 2.5 cm/yr, about 1.0 cm/yr and about 2.0 cm/yr, about 1.0 cm/yr and about 1.5 cm/yr, about 1.5 cm/yr and about 14.0 cm/yr, about 1.5 cm/yr and about 13.0 cm/yr, about 1.5 cm/yr and about 12.0 cm/yr, about 1.5 cm/yr and about 11.0 cm/yr, about 1.5 cm/yr and about 10.0 cm/yr, about 1.5 cm/yr and about 9.0 cm/yr, about 1.5 cm/yr and about 8.0 cm/yr, about 1.5 cm/yr and about 7.0 cm/yr, about 1.5 cm/yr and about 6.0 cm/yr, about 1.5 cm/yr and about 5.0 cm/yr, about 1.5 cm/yr and about 4.5 cm/yr, about 1.5 cm/yr and about 4.0 cm/yr, about 1.5 cm/yr and about 3.5 cm/yr, about 1.5 cm/yr and about 3.0 cm/yr, about 1.5 cm/yr and about 2.5 cm/yr, about 1.5 cm/yr and about 2.0 cm/yr, about 2.0 cm/yr and about 14 cm/yr, about 2.0 cm/yr and about 13.0 cm/yr, about 2.0 cm/yr and about 12.0 cm/yr, about 2.0 cm/yr and about 11.0 cm/yr, about 2.0 cm/yr and about 10.0 cm/yr, about 2.0 cm/yr and about 9.0 cm/yr, about 2.0 cm/yr and about 8.0 cm/yr, about 2.0 cm/yr and about 7.0 cm/yr, about 2.0 cm/yr and about 6.0 cm/yr, about 2.0 cm/yr and about 5.0 cm/yr, about 2.0 cm/yr and about 4.5 cm/yr, about 2.0 cm/yr and about 4.0 cm/yr, about 2.0 cm/yr and about 3.5 cm/yr, about 2.0 cm/yr and about 3.0 cm/yr, about 2.0 cm/yr and about 2.5 cm/yr, about 2.5 cm/yr and about 14 cm/yr, about 2.5 cm/yr and about 13.0 cm/yr, about 2.5 cm/yr and about 12.0 cm/yr, about 2.5 cm/yr and about 11.0 cm/yr, about 2.5 cm/yr and about 10.0 cm/yr, about 2.5 cm/yr and about 9.0 cm/yr, about 2.5 cm/yr and about 8.0 cm/yr, about 2.5 cm/yr and about 7.0 cm/yr, about 2.5 cm/yr and about 6.0 cm/yr, about 2.5 cm/yr and about 5.0 cm/yr, about 2.5 cm/yr and about 4.5 cm/yr, about 2.5 cm/yr and about 4.0 cm/yr, about 2.5 cm/yr and about 3.5 cm/yr, about 2.5 cm/yr and about 3.0 cm/yr, about 3.0 cm/yr and about 14 cm/yr, about 3.0 cm/yr and about 13.0 cm/yr, about 3.0 cm/yr and about 12.0 cm/yr, about 3.0 cm/yr and about 11.0 cm/yr, about 3.0 cm/yr and about 10.0 cm/yr, about 3.0 cm/yr and about 9.0 cm/yr, about 3.0 cm/yr and about 8.0 cm/yr, about 3.0 cm/yr and about 7.0 cm/yr, about 3.0 cm/yr and about 6.0 cm/yr, about 3.0 cm/yr and about 5.0 cm/yr, about 3.0 cm/yr and about 4.5 cm/yr, about 3.0 cm/yr and about 4.0 cm/yr, about 3.0 cm/yr and about 3.5 cm/yr, about 3.5 cm/yr and about 14 cm/yr, about 3.5 cm/yr and about 13.0 cm/yr, about 3.5 cm/yr and about 12.0 cm/yr, about 3.5 cm/yr and about 11.0 cm/yr, about 3.5 cm/yr and about 10.0 cm/yr, about 3.5 cm/yr and about 9.0 cm/yr, about 3.5 cm/yr and about 8.0 cm/yr, about 3.5 cm/yr and about 7.0 cm/yr, about 3.5 cm/yr and about 6.0 cm/yr, about 3.5 cm/yr and about 5.0 cm/yr, about 3.5 cm/yr and about 4.5 cm/yr, about 3.5 cm/yr and about 4.0 cm/yr, about 4.0 cm/yr and about 14 cm/yr, about 4.0 cm/yr and about 13.0 cm/yr, about 4.0 cm/yr and about 12.0 cm/yr, about 4.0 cm/yr and about 11.0 cm/yr, about 4.0 cm/yr and about 10.0 cm/yr, about 4.0 cm/yr and about 9.0 cm/yr, about 4.0 cm/yr and about 8.0 cm/yr, about 4.0 cm/yr and about 7.0 cm/yr, about 4.0 cm/yr and about 6.0 cm/yr, about 4.0 cm/yr and about 5.0 cm/yr, about 4.0 cm/yr and about 4.5 cm/yr, about 4.5 cm/yr and about 14 cm/yr, about 4.5 cm/yr and about 13.0 cm/yr, about 4.5 cm/yr and about 12.0 cm/yr, about 4.5 cm/yr and about 11.0 cm/yr, about 4.5 cm/yr and about 10.0 cm/yr, about 4.5 cm/yr and about 9.0 cm/yr, about 4.5 cm/yr and about 8.0 cm/yr, about 4.5 cm/yr and about 7.0 cm/yr, about 4.5 cm/yr and about 6.0 cm/yr, about 4.5 cm/yr and about 5.0 cm/yr, about 5.0 cm/yr and about 14 cm/yr, about 5.0 cm/yr and about 13.0 cm/yr, about 5.0 cm/yr and about 12.0 cm/yr, about 5.0 cm/yr and about 11.0 cm/yr, about 5.0 cm/yr and about 10.0 cm/yr, about 5.0 cm/yr and about 9.0 cm/yr, about 5.0 cm/yr and about 8.0 cm/yr, about 5.0 cm/yr and about 7.0 cm/yr, or about 5.0 cm/yr and about 6.0 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of between about 1.0 cm/yr and about 14 cm/yr.

[0249] In some embodiments of any of the preceding aspects, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 3.0 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 3.1 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 3.2 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 3.3 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 3.4 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 3.5 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 3.6 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 3.7 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 3.8 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 3.9 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 4.0 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 4.1 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 4.2 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 4.3 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 4.4 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 4.5 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 4.6 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 4.7 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 4.8 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 4.9 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 5.0 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 5.1 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 5.2 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 5.3 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 5.4 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 5.5 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 5.6 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 5.7 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 5.8 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 5.9 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 6.0 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 6.1 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 6.2 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 6.3 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 6.4 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 6.5 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 6.6 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 6.7 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 6.8 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 6.9 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 7.0 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 7.1 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 7.2 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 7.3 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 7.4 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 7.5 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 7.6 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 7.7 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 7.8 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 7.9 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 8.0 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 8.1 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 8.2 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 8.3 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 8.4 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 8.5 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 8.6 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 8.7 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 8.8 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 8.9 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 9.0 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 9.1 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 9.2 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 9.3 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 9.4 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 9.5 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 9.6 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 9.7 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 9.8 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 9.9 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 10.0 cm/yr.

In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 10.1 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 10.2 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 10.3 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 10.4 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 10.5 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 10.6 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 10.7 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 10.8 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 10.9 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 11.0 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 11.1 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 11.2 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 11.3 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 11.4 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 11.5 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 11.6 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 11.7 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 11.8 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 11.9 cm/yr. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits an absolute AHV of about 12.0 cm/yr.

[0250] In some embodiments of any of the preceding aspects, during or after treatment using the methods described herein, the subject does not experience a treatment-related adverse event. In certain embodiments, during or after treatment using the methods described herein, the subject does not experience a serious adverse event. In certain embodiments, during or after treatment using the methods described herein, the subject does not experience a serious treatment-related adverse event.

[0251] In some embodiments of any of the preceding aspects, the methods described herein result in the subject (e.g., the pediatric patient) exhibiting an increase, relative to baseline, in an anthropometric measurement selected from the group consisting of standing height, sitting height, upper and lower arm length, thigh length, knee height, arm span, and combinations thereof. In certain embodiments, the methods described herein result in the subject (e.g., the pediatric patient) exhibiting a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, or 100% increase, relative to baseline, in an anthropometric measurement selected from the group consisting of standing height, sitting height, upper and lower arm length, thigh length, knee height, arm span, and combinations thereof. In some embodiments, the methods described herein result in the subject exhibiting an increase in height for age with a z-score (standard deviation from the mean) of at least about 0.1, about 0.15, about 0.2, about 0.25, about 0.3, about 0.35, about 0.4, about 0.45, or about 0.5.

[0252] In some embodiments of any of the preceding aspects, the methods described herein result in the subject (e.g., the pediatric patient) exhibiting an absolute increase in an anthropometric measurement selected from the group consisting of standing height, sitting height, upper and lower arm length, thigh length, knee height, arm span, and combinations thereof. In certain embodiments, the methods described herein result in the subject (e.g., the pediatric patient) exhibiting an absolute increase of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, or 100% in an anthropometric measurement selected from the group consisting of standing height, sitting height, upper and lower arm length, thigh length, knee height, arm span, and combinations thereof.

[0253] In some embodiments of any of the preceding aspects, the methods described herein result in the subject (e.g., the pediatric patient) exhibiting a decrease, relative to baseline, in weight. In certain embodiments, the methods described herein result in the subject (e.g., the pediatric patient) exhibiting a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% decrease, relative to baseline, in weight. [0254] In certain embodiments, the methods described herein result in the subject (e.g., the pediatric patient) exhibiting an absolute decrease in weight. In certain embodiments, the methods described herein result in the subject (e.g., the pediatric patient) exhibiting an absolute decrease of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% in weight.

[0255] In some embodiments of any of the preceding aspects, the methods described herein result in the subject (e.g., the pediatric patient) exhibiting a proportional increase, relative to baseline, in head circumference. In certain embodiments, the methods described herein result in the subject (e.g., the pediatric patient) exhibiting an absolute proportional increase in head circumference. For example, the methods described herein may bring the body of the subject into proportion to the head. In contrast, subjects not treated using the methods described herein may have macroencephaly.

[0256] In some embodiments of any of the preceding aspects, the methods described herein result in the subject (e.g., the pediatric patient) exhibiting a normalization, relative to baseline, of a body proportion measurement ratio. In certain embodiments, the methods described herein result in the subject (e.g., the pediatric patient) exhibiting an absolute normalization of a body proportion measurement ratio. For example, the methods described herein may result in the limbs of the subject growing to be more proportionate compared to the trunk. In contrast, subjects not treated using the methods described herein may have limbs that are disproportionately short compared to the trunk.

[0257] In some embodiments of any of the preceding aspects, the body proportion measurement ratio is selected from the group consisting of upper to lower body segment ratio, upper arm to forearm ratio, upper leg to lower leg length ratio, arm span to standing height ratio, head circumference to standing height ratio, and combinations thereof.

[0258] In some embodiments of any of the preceding aspects, the methods described herein result in the subject (e.g., the pediatric patient) exhibiting an increase, relative to baseline, in a biomarker of bone turnover selected from the group consisting of type X collagen degradation fragment, collagen X marker, and combinations thereof. In certain embodiments, the methods described herein result in the subject (e.g., the pediatric patient) exhibiting a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, or 100% increase, relative to baseline, in a biomarker of bone turnover selected from the group consisting of type X collagen degradation fragment, collagen X marker, and a combination thereof.

[0259] In some embodiments of any of the preceding aspects, during or after treatment using the methods described herein, the subject exhibits a mean change in collagen X marker from baseline of at least about 5%. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change in collagen X marker from baseline of at least about 5.0%, such as at least about 10.0%, about 11.0%, about 12.0%, about 13.0%, about 14.0%, about 15.0%, about 16.0%, about 17.0%, about 18.0%, about 19.0%, about 20.0%, about 21.0%, about 22.0%, about 23.0%, about 24.0%, about 25.0%, about 26.0%, about 27.0%, about 28.0%, about 29.0%, about 30.0%, about 31.0%, about 32.0%, about 33.0%, about 34.0%, about 35.0%, about 36.0%, about 37.0%, about 38.0%, about 39.0%, about 40.0%, or greater. In certain embodiments, during or after treatment using the methods described herein, the subject exhibits a mean change in collagen X marker from baseline of between about 10.0% and about 40.0%, such as between about 10.0% and about 35.0%, about 10.0% and about 30.0%, about 10.0% and about 25.0%, about 10.0% and about 20.0%, about 10.0% and about 15.0%, about 15.0% and about 40.0%, about 15.0% and about 35.0%, about 15.0% and about 30.0%, about 15.0% and about 25.0%, about 15.0% and about 20.0%, about 20.0% and about 40.0%, about 20.0% and about 35.0%, about 20.0% and about 30.0%, about 20.0% and about 25.0%, about 25.0% and about 40.0%, about 25.0% and about 35.0%, or about 25.0% and about 30.0%. [0260] In some embodiments of any of the preceding aspects, the methods described herein result in the subject (e.g., the pediatric patient) exhibiting an increase, relative to baseline, in mobility. In certain embodiments, the methods described herein result in the subject (e.g., the pediatric patient) exhibiting a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, or 100% increase, relative to baseline, in mobility.

[0261] In some embodiments of any of the preceding aspects, the methods described herein result in the subject (e.g., the pediatric patient) exhibiting a decrease, relative to baseline, in the number of episodes of otitis media. In certain embodiments, the methods described herein result in the subject (e.g., the pediatric patient) exhibiting a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, or 100% decrease, relative to baseline, in the number of episodes of otitis media. [0262] In some embodiments of any of the preceding aspects, the methods described herein result in the subject (e.g., the pediatric patient) exhibiting a decrease, relative to baseline, in the number of episodes and/or severity of sleep apnea. In certain embodiments, the methods described herein result in the subject (e.g., the pediatric patient) exhibiting a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, or 100% decrease, relative to baseline, in the number of episodes and/or severity of sleep apnea.

[0263] In some embodiments of any of the preceding aspects, the methods described herein result in the subject (e.g., the pediatric patient) exhibits an increase in quality of life, wherein quality of life is assessed using the Pediatric Quality of Life Inventory. In some embodiments, the methods described herein result in a reduction in the severity and/or frequency of seizures and/or convulsive events in the subject (e.g., in subjects with hypochondroplasia). In some embodiments, the methods described herein result in a reduction in the frequency of seizures in the subject having hypochondroplasia. In some embodiments, the methods described herein result in an improvement of psychomotor function, attention, verbal learning, and/or executive function in the subject (e.g., in subjects with hypochondroplasia). Without wishing to be bound by theory, an improvement in cognitive function in a subject, such as a subject with hypochondroplasia, may result at least in part due to infigratinib and/or a metabolite (e.g., a compound of formula (II), (III), or (IV)) crossing the blood-brain barrier.

[0264] In some embodiments of any of the preceding aspects, a subject may be treated by the methods described herein until the subject exhibits closed epiphyses and/or closed growth plates.

EXAMPLES

[0265] In order that the disclosure described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

Example 1: Synthesis of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-l-{6-4-(4-ethyl-piperazin- l-yl)-phenylaminol-pyrimidin-4-yl}-l-methyl-urea (infigratinib)

Step A: Synthesis ofN-4-(4-ethyl-piperazin-l-yl)-phenyl)-N’-methyl-pyrimidine-4, 6-diamine [0266] A mixture of 4-(4-ethylpiperazin-l-yl)-aniline (1 g, 4.88 mmol), (6-chloro-pyrimidin-4- yl)-methyl-amine (1.81 g, 12.68 mmol. 1.3 eq.), and 4N HC1 in dioxane (15 mL) is heated in a sealed tube to 150 °C for 5 hours. The reaction mixture is concentrated, diluted with dichloromethane (DCM) and a saturated aqueous solution of sodium bicarbonate. The aqueous layer is separated and extracted with DCM. The organic phase is washed with brine, dried (sodium sulfate), filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM/MeOH, 93:7) followed by trituration in diethyl ether affords the title compound as a white solid: ESI-MS: 313.2[MH]⁺; tR =1.10 min (gradient J); TLC: Rr = 0.21 (DCM/ MeOH, 93:7).

Step B: Synthesis of 4-(4-ethylpiperazin-l-yl)-aniline

[0267] A suspension of l-ethyl-4-(4-nitro-phenyl)-piperazine (6.2 g, 26.35 mmol) and Raney Nickel (2 g) in MeOH (120 mL) is stirred for 7 hours at RT, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated to afford 5.3 g of the title compound as a violet solid: ESI-MS: 206.1 [MH]⁺; TLC: Rr = 0.15 (DCM/MeOH + 1% NH₃ ^aq, 9: 1).

Step C: Synthesis of l-ethyl-4-(4-nitro-phenyl)-piperazine

[0268] A mixture of l-bromo-4-nitrobenzene (6 g, 29.7 mmol) and 1 -ethylpiperazine (7.6 mL, 59.4 mmol, 2 eq.) is heated to 80 °C for 15 hours. After cooling to RT, the reaction mixture is diluted with water and DCM/MeOH, 9: 1. The aqueous layer is separated and extracted with DCM/MeOH, 9: 1. The organic phase is washed with brine, dried (sodium sulfate), filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM/MeOH + 1% NH₃ ^aq, 9: 1) affords 6.2 g of the title compound as a yellow solid: ESI-MS: 236.0 [MH]⁺; tR= 2.35 min (purity: 100%, gradient J); TLC: Rr = 0.50 (DCM/MeOH + 1% NH₃ ^aq, 9: 1).

Step D: Synthesis of (6-chloro-pyrimidin-4-yl)-methyl-amine

[0269] This material was prepared by a modified procedure published in the literature (J. Appl. Chem. 1955, 5, 358): To a suspension of commercially available 4,6-dichloropyrimidine (20 g, 131.6 mmol, 1.0 eq.) in isopropanol (60 mL) is added 33% methylamine in ethanol (40.1 mL, 328.9 mmol, 2.5 eq.) at such a rate that the internal temperature does not rise above 50 °C. After completion of the addition the reaction mixture was stirred for 1 hour at room temperature. Then, water (50 mL) is added and the suspension formed is chilled in an ice bath to 5 °C. The precipitated product is fdtered off, washed with cold isopropanol/water 2: 1 (45 mL) and water. The collected material is vacuum dried over night at 45 °C to afford the title compound as colorless powder: tR = 3.57 min (purity: >99%, gradient A), ESI-MS: 144.3/146.2 [MH]⁺.

Step E: Synthesis of 3-(2, 6-dichloro-3,5-dimethoxy-phenyl)-l-{6-4-(4-eth l-piperazin-l-yl)-

[0270] The title compound was prepared by adding 2, 6-dichloro-3, 5 -dimethoxyphenyl- isocyanate (1.25 eq.) to a solution of N-4-(4-ethyl-piperazin-l-yl)-phenyl)-N’-methyl- pyrimidine-4,6-diamine (2.39 g, 7.7 mmol, 1 eq.) in toluene and stirring the reaction mixture for 1.5 hours at reflux. Purification of the crude product by silica gel column chromatography (DCM/MeOH + 1% NH3^aq, 95:5) affords the title compound as a white solid: ESI-MS: 560.0/561.9 [MH]⁺; t_R = 3.54 min (purity: 100%, gradient J); TLC: Rr = 0.28 (DCM/MeOH + l% NH₃ ^aq, 95:5). Analysis: C26H31N7O3CI2, calc. C, 55.72%; H, 5.57%; N, 17.49%; O, 8.56%; Cl, 12.65%. Found C, 55.96%: H, 5.84%: N, 17.17%; O, 8.46%; Cl, 12.57%.

Example 2: Synthesis of the Monophosphate Salt Form A of 3-(2,6-dichloro-3,5-dimethoxy- phenyl)-l-{6-4-(4-ethyl-piperazin-l-yl)-phenylaminol-pyrimidin-4-yl}-l-methyl-urea (BGJ398)

[0271] To a round bottom flask was added 3-(2,6-dichloro-3,5-dimethoxyphenyl)-l-(6-4-(4- ethylpiperazin-l-yl)phenylaminol-pyrimidine-4-yl)-l-methyl-urea (134g, 240 mmol) and isopropanol (IPA) (2000 mL). The suspension was stirred and heated to 50 °C and a solution of phosphoric acid (73.5 g, 750 mmol) in water (2000 mL) added to it portions. The mixture was stirred at 60 °C for 30 minutes and filtered through a polypropylene pad. The pad was washed with warm IPA/water (1: 1, 200 mL) and the filtrates were combined. To this clear solution, IPA (6000 mL) was added and the mixture was stirred under reflux for 20 minutes, cooled slowly to room temperature (25 °C), and stirred for 24 hours. The white salt product was collected by filtration, washed with IPA (2x500 mL) and dried in the oven at 60 °C under reduced pressure for two days to provide the anhydrous crystalline monophosphate salt (110 g). Yield 70%. Purity>98% by HPLC. Analysis: C26H34N7O7CI2P, calc. C, 47.42%; H, 5.20%; N, 14.89%; O, 17.01%; Cl, 10.77%; P. 4.70%. Found C, 47.40%; H, 5.11%: N, 14.71%; O, 17.18%: Cl, 10.73%; P 4.87%. Example 3: A Pharmacological Study of Infigratinib and Major Metabolites

1. Primary Pharmacodynamics

1.1. In Vitro Studies

1.1.1. Biochemical Kinase and Cellular Activity of Infigratinib

1.1.1.1 Kinase Selectivity in Biochemical Assays

[0272] The in vitro inhibitory activities of infigratinib were assessed using a 126-kinase panel (Kinase Platform-Novartis) and the select ICso values are listed in Table 2. Infigratinib inhibited FGFR1, FGFR2, and FGFR3 with ICso values of 0.0011 pM (1.1 nM), 0.001 pM (1 nM), 0.002 pM (2 nM), respectively. The ICso values for FGFR4, VEGFR2/KDR, LYN (1-512) and KIT (544-976) were 0.061 pM (61 nM), 0.21 pM (210 nM), 0.3 pM (300 nM) and 0.81 pM (810 nM), respectively. The inhibitory ICso values for all other kinases in the 126-kinase panel were >1 pM or 10 pM. Collectively, the biochemical kinase data show that infigratinib is a potent and selective FGFR1-3 inhibitor.

Table 2. Kinase Activity and Selectivity of Infigratinib in Biochemical Assays

lumbers in parentheses refer to the amino acid location in the constructs of the recombinant kinases.

1.1.1.2 Activity of Infigratinib Against the FGFRs in Cell-Based Assays

[0273] FGFR activation results in autophosphorylation on specific tyrosine residues. Thus, the cellular activity of infigratinib against the four FGFRs was measured by quantifying changes in the phosphor-tyrosine content of the receptors by ELISA. HEK293 cells expressing the indicated FGFRs in Table 3 were treated for 40 min with increasing concentrations of infigratinib. FGFR tyrosine phosphorylation was measured by ELISA assay and the ICso value determined at the infigratinib concentration inhibiting tyrosine phosphorylation by 50% of that measured in vehicle -treated cells. ICso values shown in Table 3 are the average ICso values for several independent experiments. FGFR3^K650E and FGFR3^S249C are two mutated, constitutively activated forms of FGFR3 commonly found in human tumors.

[0274] Infigratinib inhibited tyrosine phosphorylation of FGFR1-3 with ICso values in the single-digit nM range, whereas the activity of infigratinib against FGFR4 was approximately 35- fold lower (Table 3).

Table 3. Activity of Infigratinib Against FGFR1, FGFR2, FGFR3 and FGFR4 in Cell- Based Assays

WT = wild-type.

Number in parentheses represents number of independent experiments conducted.

1.1.2 Binding and Cellular Activity of the Major Human Metabolites Against FGFR1, FGFR2, FGFR3 and FGFR4

[0275] Infigratinib and its major metabolites, the compounds of formulas (II) and (IV), were assessed in binding and cellular assays to determine their activities against FGFR1, FGFR2, FGFR3, and FGFR4 (Table 4 and Table 5).

[0276] Binding Kd for the compounds of formulas (II) and (IV) were determined using the KINOMEscan™ assay system. The compounds of formulas (II) and (IV) exhibited FGFR binding activity comparable to infigratinib (Table 4).

[0277] HEK293 cells expressing the indicated FGFRs in Table 5 were treated for 40 min with increasing concentrations of infigratinib. FGFR tyrosine phosphorylation was measured by ELISA assay and the ICso value determined at the infigratinib or the compound of formula (IV) concentration inhibiting tyrosine phosphorylation by 50% of that measured in vehicle-treated cells. ICso values shown in Table 4 are the average ICso values for several independent experiments. The compound of formula (IV) was less potent than infigratinib in a cell-based assay measuring FGFR tyrosine phosphorylation.

[0278] The compounds of formulas (II) and (IV) showed similar activity to infigratinib for both binding and pharmacologic activity, and similar to infigratinib the metabolites were more potent against FGFR1-3 than FGFR4 (Table 4, Table 5, Table 6, and Table 7). Table 4. In Vitro Binding of Infigratinib and Metabolites to FGFR1, FGFR2, FGFR3 and

FGFR4

Kd values of infigratinib and infigratinib metabolites, the compounds of formulas (II) and (IV), were determined using the KINOMEscanTM assay system. Table 5. Activity of Infigratinib and the compounds of formula (IV) and (II) Against

FGFR1, FGFR2, FGFR3, and FGFR4 in Cell-Based Assays

ND=no data; WT=wild type. ^a Formula (II) was not tested in this assay.

Number in parentheses represents number of independent experiments conducted. Table 6. Potency of infigratinib and metabolites.

Stable cell lines were generated forFGFR l-4 receptor (HEK 293 cell line). In vitro potency was evaluate using pFGFRl-4 ELISA assay. Table 7. Binding kinetics of compounds of formulas II and III and infigratinib against FGFR1, FGFR2, FGFR3, and FGFR4

1.1.3 Cellular Activity of Infigratinib and Human Metabolites Against FGFR3-G380R phosphorylation or ERK1/2 Phosphorylation

[0279] ATDC5 cells stably expressing human FGFR3-IIIc-G380R cDNA were treated for 60 minutes with increasing amounts of infigratinib and its metabolites, followed by FGF2 stimulation for 30 minutes. [0280] For FGFR3-G380R phosphorylation: FGFR tyrosine phosphorylation was measured by

ELISA assay, and the ICso was determined as the drug concentration inhibiting tyrosine phosphorylation to 50% of that measured for vehicle-treated cells. For pERK/ERK: The phosphorylation of ERK1/2 and ERK was measured by ELISA assay, and the ICso was determined as the drug concentration inhibiting tyrosine phosphorylation to 50% of that measured for vehicle-treated cells. Table 8. Cellular Activities of Infigratinib and Metabolites Against FGFR3-G380R or

ERK1/2 Phosphorylation

Abbreviations: ELISA=enzyme-linked immunosorbent assay; ERK=extracellular signal- regulated kinase; FGFR=fibroblast growth factor receptor; ICso=half-maximal inhibitory concentration; p=phosphorylated; Std. Deviation=standard deviation.

Note: IC50 values shown are the average IC50 values for several independent (n) assays ± Std. deviation.

[0281] The in vitro potency of infigratinib and its metabolites has been assessed against 9 different pathogenic FGFR3 variants (N540K, N540S, N540T, K650Q, K650N, K650T, R223C, T264M, S35 IF) associated with HCH and compared to ACH-associated FGFR3 variant, G380R. Stable cells lines were generated for each variant in ATDC5 cells, a mouse chondrogenic cell line. These stable cell lines for each variant were incubated with infigratinib (BGJ398) and its metabolites formula (II), formula (III), and formula (IV) under the serum-free condition, and then stimulated with FGF2. The quantities of p-ERKl/2 and total ERK1/2 in the cell lysates were quantified using ELISA. The mean ICso values of infigratinib and its metabolites against p- ERK were determined by three or more independent experiments for 9 FGFR3 variants for HCH variants and the FGFR3 variant for ACH variant were summarized.

[0282] The in vitro potency of infigratinib and its metabolites against HCH- or ACH-related FGFR3 pathogenic variants is summarized in Table 9.

Table 9. In vitro Potency of Infigratinib and its Metabolites against HCH or ACH FGFR3 Pathogenic Variants (IC50 ± SD [nM])

Formula

Variant Infigratinib Formula (II) Formula (III) (IV)

7.41±1.57 5.08±1.20 251.7±96.7 8.2H1.55

N540K (n=5) (n=3) (n=4) (n=4)

2.64±0.25 4.85±1.93 6.12±2.25 2.66±1

N540S

(n=4) (n=3) (n=4) (n=4)

3.24±0.29 7.95±3.75 14.7±7.3 1.99±0.11

N540T

(n=4) (n=3) (n=5) (n=3)

2.99±0.29 6.02±0.69 49.9±8.4 3.70±0.95

K650Q

(n=4) (n=3) (n=3) (n=3)

1.18±0.30 2.1H0.66 21.8±1.7 3.23±0.92

K650N

(n=4) (n=4) (n=6) (n=4)

1.51±0.34 2.09±0.6 14.5±3.9 1.55±0.43

K650T

(n=4) (n=4) (n=6) (n=4)

1.96±0.87 2.79±0.63 17.4±7.1 2.09±0.49

R223C

(n=4) (n=3) (n=7) (n=4)

2.74±1.6 3.08±1.39 65.1±17 2.21±0.51

T264M

(n=4) (n=3) (n=5) (n=4)

3.41±1.11 4.44±1.25 7.0±1.5 2.22±0.57

S351F

(n=3) (n=4) (n=7) (n=3)

G380R 1.99±0.32 4.15±0.74 16.3±2.87 1.91±0.28

(ACH variant) (n=6) (n=6) (n=6) (n=4)

Abbreviations: ACI I-achondroplasia: HCH=hypochondroplasia; n= number of experiments; SD= standard deviation; IC5o= half maximal inhibitory concentration. Example 4: A Phase 2 Clinical Study of Oral Infigratinib Monophosphate (BGJ398) in

Pediatric Patients with Achondroplasia

Objectives

[0283] Dose Escalation: Primary Objective: identified a dose of oral infigratinib, based on safety and efficacy evaluations, for children with achondroplasia (ACH) to be used for further study.

[0284] Dose Expansion: Primary Objective: provided preliminary evidence of efficacy of oral infigratinib for the treatment of ACH, as assessed by change from baseline in height velocity in children with ACH.

[0285] Pharmacokinetic (PK) Substudy: Primary Objective: evaluated the pharmacokinetic (PK) profile of infigratinib and major active metabolites in children with ACH after administration of oral infigratinib.

[0286] Dose Escalation, Expansion, and PK Substudy:

Secondary Objectives: evaluated the safety and tolerability of oral infigratinib in children with ACH; evaluated changes from baseline in anthropometric parameters after administration of oral infigratinib; and evaluated the pharmacokinetic and pharmacodynamic (PK/PD) profile of infigratinib in children with ACH after administration of oral infigratinib.

Exploratory Objective: Evaluated changes in ACH disease burden and changes in biomarkers of infigratinib activity.

Methodology

[0287] Evaluated the safety, tolerability, and efficacy of infigratinib, a fibroblast growth factor receptor (FGFR) 1-3-selective tyrosine kinase inhibitor, in children 3 to 11 years of age with ACH who had previously been administered infigratinib for at least 6 months. The study included dose escalation with extended treatment, and dose expansion.

[0288] Dose Escalation with Extended Treatment (total of 18 months treatment and follow-up): Eligible subjects 3 to 11 years of age were enrolled in ascending dose cohorts of approximately 10 subjects. The proportion of subjects <8 years and >8 years of age are approximately balanced between cohorts.

5 dose cohorts were investigated. Each cohort commenced after the prior dose has been deemed safe by the Data Review Committee (DRC) based on prespecified criteria (see Cohort Dose Escalation and Cohort Dose De-escalation below). Subjects in each cohort were treated and followed up for 6 months at their assigned dose. After the 6-month study visit, subjects continued treatment for an additional 12 months (extended treatment period). To avoid long-term treatment with a possibly non- or subefficacious dose, subjects in Cohorts 1 and 2 had their dose increased to the next dose level at their 6-month and 12-month study visits, if no safety concerns were identified and their annualized height velocity did not increase at least 25% over baseline (a maximum of 2 dose increases was allowed) (not applicable in the U.S.). Dose increase at 12 months occurred if the dose identified for further study has not been determined by the time the subject reached 12 months of treatment. Subjects in all cohorts may have had their dose adjusted to the dose identified for further study, at the time this dose was determined. The dose identified for further study was selected based on thorough review of efficacy and safety findings from the dose escalation after all subjects had the potential to complete 6 months of infigratinib treatment.

[0289] Dose Expansion (total of 12 months treatment):

To support and confirm the dose/dose regimen identified for further study, 20 subjects were enrolled into the dose expansion and received infigratinib treatment at the identified dose for 12 months.

[0290] PK Substudy

This substudy enrolled approximately 6 children > 8 years old in each of the dose cohorts (Cohorts 2-5 only); the doses of infigratinib (mg/kg/day) administered in each PK dose cohort are the same as the doses used in Cohorts 2, 3, 4, and 5 of the Dose Escalation with Extended Treatment Period. The Cohort 1 dose of the Dose Escalation was not be explored in the PK Substudy.

Enrollment in each PK dose cohort commenced after enrollment of children > 8 years of age in the corresponding dose cohort of Dose Escalation with Extended Treatment Period had been completed.

Subjects followed the same visit schedule and assessments of safety and efficacy as in the Dose Escalation with Extended Treatment Period but are subjected to intense PK sampling at prespecified visits and did not have blood samples collected for evaluation of bone biomarkers. Subjects in each PK dose cohort were treated and followed for up to 6 months at their assigned dose. After the 6-month study visit, subjects continued treatment for an additional 12 months. Subjects in PK Cohort 2 may have had their dose increased to the next dose level at their 6- month and 12-month study visits, if no safety concerns were identified and their annualized height velocity did not increase at least 25% over baseline (a maximum of 2 dose increases is allowed). Subjects may also have had their dose adjusted to the dose identified for further study, at the time this dose is determined based on the data from the Dose Escalation (as described above).

[0291] All Subjects:

After completing study activities, all subjects may have had the opportunity to enroll in an openlabel long-term extension study (administered under a separate protocol) to assess the safety and efficacy of long-term administration of infigratinib in children with ACH.

Starting Dose and Determination of Other Cohort Doses

[0292] Starting Dose (Cohort 1):

The starting dose in this study was based on the no observed adverse effect level (NOAEL) from a rat juvenile toxicity study with a 10-fold safety margin.

[0293] Other Dose Cohorts:

Ascending dose cohorts initiated after safety of the prior cohort was confirmed by a Data Review Committee (DRC). Each successive dose is double the previous dose.

Enrollment of additional dose cohorts or expansion of an existing cohort is determined based on ongoing analyses of the data by the DRC and Sponsor.

[0294] Maximum Dose Cohort

The maximum dose cohort was determined based on ongoing analyses of safety and efficacy data. De-escalation of a dose cohort may have been done for safety reasons based on prespecified criteria (see Cohort Dose Escalation and Cohort Dose De-escalation below).

If no safety concern was identified, the enrollment of new dose cohorts may have continued until the median annualized height velocity (based on a 6-month period) was > 8 cm/year (based on a 6-month assessment period) for the maximum dose cohort. This height velocity corresponds to the average of the 97^th percentile height velocity in children without ACH, across the ages included in this study.

Number of Subjects

[0295] A total of approximately 87 subjects were enrolled: approximately 54 subjects in Dose Escalation with Extended Treatment, approximately 18 subjects in the PK Substudy, and approximately 15 subjects in Dose Expansion. Diagnosis and Main Criteria for Inclusion

[0296] Inclusion Criteria:

1. Signed informed consent by subject or parent(s) or legally authorized representative (LAR) and signed informed assent by the subject (when applicable).

2. 3 to 11 years of age (inclusive) at screening. The PK Substudy only enrolls subjects > 8 years old.

3. Diagnosis of ACH, documented clinically and confirmed by genetic testing.

4. At least a 6-month period of growth assessment in the PROPEL study (Protocol QBGJ398- 001) before study entry.

5. Ambulatory and able to stand without assistance.

6. If a girl >10 years of age, negative pregnancy test.

7. If sexually active, willing to use a highly effective method of contraception while taking study drug and for 3 months after the last dose of study drug.

8. Subjects and parent(s) or LAR are willing and able to comply with study visits and study procedures.

9. Able to swallow oral medication.

10. Willing to stop consumption of grapefruit, grapefruit juice, grapefruit hybrids, pomegranates, star fruits, pomelos, Seville oranges, or products containing juice of these fruits; and have not consumed these within 7 days before the first dose of study drug.

[0297] Exclusion Criteria:

1. Hypochondroplasia or short stature condition other than ACH (e.g., trisomy 21, pseudoachondroplasia, psychosocial short stature).

2. In females, having had their menarche.

3. Height < -2 or > +2 standard deviations for age and sex based on reference tables on growth in children with ACH (Horton 1978).

4. Annualized height velocity <1.5 cm/year over a period >6 months prior to screening.

5. Significant concurrent disease or condition that, in the view of the Investigator and/or Sponsor, would confound assessment of efficacy or safety of infigratinib, including but not limited to the following: cardiac or vascular disease; hyperthyroidism; abnormal thyroid levels or recently diagnosed hypothyroidism that has not been stable on therapy for at least 3 months; insulin-requiring diabetes mellitus; adrenal insufficiency; autoimmune inflammatory disease; autoimmune inflammatory disease; inflammatory bowel disease; presence of a functioning ventriculoperitoneal shunt; or diagnosis of severe sleep apnea (pre-existing or done at screening based on the sleep study) requiring surgery or continuous positive airway pressure (CPAP) machine.

6. Significant abnormality in screening laboratory results, including but not limited to the following: hemoglobin <10.0 g/dL; total bilirubin >1.5x upper limit of normal (ULN); AST/SGOT or ALT/SGPT >2x ULN; or calculated or measured creatinine clearance of <60 mL/min.

7. Current evidence of comeal or retinal disorder/keratopathy including, but not limited to, bullous/band keratopathy, comeal abrasion, inflammation/ulceration, or keratoconjunctivitis, confirmed by ophthalmic examination.

8. History and/or current evidence of extensive ectopic tissue calcification.

9. History of malignancy.

10. Currently receiving treatment with agents that are known strong inducers or inhibitors of CYP3A4 and medications which increase semm phosphorus and/or calcium concentration. Subjects are not permitted to receive vitamin D analogues for the treatment of vitamin D deficiency or to initiate multivitamin supplementation containing any form of vitamin D (Over- the-counter [OTC] multivitamin supplements containing vitamin D that were initiated > 3 months before screening are allowed at the same dose). Subjects receiving medications that alter the pH of the gastrointestinal tract, including antacids, H2 antagonists (e.g., ranitidine), and proton-pump inhibitors (e.g., omeprazole); or enzyme -inducing anti-epileptic drugs, including carbamazepine, phenytoin, phenobarbital, and primidone are excluded.

11. Current evidence of endocrine alterations of calcium/phosphorus homeostasis: a. Inorganic phosphorus outside of normal limits. b. Total serum calcium (corrected) outside of normal limits.

12. Allergy to any components of the study drug.

13. Treatment with growth hormone, insulin-like growth factor 1 (IGF-1), or anabolic steroids in the previous 6 months or long-term treatment (> 3 months) at any time.

14. Treatment with a C-type natriuretic peptide (CNP) analog, fibroblast growth factor (FGF) ligand trap, or treatment targeting FGFR inhibition at any time.

15. Regular long-term treatment (> 3 weeks) with supraphysiologic doses of glucocorticoid therapy (i.e., >15mg/m2/day of hydrocortisone or equivalence) or treatment with glucocorticoids at anti-inflammatory doses for over 3 weeks within 6 months of the screening visit (low -dose ongoing inhaled steroid for asthma is acceptable).

16. Treatment with any other investigational product or investigational medical device for the treatment of ACH or short stature.

17. Previous limb-lengthening surgery or guided growth surgery.

18. Fracture within 6 months of screening (due to potential effects on bone biomarkers and bone morphology).

Test Product, Dose and Mode of Administration

[0298] Five dose cohorts are used:

Cohort 1: 0.016 mg/kg

Cohort 2: 0.032 mg/kg

Cohort 3: 0.064 mg/kg

Cohort 4: 0.128 mg/kg

Cohort 5: 0.250 mg/kg

[0299] Infigratinib was provided for oral dosing with a starting dose (Cohort 1) of 0.016 mg/kg QD, which corresponds to one-tenth of the nonclinical NOAEL.

Endpoints

[0300] Dose Escalation: Primary Endpoint

Treatment-emergent adverse events (TEAEs) that lead to dose decrease or discontinuation. Change from baseline in height velocity (annualized to cm/year). (Baseline is defined as the annualized height velocity obtained from a minimum of 6 months of observation in the PROPEL study.)

[0301] Dose Expansion: Primary Endpoint

Change from baseline in height velocity (annualized to cm/year).

[0302] PK Substudy: Primary Endpoint

PK parameters of infigratinib and major active metabolites (e.g., Cmax, Clast, Tmax, AUC24, T1/2, AUCinf, CL/F, Vz/F, and Race) .

[0303] Dose Escalation, Dose Expansion and PK Substudy: Secondary Endpoints

Safety evaluations by incidence, type, severity, and causality of adverse events (Aes), serious adverse events (SAEs), laboratory test results (urinalysis, chemistry, hematology), clinically significant changes in vital signs, physical examination (including ophthalmic and dental evaluation), electrocardiograms, and imaging.

Absolute height velocity (annualized to cm/year), expressed numerically and as Z-score in relation to non-ACH tables.

Absolute (expressed as absolute value and Z-score in relation to ACH and non-ACH standardized pediatric growth curves) and change from baseline in anthropometric parameters, including body proportions. Anthropometric measurements may have included, but may not have been limited to, standing height, sitting height, weight, head circumference, upper and lower arm length, thigh length, knee height, and arm span. Body proportion measurement ratios may have included, but may not have been limited to, upper to lower body segment ratio, upper arm to forearm length ratio, upper leg to lower leg length ratio, arm span to standing height ratio, and head circumference to standing height ratio.

PK parameters (e.g., C max and tmax)

Changes in PD parameters (biomarkers of bone turnover that may include type X collagen degradation fragment, collagen X marker [CXM]) (not applicable for the PK Substudy).

[0304] Dose Escalation and Dose Expansion: Exploratory Endpoint

Changes in disease-specific complications, such as changes in mobility (assessed by elbow, hip, and knee range of motion), changes in the number of episodes of otitis media per year, changes in number of episodes and/or severity of sleep apnea, and changes in quality of life [QoL] as assessed by PedsQL (generic core scale short form, child and parent reports).

• Baseline for range of motion and PedsQL corresponded to the values obtained at the baseline visit.

• Baseline for the number of episodes of otitis media will be the number of episodes recorded during the PROPEL study [expressed as episodes/year] .

• Baseline for sleep apnea, corresponded to the polysomnogram performed at screening [to rule out severe sleep apnea] .

Phosphorylation change in extracellular signal-regulated kinases 1 and 2 (ERK1/2), signal transducers and activators of transcription (STATs) in blood cells. Data Review Committee (PRC): Cohort Dose Escalation: Cohort Dose De-escalation; Dose Decrease/ Discontinuation for an Individual Subject

[0305] Data Review Commitee (PRC)

This study utilized a DRC that monitored subject safety and key efficacy data and provided recommendations to the Sponsor regarding dose escalation, de-escalation, and/or expansion of dose cohorts.

Cohort dose escalation and de-escalation was decided by the DRC based on the Bayesian optimal interval (BOIN) design (Liu and Yuan, Bayesian optimal interval designs for phase I clinical trials, J. R. Stat. Soc. Ser. C Appl. Stat., 2015, 64, 507-523) with a target toxicity rate of 25%.

[0306] Cohort Dose Escalation

Each cohort commenced after safety (ECG, vital signs, physical exams, TEAE assessment and clinical labs) of the prior dose cohort was reviewed and confirmed by the DRC. During dose escalation, the opening of a new ascending dose cohort was decided by the DRC based on review of safety data from approximately 10 subjects in each cohort after they completed at least 4 weeks of treatment and safety assessments. If after at least 4 weeks of treatment, <1/10 subjects met a dose decrease/discontinuation criterion (see below: Dose Decrease/Discontinuation for an Individual Subject), and no other safety concern was identified by the DRC, the next dose cohort opens.

[0307] Cohort Dose De-escalation

The need for a cohort dose de-escalation was determined by the DRC based on the safety assessment and incidence of TEAEs that leads to dose decrease/discontinuation for an individual subject (see below). At any point and after 3 subjects received treatment in a cohort, if > 30% of subjects in the cohort met the dose decrease/discontinuation criteria, then enrollment in that and/or any higher dose cohort (if applicable) was paused and the DRC was convened. The DRC determined if the dose of the current or higher cohort was to be de-escalated (i.e., subjects in current cohort continue treatment at the next lower dose for efficacy assessment) or if treatment could continue at the same dose and/or if a cohort expansion was needed to continue evaluating the safety of that dose level. [0308] Dose Decrease/Discontinuation for an Individual Subject

Although the DRC monitored subject safety and considered the number of subjects meeting the dose decrease/discontinuation criteria to determine whether a cohort dose escalation could proceed or if a dose de-escalation was needed at the cohort level, dose modifications in an individual subject were managed by the Investigator.

The following was considered an AE that required dose reduction/discontinuation in an individual subject:

1. Phosphorus level > 4.5 mg/dL (or age-adjusted upper level of normal for reporting laboratory), confirmed by a repeat value.

2. Calcium level > 10.7 mg/dL (or age-adjusted upper level of normal for reporting laboratory), confirmed by a repeat value.

3. Grade 2 or higher related (as assessed by the Investigator) treatment-emergent AE.

4. Grade 1 or higher comeal toxicity.

Subjects who experienced at least one of the above-described Aes had their dose modified as described below:

• Suspended dose in individual subject until o Phosphorus and/or calcium levels return to normal values; or o Grade > 2 treatment-related Aes decrease in severity to below Grade 2 o Abnormal ocular findings resolve

• Reinitiated dosing at the next lower dose level

• If the AE that led to dose suspension did not resolve within 4 weeks with adequate supportive care, the subject was discontinued.

[0309] PK Substudy

Cohort dose escalation was decided by the DRC based on data from at least 4 weeks of treatment and safety assessments of the subjects enrolled in the Dose Escalation portion of the study. Any available safety data from children enrolled in the corresponding PK Dose Cohort was provided to the DRC for their review, but dose escalation could proceed even if all subjects in the PK Dose Cohort had not enrolled or subjects enrolled had not completed the one-month assessment. Children enrolled in the PK Substudy were subjected to the dose decrease/discontinuation criteria defined in the study and were accounted for in the cohort dose de-escalation criteria, meaning that if at any point in the study, > 30% of all the children enrolled at a particular dose cohort (Dose Escalation with Extended Treatment Period and PK Substudy) met dose decrease/discontinuation criteria, cohort de-escalation criteria still applied.

Subject Discontinuation/ Withdrawal from the Study or Study Drug

[0310] Early withdrawal from the study or study drug may have occurred for any of the following reasons:

• Subject (or parent/LAR) request, or withdrawal of consent.

• Aes that led to dose suspension did not resolve within 4 weeks with adequate supportive care.

• The Investigator considered that was in the subject’s best interest to discontinue from the study drug or study, including but not limited to worsening of disproportionate growth, development of or worsening of tibial bowing, occurrence of infigratinib-related fracture of bone and growth plate, and worsening of elbow joint range of motion.

• Subject reached final height or near final height as defined by Tanner stage of puberty > 4 and growth velocity < 1.5 cm/year (Marshall and Tanner, Variations in pattern of pubertal changes in girls, Arch. Dis. Child, 1969, 44(235), 291-303; Marshall and Tanner, Variations in pattern of pubertal changes in girls, Arch. Dis. Child, 1970, 45(239), 13-23).

• Subject had a height velocity of < 1.5 cm/year over at least a 6-month period.

• Subject developed a clinically significant condition that may have confounded the assessment of efficacy or safety or required the treatment with a prohibited medication such as vitamin D analogues; medications that alter the pH of the gastrointestinal tract, including antacids, H2 antagonists (e.g., ranitidine), and proton-pump inhibitors (e.g., omeprazole); or enzyme-inducing anti-epileptic drugs, including carbamazepine, phenytoin, phenobarbital, and primidone.

• Female subject became pregnant.

• Protocol deviation (at the Sponsor’s discretion).

• Study termination by the Sponsor.

• Lost to follow up. Statistical Methods

[0311] Sample Size

Dose escalation and de-escalation rules were based on the BOIN design with a target toxicity rate of 25%. Selection of the interval boundaries was based on a maximum toxicity of 15% for a subtherapeutic dose and a minimum toxicity of 35% for an overly toxic dose. In addition, if there was a > 95% chance that the rate of TEAEs that lead to dose decrease or discontinuation was > 25% based on observed data, then the current dose cohort was eliminated from the trial; if the first dose level was eliminated, the trial may have been terminated or a lower dose may have been evaluated according to DRC recommendation.

The selection of the dose for dose expansion was based on the assessment of approximately 10 subjects per cohort. If a true AE incidence was 25%, 10 subjects per cohort allowed observation of at least one AE with 94.4% confidence. With 10 subjects per cohort, there was also a 62.5% chance of obtaining a 95% confidence interval (CI) for height velocity with a half- width that is at most 1.5 cm/year, assuming the change from baseline of height velocity followed a normal distribution and the standard deviation was 2 cm/year.

In dose expansion, approximately 20 subjects were enrolled at the selected dose level. An annualized height velocity increase of < 0.5 cm/year was considered not clinically relevant and was used as the null hypothesis. Assuming an increase in height velocity of 2 cm/year after initiation of infigratinib treatment, with a standard deviation of 2 cm/year, 20 subjects provided approximately 88.9% power to demonstrate that treatment with infigratinib could increase the height velocity > 0.5 cm/year at a one-sided significance level of 0.025.

[0312] Dose Escalation

For dose escalation, all analyses were performed separately for each dosing cohort based on the originally received dose and in total. Ongoing analyses were performed to support DRC reviews. The selection of the dose to explore in dose expansion was based on thorough review of safety and efficacy data after all subjects had the potential to complete 6 months of infigratinib treatment.

[0313] Dose Expansion

Subjects enrolled in dose expansion were analyzed for both safety and efficacy. These data were used to make inferences about change from baseline in height velocity. Ongoing analyses may have been performed, and the final analysis for dose expansion occurred after all subjects had the opportunity to complete 12 months of treatment in dose expansion. [0314] PK Substudv

In the PK Substudy, the objective was to characterize the single and multiple doses PK of infigratinib and its major active metabolites (e.g., the compounds of formulas (II), (III), and (IV)). Data was collected for approximately 6 subjects per dose cohort in the PK Substudy at various timepoints from predose to 24 hours postdose. For these subjects, PK parameters may have been determined from PK profdes after the first dose on Day 1 and Day 21 after repeated daily dosing using non-compartmental method(s).

[0315] Statistical Analyses

All safety analyses were performed using the safety analysis set, defined as subjects who received at least one dose of study drug. Analyses on growth parameter endpoints were performed for subjects who had a baseline and at least one post-baseline growth parameter assessment.

Baseline and demographic variables were summarized. Safety summaries present Aes recorded through the last dose date +30 days. All TEAEs were summarized and listed. TEAEs that lead to dose decrease or discontinuation were summarized. Laboratory measures, changes to diseasespecific complications, and surgical procedures were summarized.

For subjects enrolled in dose escalation, the change from baseline on annualized height velocity, in addition to weight, height, head circumference, and body proportions at baseline and postbaseline; and changes in these parameters, were summarized based on the first 6-month assessments. For assessments done after 6 months, the summaries were provided in 6-month intervals by the originally received dose.

For subjects enrolled in dose expansion, the change from baseline on annualized height velocity were tested using one-sample t-test to assess whether the increase was > 0.5 cm/year.

Descriptive statistics, including 95% confidence intervals, were also provided for height velocity parameters, in addition to weight, height, head circumference, and body proportions at baseline and post-baseline; and changes in these parameters from baseline.

Descriptive statistics were also provided to explore the association between biomarkers and height velocity. Assessments of disease-specific complications were summarized by visit. For PK data, descriptive statistics (mean, SD, CV% GeoMean, or median [range]) were presented for all PK parameters for each dose cohort. Assessment of dose-proportionality and steady-state attainment was conducted when appropriate. AUC of metabolite to parent ratio may have been assessed, when feasible. Descriptive graphical plots of individual plasma concentration along with its time course were generated. Exploratory analysis of the relationship between PK and PD may have been conducted. The plasma samples from all patients was assayed for infigratinib and its major active metabolites using a validated bioanalytical LC- MS/MS assay.

All concentrations below the lower limit of quantification (LLOQ) or missing data were labeled as such in the concentration data listings. Concentrations below the LLOQ were treated as zero in summary statistics.

Pharmacokiniteic Results

[0316] Exposure of infigratinib and its active metabolites, the compounds of formulas (II), (III), and (IV) was evaluated at dose levels of 0.016 to 0.25 mg/kg in children of 3 to 11 years with achondroplasia in the dose escalation phase of this study via intense and sparse PK sampling.

Lor children participating in the PK substudy, intense PK samples evaluating plasma concentrations of infigratinib and its active metabolites (BQR917, and the compounds of formulas (II), (III), and (IV)), were collected at predose and at 1, 2, 4, 6, 8, and 24 hours postdose on Days 1 and 21. Sparse PK samples were also collected predose at the 3 month, 6 month, 12 month, and 18 month or EOT visit. In addition, sparse PK samples were collected from all children in the Dose Escalation phase of the study; at predose and 4 (-2) and 24 hours postdose on Days 1 and 21, and predose at the 3 month, 6 month, 12 month, and 18 month or EOT visit.

[0317] As of the cutoff for PK data in May 2023, intense PK data were available from 18 children (6 in PK Cohort 2, 4 in PK Cohort 3, 4 in PK Cohort 4, and 4 in PK Cohort 5). Mean PK parameters for infigratinib and active metabolites of interest on Day 1 and Day 21 are presented in Table 10.

[0318] The median Tmax was 2-3 hours for infigratinib, 3-8 hours for the compound of formula (II) and the compound of formula (III), and 2-5 hours for the compound of formula (IV). Exposure of infigratinib and its active metabolites increased with increasing dose. Exposure of metabolites the compound of formula (II) and the compound of formula (III) was higher than infigratinib with mean metabolite to parent ratio about 10 and variable among the children. Exposure of metabolite the compound of formula (IV) was lower than infigratinib. Since the number of children with intense PK data is small, the variability was high. Preliminary dose proportionality assessment using the power model showed that infigratinib and its active metabolites, the compounds of formulas (II), (III), and (IV) appeared to be dose-proportional from 0.016 to 0.25 mg/kg QD. Based on potency adjusted unbound steady-state AUC, compound of formula (II) is estimated to contribute to a majority of the overall pharmacologic activity, infigratinib, compound of formula (III) and compound of formula (IV) are estimated to contribute to the rest of overall activity.

[0319] FIGS. 1A-1D show the intense and sparse mean concentrations in plasma of (i) infigratinib (BGJ398), (ii) the compound of formula (IV), (iii) the compound of formula (II), and (iv) the compound of formula (III) in subjects enrolled in cohort 4 (i.e., 0.128 mg/kg) on days 1 and 21 of treatment. [0320] FIGS. 2A-2D show the intense and sparse mean concentrations in plasma of (i) infigratinib (BGJ398), (ii) the compound of formula (IV), (iii) the compound of formula (II), and (iv) the compound of formula (III) in subjects enrolled in cohort 5 (i.e., 0.250 mg/kg) on days 1 and 21 of treatment.

[0321] FIGS. 3A-3D show the intense and sparse mean concentrations in plasma of (i) infigratinib (BGJ398), (ii) the compound of formula (IV), (iii) the compound of formula (II), and (iv) the compound of formula (III) in subjects enrolled in cohort 5 (i.e., 0.064 mg/kg) on days 1 and 21 of treatment.

Table 10. Preliminary Pharmacokinetic Parameters for Infigratinib and the compounds of formulas (II), (III), and (IV) following Once Daily Oral Infigratinib Administration

(Cohorts 2, 3, 4, and 5)

Abbreviations: AUCiast=area under the concentration-time curve from time 0 to the last observed concentration; Cmax=maximum concentration; CV=coefficient of variation; max=maximum; min=minimum; Tmax=time to maximum concentration. ^a median (min-max). ^b Mean (%CV).

Example 5: A Phase 3 Clinical Study of Oral Infigratinib Monophosphate (BGJ398) in Pediatric Patients with Achondroplasia

Objectives and Endpoints

Primary

[0322] Objective: evaluate the efficacy of infigratinib in pediatric subjects with achondroplasia (ACH) in patients 3 to <18 years of age who have potential to grow. Endpoint: change from baseline (BL) at week 52 in annualized height velocity (AHV) compared to placebo.

Secondary

[0323] Objective: evaluate changes in other key indicators of growth and body proportions. Endpoints: change from BL to week 52 in height Z-score (in relation to ACH tables) compared to placebo. Change from BL to week 52 in upper to lower body segment ratio, compared to placebo.

Other Secondary

[0324] Objective: evaluate changes in other parameters of growth and body proportions. Endpoints: change from BL to week 52 in height Z-score in relation to non-ACH tables. AHV at week 52 compared to placebo. Change from BL to week 52 in other body proportions, including upper arm to forearm length ratio, upper leg to lower leg length ratio, arm span to standing height ratio, and head circumference to standing height ratio, compared to placebo. Absolute value and change from BL to week 52 in body mass index (BMI), compared to placebo.

[0325] Objective: evaluate the safety and tolerability of infigratinib in children with ACH. Endpoints: incidence, type, severity, and causality of adverse events (Aes), Aes that require dose decrease or discontinuation according to study protocol, serious adverse events (SAEs), abnormal laboratory test results (including hyperphosphatemia), clinically significant changes in vital signs, physical examinations, ophthalmic and dental evaluations, and imaging (x rays, dual x-ray absorptiometry (DXA) scan).

[0326] Objective: evaluate the efficacy of infigratinib in children with ACH who are >5 years of age. Endpoint: change from BL to week 52 in AHV in children >5 years of age, compared to placebo.

[0327] Objective: evaluate the impact of infigratinib on changes in height and body proportion. Endpoint: change from BL to week 52 in the Physical Functioning scale of the pediatric quality of life (PedsQL) child report compared to placebo.

[0328] Objective: evaluate changes in cognitive functions. Endpoint: change from BL to week 52 in cognitive functions as assessed by computerized tests, compared to placebo.

[0329] Objective: evaluate the pharmacokinietic (PK) profile of infigratinib and its active metabolites in children with ACH after administration of oral infigratinib. Endpoint: plasma concentrations and PK parameters of infigratinib and its active metabolites.

[0330] Objective: evaluate pharmacodynamic (PD) indicators of bone growth. Endpoint: change from BL to week 52 in collagen X marker (CXM) compared to placebo.

[0331] Objective: evaluate the acceptability and palatability of infigratinib. Endpoint: taste assessment using a 5-point hedonic scale.

Exploratory

[0332] Objective: evaluate changes in ACH disease-specific complications. Endpoints: changes from BL to week 52, compared to placebo, in disease-specific complications including: (1) number of episodes of otitis media per year; (2) number of episodes and/or severity of sleep apnea; (3) range of motion (elbow); (4) body composition as assessed by DXA scans; and (5) change in bone morphology/quality by x-ray and DXA, compared to placebo.

[0333] Objective: evaluate changes in health related quality of life (HRQoL), overall body pain, and functional abilities (except physical domain of the PedsQL). Endpoints: changes from BL to week 52, compared to placebo, in (1) Emotional, Social, and School Functioning scales of the PedsQL (child and parent reports); (2) Physical and Psychosocial Health Summary scores and Total score of the PedsQL (child and parent reports); (3) Physical Functioning scale of the PedsQL (parent report); (4) Physical, Social, and Emotional scales and Total score of the Quality of Life in Short Stature Youth questionnaire (QoLISSY)-Core (child and parent reports); (5) Self-care, Mobility, Cognition and Total scores of the Functional Independence Measure for Children (WeeFIM); (6) overall pain as assessed by Numeric Rating Scale for pain (Pain-NRS), child and parent reports; and (7) severity of the physical functioning challenges as assessed by Patient/Parent Global Impression of Severity (PGI-S) and Patient/Parent Global Impression of Change (PGI-C).

[0334] Objective: evaluate treatment benefit as assessed by a qualitative interview of the subject and caregiver. Endpoints: subject and caregiver evaluation of treatment benefit as assessed by a qualitative interview.

Overall Design

[0335] This is a Phase 3, multicenter, double-blind, randomized, placebo-controlled study to evaluate the efficacy and safety of infigratinib in children with ACH who have completed at least 26 weeks (ie, 6 months) of participation in the PROPEL study (Protocol QBGJ398-001). After completing screening activities and if deemed eligible, a total of approximately 110 subjects who are 3 to <18 years of age are enrolled and randomly assigned in a 2: 1 ratio to receive either infigratinib or placebo for a period of 52 weeks.

[0336] Randomization in both treatment arms is stratified by age and pubertal development as follows:

• with <20% of subjects >3 to <5 years of age;

• and <20% of subjects (approximately 50% male/female distribution) who have initiated their pubertal development (Tanner stage >2);

• and no more than 5% of pediatric subjects with Tanner stage 4.

[0337] Subjects receive treatment with daily doses of oral infigratinib (sprinkle capsules) at 0.25 mg/kg/day, or placebo. Study treatment is suspended or decreased to a lower dose level of 0.128 mg/kg/day (or placebo) if a criterion for dose decrease or discontinuation is met.

[0338] After completing the study (ie, completing the EOT Visit), eligible subjects have the option to receive treatment with infigratinib until they reach final height/near final height in a separate study, PROPEL OLE (QBGJ398-203). Subjects who do not to continue in the PROPEL OLE study have a safety follow-up visit 1 month after the last dose of the study drug (infigratinib or placebo).

[0339] This study utilizes a Data Monitoring Committee (DMC) that monitors subjects’ safety. [0340] This study design includes assessor, investigator, parent/legal guardian/caregiver, and subject blinding. Health Measurement/Observation

[0341] Anthropometric measurements are assessed and used to calculate AHV (primary endpoint) and other growth parameters, including body proportions. Other measurements include range of motion (elbow), radiographic imaging, cognitive, and quality of life assessments. Blood samples are collected for PK, PD, and safety assessments (including hyperphosphatemia). Additional safety assessments include monitoring of Aes, ECGs, vital signs, and abbreviated physical examinations, weight measurements, ophthalmic examinations, and dental examinations. Palatability of study treatment is also assessed via a hedonic scale.

Visit Frequency

[0342] Approximately 5 visits during the first month of treatment followed by monthly visits through Month 3 and visits every 3 months through the remainder of the treatment period.

Number of Subjects

[0343] Approximately 110 subjects are enrolled and randomized.

[0344] Note: “Enrolled” refer herein to subjects who agreed and/or whose legal guardian agreed to his/her participation in a clinical study following completion of the informed consent process and has completed the screening process and has been deemed eligible by the investigator, and whose enrollment in the study has been approved by the medical monitor. Potential subjects who are screened for the purpose of determining eligibility for the study, but do not participate in the study (ie, screen failure), are not considered enrolled. A subject is considered enrolled if the informed consent is not withdrawn prior to participating in any study activity after screening.

Diagnosis and Main Criteria for Inclusion

Inclusion Criteria

[0345] Age: subject must be 3 to <18 years of age at screening with growth potential defined as AHV of >1.5 cm/year over a period of at least 6 months, pubertal Tanner stage <4, and bone age <13 years in females and <15 years in males.

[0346] Type of Subject and Disease Characteristics: (1) subjects who have a diagnosis of ACH that has been documented clinically and confirmed by genetic testing; (2) subjects must have completed at least 26 weeks in the PROPEL study (Protocol QBGJ398-001) before study entry; (3) subjects are able to swallow oral medication; (4) subjects and parent(s), legal guardian(s), or caregivers are willing and able to comply with study visits and study procedures; and (5) subjects are ambulatory and able to stand without assistance.

[0347] Sex and Contraceptive/Barrier Requirements: (1) negative pregnancy test in girls >10 years of age or girls of any age who have experienced menarche; and (2) if sexually active, subjects must be willing to use a highly effective method of contraception while taking study drug and for 3 months after the last dose of study drug.

[0348] Informed Consent: signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol, must be obtained for each subject from their parent(s) or legal guardian and signed informed consent/assent must be obtained from the subject (when applicable) before any study-specific activity is performed.

Exclusion Criteria

[0349] Subjects are excluded from the study if any of the following criteria apply:

[0350] Medical Conditions: (1) subjects who have hypochondroplasia or short stature condition other than ACH; (2) significant concurrent disease or condition that, in the view of the investigator and/or sponsor, would confound assessment of efficacy or safety of infigratinib, including but not limited to: (a) clinically significant cardiac or vascular disease, (b) significant electrocardiogram (ECG) abnormalities (in at least 2 of the triplicates, based on the central cardiology review) such as (but not limited to) evidence of a previous myocardial infarction, left ventricular hypertrophy, flat T waves (particularly in the inferior leads) or more than minor nonspecific ST-T wave changes, QRS >99 msec, PR interval >200 msec; qt interval corrected for heart rate using Fridericia’s formula (QTcF) >450 msec; or complete right or left bundle branch block, (c) hyperthyroidism, (d) thyroid hormones outside of normal range or recently diagnosed hypothyroidism that has not been stable on therapy for at least 3 months, I uncontrolled hemoglobin (HbAlc) (>9%) or insulin-requiring diabetes mellitus, (f) adrenal insufficiency, (g) autoimmune inflammatory disease, (h) inflammatory bowel disease, (i) presence of a functioning ventriculoperitoneal shunt, (j) conditions likely to require in-patient surgical intervention during the study, and (k) diagnosis of severe sleep apnea done at screening (apnea-hypopnea index (AHI) of >10). Children with pre-existing severe sleep apnea using continuous positive airway pressure (CPAP) for >6 months before screening, and who are stable and compliant to treatment can enroll. Compliance to treatment is defined as the use of the CPAP for >70% of the nights and for >5 hours per night for a period of at least 3 months prior to screening and must be confirmed by a pulmonologist. Adequate treatment is defined by the presence of residual obstructive sleep apnea (OSA) classified as mild (AHI of <5) confirmed at screening; (3) current evidence of clinically significant comeal or retinal disorder/keratopathy including, but not limited to, bullous/band keratopathy, comeal abrasion, inflammation/ulceration, or keratoconjunctivitis, confirmed by ophthalmic examination; (4) concurrent circumstance, disease or condition that, in the view of the investigator and/or sponsor, would interfere with study participation or safety evaluations and/or would require treatment with a prohibited medication, and/or would place the subject at high risk for poor treatment compliance or for not completing the study; (5) history and/or current evidence of extensive ectopic tissue calcification; and (6) history of malignancy.

[0351] Prior/Concomitant Therapy: (1) having received or planning to receive treatment with any other investigational or approved product for the treatment of ACH or short stature, including, but not limited to, recombinant human growth hormone (r-hGH), C-type natriuretic peptide (CNP) analog, fibroblast growth factor (FGF) ligand trap, or treatment targeting fibroblast growth factor receptor (FGFR) inhibition at any time. Children that received any of these drugs for <30 days and with the last dose >6 months prior to the start of the screening are eligible; (2) regular long-term treatment (>3 weeks) with supraphysiologic doses of glucocorticoid therapy (i.e., >15 mg/m2/day of hydrocortisone or equivalence) or treatment with glucocorticoids at anti-inflammatory doses for over 3 weeks within 6 months of the screening visit (low-dose ongoing inhaled steroid for asthma is acceptable); (3) previous limb-lengthening surgery at any time or planned/expected to have limb-lengthening surgery or guided growth surgery during the study period. Guided growth surgery with plates removed at least 12 months prior to screening is allowed if completely healed without sequelae based on investigator judgment; (4) currently receiving treatment with agents that are known strong inducers or inhibitors of CYP3A4 or prolonged treatment (>1 week) with medications that alter the pH of the gastrointestinal tract, including antacids, H2 antagonists (eg, ranitidine, famotidine), and proton-pump inhibitors (eg, omeprazole); or antiepileptic drugs that are CYP3A4 and/or P-gp inducers, including carbamazepine, phenytoin, phenobarbital, and primidone; and (5) current evidence of endocrine alterations of calcium/phosphorus homeostasis. Subjects receiving vitamin D analogues or calcidiol supplementation are not allowed to participate. Subjects receiving vitamin D (cholecalciferol) at recommended daily low doses for supplementation (ie, 400-800 lU/day) that was initiated >30 days before screening are allowed.

[0352] Diagnostic assessments: subjects who have significant abnormality in screening laboratory results, including but not limited to the following: (a) hemoglobin <10.0 g/dL, (b) total bilirubin >1.5 x upper limit of normal (ULN), (c) aspartate aminotransferase/serum glutamic-oxaloacetic transaminase (AST/SGOT) or alanine aminotransferase/serum glutamic- pyruvic transaminase (ALT/SGPT) >2x ULN, and (d) glomerular filtration rate <80 mL/min/1.73m2 (or calculated creatinine clearance of <88 mL/min).

[0353] Other Exclusions: (1) having had a fracture of the long bones (ie, extremities) or spine within 12 months prior to screening; (2) pregnant or breastfeeding at the screening visit or planning to become pregnant (self or partner) at any time during the study; and (3) allergy or hypersensitivity to any components of the study drug.

Treatment Groups and Duration

[0354] Subjects are enrolled and randomly assigned in a 2: 1 randomization ratio to receive either infigratinib or placebo for a period of 52 weeks. After completing the end of treatment (EOT) Visit at Week 52 (Month 12), eligible subjects are offered the option to receive treatment with infigratinib until they reach final height/near final height in a separate study, PROPEL OLE (QBGJ398-203). Subjects who do not to continue in the PROPEL OLE study have a safety follow-up visit 1 month after last dose of study drug (infigratinib or placebo).

Statistical Methods

[0355] Sample Size: approximately 110 subjects are enrolled and randomized in a 2: 1 ratio (infigratinib vs. placebo) in this study. A sample of 93 evaluable subjects provide approximately 90% power to detect a difference of 1.3 cm/year between infigratinib group and the placebo group in change from BL in AHV at 52 weeks with a pooled standard deviation (SD) of 1.8, using a 2 sided 2-sample t-test at a 0.05 significant level. Assuming a 15% screen failure rate and a 9% random premature discontinuation rate, the sample size for this study is planned to be approximately 110 subjects.

[0356] Efficacy Analyses: the primary endpoint is the change from BL to Week 52 in the AHV. The primary analysis compares subjects administered infigratinib versus those administered placebo in full set analysis (FAS), defined as all subjects who are randomized and receive at least 1 dose of study drug and analyzed according to the treatment to which subjects are randomized.

[0357] The change from BL in AHV between infigratinib and placebo groups at week 52 is analyzed using an analysis of covariance (ANCOVA), with fixed-effect terms including treatment group, sex and Tanner stage, and age and the BL AHV as covariate. The null hypothesis is the differences in least-squares means of change from BL in AHV between infigratinib versus placebo at week 52 equal zero.

[0358] Subjects who discontinue study treatment should be encouraged to continue to undergo the protocol-specified assessments for the remainder of the study. In accordance with the intention-to-treat principle, the assessments that are collected after early discontinuation from study treatment are also used to calculate the AHV and included in the analysis. In cases where data are missing despite all efforts, the missing data is assumed following a mechanism as missing not at random (MNAR). The missing standing height at Week 52 is imputed using multiple imputation (MI) with pattern-mixture models (PMM). To perform the PMM, the standing heights collected from subjects in the same randomization group who also discontinue treatment prematurely but remain in the study is used as reference. If there are less than 5 subjects in the reference set, the missing standing height due to early discontinuation at Week 52 is imputed by applying the BL AHV to the last available post BL height assessment.

[0359] Following the conclusion of the primary analyses, sensitivity analyses are performed to assess the robustness of the primary analysis result. [0360] Key secondary endpoints include change from BL in height Z-score at Week 52 and change from BL in upper to lower body segment ratio at Week 52. The null hypothesis is the differences in least-squares means of change from BL in corresponding endpoints between infigratinib versus placebo at week 52 equal zero. The key secondary endpoints are analyzed similarly to the primary endpoint.

[0361] To adjust for multiplicity and provide strong control of the overall family wise type I error rate (FWER), the sequential stepwise testing procedure in conjunction with the fallback procedure and Holm procedure is used in the primary, key secondary and selected other secondary endpoints. The FWER is controlled at a=0.05.

[0362] The primary endpoint is formally tested at a significant level of a=0.05 level. Only if the primary endpoint shows statistical significance does the analysis proceed to formally test the key secondary endpoints and selected other secondary endpoints.

[0363] The key secondary endpoints are sequentially tested using a reduced significance level of a=0.04. In the event that both key secondary endpoints yield statistically significant results, the reserved a is reallocated to select other secondary endpoints through the fallback procedure.

[0364] For the selected other secondary endpoints, an initial significance level of a=0.01 is allocated. The step-down Holm procedure is utilized. The procedure is terminated whenever an endpoint fails to reach the threshold for rejection, thus maintaining control over the FWER.

[0365] The multiplicity procedure will be applied to the FAS analysis set only. Other endpoints that are not covered by the aforementioned procedures do not undergo formal adjustments for multiplicity.

[0366] Safety Analyses: all randomized subjects who have received at least 1 dose of study drug are included in the safety analysis. Safety data is summarized descriptively.

[0367] Adverse events are summarized by System Organ Class (SOC) and preferred term (PT) using the most current available version of the Medical Dictionary for Regulatory Activities (MedDRA). All treatment-emergent adverse events (TEAEs), treatment-related Aes (those considered by the investigator as at least possibly drug related), SAEs, and discontinuations due to Aes are summarized in separate tables. By-subject listings are provided for all Aes including SAEs, and events leading to discontinuation of treatment.

[0368] Vital signs, laboratory results, ophthalmic and dental evaluations, radiographic imaging, and physical examination findings, are also components of the primary safety endpoint.

Laboratory parameters for hematology and serum blood chemistry, ophthalmic assessments, bone mineral density (BMD) using DXA, and dental examination results are summarized at BL and by visit. Vital sign values, including blood pressure, heart rate, respiration rate, and temperature, are summarized descriptively at each assessed timepoint including change from BL. Physical examination results are summarized using descriptive statistics.

Data Monitoring/Other Committee

[0369] A DMC including at least 3 unblinded independent members review and provide input on the safety data collected in the study. The DMC data review occurs at a scheduled meeting, when at least 60% of subjects have completed at least 6 months of treatment, or on an ad hoc basis, as needed.

Example 6: An In Vitro Study of the Potentency of Infigratinib and Metabolites at FGFR3 Variants Associated with Hypochondroplasia (HCH)

[0370] This study assessd the in vitro potency of infigratinib and its metabolites, the compounds of formulas (II), (III), and (IV) at 9 FGFR3 variants associated with HCH.

[0371] Stable cell lines were generated for each variant (chondrogenic ATDC5 cell line).

[0372] In vitro potency was evaluated using a pERK/ERK ELISA assay. Each treatment consisted of 3-5 experiments, with each experiment having 2-3 technical replicates. Each experiment also included the FGFR3c-G380R variant, a variant associated with achondroplasia, as a positive control.

[0373] The results of the study are summarized in Table 11 and in FIGS. 4A-4D.

Table 11. Inhibition of Cellular Phosphorylation (pERK/ERK) for Infigratinib and Infigratinib Metabolites

INCORPORATION BY REFERENCE

[0374] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims.

Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art. EQUIVALENTS

[0375] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

CLAIMS We claim:

1. A method of delivering or providing a compound of formula (II) to a subject in need of treatment for a skeletal dysplasia, comprising administering infigratinib, or a pharmaceutically acceptable salt thereof, to the subject in an amount sufficient to deliver an effective amount of a compound of formula (II) to the subject, wherein the compound of formula (II) has the structure:

2. A method of treating a skeletal dysplasia in a subject in need thereof, comprising administering infigratinib, or a pharmaceutically acceptable salt thereof, to the subject in an amount sufficient to deliver an effective amount of a compound of formula (II) to the subject, wherein the compound of formula (II) has the structure:

3. A method of delivering or providing a compound of formula (III) to a subject in need of treatment for a skeletal dysplasia, comprising administering infigratinib, or a pharmaceutically acceptable salt thereof, to the subject in an amount sufficient to deliver an effective amount of a compound of formula (III) to the subject, wherein the compound of formula (III) has the structure:

4. A method of treating a skeletal dysplasia in a subject in need thereof, comprising administering infigratinib, or a pharmaceutically acceptable salt thereof, to the subject in an amount sufficient to deliver an effective amount of a compound of formula (III) to the subject, wherein the compound of formula (III) has the structure:

5. A method of delivering or providing a compound of formula (IV) to a subject in need of treatment for a skeletal dysplasia, comprising administering infigratinib, or a pharmaceutically acceptable salt thereof, to the subject in an amount sufficient to deliver an effective amount of a compound of formula (IV) to the subject, wherein the compound of formula (IV) has the structure:

6. The method of any one of claims 1-5, wherein the subject is in need of FGFR3 modulation.

7. A method of treating a condition, disease, or disorder requiring FGFR3 modulation in a subject in need thereof, comprising administering infigratinib, or a pharmaceutically acceptable salt thereof, to the subject in an amount sufficient to modulate the pharmaceutical activity of a compound of formula (II) on FGFR3, wherein the compound of formula (II) has the structure:

8. A method of treating a condition, disease, or disorder requiring FGFR3 modulation in a subject in need thereof, comprising administering infigratinib, or a pharmaceutically acceptable salt thereof, to the subject in an amount sufficient to modulate the pharmaceutical activity of a compound of formula (III) on FGFR3, wherein the compound of formula (III) has the structure:

9. A method of treating a condition, disease, or disorder requiring FGFR3 modulation in a subject in need thereof, comprising administering infigratinib, or a pharmaceutically acceptable salt thereof, to the subject in an amount sufficient to modulate the pharmaceutical activity of a compound of formula (IV) on FGFR3, wherein the compound of formula (IV) has the structure:

10. The method of any one of claims 7-9, wherein the condition, disease, or disorder is a skeletal dysplasia.

11. The method of any one of claims 1-6 and 10, wherein the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia (e g., thanatophoric dysplasia type I or thanatophoric dysplasia type II), osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, Crouzon syndrome (e.g., Crouzon syndrome acanthosis nigricans), craniosynostosis, Kallmann syndrome, hypogonadotropic hypogonadism, cleft palate and other craniofacial defects, scoliosis, Type 1 or classic Pfeiffer syndrome, osteoglophonic dysplasia, craniosynostosis, mandibular progmathism, hypertelorism, brachydactyly, inter- phalangeal joint fusion, Jackson-Weiss syndrome, Antley-Bixler syndrome, Apert syndrome, Crouzon syndrome, X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, and trigonocephaly.

12. The method of claim 11, wherein the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia (e.g., thanatophoric dysplasia type I or thanatophoric dysplasia type II), osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, and Crouzon syndrome (e.g., Crouzon syndrome acanthosis nigricans).

13. The method of claim 12, wherein the skeletal disorder is achondroplasia.

14. The method of claim 12, wherein the skeletal disorder is hypochondroplasia.

15. The method of any one of claims 1-14, wherein administering infigratinib, or a pharmaceutically acceptable salt thereof, comprises administering a daily dose of about 0.1 mg to about 50.0 mg of infigratinib, or a pharmaceutically acceptable salt thereof, to the subject.

16. The method of claim 15, administering the daily dose of about 0.1 mg to about 50 mg of infigratinib, or a pharmaceutically acceptable salt thereof, results in an increased Cmax ratio of the compound of formula (II) to infigratinib in the subject, as compared to administering a daily dose of 125 mg of infigratinib, or a pharmaceutically acceptable salt thereof.

17. The method of claim 15 or 16, wherein administering the daily dose of about 0.1 mg to about 50 mg of infigratinib, or a pharmaceutically acceptable salt thereof, results in an increased Cmax ratio of the compound of formula (II) to infigratinib in the subject about 4 hours after administration, as compared to administering a daily dose of 125 mg of infigratinib, or a pharmaceutically acceptable salt thereof.

18. The method of any one of claims 15-17, wherein administering the daily dose of about 0.1 mg to about 50 mg of infigratinib, or a pharmaceutically acceptable salt thereof, results in a Cmax of the compound of formula (II) in a range of about 0.1 ng/mL to about 21 ng/mL in the subject about 4 hours after administration.

19. The method of any one of claims 16-18, wherein the Cmax is determined on Day 1 of administration.

20. The method of any one of claims 16-18, wherein the Cmax is determined on Day 21 of administration.

21. The method of any one of claims 1-20, wherein administering infigratinib, or a pharmaceutically acceptable salt thereof, comprises administering a daily dose of about 0.1 mg to about 40.0 mg of infigratinib, or a pharmaceutically acceptable salt thereof, to the subject.

22. The method of any one of claims 1-21, wherein administering infigratinib, or a pharmaceutically acceptable salt thereof, comprises administering a daily dose of about 1.0 mg to about 20.0 mg of infigratinib, or a pharmaceutically acceptable salt thereof, to the subject.

23. The method of any one of claims 1-22, wherein administering infigratinib, or a pharmaceutically acceptable salt thereof, comprises administering a daily dose of about 1.0 mg to about 10.0 mg of infigratinib, or a pharmaceutically acceptable salt thereof, to the subject.

24. The method of any one of claims 1-23, wherein about 1.0 mg, about 1.5 mg, about 2.0 mg, about 2.5 mg, about 3.0 mg, 3.5 mg, about 4.0 mg, about 5.0 mg, about 6.0 mg, about 7.0 mg, about 8.0 mg, about 9.0 mg, about 10.0 mg, about 11.0 mg, about 12.0 mg, about 13.0 mg, about 14.0 mg, about 15.0 mg, about 16.0 mg, about 17.0 mg, about 18.0 mg, about 19.0 mg, about 20.0 mg, about 21.0 mg, about 22.0 mg, about 23.0 mg, about 24.0 mg, about 25.0 mg, about 26.0 mg, about 27.0 mg, about 28.0 mg, about 29.0 mg, about 30.0 mg, about 31.0 mg, about 32.0 mg, about 33.0 mg, about 34.0 mg, about 35.0 mg, about 36.0 mg, about 37.0 mg, about 38.0 mg, about 39.0 mg, or about 40.0 mg of infigratinib, or a pharmaceutically acceptable salt thereof, is administered daily to the subject.

25. The method of any one of claims 1-24, wherein about 1.5 mg, about 2.5 mg, 3.5 mg, about 5.0 mg, about 7.0 mg, about 10.0 mg, about 14.0 mg, or about 20.0 mg of infigratinib, or a pharmaceutically acceptable salt thereof, is administered daily to the subject.

26. The method of any one of claims 1-14, wherein administering infigratinib, or a pharmaceutically acceptable salt thereof, comprises administering a daily dose of about 0.01 milligrams per kilogram (mg/kg) to about 0.60 mg/kg of infigratinib, or a pharmaceutically acceptable salt thereof, to the subject.

27. The method of claim 26, wherein administering infigratinib, or a pharmaceutically acceptable salt thereof, comprises administering a daily dose of about 0. 1 mg/kg to about 0.50 mg/kg of infigratinib, or a pharmaceutically acceptable salt thereof, to the subject.

28. The method of claim 26 or 27, wherein administering infigratinib, or a pharmaceutically acceptable salt thereof, comprises administering a daily dose of about 0. 15 mg/kg to about 0.50 mg/kg of infigratinib, or a pharmaceutically acceptable salt thereof, to the subject.

29. The method of any one of claims 26-28, wherein administering infigratinib, or a pharmaceutically acceptable salt thereof, comprises administering a daily dose of about 0.25 mg/kg of infigratinib, or a pharmaceutically acceptable salt thereof, to the subject.

30. The method of any one of claims 1-29, wherein infigratinib is administered as infigratinib monophosphate.

31. The method of claim 30, wherein the infigratinib monophosphate is present as an anhydrous crystalline form.

32. The method of claim 31, wherein the anhydrous crystalline form of infigratinib monophosphate is characterized by an X-ray powder diffraction (XRPD) peak (2 theta) at 15.0° ± 0.2°.

33. The method of any one of claims 1-32, wherein infigratinib, or the pharmaceutically acceptable salt thereof, is administered in a solid dosage form.

34. The method of claim 33, wherein infigratinib, or the pharmaceutically acceptable salt thereof, is administered in a tablet or capsule.

35. The method of claim 33 or 34, wherein infigratinib, or the pharmaceutically acceptable salt thereof, is administered in a mini -tablet or sprinkle capsule.

36. The method of any one of claims 1-35, wherein infigratinib, or the pharmaceutically acceptable salt thereof, is administered orally.

37. The method of any one of claims 1-36, wherein the subject has an FGFR3 mutation.

38. The method of claim 37, wherein the FGFR3 mutation is a G380R or N540K mutation.

39. The method of any one of claims 1-38, wherein the subject is less than 18 years of age.

40. The method of claim 39, wherein the subject is 0 to 4 months old, 0 to 6 months old, 0 to

1 year of age, 0 to 2 years of age, 0 to 3 years of age, 0 to 5 years of age, 1 to 2 years of age, 1 to 3 years of age, 1 to 5 years of age, 2 to 3 years of age, 2 to 5 years of age, 2 to 8 years of age, 2 to 11 years of age, 2 to 17 years of age, 3 to 5 years of age, 3 to 8 years of age, 3 to 11 years of age, 3 to 17 years of age, 5 to 8 years of age, 5 to 11 years of age, 5 to 17 years of age, 8 to 11 years of age, 8 to 17 years of age, 11 to 17 years of age, or 12 to 17 years of age.

41. The method of claim 39, wherein the subject is less than 2 years of age.

42. The method of claim 39, wherein the subject is less than 3 years of age.

43. The method of claim 39, wherein the subject is less than 5 years of age.

44. The method of claim 39, wherein the subject is less than 12 years of age.

45. The method of any one of claims 1-44, wherein the subject has open epiphyses.

46. A method of modulating FGFR3, comprising contacting FGFR3 with a compound of formula (II), wherein the compound of formula (II) has the structure:

47. A method of modulating FGFR3, comprising contacting FGFR3 with a compound of formula (III), wherein the compound of formula (III) has the structure:

48. The method of claim 46 or 47 wherein the FGFR3 is disposed within a cell.

49. The method of claim 48, wherein the cell is located within a subject.

50. The method of claim 49, wherein the subject has a skeletal dysplasia.

51. The method of claim 50, wherein the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia (e.g., thanatophoric dysplasia type I or thanatophoric dysplasia type II), osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, Crouzon syndrome (e.g., Crouzon syndrome acanthosis nigricans), craniosynostosis, Kallmann syndrome, hypogonadotropic hypogonadism, cleft palate and other craniofacial defects, scoliosis, Type 1 or classic Pfeiffer syndrome, osteoglophonic dysplasia, craniosynostosis, mandibular progmathism, hypertelorism, brachydactyly, inter- phalangeal joint fusion, Jackson-Weiss syndrome, Antley-Bixler syndrome, Apert syndrome, Crouzon syndrome, X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, and trigonocephaly.

52. The method of claim 51, wherein the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia (e.g., thanatophoric dysplasia type I or thanatophoric dysplasia type II), osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, and Crouzon syndrome (e.g., Crouzon syndrome acanthosis nigricans).

53. The method of any one of claims 50-52, wherein the skeletal dysplasia is achondroplasia.

54. The method of any one of claims 50-52, wherein the skeletal dysplasia is hypochondroplasia.

55. The method of any one of claims 49-54, wherein the subject has an FGFR3 mutation.

56. The method of claim 55, wherein the FGFR3 mutation is a G380R or N540K mutation.

57. The method of any one of claims 49-56, wherein the subject is less than 18 years of age.

58. The method of claim 57, wherein the subject is 0 to 4 months old, 0 to 6 months old, 0 to 1 year of age, 0 to 2 years of age, 0 to 3 years of age, 0 to 5 years of age, 1 to 2 years of age, 1 to 3 years of age, 1 to 5 years of age, 2 to 3 years of age, 2 to 5 years of age, 2 to 8 years of age, 2 to 11 years of age, 2 to 17 years of age, 3 to 5 years of age, 3 to 8 years of age, 3 to 11 years of age, 3 to 17 years of age, 5 to 8 years of age, 5 to 11 years of age, 5 to 17 years of age, 8 to 11 years of age, 8 to 17 years of age, 11 to 17 years of age, or 12 to 17 years of age.

59. The method of claim 57, wherein the subject is less than 2 years of age.

60. The method of claim 57, wherein the subject is less than 3 years of age.

61. The method of claim 57, wherein the subject is less than 5 years of age.

62. The method of claim 57, wherein the subject is less than 12 years of age.

63. The method of any one of claims 49-62, wherein the subject has open epiphyses.

64. A method of treating a skeletal dysplasia in a subject in need thereof, comprising providing an effective amount of a compound of formula (II), or a pharmaceutically acceptable salt or N-oxide thereof, to the subject, wherein the compound of formula (II) has the structure:

65. A method of treating a skeletal dysplasia in a subject in need thereof, comprising admininstering an effective amount of a compound of formula (II), or a pharmaceutically acceptable salt or N-oxide thereof, to the subject, wherein the compound of formula (II) has the structure:

66. A method of treating a skeletal dysplasia in a subject in need thereof, comprising providing an effective amount of a compound of formula (III), or a pharmaceutically acceptable salt or N-oxide thereof, to the subject, wherein the compound of formula (III) has the structure:

67. A method of treating a skeletal dysplasia in a subject in need thereof, comprising admininstering an effective amount of a compound of formula (III), or a pharmaceutically acceptable salt or N-oxide thereof, to the subject, wherein the compound of formula (III) has the structure:

68. The method of any one of claims 64-67, wherein the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia (e.g., thanatophoric dysplasia type I or thanatophoric dysplasia type II), osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, Crouzon syndrome (e.g., Crouzon syndrome acanthosis nigricans), craniosynostosis, Kallmann syndrome, hypogonadotropic hypogonadism, cleft palate and other craniofacial defects, scoliosis, Type 1 or classic Pfeiffer syndrome, osteoglophonic dysplasia, craniosynostosis, mandibular progmathism, hypertelorism, brachydactyly, inter- phalangeal joint fusion, Jackson-Weiss syndrome, Antley-Bixler syndrome, Apert syndrome, Crouzon syndrome, X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, and trigonocephaly.

69. The method of claim 68, wherein the skeletal dysplasia is selected from the group consisting of achondroplasia, hypochondroplasia, thanatophoric dysplasia (e.g., thanatophoric dysplasia type I or thanatophoric dysplasia type II), osteogenesis imperfecta, campomelic dysplasia, achnodrogenesis, severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Muenke syndrome, and Crouzon syndrome (e.g., Crouzon syndrome acanthosis nigricans).

70. The method of claim 69, wherein the skeletal disorder is achondroplasia.

71. The method of claim 69, wherein the skeletal disorder is hypochondroplasia.

72. The method of any one of claims 64-71, wherein the subject has an FGFR3 mutation.

73. The method of claim 72, wherein the FGFR3 mutation is a G380R or N540K mutation.

74. The method of any one of claims 64-73, wherein the subject is less than 18 years of age.

75. The method of claim 74, wherein the subject is 0 to 4 months old, 0 to 6 months old, 0 to 1 year of age, 0 to 2 years of age, 0 to 3 years of age, 0 to 5 years of age, 1 to 2 years of age, 1 to 3 years of age, 1 to 5 years of age, 2 to 3 years of age, 2 to 5 years of age, 2 to 8 years of age, 2 to 11 years of age, 2 to 17 years of age, 3 to 5 years of age, 3 to 8 years of age, 3 to 11 years of age, 3 to 17 years of age, 5 to 8 years of age, 5 to 11 years of age, 5 to 17 years of age, 8 to 11 years of age, 8 to 17 years of age, 11 to 17 years of age, or 12 to 17 years of age.

76. The method of claim 74, wherein the subject is less than 2 years of age.

77. The method of claim 74, wherein the subject is less than 3 years of age.

78. The method of claim 74, wherein the subject is less than 5 years of age.

79. The method of claim 74, wherein the subject is less than 12 years of age.

80. The method of any one of claims 64-79, wherein the subject has open epiphyses.