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WO2024233525A1 - Schéma posologique de crinecerfont pour le traitement de l'hyperplasie surrénalienne congénitale chez un sujet pédiatrique - Google Patents

Schéma posologique de crinecerfont pour le traitement de l'hyperplasie surrénalienne congénitale chez un sujet pédiatrique Download PDF

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Publication number
WO2024233525A1
WO2024233525A1 PCT/US2024/028110 US2024028110W WO2024233525A1 WO 2024233525 A1 WO2024233525 A1 WO 2024233525A1 US 2024028110 W US2024028110 W US 2024028110W WO 2024233525 A1 WO2024233525 A1 WO 2024233525A1
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Prior art keywords
compound
dose
subject
glucocorticoid
amount
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English (en)
Inventor
Jean L. CHAN
Robert H. FARBER
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Neurocrine Biosciences Inc
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Neurocrine Biosciences Inc
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Priority to AU2024268015A priority Critical patent/AU2024268015A1/en
Publication of WO2024233525A1 publication Critical patent/WO2024233525A1/fr
Priority to MX2025013173A priority patent/MX2025013173A/es
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones

Definitions

  • the present application is directed to methods of administering 4-(2-chloro-4- methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5- methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, in a pediatric subject having congenital adrenal hyperplasia.
  • CAH Congenital adrenal hyperplasia
  • ACTH pituitary adrenocorticotropic hormone
  • This treatment is used to correct the cortisol deficiency and reduce the excessive ACTH levels and androgen excess.
  • the dose and duration of steroid use required to suppress ACTH are typically well above the normal physiological level used for cortisol replacement alone (as in patients with Addison’s disease).
  • This increased exposure to glucocorticoids can lead to iatrogenic Cushing’s syndrome, increased cardiovascular risk factors, glucose intolerance, reduced growth velocity, and decreased bone mineral density in CAH patients.
  • Compound A [0007] There is a significant, unmet need for methods for treating CAH.
  • the present disclosure fulfills these and other needs, as evident in reference to the following disclosure.
  • SUMMARY [0008] Provided is a method of administering 4-(2-chloro-4-methoxy-5- methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2- ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, (Compound A) as an adjunct to glucocorticoid therapy in a pediatric subject having congenital adrenal hyperplasia (CAH), the method comprising: administering daily to the subject Compound A, or a pharmaceutically acceptable salt thereof, in two doses consisting of a first dose and a second dose wherein the second dose is greater than the first dose.
  • Compound A 4-(2-chloro-4-methoxy-5- methyl
  • CAH congenital adrenal hyperplasia
  • a method of treating congenital adrenal hyperplasia (CAH) in a pediatric subject already being treated with glucocorticoid therapy comprising: administering daily to the subject 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2- cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, (Compound A) in two doses consisting of a first dose and a second dose wherein the second dose is greater than the first dose.
  • Compound A in two doses consisting of a first dose and a second dose wherein the second dose is greater than the first dose.
  • CAH congenital adrenal hyperplasia
  • the method comprising: administering to the subject a first amount of 4-(2-chloro-4-methoxy-5-methylphenyl)-N- [(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol- 2-amine, or a pharmaceutically acceptable salt thereof, (Compound A) for a first period of time, and subsequently administering to the subject a second amount of Compound A, or a pharmaceutically acceptable salt thereof, for a second period of time, wherein the second amount is administered in two doses consisting of a first dose and a second dose wherein the second dose is greater than the first dose.
  • Compound A 4-(2-chloro-4-methoxy-5-methylphenyl)-N- [(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5
  • Compound A 4-(2-chloro-4-methoxy-5- methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2- ynyl-1,3-thiazol-2-amine: (Compound A); or a pharmaceutically acceptable salt thereof; for use in a method of treating congenital adrenal hyperplasia (CAH) in a pediatric subject already being treated with glucocorticoid therapy, the method comprising: (1) administering to the subject a first amount of Compound A, or a pharmaceutically acceptable salt thereof, for a first period of time, and (2) subsequently administering to the subject a second amount of Compound A, or a pharmaceutically acceptable salt thereof, for a second period of time, wherein the second amount is administered in two doses consisting of a first dose and a second dose wherein the second dose is greater than the first dose.
  • CAH congenital adrenal hyperplasia
  • Compound A 4-(2-chloro-4-methoxy-5- methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2- ynyl-1,3-thiazol-2-amine: (Compound A); or a pharmaceutically acceptable salt thereof; in the manufacture of a medicament for treating congenital adrenal hyperplasia (CAH) in a pediatric subject already being treated with glucocorticoid therapy, by a method comprising the steps: (1) administering to the subject a first amount of Compound A, or a pharmaceutically acceptable salt thereof, for a first period of time, and (2) subsequently administering to the subject a second amount of Compound A, or a pharmaceutically acceptable salt thereof, for a second period of time, wherein the second amount is administered in two doses consisting of a first dose and a second dose wherein the second dose is greater than
  • the organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4- hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethanesulfonic, 1,2-ethane-disulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 4- chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-toluenesulfonic, camphor
  • “pharmaceutically acceptable salt” refers to base addition salts with an inorganic or an organic base.
  • Inorganic bases which may be used to prepare salts include, but are not limited to, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, manganese, aluminum hydroxides, carbonates, bicarbonates, phosphates, and the like.
  • Organic bases from which may be used to prepare salts include, but are not limited to, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • “about” means ⁇ 20% of the stated value, and includes more specifically values of ⁇ 10%, ⁇ 5%, ⁇ 2%, and ⁇ 1% of the stated value.
  • baseline refers to the period of time just prior to initiation of therapy.
  • adjusting administration As used herein, “adjusting administration”, “altering administration”, “adjusting dosing”, or “altering dosing” are all equivalent and mean tapering off, reducing, or increasing the dose of the substance, ceasing to administer the substance to the patient, or substituting a different active agent for the substance.
  • administering to a patient refers to the process of introducing a composition or dosage form into the patient via an art-recognized means of introduction.
  • “b.i.d.” refers to twice daily. In some embodiments, the twice daily doses are separated by about 12 hours.
  • co-administer and “co-administration” and variants thereof mean the administration of at least two drugs to a patient either subsequently, simultaneously, or consequently proximate in time to one another (e.g., within the same day, or week or period of 30 days, or sufficiently proximate that each of the at least two drugs can be simultaneously detected in the blood plasma).
  • two or more active agents can be co-formulated as part of the same composition or administered as separate formulations. This also may be referred to herein as “concomitant” administration or variants thereof.
  • congenital adrenal hyperplasia or “CAH” refers to a group of genetic disorders that affect the adrenal glands.
  • Congenital adrenal hyperplasia is a group of autosomal recessive genetic disorders that result in little or no cortisol biosynthesis.
  • One clinical manifestation of the absence of cortisol is the lack of feedback inhibition on CRF which causes dysregulation of the HPA axis.
  • the most frequent form of the disease is 21-hydroxylase deficiency caused by mutations in the CYP21A2 gene located on chromosome 6p21, which accounts for approximately 95% of CAH cases, the 21- hydroxylase enzyme deficiency also causes a shunting of cortisol precursor steroids leading to excess androgen (e.g., 17-hydroxyprogesterone, androstenedione, and testosterone) product.
  • Non-classic CAH patients are either homozygous or compound heterozygotes, often with a classical CAH allele.
  • a “dose” means the measured quantity of an active agent to be taken at one time by a patient.
  • the quantity is the molar equivalent to the corresponding amount of Compound A free base.
  • the dosage for strength refers to the mass of the molar equivalent of the corresponding free base, Compound A.
  • “dosing regimen” means the dose of an active agent taken at a first time by a patient and the interval (time or symptomatic) at which any subsequent doses of the active agent are taken by the patient such as from about 100 mg to about 300 mg once daily or from about 20 mg to about 160 mg twice daily, e.g., about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg once daily; or about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, or about 160 mg twice daily.
  • the additional doses of the active agent can be different from the dose taken at the first time.
  • a first dose may range from about 20 mg to about 160 mg, e.g., about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, or about 160 mg; and a second dose may range from about 100 mg to about 300 mg, e.g., about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg.
  • a “dosage” is the prescribed administration of a specific amount, number, and frequency of doses over a specific period of time.
  • an agent, compound, drug, composition, or combination is an amount which is nontoxic and effective for producing some desired therapeutic effect upon administration to a subject or patient (e.g., a human subject or patient).
  • the precise therapeutically effective amount for a subject may depend upon, e.g., the subject’s size and health, the nature and extent of the condition, the therapeutics or combination of therapeutics selected for administration, and other variables known to those of skill in the art. The effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician.
  • labeling means all labels or other means of written, printed, graphic, electronic, verbal, or demonstrative communication that is upon a pharmaceutical product or a dosage form or accompanying such pharmaceutical product or dosage form.
  • a medical care worker means a worker in the health care field who may need or utilize information regarding an active agent, including a dosage form thereof, including information on safety, efficacy, dosing, administration, or pharmacokinetics.
  • Examples of medical care workers include physicians, pharmacists, physician's assistants, nurses, aides, caretakers (which can include family members or guardians), emergency medical workers, and veterinarians.
  • Medical Guide means an FDA-approved patient labeling for a pharmaceutical product conforming to the specifications as set forth in 21 CFR 208 and other applicable regulations which contains information for patients on how to safely use a pharmaceutical product.
  • a medication guide is scientifically accurate and is based on, and does not conflict with, the approved professional labeling for the pharmaceutical product under 21 CFR 201.57, but the language need not be identical to the sections of approved labeling to which it corresponds.
  • a medication guide is typically available for a pharmaceutical product with special risk management information.
  • “patient” or “individual” or “subject” means a mammal, including a human, for whom or which therapy is desired, and generally refers to the recipient of the therapy.
  • patient package insert means information for patients on how to safely use a pharmaceutical product that is part of the FDA-approved labeling.
  • “pediatric” refers to a subject who is about 17 years of age or younger (i.e., to birth).
  • the pediatric subject is an adolescent, i.e., a subject who is from about 12 to about 17 years of age.
  • the pediatric subject is a child, i.e., a subject who is from about 2 years to less than about 12 years of age.
  • the pediatric subject is an infant, i.e., a subject who is from about 1 month to about 2 years of age. In some embodiments, the pediatric subject is a neonate, i.e., a subject who is about 1 month of age or younger (i.e., to birth).
  • pharmaceutically acceptable refers to a material that is not biologically or otherwise undesirable, i.e., the material may be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • “pharmaceutically acceptable” refers to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
  • “Pharmacologically active” or simply “active” as in a “pharmacologically active” (or “active”) derivative or analog, refers to a derivative or analog having the same type of pharmacological activity as the parent compound and approximately equivalent in degree.
  • the term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, co-solvents, complexing agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, which are not biologically or otherwise undesirable.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic formulations is contemplated. Supplementary active ingredients can also be incorporated into the formulations.
  • various excipients such as are commonly used in the art, can be included.
  • a “product” or “pharmaceutical product” means a dosage form of an active agent plus published material, and optionally packaging.
  • product insert means the professional labeling (prescribing information) for a pharmaceutical product, a patient package insert for the pharmaceutical product, or a medication guide for the pharmaceutical product.
  • “professional labeling” or “prescribing information” means the official description of a pharmaceutical product approved by a regulatory agency (e.g., FDA or EMEA) regulating marketing of the pharmaceutical product, which includes a summary of the essential scientific information needed for the safe and effective use of the drug, such as, for example, indication and usage; dosage and administration; who should take it; adverse events (side effects); instructions for use in special populations (pregnant women, children, geriatric, etc.); safety information for the patient, and the like.
  • FDA regulatory agency
  • published material means a medium providing information, including printed, audio, visual, or electronic medium, for example a flyer, an advertisement, a product insert, printed labeling, an internet web site, an internet web page, an internet pop- up window, a radio or television broadcast, a compact disk, a DVD, an audio recording, or other recording or electronic medium.
  • q.A.M.” means once daily in the morning.
  • q.P.M.” means once daily in the evening.
  • risk means the probability or chance of adverse reaction, injury, or other undesirable outcome arising from a medical treatment.
  • an “acceptable risk” means a measure of the risk of harm, injury, or disease arising from a medical treatment that will be tolerated by an individual or group. Whether a risk is “acceptable” will depend upon the advantages that the individual or group perceives to be obtainable in return for taking the risk, whether they accept whatever scientific and other advice is offered about the magnitude of the risk, and numerous other factors, both political and social.
  • An “acceptable risk” of an adverse reaction means that an individual or a group in society is willing to take or be subjected to the risk that the adverse reaction might occur since the adverse reaction is one whose probability of occurrence is small, or whose consequences are so slight, or the benefits (perceived or real) of the active agent are so great.
  • An “unacceptable risk” of an adverse reaction means that an individual or a group in society is unwilling to take or be subjected to the risk that the adverse reaction might occur upon weighing the probability of occurrence of the adverse reaction, the consequences of the adverse reaction, and the benefits (perceived or real) of the active agent.
  • “At risk” means in a state or condition marked by a high level of risk or susceptibility. Risk assessment consists of identifying and characterizing the nature, frequency, and severity of the risks associated with the use of a product.
  • safety means the incidence or severity of adverse events associated with administration of an active agent, including adverse effects associated with patient-related factors (e.g., age, gender, ethnicity, race, target illness, abnormalities of renal or hepatic function, co-morbid illnesses, genetic characteristics such as metabolic status, or environment) and active agent-related factors (e.g., dose, plasma level, duration of exposure, or concomitant medication).
  • patient-related factors e.g., age, gender, ethnicity, race, target illness, abnormalities of renal or hepatic function, co-morbid illnesses, genetic characteristics such as metabolic status, or environment
  • active agent-related factors e.g., dose, plasma level, duration of exposure, or concomitant medication
  • CAH congenital adrenal hyperplasia
  • CAH congenital adrenal hyperplasia
  • a method of treating congenital adrenal hyperplasia (CAH) in a pediatric subject already being treated with glucocorticoid therapy comprising: administering daily to the subject 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2- cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine, or a pharmaceutically acceptable salt thereof, (Compound A) in two doses consisting of a first dose and a second dose wherein the second dose is greater than the first dose.
  • Compound A in two doses consisting of a first dose and a second dose wherein the second dose is greater than the first dose.
  • administering Compound A, or a pharmaceutically acceptable salt thereof refers to administration of Compound A, or a pharmaceutically acceptable salt thereof, with food.
  • Compound A, or a pharmaceutically acceptable salt thereof is administered with food.
  • the administration of Compound A, or a pharmaceutically acceptable salt thereof, with food exhibits a positive food effect.
  • an increased, or positive, food effect is observed when Compound A, or a pharmaceutically acceptable salt thereof is administered to a subject in a fed state.
  • administering Compound A, or a pharmaceutically acceptable salt thereof refers to administration of Compound A, or a pharmaceutically acceptable salt thereof, with the subject’s breakfast and evening meal.
  • the subject weighs greater than or equal to about 55 kg.
  • the first dose is equivalent to about 100 mg Compound A free base q.A.M. In some embodiments, the first dose is equivalent to about 0 mg Compound A free base q.A.M.
  • the second dose is equivalent to about 200 mg Compound A free base q.P.M. In some embodiments, the second dose is equivalent to about 300 mg Compound A free base q.P.M. [0055] In some embodiments, the subject weighs greater than or equal to about 55 kg and the first dose is equivalent to about 100 mg Compound A free base q.A.M. In some embodiments, the subject weighs greater than or equal to about 55 kg and the first dose is equivalent to about 0 mg Compound A free base q.A.M. In some embodiments, the subject weighs greater than or equal to about 55 kg and the second dose is equivalent to about 200 mg Compound A free base q.P.M.
  • the subject weighs greater than or equal to about 55 kg and the second dose is equivalent to about 300 mg Compound A free base q.P.M. In some embodiments, the subject weighs greater than or equal to about 55 kg, the first dose is equivalent to about 100 mg Compound A free base q.A.M. and the second dose is equivalent to about 200 mg Compound A free base q.P.M. In some embodiments, the subject weighs greater than or equal to about 55 kg, the first dose is equivalent to about 0 mg Compound A free base q.A.M. and the second dose is equivalent to about 200 mg Compound A free base q.P.M.
  • the subject weighs greater than or equal to about 55 kg, the first dose is equivalent to about 0 mg Compound A free base q.A.M. and the second dose is equivalent to about 300 mg Compound A free base q.P.M.
  • the subject prior to the administering of a first dose equivalent to about 0 mg Compound A free base q.A.M. and a second dose equivalent to about 200 mg Compound A free base q.P.M., the subject that weighs greater than or equal to about 55 kg demonstrated adequate disease control and was being administered a first dose equivalent to about 100 mg Compound A free base q.A.M. and a second dose equivalent to about 200 mg Compound A free base q.P.M.
  • the subject that weighs greater than or equal to about 55 kg demonstrated adequate disease control and was being administered a first dose equivalent to about 100 mg Compound A free base q.A.M. and a second dose equivalent to about 200 mg Compound A free base q.P.M. and a glucocorticoid at a target dose.
  • the subject that weighs greater than or equal to about 55 kg demonstrated adequate disease control and was being administered a first dose equivalent to about 100 mg Compound A free base q.A.M. and a second dose equivalent to about 200 mg Compound A free base q.P.M. and a glucocorticoid at a target dose.
  • a first dose equivalent to about 0 mg Compound A free base q.A.M. and a second dose equivalent to about 300 mg Compound A free base q.P.M. prior to the administering of a first dose equivalent to about 0 mg Compound A free base q.A.M. and a second dose equivalent to about 300 mg Compound A free base q.P.M., the subject that weighs greater than or equal to about 55 kg demonstrated adequate disease control and was being administered a first dose equivalent to about 100 mg Compound A free base q.A.M.
  • the subject demonstrated adequate disease control if their androstenedione levels are ⁇ 120% of the subject’s baseline or ⁇ upper limit of normal (ULN) for age and sex of the subject. [0059] In some embodiments, the subject demonstrated adequate disease control in the opinion of the investigator.
  • the subject weighs greater than or equal to about 55 kg and prior to administration of Compound A, or a pharmaceutically acceptable salt thereof, in two doses consisting of a first dose and a second dose wherein the second dose is greater than the first dose, the subject had been administered Compound A, or a pharmaceutically acceptable salt thereof, as a twice daily dose, each dose having an equivalent amount of Compound A free base for a first period of time.
  • each dose is in an amount equivalent to about 100 mg of Compound A free base.
  • the subject weighs from about 20 kg to about 55 kg.
  • the first dose is in an amount equivalent to about 50 mg Compound A free base.
  • the first dose is in an amount equivalent to about 0 mg Compound A free base.
  • the second dose is in an amount equivalent to about 100 mg Compound A free base. In some embodiments, the second dose is in an amount equivalent to about 150 mg Compound A free base.
  • the subject weighs from about 20 kg to about 55 kg and the first dose is in an amount equivalent to about 50 mg Compound A free base. In some embodiments, the subject weighs from about 20 kg to about 55 kg and the first dose is in an amount equivalent to about 0 mg Compound A free base. In some embodiments, the subject weighs from about 20 kg to about 55 kg and the second dose is in an amount equivalent to about 100 mg Compound A free base.
  • the subject weighs from about 20 kg to about 55 kg and the second dose is in an amount equivalent to about 150 mg Compound A free base. In some embodiments, the subject weighs from about 20 kg to about 55 kg, the first dose is in an amount equivalent to about 50 mg Compound A free base, and the second dose is in an amount equivalent to about 100 mg Compound A free base. In some embodiments, the subject weighs from about 20 kg to about 55 kg, the first dose is in an amount equivalent to about 0 mg Compound A free base, and the second dose is in an amount equivalent to about 100 mg Compound A free base.
  • the subject weighs from about 20 kg to about 55 kg, the first dose is in an amount equivalent to about 0 mg Compound A free base, and the second dose is in an amount equivalent to about 150 mg Compound A free base.
  • the subject prior to the administering of a first dose equivalent to about 0 mg Compound A free base q.A.M. and a second dose equivalent to about 100 mg Compound A free base q.P.M., the subject that weighs from about 20 kg to about 55 kg demonstrated adequate disease control and was being administered a first dose equivalent to about 50 mg Compound A free base q.A.M. and a second dose equivalent to about 100 mg Compound A free base q.P.M.
  • the subject that weighs from about 20 kg to about 55 kg demonstrated adequate disease control and was being administered a first dose equivalent to about 50 mg Compound A free base q.A.M. and a second dose equivalent to about 100 mg Compound A free base q.P.M. and a glucocorticoid at a target dose.
  • a first dose equivalent to about 0 mg Compound A free base q.A.M. prior to the administering of a first dose equivalent to about 0 mg Compound A free base q.A.M.
  • a first dose equivalent to about 0 mg Compound A free base q.A.M. and a second dose equivalent to about 150 mg Compound A free base q.P.M. prior to the administering of a first dose equivalent to about 0 mg Compound A free base q.A.M. and a second dose equivalent to about 150 mg Compound A free base q.P.M., the subject that weighs from about 20 kg to about 55 kg demonstrated adequate disease control and was being administered a first dose equivalent to about 50 mg Compound A free base q.A.M.
  • the subject demonstrated adequate disease control if their androstenedione levels are ⁇ 120% of the subject’s baseline or ⁇ upper limit of normal (ULN) for age and sex of the subject.
  • the subject demonstrated adequate disease control in the opinion of the investigator.
  • the subject weighs from about 20 kg to about 55 kg and prior to administration of Compound A, or a pharmaceutically acceptable salt thereof, in two doses consisting of a first dose and a second dose wherein the second dose is greater than the first dose, the subject had been administered Compound A, or a pharmaceutically acceptable salt thereof, as a twice daily dose, each dose having an equivalent amount of Compound A free base for a first period of time.
  • each dose is in an amount equivalent to about 50 mg of Compound A free base.
  • the subject weighs from about 10 kg to about 20 kg.
  • the first dose is in an amount equivalent to about 25 mg Compound A free base.
  • the first dose is in an amount equivalent to about 0 mg Compound A free base.
  • the second dose is in an amount equivalent to about 50 mg Compound A free base. In some embodiments, the second dose is in an amount equivalent to about 75 mg Compound A free base.
  • the subject weighs from about 10 kg to about 20 kg and the first dose is in an amount equivalent to about 25 mg Compound A free base. In some embodiments, the subject weighs from about 10 kg to about 20 kg and the first dose is in an amount equivalent to about 0 mg Compound A free base. In some embodiments, the subject weighs from about 10 kg to about 20 kg and the second dose is in an amount equivalent to about 50 mg Compound A free base.
  • the subject weighs from about 10 kg to about 20 kg and the second dose is in an amount equivalent to about 75 mg Compound A free base. In some embodiments, the subject weighs from about 10 kg to about 20 kg, the first dose is in an amount equivalent to about 25 mg Compound A free base, and the second dose is in an amount equivalent to about 50 mg Compound A free base. In some embodiments, the subject weighs from about 10 kg to about 20 kg, the first dose is in an amount equivalent to about 0 mg Compound A free base, and the second dose is in an amount equivalent to about 50 mg Compound A free base.
  • the subject weighs from about 10 kg to about 20 kg, the first dose is in an amount equivalent to about 0 mg Compound A free base, and the second dose is in an amount equivalent to about 75 mg Compound A free base.
  • the subject prior to the administering of a first dose equivalent to about 0 mg Compound A free base q.A.M. and a second dose equivalent to about 50 mg Compound A free base q.P.M., the subject that weighs from about 10 kg to about 20 kg demonstrated adequate disease control and was being administered a first dose equivalent to about 25 mg Compound A free base q.A.M. and a second dose equivalent to about 50 mg Compound A free base q.P.M.
  • the subject that weighs from about 10 kg to about 20 kg demonstrated adequate disease control and was being administered a first dose equivalent to about 25 mg Compound A free base q.A.M. and a second dose equivalent to about 50 mg Compound A free base q.P.M. and a glucocorticoid at a target dose.
  • the subject that weighs from about 10 kg to about 20 kg demonstrated adequate disease control and was being administered a first dose equivalent to about 25 mg Compound A free base q.A.M. and a second dose equivalent to about 50 mg Compound A free base q.P.M. and a glucocorticoid at a target dose.
  • the subject demonstrated adequate disease control if their androstenedione levels are ⁇ 120% of the subject’s baseline or ⁇ upper limit of normal (ULN) for age and sex of the subject. [0077] In some embodiments, the subject demonstrated adequate disease control in the opinion of the investigator.
  • the subject weighs from about 10 kg to about 20 kg and, prior to administration of Compound A, or a pharmaceutically acceptable salt thereof, in two doses consisting of a first dose and a second dose wherein the second dose is greater than the first dose, the subject had been administered Compound A, or a pharmaceutically acceptable salt thereof, as a twice daily dose, each dose having an equivalent amount of Compound A free base for a first period of time. In some embodiments, each dose is in an amount equivalent to about 25 mg of Compound A free base. [0079] In some embodiments, the method further comprises adjusting for a missed q.A.M. dose. In some embodiments, the method further comprises adjusting for a missed q.P.M. dose.
  • the amount of the missed dose is administered as soon as possible, even if it is soon before the next scheduled dose, and then the regular dosing schedule is resumed.
  • the method further comprises subsequently administering to the subject a third amount of Compound A, or a pharmaceutically acceptable salt thereof, for a third period of time, wherein the third amount is administered in a q.P.M. dose.
  • CAH congenital adrenal hyperplasia
  • the method comprising: administering to the subject a first amount of 4-(2-chloro-4-methoxy-5-methylphenyl)-N- [(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol- 2-amine, or a pharmaceutically acceptable salt thereof, (Compound A) for a first period of time, and subsequently administering to the subject a second amount of Compound A, or a pharmaceutically acceptable salt thereof, for a second period of time, wherein the
  • the method further comprises subsequently administering to the subject a third amount of Compound A, or a pharmaceutically acceptable salt thereof, for a third period of time, wherein the third amount is administered in a q.P.M. dose.
  • the method further comprises: (3) subsequently administering to the subject a third amount of Compound A, or a pharmaceutically acceptable salt thereof, for a third period of time, wherein the third amount is administered in a q.P.M. dose.
  • the method further comprises: (3) subsequently administering to the subject a third amount of Compound A, or a pharmaceutically acceptable salt thereof, for a third period of time, wherein the third amount is administered in a q.P.M. dose.
  • administering Compound A, or a pharmaceutically acceptable salt thereof refers to administration of Compound A, or a pharmaceutically acceptable salt thereof, with food.
  • the administration of Compound A, or a pharmaceutically acceptable salt thereof, with food exhibits a positive food effect.
  • an increased, or positive, food effect is observed when Compound A, or a pharmaceutically acceptable salt thereof is administered to a subject in a fed state.
  • administering Compound A, or a pharmaceutically acceptable salt thereof refers to administration of Compound A, or a pharmaceutically acceptable salt thereof, with the subject’s breakfast and evening meal.
  • the subject weighs greater than or equal to about 55 kg.
  • the first amount is equivalent to about 100 mg Compound A free base b.i.d. In some embodiments, the first amount is equivalent to about 100 mg Compound A free base q.A.M.
  • the second amount is equivalent to about 100 mg of Compound A free base q.A.M. and about 200 mg Compound A free base q.P.M.
  • the third amount is equivalent to about 200 mg Compound A free base q.P.M. In some embodiments, the third amount is equivalent to about 300 mg Compound A free base q.P.M.
  • the first period of time is from about 1 week to about 1 year. [0090] In some embodiments, the second period of time is at least about 1 week. [0091] In some embodiments, the third period of time is at least about 1 week.
  • the subject weighs from about 20 kg to about 55 kg.
  • the first amount is equivalent to about 50 mg Compound A free base b.i.d. In some embodiments, the first amount is equivalent to about 50 mg Compound A free base q.A.M. and about 50 mg Compound A free base q.P.M.
  • the second amount is equivalent to about 50 mg of Compound A free base q.A.M. and about 100 mg Compound A free base q.P.M.
  • the third amount is equivalent to about 100 mg Compound A free base q.P.M.
  • the third amount is equivalent to about 150 mg Compound A free base q.P.M.
  • the first period of time is from about 1 week to about 1 year.
  • the second period of time is at least about 1 week.
  • the third period of time is at least about 1 week.
  • the subject weighs from about 10 kg to about 20 kg.
  • the first amount is equivalent to about 25 mg Compound A free base b.i.d.
  • the first amount is equivalent to about 25 mg Compound A free base q.A.M. and about 25 mg Compound A free base q.P.M.
  • the second amount is equivalent to about 25 mg of Compound A free base q.A.M. and about 50 mg Compound A free base q.P.M.
  • the third amount is equivalent to about 50 mg Compound A free base q.P.M. In some embodiments, the third amount is equivalent to about 75 mg Compound A free base q.P.M.
  • the first period of time is from about 1 week to about 1 year. [00104] In some embodiments, the second period of time is at least about 1 week. [00105] In some embodiments, the third period of time is at least about 1 week. [00106] In some embodiments, the first period of time is between 1 week and 1 year.
  • the first period of time is from about 1 week to about 1 year. In some embodiments, the first period of time is at least 6 months. In some embodiments, the first period of time is less than 6 months. In some embodiments, the first period of time is more than 6 months. In some embodiments, the first period of time is about 6 months. In some embodiments, the first period of time is at least one year. In some embodiments, the first period of time is greater than one year. In some embodiments, the first period of time is about one year. [00107] In some embodiments, the second period of time is at least about 1 week. In some embodiments, the second period of time is between 1 week and 1 year. In some embodiments, the second period of time is from about 1 week to about 1 year.
  • the second period of time is at least 6 months. In some embodiments, the second period of time is less than 6 months. In some embodiments, the second period of time is more than 6 months. In some embodiments, the second period of time is about 6 months. In some embodiments, the second period of time is at least one year. In some embodiments, the second period of time is greater than one year. In some embodiments, the second period of time is less than one year. In some embodiments, the second period of time is about one year. In some embodiments, the third period of time is at least about 1 week. In some embodiments, the third period of time is between 1 week and 1 year. In some embodiments, the third period of time is from about 1 week to about 1 year.
  • the third period of time is at least 6 months. In some embodiments, the third period of time is less than 6 months. In some embodiments, the third period of time is more than 6 months. In some embodiments, the third period of time is about 6 months. In some embodiments, the third period of time is at least one year. In some embodiments, the third period of time is greater than one year. In some embodiments, the third period of time is less than one year. In some embodiments, the third period of time is about one year. [00108] In some embodiments, the second period of time begins immediately after the conclusion of the first period of time. In some embodiments, the second period of time begins within 1 day after the conclusion of the first period of time.
  • the second period of time begins within 1 week after the conclusion of the first period of time. In some embodiments, the second period of time begins within 1 month after the conclusion of the first period of time. In some embodiments, the second period of time begins within 6 months after the conclusion of the first period of time. In some embodiments, the second period of time begins about 1 day after the conclusion of the first period of time. In some embodiments, the second period of time begins about 1 week after the conclusion of the first period of time. In some embodiments, the second period of time begins about 1 month after the conclusion of the first period of time. In some embodiments, the second period of time begins about 6 months after the conclusion of the first period of time.
  • the third period of time begins immediately after the conclusion of the second period of time. In some embodiments, the third period of time begins within 1 day after the conclusion of the second period of time. In some embodiments, the third period of time begins within 1 week after the conclusion of the second period of time. In some embodiments, the third period of time begins within 1 month after the conclusion of the second period of time. In some embodiments, the third period of time begins within 6 months after the conclusion of the second period of time. In some embodiments, the third period of time begins about 1 day after the conclusion of the second period of time. In some embodiments, the third period of time begins about 1 week after the conclusion of the second period of time.
  • the third period of time begins about 1 month after the conclusion of the second period of time. In some embodiments, the third period of time begins about 6 months after the conclusion of the second period of time. [00110] In some embodiments, the method further comprises adjusting for a missed q.A.M. dose. In some embodiments, the method further comprises adjusting for a missed q.P.M. dose. In some embodiments, in the event of a missed dose, the amount of the missed dose is administered as soon as possible, even if it is soon before the next scheduled dose, and then the regular dosing schedule is resumed. [00111] In some embodiments, the glucocorticoid therapy is a daily dose of a glucocorticoid administered to the subject.
  • the daily dose of the glucocorticoid is administered once daily or through multiple administrations. In some embodiments, the daily dose of the glucocorticoid is administered once daily. In some embodiments, the daily dose of the glucocorticoid is administered through multiple administrations. [00113] In some embodiments, the glucocorticoid is selected from hydrocortisone, prednisone, methylprednisolone, prednisolone, dexamethasone, and fludrocortisone, or a combination thereof.
  • the glucocorticoid is selected from hydrocortisone, prednisone, methylprednisolone, prednisolone, and dexamethasone, or a combination thereof.
  • the glucocorticoid is hydrocortisone.
  • the glucocorticoid is prednisone.
  • the glucocorticoid is methylprednisolone.
  • the glucocorticoid is prednisolone.
  • the glucocorticoid is dexamethasone.
  • the glucocorticoid is fludrocortisone.
  • the subject prior to the administering of Compound A, or a pharmaceutically acceptable salt thereof, the subject was receiving a glucocorticoid at a target dose.
  • the subject prior to the administering of the second amount of Compound A, or a pharmaceutically acceptable salt thereof, the subject was receiving a glucocorticoid at a target dose.
  • the subject prior to the administering of the second amount of Compound A, or a pharmaceutically acceptable salt thereof, for the second period of time, the subject was receiving a glucocorticoid at a target dose.
  • the subject prior to the administering of the third amount of Compound A, or a pharmaceutically acceptable salt thereof, the subject was receiving a glucocorticoid at a target dose. In some embodiments, prior to the administering of the third amount of Compound A, or a pharmaceutically acceptable salt thereof, for the third period of time, the subject was receiving a glucocorticoid at a target dose.
  • the target dose of glucocorticoid treatment is ⁇ 11 mg/m 2 /day hydrocortisone equivalents.
  • the target dose of glucocorticoid treatment is about 8 mg/m 2 /day to about 10 mg/m 2 /day hydrocortisone equivalents. [00119] In some embodiments, the target dose of glucocorticoid treatment is about 8 mg/m 2 /day hydrocortisone equivalents. [00120] In some embodiments, the glucocorticoid is hydrocortisone. In some embodiments, the glucocorticoid is methylprednisolone using a hydrocortisone dose equivalent conversion factor of about 4X.
  • the glucocorticoid is prednisolone using a hydrocortisone dose equivalent conversion factor of about 4X. In some embodiments, the glucocorticoid is prednisone using a hydrocortisone dose equivalent conversion factor of about 4X. In some embodiments, the glucocorticoid is methylprednisolone using a hydrocortisone dose equivalent conversion factor of about 5X. In some embodiments, the glucocorticoid is prednisolone using a hydrocortisone dose equivalent conversion factor of about 5X. In some embodiments, the glucocorticoid is prednisone using a hydrocortisone dose equivalent conversion factor of about 5X.
  • the glucocorticoid is dexamethasone using a hydrocortisone dose equivalent conversion factor from about 26X to about 80X. In some embodiments, the glucocorticoid is dexamethasone using a hydrocortisone dose equivalent conversion factor of about 60X. In some embodiments, the glucocorticoid is dexamethasone using a hydrocortisone dose equivalent conversion factor of about 80X. [00121] In some embodiments, prior to the administering of Compound A, or a pharmaceutically acceptable salt thereof, the subject demonstrated adequate disease control.
  • the subject prior to the administering of the second amount of Compound A, or a pharmaceutically acceptable salt thereof, the subject had inadequate efficacy. In some embodiments, prior to the administering of the second amount of Compound A, or a pharmaceutically acceptable salt thereof, for the second period of time, the subject had inadequate efficacy. [00123] In some embodiments, prior to the administering of the third amount of Compound A, or a pharmaceutically acceptable salt thereof, the subject demonstrated adequate disease control. [00124] In some embodiments, prior to the administering of Compound A, or a pharmaceutically acceptable salt thereof, the subject demonstrated adequate disease control and was being administered a glucocorticoid at the target dose.
  • the subject prior to the administering of the second amount of Compound A, or a pharmaceutically acceptable salt thereof, the subject had inadequate efficacy and was being administered a glucocorticoid at the target dose. In some embodiments, prior to the administering of the second amount of Compound A, or a pharmaceutically acceptable salt thereof, for the second period of time, the subject had inadequate efficacy and was being administered a glucocorticoid at the target dose. [00126] In some embodiments, prior to the administering of the third amount of Compound A, or a pharmaceutically acceptable salt thereof, the subject demonstrated adequate disease control and was being administered a glucocorticoid at the target dose.
  • the subject demonstrated adequate disease control if their androstenedione levels are ⁇ 120% of the subject’s baseline or ⁇ upper limit of normal (ULN) for age and sex of the subject.
  • the subject had adequate efficacy if their androstenedione levels are ⁇ 120% of the subject’s baseline or ⁇ upper limit of normal (ULN) for age and sex of the subject.
  • the subject demonstrated adequate disease control in the opinion of the investigator. In some embodiments, the subject had adequate efficacy in the opinion of the investigator. In some embodiments, the subject demonstrated adequate disease control in the opinion of the prescriber or health care provider.
  • the subject had adequate efficacy in the opinion of the prescriber or health care provider.
  • the method further comprises monitoring the subject for adequate disease control, wherein if the disease control is inadequate and the glucocorticoid therapy is at or above the target dose of the subject, then the amount of Compound A, or a pharmaceutically acceptable salt thereof, is adjusted.
  • the use further comprises monitoring the subject for adequate disease control, wherein if the disease control is inadequate and the glucocorticoid therapy is at or above the target dose of the subject, then the amount of Compound A, or a pharmaceutically acceptable salt thereof, is adjusted.
  • the subject demonstrated inadequate disease control if their androstenedione levels are > 120% of the subject’s baseline or > upper limit of normal (ULN) for age and sex of the subject.
  • the subject had inadequate efficacy if their androstenedione levels are > 120% of the subject’s baseline or > upper limit of normal (ULN) for age and sex of the subject.
  • the subject demonstrated inadequate disease control in the opinion of the investigator. In some embodiments, the subject had inadequate efficacy in the opinion of the investigator. In some embodiments, the subject demonstrated inadequate disease control in the opinion of the prescriber or health care provider.
  • Compound A, or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt of Compound A.
  • Compound A, or a pharmaceutically acceptable salt thereof is the free base of Compound A.
  • the free base of Compound A is crystalline.
  • the free base of Compound A is a crystalline form as described in International Application Publication No. WO 2021/111179.
  • Compound A, or a pharmaceutically acceptable salt thereof is administered in a pharmaceutical composition further comprising one or more pharmaceutically acceptable excipients.
  • the methods and uses described herein comprise administering a pharmaceutical composition that is the formulation described in Example 2 herein. In some embodiments, the methods and uses described herein comprise administering a pharmaceutical composition that is a formulation described in WO 2020/115555.
  • the pharmaceutical composition is in an oral solution dosage form comprising: (a) Compound A, or a pharmaceutically acceptable salt thereof; (b) one or more of a sweetener, an anti-oxidant, and a flavor; and (c) a liquid vehicle.
  • the pharmaceutical composition comprises about 1 w/v% to about 50 w/v% of the compound of Compound A, or a pharmaceutically acceptable salt thereof, based on the weight of the free base.
  • the pharmaceutical composition comprises about 1 w/v% to about 10 w/v% of the compound of Compound A, or a pharmaceutically acceptable salt thereof, based on the weight of the free base. In some embodiments, the pharmaceutical composition comprises about 5 w/v% of the compound of Compound A, or a pharmaceutically acceptable salt thereof, based on the weight of the free base. In some embodiments, the pharmaceutical composition comprises about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 w/v% of the compound of Compound A, or a pharmaceutically acceptable salt thereof, based on the weight of the free base, or within a range of any of the preceding values. [00138] In some embodiments, the pharmaceutical composition comprises a sweetener.
  • a sweetener is a formulation component added to improve taste.
  • the pharmaceutical composition comprises about 0.01 w/v% to about 1.5 w/v% of the sweetener. In some embodiments, the pharmaceutical composition comprises about 0.1 w/v% to about 0.5 w/v% of the sweetener. In some embodiments, the pharmaceutical composition comprises about 0.15 w/v% of the sweetener. In some embodiments, the pharmaceutical composition comprises about 0.1, 0.2, 0.3, 0.4, or 0.5 w/v% of the sweetener, or within a range of any of the preceding values.
  • the sweetener is selected from saccharin, sucrose, sucralose, aspartame, dextrose, fructose, maltitol, mannitol, sorbitol, and schoolame. In some embodiments, the sweetener is saccharin.
  • the pharmaceutical composition comprises an anti- oxidant.
  • An anti-oxidant is a formulation component included to improve stability by preventing oxidation. In some embodiments, the pharmaceutical composition comprises about 0.01 w/v% to about 1.5 w/v% of the anti-oxidant. In some embodiments, the pharmaceutical composition comprises about 0.1 w/v% to about 0.5 w/v% of the anti- oxidant.
  • the pharmaceutical composition comprises about 0.17 w/v% of the anti-oxidant. In some embodiments, the pharmaceutical composition comprises about 0.1, 0.2, 0.3, 0.4, or 0.5 w/v% of the anti-oxidant, or within a range of any of the preceding values.
  • the anti-oxidant is selected from butylated hydroxytoluene, vitamin E TPGS, butylated hydroxyanisole, ascorbic acid, lecithin, tert- butylhydroquinone, and citric acid. In some embodiments, the anti-oxidant is butylated hydroxytoluene.
  • the pharmaceutical composition comprises a flavor.
  • a flavor is a formulation component added to mask taste through aromatics.
  • the pharmaceutical composition comprises about 0.01 w/v% to about 0.5 w/v% of the flavor. In some embodiments, the pharmaceutical composition comprises about 0.05 w/v% to about 0.2 w/v% of the flavor. In some embodiments, the pharmaceutical composition comprises about 0.10 w/v% of the flavor. In some embodiments, the pharmaceutical composition comprises about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19 or 0.2 w/v% of the flavor, or within a range of any of the preceding values.
  • the flavor is selected from FONA orange flavor, FONA Juicy Flavor, FONA Grape Flavor, Firmenich SA Lemon Flavor, Firmenich Tetrarome Orange Flavor, IFF Cherry Flavor, and IFF Grape Flavor.
  • the flavor is FONA orange flavor.
  • the flavor is orange flavor.
  • a liquid vehicle is a solvent capable of dissolving or partially dissolving the compound of Compound A, or a pharmaceutically acceptable salt thereof, for the purposes of delivery as an oral dosing solution.
  • the pharmaceutical composition comprises about 50 w/v% to about 99.9 w/v% of the liquid vehicle.
  • the pharmaceutical composition comprises about 90 w/v% to about 99 w/v% of the liquid vehicle. In some embodiments, the pharmaceutical composition comprises about 92 w/v% to about 97 w/v% of the liquid vehicle. In some embodiments, the pharmaceutical composition comprises about 94.6 w/v% of the liquid vehicle. In some embodiments, the pharmaceutical composition comprises about 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 w/v% of the liquid vehicle, or within a range of any of the preceding values.
  • the liquid vehicle is selected from medium-chain triglycerides, propylene glycol dicaprylate/dicaprate, glycerin, propylene glycol, polyethylene glycol, olive oil, soybean oil, corn oil, and transcutol.
  • the liquid vehicle is medium-chain triglycerides.
  • the medium-chain triglycerides is Labrafac TM Lipophile WL1349.
  • the pharmaceutical composition further comprises a surfactant.
  • a surfactant is a formulation component added to improve solubility or emulsion properties.
  • the pharmaceutical composition comprises about 1 w/v% to about 50 w/v% of the surfactant.
  • the pharmaceutical composition comprises about 10 w/v% to about 30 w/v% of the surfactant. In some embodiments, the pharmaceutical composition comprises about 20 w/v% of the surfactant. In some embodiments, the pharmaceutical composition comprises about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 w/v% of the surfactant, or within a range of any of the preceding values.
  • the surfactant is selected from oleoyl polyoxyl-6 glycerides, linoleoyl polyoxyl-6 glycerides, Polysorbate 80, Polysorbate 20, vitamin E polyethylene glycol succinate, Gelucire, lauroyl polyoxyl-32 glycerides, sodium lauryl sulfate, Poloxamer, corn oil PEG-6 esters, and hydrogenated palm/palm kernel oil PEG-6 esters.
  • the surfactant is oleoyl polyoxyl-6 glycerides.
  • the oleoyl polyoxyl-6 glycerides is LABRAFIL TM M 1944 CS.
  • the pharmaceutical composition comprises about 50 w/v% to about 90 w/v% of the liquid vehicle. In some embodiments, the pharmaceutical composition comprises about 70 w/v% to about 80 w/v% of the liquid vehicle. In some embodiments, the pharmaceutical composition comprises about 75 w/v% of the liquid vehicle. In some embodiments, the pharmaceutical composition comprises about 74.6 w/v% of the liquid vehicle. In some embodiments, the pharmaceutical composition comprises about 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 w/v% of the liquid vehicle, or within a range of any of the preceding values.
  • the liquid vehicle is selected from medium-chain triglycerides, propylene glycol dicaprylate/dicaprate, glycerin, propylene glycol, polyethylene glycol, olive oil, soybean oil, corn oil, and transcutol.
  • the liquid vehicle is medium-chain triglycerides.
  • the medium-chain triglycerides is Labrafac TM Lipophile WL1349.
  • the pharmaceutical composition comprises: (a) Compound A, or a pharmaceutically acceptable salt thereof; (b) a sweetener; (c) an anti-oxidant; (d) a flavor; and (e) a liquid vehicle.
  • the pharmaceutical composition further comprises a surfactant.
  • the pharmaceutical composition comprises: (a) about 4 w/v% to about 6 w/v% of Compound A, or a pharmaceutically acceptable salt thereof, based on the weight of the free base; (b) about 0.1 w/v% to about 0.2 w/v% of a sweetener; (c) about 0.1 w/v% to about 0.2 w/v% of an anti-oxidant; (d) about 0.05 w/v% to about 0.2 w/v% of a flavor; and (e) about 92 w/v% to about 97 w/v% of a liquid vehicle.
  • the pharmaceutical composition comprises: (a) about 5 w/v% of Compound A, or a pharmaceutically acceptable salt thereof, based on the weight of the free base; (b) about 0.15 w/v% of a sweetener; (c) about 0.17 w/v% of an anti-oxidant; (d) about 0.1 w/v% of a flavor; and (e) about 94.6 w/v% of a liquid vehicle.
  • the pharmaceutical composition comprises: (a) about 4 w/v% to about 6 w/v% of Compound A, or a pharmaceutically acceptable salt thereof, based on the weight of the free base; (b) about 0.1 w/v% to about 0.2 w/v% of a sweetener; (c) about 0.1 w/v% to about 0.2 w/v% of an anti-oxidant; (d) about 0.05 w/v% to about 0.2 w/v% of a flavor; (e) about 15 w/v% to about 25 w/v% of a surfactant; and (f) about 70 w/v% to about 80 w/v% of a liquid vehicle.
  • the pharmaceutical composition comprises: (a) about 5 w/v% of Compound A, or a pharmaceutically acceptable salt thereof, based on the weight of the free base; (b) about 0.15 w/v% of a sweetener; (c) about 0.17 w/v% of an anti-oxidant; (d) about 0.1 w/v% of a flavor; (e) about 20 w/v% of a surfactant; and (f) about 75 w/v% of a liquid vehicle.
  • the pharmaceutical composition comprises: (a) Compound A, or a pharmaceutically acceptable salt thereof; (b) saccharin; (c) butylated hydroxytoluene; (d) FONA orange flavor; and (e) medium-chain triglycerides. [00157] In some embodiments, the pharmaceutical composition further comprises oleoyl polyoxyl-6 glycerides.
  • the pharmaceutical composition comprises: (a) about 4 w/v% to about 6 w/v% of Compound A, or a pharmaceutically acceptable salt thereof, based on the weight of the free base; (b) about 0.1 w/v% to about 0.2 w/v% of saccharin; (c) about 0.1 w/v% to about 0.2 w/v% of butylated hydroxytoluene; (d) about 0.05 w/v% to about 0.2 w/v% of FONA orange flavor; and (e) about 92 w/v% to about 97 w/v% of medium-chain triglycerides.
  • the pharmaceutical composition comprises: (a) about 5 w/v% of Compound A, or a pharmaceutically acceptable salt thereof, based on the weight of the free base; (b) about 0.15 w/v% of saccharin; (c) about 0.17 w/v% of butylated hydroxytoluene; (d) about 0.1 w/v% of FONA orange flavor; and (e) about 94.6 w/v% of medium-chain triglycerides.
  • the pharmaceutical composition comprises: (a) about 4 w/v% to about 6 w/v% of Compound A, or a pharmaceutically acceptable salt thereof, based on the weight of the free base; (b) about 0.1 w/v% to about 0.2 w/v% of saccharin; (c) about 0.1 w/v% to about 0.2 w/v% of butylated hydroxytoluene; (d) about 0.05 w/v% to about 0.2 w/v% of FONA orange flavor; (e) about 15 w/v% to about 25 w/v% of oleoyl polyoxyl-6 glycerides; and (f) about 70 w/v% to about 80 w/v% of medium-chain triglycerides.
  • the pharmaceutical composition comprises: (a) about 5 w/v% of Compound A, or a pharmaceutically acceptable salt thereof, based on the weight of the free base; (b) about 0.15 w/v% of saccharin; (c) about 0.17 w/v% of butylated hydroxytoluene; (d) about 0.1 w/v% of FONA orange flavor; (e) about 20 w/v% of oleoyl polyoxyl-6 glycerides; and (f) about 75 w/v% of medium-chain triglycerides.
  • the pharmaceutical composition comprises the compound of Compound A as a free base.
  • the pharmaceutical composition comprises the compound of Compound A as the free base of Compound A.
  • the pharmaceutical composition is formulated in unit dosage form, wherein the compound of Compound A, or a pharmaceutically acceptable salt thereof, is present in an amount of about 5 mg/mL to about 200 mg/mL, based on the weight of the free base. In some embodiments, the compound of Compound A, or a pharmaceutically acceptable salt thereof, is present in the unit dosage form in an amount of about 75 mg/mL to about 150 mg/mL, based on the weight of the free base.
  • the compound of Compound A, or a pharmaceutically acceptable salt thereof is present in the unit dosage form in an amount of about 50 mg/mL, based on the weight of the free base. In some embodiments, the compound of Compound A, or a pharmaceutically acceptable salt thereof, is present in the unit dosage form in an amount of about 100 mg/mL, based on the weight of the free base.
  • the liquid pharmaceutical composition has a viscosity between about 1 to about 50 centipoise at about 25 o C.
  • the CAH is classical Congenital Adrenal Hyperplasia.
  • the CAH is non-classical Congenital Adrenal Hyperplasia.
  • Example 1 Phase 3 Compound A Pediatric Studies
  • CAH congenital adrenal hyperplasia
  • Eligible subjects will be randomly assigned in a 2:1 ratio (active:placebo) to either Compound A (25 mg b.i.d. via oral solution for subjects 10 to ⁇ 20 kg, 50 mg b.i.d. via oral solution for subjects 20 to ⁇ 55 kg, or 100 mg b.i.d. via oral capsules for subjects ⁇ 55 kg) or matching placebo (oral solution placebo for subjects ⁇ 55 kg and oral capsule placebo for subjects ⁇ 55 kg).
  • Dose assignment from Day 1 to Week 28 will be based on the subject’s weight at Day 1. After the 28-week placebo-controlled treatment period, there will be a 24- week, open-label treatment period, during which all subjects will receive Compound A at doses based on their Week 28 body weight.
  • subjects For blood tests obtained at the study site, subjects should bring their morning dose of glucocorticoid, fludrocortisone (if applicable), and study drug (after Day 1) with them to the study site to take at the study site (with dosing to occur between approximately 0800 and 0830 hours with breakfast). Except for the screening visit, subjects should be fasting after midnight the night before until after the predose blood sample collection(s) but should be encouraged to drink water to avoid any hypovolemic status. Subjects ⁇ 6 years of age for whom the investigator deems that fasting until 0800 hours is not feasible can have a snack(s) if needed but should wait to have breakfast with morning dosing.
  • Glucocorticoid-Stable Period On Day 1, subjects who are ⁇ 6 years of age with a body weight ⁇ 20 kg should arrive at the study site for the serial blood sampling procedure and dosing, with dosing to occur between approximately 0800 and 0830 hours. Blood samples will be obtained serially over approximately 6 hours, with 2 baseline samples obtained approximately 15 minutes before the morning glucocorticoid dose and again immediately prior to the morning glucocorticoid dose administration (with dosing to occur between approximately 0800 and 0830 hours) and at 2, 3, 4, and 6 hours after the morning glucocorticoid dose, for a total of 6 blood sampling time points.
  • Subjects who are ⁇ 6 years of age or with a body weight ⁇ 20 kg will have a blood sample collection prior to their morning glucocorticoid dose only (with dosing to occur between approximately 0800 and 0830 hours).
  • salivary samples for adrenal androgens and precursors will be collected in the early morning (0600 hours), at approximately 0800 hours prior to the morning glucocorticoid dose, at approximately 3 and 6 hours after the morning glucocorticoid dose, and in the evening (within 30 minutes prior to the evening dose of glucocorticoid; if subject is not on an evening glucocorticoid dose, then prior to bedtime).
  • the salivary samples at approximately 0800 hours prior to dosing and 3 and 6 hours after dosing should be collected at approximately the same time as any corresponding blood samples (as applicable). Any midday glucocorticoid dose that the subject is receiving should be taken after the 6-hour postdose blood and salivary samples are collected.
  • the exact timing of the blood and saliva samples, and the morning glucocorticoid, mineralocorticoid, and/or study drug dose (and breakfast) may be adjusted by ⁇ 1 hour to accommodate site and subject schedules if needed as long as this is done consistently per subject and the relative times between the sample(s) and the dose(s) are maintained.
  • Subjects will be randomized on Day 1 in a 2:1 ratio (active:placebo).
  • Randomization will be stratified by pubertal stage (Tanner breast or genital stage 1 or 2 versus 3, 4 or 5) and sex. From the evening of the Day 1 visit (after all Day 1 assessments have been performed) until the morning of the Week 28 visit, all subjects will receive blinded study drug based on their Day 1 weight (25 mg b.i.d. via oral solution for subjects 10 to ⁇ 20 kg, 50 mg b.i.d. via oral solution for subjects 20 to ⁇ 55 kg, or 100 mg b.i.d. via oral capsules for subjects ⁇ 55 kg). Study drug will be administered b.i.d. with the subject’s breakfast and evening meals (each dose separated by approximately 12 hours).
  • Glucocorticoid-Adjustment Period [00175] At the Week 4 visit, subjects ⁇ 6 years of age with a body weight ⁇ 20 kg should arrive at the study site for the serial blood sampling procedure and dosing, with dosing to occur between approximately 0800 and 0830 hours with breakfast.
  • Blood samples will be obtained serially over approximately 6 hours, with 2 baseline samples (obtained approximately 15 minutes before and again immediately prior to the morning glucocorticoid and study drug dose, with dosing to occur between approximately 0800 and 0830 hour). Blood samples will also be obtained at 2, 3, 4, and 6 hours after dosing. Pharmacokinetic (PK) blood samples will be obtained at the same time points with the exception of only 1 required predose sample. Subjects who are ⁇ 6 years of age or with a body weight ⁇ 20 kg will have blood sample collection prior to the morning glucocorticoid and study drug dose only (with dosing to occur between approximately 0800 and 0830 hours with breakfast).
  • salivary samples for adrenal androgens and precursors will be collected in the early morning (0600 hours), at 6 hours after the morning glucocorticoid and study drug dose, and in the evening (within 30 minutes prior to the evening dose of glucocorticoid; if subject is not on an evening glucocorticoid dose, then prior to bedtime).
  • the salivary samples at approximately 0800 hours prior to dosing and 3 and 6 hours after dosing should be collected at approximately the same time as any corresponding blood samples (as applicable). Any midday glucocorticoid dose that the subject is receiving should be taken after the 6-hour postdose blood and salivary samples are collected.
  • the exact timing of the blood and saliva samples, and the morning glucocorticoid, mineralocorticoid, and/or study drug dose may be adjusted by ⁇ 1 hour to accommodate site and subject schedules if needed, as long as the relative times between the sample(s) and the dose(s) are maintained.
  • glucocorticoid dose should be adjusted according to their androstenedione (A4) levels, with the goal to reach a target dose of 8 to 10 mg/m 2 /day (in hydrocortisone dose equivalents adjusted for body surface area [BSA]) at Week 28, while A4 is controlled, i.e., ⁇ 120% of the baseline value or ⁇ upper limit of normal (ULN), according to sex and either age (for Tanner stage 1) or pubertal stage (for Tanner stages 2 to 5).
  • A4 is controlled, i.e., ⁇ 120% of the baseline value or ⁇ upper limit of normal (ULN), according to sex and either age (for Tanner stage 1) or pubertal stage (for Tanner stages 2 to 5).
  • the calculation of glucocorticoid dose in hydrocortisone equivalents adjusted for BSA at Day 1 and Week 28 will be based on height and weight measurement at Day 1 and Week 28, respectively.
  • Glucocorticoid dose adjustments can occur in as few as 1 or up to 4 steps, depending on the starting and target glucocorticoid doses and the amount of dose adjustment at each step. Reductions in the glucocorticoid dose should follow the guideline of first reducing the most nonphysiologic glucocorticoid type and timing.
  • the target glucocorticoid dose should be within the range of 8 to 10 mg/m 2 /day while A4 levels are controlled and as long as there is no evidence of glucocorticoid insufficiency.
  • the dose could be lower than this range if the investigator considers this appropriate depending on practical issues considered in clinical practice related to available dosage strengths but will not be mandated to be lower than this range.
  • the investigator will evaluate the subject for any symptoms suggestive of glucocorticoid insufficiency using a standardized checklist and will arrange for follow-up if needed after the dose reduction.
  • the first glucocorticoid dose adjustment step at approximately Week 6 (or when the Week 4 lab results are available) should be guided by the change in A4 at Week 4 from baseline.
  • a suggested guideline is provided in the table below, but the exact amount adjusted may differ from this guideline based on practical issues considered in clinical practice related to available dosage strengths.
  • the investigator should contact the subject/guardian once the Week 4 lab results are available in order to provide guidance on the amount of the first glucocorticoid dose adjustment.
  • the first glucocorticoid dose adjustment step guidance is summarized in Table 1 below.
  • Table 1: First Glucocorticoid Dose Adjustment Guidance ULN upper limit of normal a Within reasonable variability in the opinion of the investigator [00179]
  • a follow-up blood test should be arranged approximately 2 weeks later at Week 8 (at home or the study site).
  • subsequent glucocorticoid dose adjustment steps should occur when lab results are available (at approximately Week 10, Week 14, and Week 18) with follow-up blood and salivary tests at Week 12 (at home or the study site, if the glucocorticoid dose was previously modified), Week 16 (at home or the study site), and Week 20 (at home or the study site, if the glucocorticoid dose was previously modified).
  • the target amount of glucocorticoid dose reduction at each step is approximately 1 to 4 mg/m 2 /day but should be guided by the A4 level at the preceding blood test as well as on practical issues considered in clinical practice related to available dosage strengths.
  • the subsequent glucocorticoid dose adjustment step guidance is summarized in Table 2 below.
  • salivary samples will be collected over the course of the day: at approximately 0600 hours, at approximately 0800 hours prior to morning glucocorticoid and study drug dosing and 3 and 6 hours after dosing, and within 30 minutes prior to the evening dose of glucocorticoid (if subject is not taking evening glucocorticoid dose, then prior to bedtime). Any midday glucocorticoid dose that the subject is receiving should be taken after the 6-hour postdose salivary sample is collected.
  • Open-Label Treatment Period (Week 28 to Week 52) [00183] From the evening of the Week 28 visit (after all Week 28 assessments have been performed) until the morning of the Week 52 visit, all subjects will receive active study drug based on their Week 28 weight (Compound A; 25 mg b.i.d. via oral solution for subjects 10 to ⁇ 20 kg, 50 mg b.i.d. via oral solution for subjects 20 to ⁇ 55 kg, or 100 mg b.i.d. via oral capsules for subjects ⁇ 55 kg) with breakfast and evening meals. Subjects and investigators will remain blinded to subjects’ randomized treatment group assignment during the entire study.
  • Week 28 weight Compound A; 25 mg b.i.d. via oral solution for subjects 10 to ⁇ 20 kg, 50 mg b.i.d. via oral solution for subjects 20 to ⁇ 55 kg, or 100 mg b.i.d. via oral capsules for subjects ⁇ 55 kg
  • glucocorticoid regimen From Week 28 until Week 32, subjects should maintain a stable glucocorticoid regimen to the extent possible, except for stress dosing if needed for illness or other significant physical stress.
  • a blood sample will be collected at Week 32 (at home or the study site).
  • further adjustments in glucocorticoid dose should be made following guidelines similar to that used during the placebo-controlled period with the goal to reach a target dose of 8 to 10 mg/m 2 /day in hydrocortisone dose equivalents adjusted for BSA at Week 52, while A4 is controlled.
  • the calculation of glucocorticoid dose in hydrocortisone equivalents adjusted for BSA at Week 52 will be based on height and weight measurement at Week 52. BSA will be updated at Week 40 if height measurement is obtained at Week 40.
  • the first glucocorticoid dose adjustment step during this period should be guided by the serum A4 change at Week 32 (compared with Week 28), after the subject has been on open-label active study drug as well as stable glucocorticoid regimen (to the extent possible) for 4 weeks.
  • a suggested guideline is provided below but the exact amount adjusted may differ from this guideline based on practical issues considered in clinical practice related to available dosage strengths.
  • subsequent glucocorticoid dose adjustments should occur at approximately Week 38 and Week 42 (or when lab results are available) with follow-up blood and salivary tests at Week 40 (at home or the study site) and Week 44 (at home or the study site, if the glucocorticoid dose was previously modified during the open-label treatment period).
  • the target amount of glucocorticoid dose reduction at each step is approximately 1 to 4 mg/m 2 /day but should be guided by the A4 level at the preceding blood test as well as practical issues considered in clinical practice related to available dosage strengths.
  • Table 4 The open label extension subsequent glucocorticoid dose adjustment guidance is summarized in Table 4 below.
  • Table 4 Open Label Extension Subsequent Glucocorticoid Dose Adjustment Guidance [00188] At all visits, if A4 is >120% of baseline and >ULN, increase glucocorticoid dose as appropriate in order to maintain A4 control. [00189] For the Week 52 visit, subjects should hold their morning glucocorticoid and study drug dose until after the predose blood samples are collected, with dosing to occur between approximately 0800 and 0830 hours with breakfast. For subjects ⁇ 6 years of age with a body weight ⁇ 20 kg, another blood sample will be collected approximately 3 hours after the morning glucocorticoid and study drug dose.
  • salivary samples will be collected over the course of the day: at approximately 0600 hours, at approximately 0800 hours prior to morning glucocorticoid and study drug dosing and 3 and 6 hours after dosing, and within 30 minutes prior to the evening dose of glucocorticoid (if subject is not taking evening glucocorticoid dose, then prior to bedtime). Any midday glucocorticoid dose that the subject is receiving should be taken after the 6-hour postdose salivary sample is collected.
  • Open-Label Extension for Continued Compound A Access (Week 52 Onwards) [00190] During the OLE, subjects will continue to receive Compound A at the appropriate dose based on their body weight at each study visit (25 mg b.i.d.
  • Dose can be increased for inadequate efficacy once at the specified weight-based dose (e.g., 50 mg b.i.d. can be increased to 50 mg q.A.M. and 100 mg q.P.M.) but not further unless the subject crosses into the next weight category.
  • the Compound A dose should be increased first based on weight (not doubling the evening dose); efficacy should be assessed at the next scheduled study visit, and if efficacy remains inadequate the evening dose can be doubled at that time. If the Compound A dose is increased due to inadequate efficacy, a follow-up study visit should be performed approximately 1 month after the dose increase for efficacy, PK, and safety assessments. This follow-up study visit is not required for subjects who increase their dose due to crossing into the next weight category. Changes to the Compound A dose (whether based on crossing into the next weight category or based on inadequate efficacy) should generally only be made at scheduled study visits.
  • subjects taking Compound A 50 mg b.i.d. or higher may elect to switch the Compound A formulation (oral solution or capsule) based on preference, e.g., if the subject was receiving Compound A 50 mg b.i.d. oral solution from Week 28 to Month 12 but prefers capsule, they could switch to 50 mg b.i.d. capsule if remaining in the same weight category.
  • the formulation should remain the same for the rest of the OLE (unless there is a tolerability issue, in which case the subject can revert back to the previous formulation, ideally within approximately 1 month).
  • glucocorticoid dose reduction will not require dose reduction below 8 mg/m 2 /day hydrocortisone equivalents.
  • the investigator should contact the subject/guardian (within 2 weeks) to assess how the subject is tolerating the glucocorticoid dose reduction.
  • any midday glucocorticoid dose that the subject is receiving should be taken after the 6-hour postdose salivary sample is collected.
  • Investigational product, dosage, and mode of administration [00194] Compound A (25 mg b.i.d. via oral solution for subjects 10 to ⁇ 20 kg, 50 mg b.i.d. via oral solution for subjects 20 to ⁇ 55 kg, or 100 mg b.i.d. via oral capsules for subjects ⁇ 55 kg) with subjects’ breakfast and evening meals (each dose separated by approximately 12 hours) from Day 1 to Month 12.
  • the Compound A dose should be based on the subject’s weight at the study visit (25 mg b.i.d. if weight is 10 to ⁇ 20 kg, 50 mg b.i.d.
  • Each Compound A oral capsule contains 50 mg of Compound A.
  • the oral solution contains 50 mg of Compound A per 1 mL and will be administered via a graduated oral dosing syringe. Further guidance on changes to Compound A dosing in the OLE is provided in Table 5 below. Table 5: Guidance for Dose Adjustment During the Open Label Extension b.i.d.
  • Criteria for evaluation include: Efficacy: • Hormone measurements: A4 (serum and saliva), 17-hydroxyprogeterone (17-OHP; serum and saliva), adrenocorticotropic hormone (ACTH) (plasma), luteinizing hormone (LH; serum), follicle-stimulating hormone (FSH; serum), testosterone (serum and saliva), cortisol (serum and saliva), plasma renin activity (PRA) (measured upright) • Daily glucocorticoid regimen expressed in hydrocortisone dose equivalents adjusted for BSA (mg/m 2 /day) • Body weight and body mass index (absolute and standard deviation score [SDS] units) • Growth (assessed as Bayley-Pinneau predicted adult height, height, and height velocity in absolute and SDS units; only
  • the first key secondary endpoint is the change from baseline to Week 4 in serum 17-OHP.
  • the second key secondary endpoint is the percent change from baseline to Week 28 in glucocorticoid daily dose (in hydrocortisone dose equivalents adjusted for BSA [mg/m 2 /day]), while Week 28 serum A4 is ⁇ 120% of the baseline value or ⁇ ULN, according to sex and either age (for Tanner stage 1) or pubertal stage (for Tanner stages 2 to 5).
  • These endpoints will be analyzed using an analysis of covariance model and will include treatment group (Compound A versus placebo), stratification factors used in the randomization and, as appropriate, baseline value.
  • Secondary endpoints will include: • The achievement of a reduction in glucocorticoid daily dose to physiologic levels ( ⁇ 11 mg/m 2 /day in hydrocortisone dose equivalent adjusted for BSA) at Week 28, while Week 28 serum A4 is ⁇ 120% of the baseline value or ⁇ ULN, according to sex and either age (for Tanner stage 1) or pubertal stage (for Tanner stages 2 to 5). • Change from baseline to Week 28 in body mass index SDS. • Change from baseline to Week 28 in mean 24-hour salivary 17-OHP. • Acceptability and palatability of the study drug at Week 4.
  • Example 2 Liquid Formulation for Compound A
  • Table 6 shows a liquid formulation of Compound A as the free base (concentration of 50 mg/mL). A representative manufacturing process example for the preparation of the liquid formulation is shown in International Application Publication No. WO 2020/115555. Table 6: Representative Liquid Formulation for Compound A (Free Base) [00199] The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S.

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Abstract

L'invention concerne des méthodes d'administration de 4-(2-chloro-4-méthoxy-5-méthylphényl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-méthylphényl)éthyl]-5-méthyl-N-prop-2-ynyl-1,3-thiazol-2-amine, ou d'un sel pharmaceutiquement acceptable de celui-ci, chez un sujet pédiatrique atteint d'une hyperplasie surrénalienne congénitale.
PCT/US2024/028110 2023-05-08 2024-05-07 Schéma posologique de crinecerfont pour le traitement de l'hyperplasie surrénalienne congénitale chez un sujet pédiatrique Pending WO2024233525A1 (fr)

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