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WO2025240605A1 - Traitement combiné - Google Patents

Traitement combiné

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Publication number
WO2025240605A1
WO2025240605A1 PCT/US2025/029344 US2025029344W WO2025240605A1 WO 2025240605 A1 WO2025240605 A1 WO 2025240605A1 US 2025029344 W US2025029344 W US 2025029344W WO 2025240605 A1 WO2025240605 A1 WO 2025240605A1
Authority
WO
WIPO (PCT)
Prior art keywords
crinecerfont
pharmaceutical composition
solvate
subject
hydrocortisone
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/029344
Other languages
English (en)
Inventor
Robert H. FARBER
Jean L. CHAN
Vivian H. Lin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Neurocrine Biosciences Inc
Original Assignee
Neurocrine Biosciences Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Neurocrine Biosciences Inc filed Critical Neurocrine Biosciences Inc
Publication of WO2025240605A1 publication Critical patent/WO2025240605A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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

Definitions

  • the present disclosure relates generally to the treatment of adrenal dysfunction (such as congenital adrenal hyperplasia) with a combination of 2 ⁇ thiazolamine, 4-(2- chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4- methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont) and certain pharmaceutical compositions of hydrocortisone (such as a delayed release oral pharmaceutical composition of hydrocortisone).
  • the compound of Formula (I) [0003] 2 ⁇ thiazolamine, 5-methylphenyl)-N-[(1S)-2- cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), is a selective corticotropin-releasing hormone receptor 1 (CRF1) receptor antagonist that is being developed for the treatment of congenital adrenal hyperplasia associated with high adrenocorticotropin and adrenal steroid insufficiency.
  • CRF1 corticotropin-releasing hormone receptor 1
  • the compound of Formula (I) can be prepared according to the methods described in U.S.
  • the uncontrolled symptoms of androgen excess indeed, have a substantial impact on the day-to-day functioning and development of these patients.
  • the glucocorticoid doses required to treat the androgen excess are typically well above the normal physiologic doses used for cortisol replacement alone (as in patients with Addison’s disease). This increased exposure to glucocorticoids can lead to weigh t gain, iatrogenic Cushing’s syndrome, increased cardiovascular risk factors, glucose intolerance, and decreased bone mineral density in CAH patients (Elnecave et al., J Pediatr Endocrinol Metab. 2008 Dec;21(12):1155-62; King et al., J Clin Endocrinol Metab.
  • formulation of crinecerfont, or a pharmaceutically acceptable salt thereof may be in the form of a lipidic semi-solid formulation, an oral solution dosage formulation, or a spray-dried dispersion such as those described in WO 2021/252669 A1, which is hereby incorporated by reference in its entirety.
  • Hydrocortisone may be administered in various compositions or formulations to patients with CAH.
  • the hydrocortisone formulation may be a delayed release oral pharmaceutical composition such as those described in U.S. Patent Nos. 9,750,704 and 10,166,194, each of which is hereby incorporated by reference in its entirety.
  • the hydrocortisone formulation may be an immediate release formulation, such as those described in U.S.
  • hydrocortisone formulation may be an oral liquid formulation of hydrocortisone, such as those described in WO 2024/107635 A1, which is hereby incorporated by reference in its entirety.
  • Corticotropin-releasing factor is a hypothalamic hormone released directly into the hypophyseal portal vasculature and acts on specific CRF1 receptors on corticotropes in the anterior pituitary to stimulate the release of ACTH. Blockade of these receptors has been shown to decrease the release of ACTH in both animals and humans.
  • SUMMARY [0009] Provided herein are methods related to treating adrenal dysfunction (such as congenital adrenal hyperplasia) which comprise administering 2 ⁇ thiazolamine, 4 -(2- chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4- methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof, and administering certain formulations of hydrocortisone (such as a delayed release oral pharmaceutical composition of hydrocortisone).
  • a delayed release oral pharmaceutical composition of hydrocortisone such as a delayed release oral pharmaceutical composition of hydrocortisone
  • compositions comprising 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5- methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N- 2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof, and hydrocortisone.
  • a method of treating congenital adrenal hyperplasia in a subject comprising: administering to the subject a therapeutically effective amount of 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4- methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt or solvate thereof; and administering to the subject a therapeutically effective amount of a delayed release oral pharmaceutical composition of hydrocortisone.
  • kits comprising: 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl- 1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt or solvate thereof; and d elayed release oral pharmaceutical composition of hydrocortisone; packaged together; o ptionally further comprising instructions for their administration.
  • twin pack comprising: 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1- (3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt or solvate thereof; and d elayed release oral pharmaceutical composition of hydrocortisone; optionally further comprising instructions for their administration.
  • a pharmaceutical composition comprising: 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1- (3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt or solvate thereof; hydrocortisone; and a t least one pharmaceutically acceptable carrier, diluent, or excipient.
  • a fixed dose combination product comprising: 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1- (3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt or solvate thereof; and a delayed release oral pharmaceutical composition of hydrocortisone.
  • a method of treating congenital adrenal hyperplasia in a subject comprising: a dministering to the subject a therapeutically effective amount of 2 ⁇ thiazolamine, 4 - (2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4- methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt or solvate thereof; and instructing the subject to administer to themselves a delayed release oral pharmaceutical composition of hydrocortisone.
  • a method of treating congenital adrenal hyperplasia in a subject comprising: administering to the subject a therapeutically effective amount of 2 ⁇ thiazolamine, 4- (2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4- methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt or solvate thereof; instructing the subject to review the drug label of a delayed release oral pharmaceutical composition of hydrocortisone; and administer to themselves the delayed release oral pharmaceutical composition of hydrocortisone consistent with the drug label of the delayed release oral pharmaceutical composition of hydrocortisone.
  • a method of treating congenital adrenal hyperplasia in a subject comprising: administering to the subject a therapeutically effective amount of a delayed release oral pharmaceutical composition of hydrocortisone; and i nstructing the subject to administer to themselves 2 ⁇ thiazolamine, 4 -(2-chloro-4- methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5- methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt or solvate thereof.
  • a method of treating congenital adrenal hyperplasia in a subject comprising: administering to the subject a therapeutically effective amount of a delayed release oral pharmaceutical composition of hydrocortisone; i nstructing the subject to review the drug label of 2 ⁇ thiazolamine, 4 -(2-chloro-4- methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5- methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt or solvate thereof; and i nstructing the subject to administer to themselves 2 ⁇ thiazolamine, 4 -(2-chloro-4- methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5- methyl-N-2-propyn-1-yl
  • a method of treating adrenal dysfunction for example, congenital adrenal hyperplasia
  • a method of treating adrenal dysfunction comprising: administering to the subject a therapeutically effective amount of 2 ⁇ thiazolamine, 4 - (2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4- methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt or solvate thereof; and administering to the subject a therapeutically effective amount of a delayed release oral pharmaceutical composition of hydrocortisone.
  • 2 ⁇ thiazolamine 4-(2-chloro-4-methoxy-5-methylphenyl)-N- [(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt or solvate thereof for use in a method of treating adrenal dysfunction (for example, congenital adrenal hyperplasia) in a subject, the method comprising: administering to the subject a therapeutically effective amount of the 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4- methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or pharmaceutically acceptable salt or solvate thereof; and administering to the subject a therapeutically effective amount of
  • 2 ⁇ thiazolamine 4-(2-chloro-4-methoxy-5-methylphenyl)-N- [(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt or solvate thereof, for use in combination with a delayed release oral pharmaceutical composition of hydrocortisone in a method of treating adrenal dysfunction (for example, congenital adrenal hyperplasia) in a subject, the method comprising: administering to the subject a therapeutically effective amount of the 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4- methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or pharmaceutically acceptable salt or solv
  • a delayed release oral pharmaceutical composition of hydrocortisone for use in a method of treating adrenal dysfunction (for example, c ongenital adrenal hyperplasia) in a subject, the method comprising: administering to the subject a therapeutically effective amount of the delayed release oral pharmaceutical composition of hydrocortisone; and administering to the subject a therapeutically effective amount of 2 ⁇ thiazolamine, 4 - (2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4- methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt or solvate thereof.
  • a delayed release oral pharmaceutical composition of hydrocortisone for use in combination with 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5- methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N- 2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt or solvate thereof, in a method of treating adrenal dysfunction (for example, congenital adrenal hyperplasia) in a subject, the method comprising: administering to the subject a therapeutically effective amount of the delayed release oral pharmaceutical composition of hydrocortisone; and administering to the subject a therapeutically effective amount of the 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4- methylphenyl)ethyl]-5-
  • 2 ⁇ thiazolamine 4-(2-chloro-4-methoxy-5- methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N- 2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for use in a method of treating adrenal dysfunction (for e xample, congenital adrenal hyperplasia) in a subject, the method comprising: administering to the subject a therapeutically effective amount of the 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4- methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or pharmaceutically acceptable salt or solvate
  • hydrocortisone in the manufacture of a delayed release oral pharmaceutical composition for use in a method of treating adrenal dysfunction (for e xample, congenital adrenal hyperplasia) in a subject, the method comprising: administering to the subject a therapeutically effective amount of the delayed release oral pharmaceutical composition of hydrocortisone; and a dministering to the subject a therapeutically effective amount of 2 ⁇ thiazolamine, 4 - (2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4- methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt or solvate thereof.
  • the congenital adrenal hyperplasia is classic congenital adrenal hyperplasia.
  • the 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5- methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N- 2-propyn-1-yl (crinecerfont) is a freebase.
  • the delayed release oral pharmaceutical composition of hydrocortisone is an oral pharmaceutical composition comprising: a core comprising hydrocortisone, a binding agent, and a carrier; and a layer comprising a delayed release polymer, talc, and a plasticizer, wherein the layer comprising a delayed release polymer is in contact with said core, wherein said delayed release polymer is a mixture of (i) poly(methacrylic acid, methyl methacrylate) in a ratio of 1:1 and (ii) poly(methacrylic acid, methyl methacrylate) in a ratio of 1:2, wherein (i) and (ii) are at a ratio of 1:4 and at 6% to 7% w/w of the composition which is adapted to delay release of hydrocortisone from said core, wherein the hydrocortisone is at a concentration of 5-8% w/w of the composition, wherein the binding agent comprises povidone at a concentration of 0.5-4.0% w/w of the composition
  • Second-tier screening tests utilizing biochemical and molecular genetic testing methods are employed by nine states in the United States and strongly recommended by an additional 5 states.
  • the biochemical method includes immunoassay with organic solvent extraction or liquid chromatography followed by tandem mass spectrometry to measure steroid ratios of 17-OHP, androstenedione, and 21- deoxycortisol to cortisol (see, e.g., Lucasr et al., Int. J. Pediatr. Endocrinol. 2010:494173, 2010).
  • the genetic screen looks for CYP21A2 mutations that are associated with CAH.
  • CAH Treatment of CAH is based on normalization of hormone and steroid levels using a variety of medications from diagnosis in infancy through adulthood.
  • Glucocorticoids are the current standard treatment in CAH and are used both to correct the endogenous cortisol deficiency and for reducing the elevated ACTH levels from the pituitary, which drives increased androgen production.
  • Addison’s disease adrenal insufficiency
  • cortisol replacement the treatment of CAH must also reduce ACTH production, to control the subsequent androgen excess as well.
  • glucocorticoid treatment includes cortisol replacement and suppression of ACTH to prevent virilization and menstrual disturbances in women and to inhibit testicular adrenal rest tumors in men.
  • Mineralocorticoid replacement is needed to achieve normal plasma renin activity for maintenance of regular blood pressure, electrolyte balance, and volume status in those patients with the salt - wasting form of CAH.
  • the regimen of glucocorticoid treatment must support normal physiology and also ensure that sufficient cortisol is available during events that may elicit a strong stress response (e.g., intercurrent illness, exercise, hypotension).
  • Treatment of CAH includes efforts to normalize the cortisol deficiency with glucocorticoids (usually hydrocortisone in children but often more potent agents with narrow therapeutic indices, such as dexamethasone, in adults) and, if necessary for salt - wasting, mineralocorticoids (usually fludrocortisone).
  • glucocorticoids usually hydrocortisone in children but often more potent agents with narrow therapeutic indices, such as dexamethasone, in adults
  • salt - wasting, mineralocorticoids usually fludrocortisone
  • Corticotropin-releasing factor was isolated from ovine hypothalami and identified as a 41 ⁇ amino acid peptide. CRF has been found to produce profound alterations in endocrine, nervous, and immune system function.
  • CRF is believed to be the major physiological regulator of the basal and stress-induced release of adrenocorticotropic hormone ("ACTH”), ß-endorphin, and other pro-opiomelanocortin (“POMC”)-derived peptides from the anterior pituitary (see, e.g., Vale et al., Science 213:1394-1397, 1981).
  • ACTH adrenocorticotropic hormone
  • POMC pro-opiomelanocortin
  • Cortisol is a critical negative feedback regulator of hypothalamic CRF secretion and pituitary ACTH release.
  • the lack of glucocorticoid synthesis and release eliminates the restraint on the hypothalamus and pituitary, which causes ACTH levels to increase.
  • the excessive ACTH stimulation causes hypertrophy of the zona fasciculata and zona reticularis resulting in adrenal hyperplasia.
  • crinecerfont may also be named 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 and 4-(2-chloro- 4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5- methyl-N-(prop-2-yn-1-yl)-1,3-thiazol-2-amine (see International Nonproprietary Names for Pharmaceutical Substances (INN), WHO Drug Information, Vol.
  • Crinecerfont has an assigned CAS No. of 752253-39-7 with a CAS name of 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4- methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (CA INDEX NAME).
  • Crinecerfont has also been referred to in the art as “SSR125543” and “NBI-74788”.
  • the solution or slurry is atomized or rapidly dried with a hot gas, e.g., air or nitrogen, that causes the solvent to evaporate quickly and uniformly.
  • a “spray -dried dispersion” refers to the powder obtained from the spray-drying process.
  • 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.
  • Subject means a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.
  • the subject is a human.
  • the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.
  • the subject has been identified or diagnosed as having congenital adrenal hyperplasia (CAH).
  • CAH congenital adrenal hyperplasia
  • the subject is suspected of having CAH.
  • the subject has a clinical record indicating that the subject has CAH (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).
  • the subject is a pediatric subject.
  • the term “pediatric subject” as used herein refers to a subject under the age of 21 years at the time of diagnosis or treatment.
  • the term “pediatric” can be further divided into various subpopulations including: neonates (from birth through the first month of life); infants (1 month up to two years of age); children (two years of age up to 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)). Berhman et al., Textbook of Pediatrics, 15th Ed.
  • a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than two years of age, from two years of age to less than 12 years of age, or 12 years of age through 21 years of age (up to, but not including, the twenty-second birthday).
  • a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than 1 year of age, from one month of age to less than four months of age, from three months of age to less than seven months of age, from six months of age to less than 1 year of age, from 1 year of age to less than 2 years of age, from 2 years of age to less than 3 years of age, from 2 years of age to less than seven years of age, from 3 years of age to less than 5 years of age, from 5 years of age to less than 10 years of age, from 6 years of age to less than 13 years of age, from 10 years of age to less than 15 years of age, or from 15 years of age to less than 22 years of age.
  • treat or “treatment” refer to therapeutic or palliative measures.
  • Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • the term “preventing,” as used herein, means the prevention of the onset, recurrence or spread, in whole or in part, of the disease or condition as described herein, or a symptom thereof.
  • the term “administration” or “administering” refers to a method of giving a dosage of a compound or pharmaceutical formulation to a vertebrate or invertebrate, including a mammal, a bird, a fish, or an amphibian.
  • the preferred method of administration can vary depending on various factors, e.g., the components of the pharmaceutical formulation, the site of the disease, and the severity of the disease.
  • terapéuticaally effective amount is an amount of a compound (e.g., crinecerfont, or a pharmaceutically acceptable salt or solvate thereof, or hydrocortisone) or an amount of a pharmaceutical composition comprising the compound, which is sufficient to achieve the desired effect and can vary according to the nature and severity of the disease condition, and the potency of the compound.
  • a therapeutic effect is the relief, to some extent, of one or more of the symptoms of the disease, and can include curing a disease. “Curing” means that the symptoms of active disease are eliminated. However, certain long-term or permanent effects of the disease can exist even after a cure is obtained (such as, e.g., extensive tissue damage).
  • pharmaceutically acceptable means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredients. Such preparations may routinely contain salts, buffering agents, preservatives, compatible carriers, and optionally other therapeutic agents. When used in medicine, the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically-acceptable salts thereof.
  • Such pharmacologically and pharmaceutically-acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, 4-toluene sulfonic, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, citric, fo rmic, malonic, succinic, and the like.
  • pharmaceutically-acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts.
  • “delayed release” is a drug release profile delivered by a dosage form which is characterized by an initial period of complete absence of drug release or very low drug release, typically less than or equal to 10% of the overall dose in the dosage form, prior to the main drug release phase.
  • “enteric polymer” is a homopolymer or copolymer or mixtures thereof that have pH dependent solubility in aqueous media characterized generally by low aqueous solubility under acidic conditions (pH1-4) and higher aqueous solubility under weakly acidic conditions and above (pH>5). The purpose is to protect the dosage from polymer dissolution mediated release in the acidic gastric environment of the gut.
  • Dissolution testing may be conducted using USP Apparatus I (Baskets), with a total of 900 mL of dissolution media, involving two subsequent sequential media changes, and a basket speed of 100 rpm.
  • Dissolution is conducted initially in 700 mL of simulated gastric fluid (USP, pH 1.2) for 2 hours, followed by further dissolution in 850 mL of media adjusted to pH 6.0 (via the addition of pre-warmed 150 mL of 0.18M trisodium ortho phosphate dodecahydrate buffer) for 1 hour, and then dissolution in 900 mL of media adjusted to pH 7.2 (via the addition of pre-warmed 50 mL of 0.23M trisodium ortho phosphate dodecahydrate buffer).
  • USP Apparatus I Baskets
  • “Eudragit L100” is a defined mixture of polymethacrylates [CAS number: 2506-15-1] with the chemical composition: poly(methacrylic acid, methyl methacrylate) in a ratio of 1:1.
  • “Eudragit S100” is a defined mixture of polymethacrylates [CAS number: 25086-15-1] with the chemical composition: poly(methacrylic acid, methyl methacrylate) in a ratio of 1:2.
  • the terms “multi-particulate” and “micro-particulate” are interchangeable and are equivalent to one another in form and function.
  • a “micro - particulate carrier” is a particulate dispersion of solid particles with a size in the range of an average diameter (D50) of 1-1000 ⁇ m on which the desired drug is dissolved, entrapped, or attached to a microparticle matrix. Average diameter values recited herein may be determined by imaging techniques.
  • “delayed release polymer” refers to a pH sensitive enteric polymer and is adapted to delay release of hydrocortisone from said core.
  • enteric polymer is a homopolymer or copolymer or mixtures thereof that have pH dependent solubility in aqueous media characterized generally by low aqueous solubility under acidic conditions (pH1-4) and higher aqueous solubility under weakly acidic conditions and above (pH>5). The purpose is to protect the dosage from polymer dissolution mediated release in the acidic gastric environment of the gut.
  • immediate release means a dosage form that is intended to release the active ingredient(s) on administration or after a short delay with no enhanced, delayed, or extended release effect.
  • the units “%w/w”, “% w/w”, “wt.%”, “%w/v”, “w/v%”, “%v/v”, “v/v%”, etc. refer to the amount of a substance in a composition or formulation with reference to the whole composition or formulation.
  • the mass of the substance with reference to the mass of the formulation %w/w; % w/w; wt.% or the mass of the substance with reference to the volume of the formulation (%w/v; w/v%) or the volume of the substance with reference to the volume of the formulation (%v/v; v/v%).
  • the term “fed state,” refers to administration to a subject of a medicament from about 1 hour before consumption of food or a nutritional composition to about 1 hour after consumption of food or a nutritional composition.
  • the term “fasted state,” as used herein, refers to a gap of at least two hours between consumption of food o r a nutritional composition and administration to a subject of a medicament.
  • a method of treating adrenal dysfunction for example, congenital adrenal hyperplasia
  • the multi-layer oral pharmaceutical composition is a d elayed release oral pharmaceutical composition of hydrocortisone as described herein.
  • a method of treating adrenal dysfunction comprising: a dministering to the subject a therapeutically effective amount of 2 ⁇ thiazolamine, 4 - (2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4- methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt or solvate thereof; and administering to the subject a therapeutically effective amount of an oral liquid formulation of hydrocortisone.
  • the 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5- methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N- 2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof is provided in a lipidic semi-solid formulation or an oral solution dosage formulation as described herein.
  • the 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5- methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N- 2-propyn-1-yl (crinecerfont) is a free base.
  • the adrenal dysfunction is congenital adrenal hyperplasia (CAH) or adrenal insufficiency.
  • CAH congenital adrenal hyperplasia
  • CAH congenital adrenal hyperplasia
  • CAH congenital adrenal hyperplasia
  • the CAH is classic CAH. In some embodiments the classic CAH is due to 21-hydroxylase deficiency.
  • the subject has a mutation in the CYP21A2 gene located on chromosome 6p21. In some embodiments the subject does not have a mutation of the 11 ⁇ -hydroxylase gene CYP11B1 (11 ⁇ -OH CAH).
  • the adrenal dysfunction is adrenal insufficiency. In some embodiments the adrenal dysfunction is primary adrenal insufficiency. In some embodiments the adrenal dysfunction is secondary adrenal insufficiency. In some embodiments the adrenal dysfunction is tertiary adrenal insufficiency.
  • the method is a method of treating congenital adrenal hyperplasia in a subject comprising: a dministering to the subject a therapeutically effective amount of 2 ⁇ thiazolamine, 4 - (2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4- methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt or solvate thereof; and administering to the subject a therapeutically effective amount of a delayed release oral pharmaceutical composition of hydrocortisone.
  • Also provided herein is a method of treating congenital adrenal hyperplasia in a subject comprising: a dministering to the subject a therapeutically effective amount of 2 ⁇ thiazolamine, 4 - (2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4- methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt or solvate thereof; and instructing the subject to administer to themselves a delayed release oral pharmaceutical composition of hydrocortisone, as described herein.
  • a method of treating congenital adrenal hyperplasia in a subject comprising: administering to the subject a therapeutically effective amount of a delayed release oral pharmaceutical composition of hydrocortisone; and i nstructing the subject to administer to themselves 2 ⁇ thiazolamine, 4 -(2-chloro-4- methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5- methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt or solvate thereof.
  • Subject characteristics comprises measuring a subject characteristic at a first time point.
  • the method comprises measuring a subject characteristic at a second time point. In some embodiments, the method comprises identifying the change in the subject characteristic between the first time point and the second time point.
  • the subject characteristic is selected from body mass, body mass index, waist circumference, body fat percentage, the blood serum level of 17- hydroxyprogesterone, the blood plasma level of adrenocorticotropic hormone, and the blood serum level of androstenedione.
  • the subject is on a stable dose of glucocorticoid (e.g., a stable dose of hydrocortisone or a stable dose of another glucocorticoid measured in hydrocortisone equivalents).
  • the subject is on a dose of glucocorticoid (e.g., a dose of hydrocortisone or a dose of another glucocorticoid measured in hydrocortisone equivalents) which is reduced with respect to the stable dose of glucocorticoid at the first time point.
  • a “stable dose” is a dosage which has been optimized for clinical need by a clinician and has been administered to the subject for a period of at least one month without a change in the dosage.
  • Weight loss [0079]
  • the method comprises measuring body mass of the subject at a first time point. In some embodiments, the method comprises measuring body mass of the subject at a second time point. In some embodiments, the method comprises measuring body mass of the subject at a first time point and a second time point. In some embodiments, the body mass of the subject at the second time point is between 1% and 25% less than the body mass of the subject at the first time point.
  • t he body mass of the subject at the second time point is at least about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25% less than the body mass of the subject at the first time point.
  • the body mass of the subject at the second time point is between 500 g and 25 kg less than the body mass of the subject at the first time point.
  • the body mass of the subject at the second time point is at least about 500 g, about 1 kg, about 2 kg, about 3 kg, about 4 kg, about 5 kg, about 6 kg, about 7 kg, about 8 kg, about 9 kg, about 10 kg, about 11 kg, about 12 kg, about 13 kg, about 14 kg, about 15 kg, about 16 kg, about 17 kg, about 18 kg, about 19 kg, about 20 kg, about 21 kg, about 22 kg, about 23 kg, about 24 kg, or about 25 kg less than the body mass of the subject at the first time point.
  • the method comprises determining body mass index (BMI) of the subject at a first time point.
  • the method comprises determining body mass index (BMI) of the subject at a second time point. In some embodiments, the method comprises determining body mass index (BMI) of the subject at a first time point and a second time point. In some embodiments, the body mass index (BMI) of the subject at the second time point is between 0.1 kg/m 2 and 10 kg/m 2 less than the body mass index (BMI) of the subject at the first time point.
  • the body mass index (BMI) of the subject at the second time point is at least about 0.1 kg/m 2 , about 0.2 kg/m 2 , about 0.3 kg/m 2 , about 0.4 kg/m 2 , about 0.5 kg/m 2 , about 0.6 kg/m 2 , about 0.7 kg/m 2 , about 0.8 kg/m 2 , about 0.9 kg/m 2 , about 1 kg/m 2 , about 1.1 kg/m 2 , about 1.2 kg/m 2 , about 1.3 kg/m 2 , about 1.4 kg/m 2 , about 1.5 kg/m 2 , about 1.6 kg/m 2 , about 1.7 kg/m 2 , about 1.8 kg/m 2 , about 1.9 kg/m 2 , about 2 kg/m 2 , about 2.1 kg/m 2 , about 2.2 kg/m 2 , about 2.3 kg/m 2 , about 2.4 kg/m 2 , about 2.5 kg/m 2 , about 2.6 kg/m 2 , about
  • Body mass index is determined by the subject's weight in kilograms (kg) divided by the square of their height in meters (m).
  • the method comprises measuring waist circumference of the subject at a first time point. In some embodiments, the method comprises measuring waist circumference of the subject at a second time point. In some embodiments, the method comprises measuring waist circumference of the subject at a first time point and a second time point. In some embodiments, the waist circumference of the subject at the second time point is between 1 cm and 30 cm less than the waist circumference of the subject at the first time point.
  • the waist circumference of the subject at the second time point is at least about 1 cm, about 2 cm, about 3 cm, about 4 cm, about 5 cm, about 6 cm, about 7 cm, about 8 cm, about 9 cm, about 10 cm, about 11 cm, about 12 cm, about 13 cm, about 14 cm, about 15 cm, about 16 cm, about 17 cm, about 18 cm, about 19 cm, about 20 cm, about 21 cm, about 22 cm, about 23 cm, about 24 cm, about 25 cm, about 26 cm, about 27 cm, about 28 cm, about 29 cm, or about 30 cm less than the waist circumference of the subject at the first time point.
  • Waist circumference is measured by placing a measuring tape around the middle of the subject, just about their hipbones, in a standing position, ensuring that the tape is horizontal around the waist, keeping the tape snug around the waist but not compressing the skin and measuring the waist circumference just after breathing out (see, e.g., “The Practical Guide Identification, Evaluation, and Treatment of Overweight and Obesity in Adults”; National Institutes of Health; National Heart, Lung, and Blood Institute; North American Association for the Study of Obesity; NIH Publication Number 00-4084; October 2000, which is hereby incorporated by reference in its entirety).
  • the method comprises measuring body fat percentage of the subject at a first time point.
  • the method comprises measuring body fat percentage of the subject at a second time point. In some embodiments, the method comprises measuring body fat percentage of the subject at a first time point and a second time point. In some embodiments, the body fat percentage of the subject at the second time point is between 1% and 25% less than the body fat percentage of the subject at the first time point.
  • the body fat percentage of the subject at the second time point is at least about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, or about 25% less than the body fat percentage of the subject at the first time point.
  • Body fat percentage of the subject is measured by a trained individual using body calipers and the method of Jackson & Pollock (Jackson & Pollock, “Practical Assessment of Body Composition”, The Physician and Sportsmedicine, 1985, vol. 13, iss.
  • Biomarkers [0083] Provided herein is a method of treating congenital adrenal hyperplasia (CAH) according to a method described herein, wherein the treating normalizes or partially normalizes levels of biomarkers associated with congenital adrenal hyperplasia.
  • CAH congenital adrenal hyperplasia
  • normalizing or partially normalizing levels of biomarkers comprises reducing levels of elevated biomarkers or increasing levels of depressed biomarkers as compared to subject without CAH.
  • the biomarkers are selected from (a) 17- hydroxyprogesterone (17-OHP); (b) adrenocorticotropic hormone (ACTH); and (c) androstenedione in the subject.
  • the change in level of any of the biomarkers is determined by comparing the blood serum level of the biomarker as measured during the circadian release on a day prior to administering according to a method described herein and the blood serum level of the biomarker as measured during the circadian release on the day after administering according to a method described herein.
  • the change in level of any of the biomarkers is determined by comparing the blood plasma level of the biomarker as measured during the circadian release on a day prior to administering according to a method described herein and the blood plasma level of the biomarker as measured during the circadian release on the day after administering according to a method described herein.
  • the circadian release of biomarkers associated with CAH occurs between the hours of 2 a.m. and 10 a.m.
  • the circadian release of biomarkers associated with CAH occurs between the hours of 6 a.m. and 10 a.m.
  • the method comprises measuring the blood serum level of 17-hydroxyprogesterone (17-OHP) of the subject at a first time point. In some embodiments, the method comprises measuring the blood serum level of 17- hydroxyprogesterone (17-OHP) of the subject at a second time point. In some embodiments, the method comprises measuring the blood serum level of 17- hydroxyprogesterone (17-OHP) of the subject at a first time point and at a second time point.
  • the blood serum level of 17-hydroxyprogesterone is reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55% or at least 60% at the second time point as compared to the first time point. In some embodiments, the blood serum level of 17-hydroxyprogesterone is reduced by at least 5%, at least 10%, at least 15%, or at least 20% at the second time point as compared to the first time point. In some embodiments, the blood serum level of 17-hydroxyprogesterone is reduced by at least 5% at the second time point as compared to the first time point.
  • the blood serum level of 17-hydroxyprogesterone is reduced by at least 10% at the second time point as compared to the first time point. In some embodiments, the blood serum level of 17-hydroxyprogesterone is reduced by at least 15% at the second time point as compared to the first time point. In some embodiments, the blood serum level of 17- hydroxyprogesterone is reduced by at least 20% at the second time point as compared to the first time point. [0088] In some embodiments, the blood serum level of 17-hydroxyprogesterone is reduced to a level within the range of 17-hydroxyprogesterone expected for a subject without CAH, i.e., less than 1,000 ng/dL or less than 200 ng/dL.
  • the method comprises measuring the blood plasma level of adrenocorticotropic hormone of the subject at a first time point. In some embodiments, the method comprises measuring the blood plasma level of adrenocorticotropic hormone of the subject at a second time point. In some embodiments, the method comprises measuring the blood plasma level of adrenocorticotropic hormone of the subject at a first time point and at a second time point.
  • the blood plasma level of adrenocorticotropic hormone is reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55% or at least 60% at the second time point as compared to the first time point. In some embodiments, the blood plasma level of adrenocorticotropic hormone is reduced by at least 5%, at least 10%, at least 15%, or at least 20% at the second time point as compared to the first time point. In some embodiments, the blood plasma level of adrenocorticotropic hormone is reduced by at least 5% at the second time point as compared to the first time point.
  • the blood plasma level of adrenocorticotropic hormone is reduced by at least 10% at the second time point as compared to the first time point. In some embodiments, the blood plasma level of adrenocorticotropic hormone is reduced by at least 15% at the second time point as compared to the first time point. In some embodiments, the blood plasma level of adrenocorticotropic hormone is reduced by at least 20% at the second time point as compared to the first time point. [0090] In some embodiments, the blood plasma level of adrenocorticotropic hormone is reduced to a level within the range of adrenocorticotropic hormone expected for a subject without CAH.
  • the method comprises measuring the blood serum level of androstenedione of the subject at a first time point. In some embodiments, the method comprises measuring the blood serum level of androstenedione of the subject at a second time point. In some embodiments, the method comprises measuring the blood serum level of androstenedione of the subject at a first time point and at a second time point. In some embodiments, the blood serum level of androstenedione is reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55% or at least 60% at the second time point as compared to the first time point.
  • the blood serum level of androstenedione is reduced by at least 5%, at least 10%, at least 15%, or at least 20% at the second time point as compared to the first time point. In some embodiments, the blood serum level of androstenedione is reduced by at least 5% at the second time point as compared to the first time point. In some embodiments, the blood serum level of androstenedione is reduced by at least 10% at the second time point as compared to the first time point. In some embodiments, the blood serum level of androstenedione is reduced by at least 15% at the second time point as compared to the first time point.
  • the blood serum level of androstenedione is reduced by at least 20% at the second time point as compared to the first time point. [0092] In some embodiments, the blood serum level of androstenedione is reduced to a level within the range of androstenedione expected for a subject without CAH, i.e., less than 200 ng/dL.
  • Time points [0093] In some embodiments, the first time point is from 1 month before beginning the administering of a method described herein to 1 month after beginning the administering of a method described herein. In some embodiments, the first time point is from 1 month before beginning the administering of a method described herein to 1 week after beginning the administering of a method described herein.
  • the first time point is from 1 week before beginning the administering of a method described herein to 1 day after beginning the administering of a method described herein. In some embodiments, the first time point is the same day as beginning the administering of a method described herein. [0094] In some embodiments, the second time point at least one month after beginning the administering of a method described herein. In some embodiments, the second time point is about 1 month, about 2 months, about 3 months, about 6 months, about 9 months, about 12 months, or more after beginning the administering of a method described herein.
  • the second time point is about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 36 weeks, about 48 weeks, about 52 weeks or more after beginning the administering of a method described herein. In some embodiments, the second time point is about 24 weeks after beginning the administering of a method described herein. [0095] In some embodiments, the first time point and the second time point are separated in time by at least about 1 month. In some embodiments, the first time point and the second time point are separated in time by about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 9 months, about 12 months, or more.
  • first time point and the second time point are separated in time by at least about 4 weeks, about 8 weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 36 weeks, about 48 weeks, about 52 weeks, or more. In some embodiments, the first time point and the second time point are separated in time by at least about 24 weeks.
  • glucocorticoid treatment also provided herein is a method of reducing the severity of one or more side effects of glucocorticoid treatment in a subject having congenital adrenal hyperplasia comprising administering to the subject 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5- methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N- 2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt or solvate thereof, and administering to the subject a delayed release oral pharmaceutical composition of hydrocortisone.
  • Glucocorticoids are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebrate animal cell. In some embodiments, the subject is concurrently receiving a dose of a glucocorticoid.
  • the glucocorticoid is selected from cortisol (hydrocortisone), cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, fludrocortisone acetate, and deoxycorticosterone acetate.
  • the glucocorticoid is cortisol (hydrocortisone).
  • the glucocorticoid is cortisone.
  • the glucocorticoid is prednisone.
  • the glucocorticoid is dexamethasone.
  • the glucocorticoid dose is measured in hydrocortisone equivalents. In some embodiments, the glucocorticoid dose is measured as a multiple of the upper limit of normal of physiologic dosing in hydrocortisone equivalents. Any glucocorticoid can be given in a dose that provides approximately the same glucocorticoid effects as normal cortisol production; this is referred to as physiologic, replacement, or maintenance dosing. [0099] The long-term effects of glucocorticoid treatment are well documented in the art (see, e.g., Oray, M. et al.
  • glucocorticoids e.g., glucocorticoids, Expert Opinion on Drug Safety. DOI: 10.1517/14740338.2016.1140743, which is hereby incorporated by reference in its entirety).
  • musculoskeletal e.g., osteoporosis, avascular necrosis of bone, and myopathy
  • endocrine and metabolic e.g., hyperglycemia, diabetes mellitus, dyslipidemia, weight gain, Cushing syndrome, Cushingoid features, growth suppression, adrenal suppression
  • gastrointestinal e.g., gastritis, peptic ulcer, gastrointestinal bleeding, visceral perforation, hepatic steatosis, pancreatitis
  • cardiovascular e.g., hypertension, coronary heart disease, ischemic heart disease, heart failure
  • dermatologic e.g., dermatoprosis, skin atrophy, ecchymosis, purpura, erosions, striae, delayed wound healing,
  • the side effects of glucocorticoid treatment are selected from osteoporosis, avascular necrosis of bone, myopathy, hyperglycemia, diabetes mellitus, dyslipidemia, weight gain, Cushing syndrome, Cushingoid features, growth suppression, adrenal suppression, gastritis, peptic ulcer, gastrointestinal bleeding, visceral perforation, hepatic steatosis, pancreatitis, hypertension, coronary heart disease, ischemic heart disease, heart failure, dermatoprosis, skin atrophy, ecchymosis, purpura, erosions, striae, delayed wound healing, easy bruising, acne, hirsutism, hair loss, mood changes, depression, euphoria, mood lability, irritability, akathisia, anxiety, cognitive impairment, psychosis, dementia, delirium, cataract, glaucoma, ptosis, mydriasis, op
  • the side effects of glucocorticoid treatment are selected from hyperglycemia, diabetes mellitus, dyslipidemia, weight gain, Cushing syndrome, Cushingoid features, growth suppression, and adrenal suppression.
  • the side effect of glucocorticoid treatment is weight gain.
  • one or more symptoms selected from quality of life, fatigue, sleep, insulin resistance, glucose tolerance, glucose control, dyslipidemia, hyperlipidemia, bone mineral density, bone turnover, fat mass, weight, central obesity, blood pressure, hirsutism severity, menstrual cyclicity, control of testicular adrenal rest tumor (TART), control of ovarian adrenal rest tumors (OART) and fertility is improved after a time period of administering, wherein the improvement in the one or more symptoms is relative to the status of the one or more symptoms prior to beginning administration.
  • the time period of administration is at least about 4 weeks. In some embodiments, the time period of administration is at least about 24 weeks.
  • the time period of administration is at least about one year. In some embodiments, the time period of administration is at least 4 weeks. In some embodiments, the time period of administration is at least 24 weeks. In some embodiments, the time period of administration is at least one year. In some embodiments, the time period of administration is less than about 1 day. In some embodiments, the time period of administration is about 1, 2, 3, 4, 5, 6 or 7 days, or within a range of any of the preceding values. In some embodiments, the time period of administration is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 weeks, or within a range of any of the preceding values.
  • the time period of administration is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, or within a range of any of the preceding values. It is understood that comparative measurements occur preferably during the morning.
  • the subject [0105] In some embodiments, the subject is a mammal subject. In some embodiments, the subject is a human subject. [0106] In some embodiments, the subject is a pediatric subject (i.e., a human pediatric subject). In some embodiments, the pediatric subject is less than or equal to six years old. In some embodiments, the pediatric subject is greater than six years old and less than eleven years old. In some embodiments, the pediatric subject is greater than ten years old and less than fifteen years old.
  • the pediatric subject is greater than fourteen years old and less than nineteen years old. In some embodiments, the pediatric subject weighs less than 55 kg. In some embodiments, the pediatric subject weighs from about 20 kg to about 55 kg. In some embodiments, the pediatric subject weighs from about 10 kg to about 20 kg. [0107] In some embodiments, the subject is an adult subject (i.e., a human adult subject). In some embodiments, the adult subject is over eighteen years old. In some embodiments, the adult subject is over twenty one years old. [0108] In some embodiments, the subject is female. In some embodiments, the subject is male.
  • the subject has a body mass index (BMI) of at least about 25 kg/m 2 before beginning the administering of a method described herein. [0110] In some embodiments, the subject has a body mass index (BMI) of at least about 30 kg/m 2 before beginning the administering of a method described herein.
  • the doses of 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)- 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof, and hydrocortisone administered to a subject can be chosen in accordance with different parameters, in particular the state of the subject and also their weight. Other factors include the desired period of treatment. In the event that a response in a subject is insufficient at the initial doses applied, higher doses (or effectively higher doses) may be employed to the extent that patient tolerance permits.
  • the administering of 2 ⁇ thiazolamine, 4-(2-chloro-4- methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5- methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof is daily.
  • the therapeutically effective amount of crinecerfont, or pharmaceutically acceptable salt or solvate thereof is a total daily dose of from 25 mg to 500 mg of crinecerfont, or a pharmaceutically acceptable salt or solvate thereof, based on the weight of the free base.
  • the therapeutically effective amount of crinecerfont, or pharmaceutically acceptable salt or solvate thereof is a total daily dose of 50 mg, 100 mg, 200 mg, or 400 mg of crinecerfont, or a pharmaceutically acceptable salt or solvate thereof, based on the weight of the free base. In some embodiments, the therapeutically effective amount of crinecerfont, or pharmaceutically acceptable salt or solvate thereof, is a total daily dose of 50 mg based on the weight of the free base. In some embodiments, the therapeutically effective amount of crinecerfont, or pharmaceutically acceptable salt or solvate thereof, is a total daily dose of 100 mg based on the weight of the free base.
  • the therapeutically effective amount of crinecerfont, or pharmaceutically acceptable salt or solvate thereof is a total daily dose of 200 mg based on the weight of the free base. In some embodiments, the therapeutically effective amount of crinecerfont, or pharmaceutically acceptable salt or solvate thereof, is a total daily dose of 400 mg based on the weight of the free base.
  • the subject is in a fed state on administering of crinecerfont, or a pharmaceutically acceptable salt thereof. In some embodiments, the fed state is with a high fat meal. In some embodiments, the fed state is with a low fat meal.
  • the therapeutically effective amount of crinecerfont, or pharmaceutically acceptable salt or solvate thereof is administered twice daily in a first daily dose and a second daily dose. In some embodiments, the therapeutically effective amount of crinecerfont, or pharmaceutically acceptable salt or solvate thereof, is administered twice daily and is equally divided between a first daily dose and a second daily dose.
  • the first daily dose of crinecerfont, or pharmaceutically acceptable salt or solvate thereof is administered in the morning.
  • the first daily dose of crinecerfont, or pharmaceutically acceptable salt or solvate thereof is selected from 25 mg, 50 mg 100 mg, and 200 mg of crinecerfont, or a pharmaceutically acceptable salt or solvate thereof, based on the weight of the free base.
  • the first daily dose of crinecerfont, or pharmaceutically acceptable salt or solvate thereof is 25 mg based on the weight of the free base.
  • the first daily dose of crinecerfont, or pharmaceutically acceptable salt or solvate thereof is 50 mg based on the weight of the free base.
  • the first daily dose of crinecerfont, or pharmaceutically acceptable salt or solvate thereof is 100 mg based on the weight of the free base. In some embodiments, the first daily dose of crinecerfont, or pharmaceutically acceptable salt or solvate thereof, is 200 mg based on the weight of the free base. In some embodiments, the second daily dose of crinecerfont, or pharmaceutically acceptable salt or solvate thereof, is administered in the evening. In some embodiments, the second daily dose of crinecerfont, or pharmaceutically acceptable salt or solvate thereof, is selected from 25 mg, 50 mg 100 mg, and 200 mg of crinecerfont, or a pharmaceutically acceptable salt or solvate thereof, based on the weight of the free base.
  • the second daily dose of crinecerfont, or pharmaceutically acceptable salt or solvate thereof is 25 mg based on the weight of the free base. In some embodiments, the second daily dose of crinecerfont, or pharmaceutically acceptable salt or solvate thereof, is 50 mg based on the weight of the free base. In some embodiments, the second daily dose of crinecerfont, or pharmaceutically acceptable salt or solvate thereof, is 100 mg based on the weight of the free base. In some embodiments, the second daily dose of crinecerfont, or pharmaceutically acceptable salt or solvate thereof, is 200 mg based on the weight of the free base.
  • the administering of hydrocortisone is daily.
  • the therapeutically effective amount of the multi -layer oral pharmaceutical composition of hydrocortisone is a total daily dose of from 2.5 mg to 80 mg of hydrocortisone. In some embodiments, the therapeutically effective amount of the multi-layer oral pharmaceutical composition of hydrocortisone is a total daily dose of from 7.5 mg to 40 mg of hydrocortisone.
  • the therapeutically effective amount of the multi-layer oral pharmaceutical composition of hydrocortisone is a total daily dose of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg hydrocortisone.
  • the therapeutically effective amount of the delayed release oral pharmaceutical composition of hydrocortisone is a total daily dose of from 10 mg to 40 mg of hydrocortisone.
  • the therapeutically effective amount of the delayed release oral pharmaceutical composition of hydrocortisone is a total daily dose of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, or 40 mg hydrocortisone.
  • the therapeutically effective amount of the delayed release oral pharmaceutical composition of hydrocortisone is a total daily dose of 10 mg hydrocortisone. In some embodiments, the therapeutically effective amount of the delayed release oral pharmaceutical composition of hydrocortisone is a total daily dose of 15 mg hydrocortisone. In some embodiments, the therapeutically effective amount of the delayed release oral pharmaceutical composition of hydrocortisone is a total daily dose of 20 mg hydrocortisone. In some embodiments, the therapeutically effective amount of the delayed release oral pharmaceutical composition of hydrocortisone is a total daily dose of 25 mg hydrocortisone. In some embodiments, the therapeutically effective amount of the delayed release oral pharmaceutical composition of hydrocortisone is a total daily dose of 30 mg hydrocortisone.
  • the therapeutically effective amount of the delayed release oral pharmaceutical composition of hydrocortisone is a total daily dose of 35 mg hydrocortisone. In some embodiments, the therapeutically effective amount of the delayed release oral pharmaceutical composition of hydrocortisone is a total daily dose of 40 mg hydrocortisone. [0119] In some embodiments, the therapeutically effective amount of the delayed release oral pharmaceutical composition of hydrocortisone is administered twice daily in a first daily dose and a second daily dose. In some embodiments, the second daily dose of the delayed release oral pharmaceutical composition of hydrocortisone delivers a greater amount of hydrocortisone than the first daily dose of the delayed release oral pharmaceutical composition of hydrocortisone.
  • the ratio between the amount of hydrocortisone delivered by the first daily dose and the second daily dose of the delayed release oral pharmaceutical composition of hydrocortisone is from 1:1.05 to 1:10. In some embodiments, the ratio between the amount of hydrocortisone delivered by the first daily dose and the second daily dose of the delayed release oral pharmaceutical composition of hydrocortisone is from 1:1.5 to 1:5. In some embodiments, the ratio between the amount of hydrocortisone delivered by the first daily dose and the second daily dose of the delayed release oral pharmaceutical composition of hydrocortisone is from 1:2 to 1:3. [0120] In some embodiments, the first daily dose of the delayed release oral pharmaceutical composition of hydrocortisone is administered in the morning.
  • the second daily dose of the delayed release oral pharmaceutical composition of hydrocortisone is administered in the evening.
  • the subject is in a fasted state on the administering of the delayed release oral pharmaceutical composition of hydrocortisone.
  • the first daily dose of the delayed release oral pharmaceutical composition of hydrocortisone is administered in the morning, at least 1 hour before a meal and at least 2 hours after the previous meal.
  • the second daily dose is of the delayed release oral pharmaceutical composition of hydrocortisone is administered in the evening, at least 2 hours after the previous meal and at least one hour before the next meal.
  • the therapeutically effective amount of the immediate release oral pharmaceutical composition of hydrocortisone is a total daily dose of from 2.5 mg to 20 mg hydrocortisone. In some embodiments, the therapeutically effective amount of the immediate release oral pharmaceutical composition of hydrocortisone is a total daily dose of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, or 20 mg hydrocortisone. In some embodiments, the therapeutically effective amount of the immediate release oral pharmaceutical composition of hydrocortisone is administered three or four times daily in divided doses. [0122] In some embodiments, the therapeutically effective amount of the oral liquid formulations of hydrocortisone is a total daily dose of from 2.5 mg to 20 mg hydrocortisone.
  • the therapeutically effective amount of the oral liquid formulations of hydrocortisone is a total daily dose of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, or 20 mg hydrocortisone. In some embodiments, the therapeutically effective amount of the oral liquid formulations of hydrocortisone is administered three or four times daily in divided doses. [0123] In some embodiments, the administering of crinecerfont, or pharmaceutically acceptable salt or solvate thereof, and the administering of the delayed release oral pharmaceutical composition of hydrocortisone is separate. In some embodiments, the administering of crinecerfont, or pharmaceutically acceptable salt or solvate thereof, and the administering of the delayed release oral pharmaceutical composition of hydrocortisone is sequential.
  • the administering of crinecerfont, or pharmaceutically acceptable salt or solvate thereof, and the administering of the delayed r elease oral pharmaceutical composition of hydrocortisone is simultaneous.
  • the crinecerfont, or pharmaceutically acceptable salt or solvate thereof is administered twice daily in a first daily dose and a second daily dose
  • the delayed release oral pharmaceutical composition of hydrocortisone is a dministered twice daily in a first daily dose and a second daily dose.
  • the first daily dose of the delayed release oral pharmaceutical composition of hydrocortisone is administered to the subject before the first daily dose of crinecerfont, or pharmaceutically acceptable salt or solvate thereof, is administered to the subject; and the second daily dose of the delayed release oral pharmaceutical composition of hydrocortisone is administered to the subject after the second daily dose of crinecerfont, or pharmaceutically acceptable salt or solvate thereof, is administered to the subject.
  • the first daily dose of the delayed release oral pharmaceutical composition of hydrocortisone is administered to the subject in a fasted state in the morning before the first daily dose of crinecerfont, or pharmaceutically acceptable salt or solvate thereof, is administered to the subject in a fed state in the morning; and the second daily dose of the delayed release oral pharmaceutical composition of hydrocortisone is administered to the subject in a fasted state in the evening after the second daily dose of crinecerfont, or pharmaceutically acceptable salt o r solvate thereof, is administered to the subject in a fed state in the evening.
  • Lipidic semi-solid formulations of crinecerfont are provided herein (e.g., for use in the methods disclosed herein)
  • a lipidic semi- solid formulation which is a pharmaceutical composition comprising: a. 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1- (3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof;
  • the pharmaceutical composition comprises about 5 %w/w to about 20% w/w of 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)- 2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof, based on the weight of the free base.
  • the pharmaceutical composition comprises about 5 %w/w, about 6 %w/w, about 7 %w/w, about 8 %w/w, about 9 %w/w, about 10 %w/w, about 11 %w/w, about 12 %w/w, about 13 %w/w, about 14 %w/w, about 15 %w/w, about 16 %w/w, about 17 %w/w, about 18 %w/w, about 19 %w/w, about 20 %w/w of 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3- fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof, based on the weight of the free base.
  • the pharmaceutical composition comprises about 10 %w/w of 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3- fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof, based on the weight of the free base.
  • the pharmaceutical composition comprises about 10 %w/w of 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3- fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont) as a free base.
  • the pharmaceutical composition comprises about 16 %w/w of 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3- fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof, based on the weight of the free base.
  • the pharmaceutical composition comprises about 16 %w/w of 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3- fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont) as a free base.
  • An oily phase vehicle is a solvent that is poorly miscible with water.
  • the pharmaceutical composition comprises about 20 %w/w to about 50 %w/w of the oily phase vehicle.
  • the pharmaceutical composition comprises about 35 %w/w to about 45 %w/w of the oily phase vehicle.
  • the pharmaceutical composition comprises about 39 %w/w of the oily phase vehicle. In some embodiments, the pharmaceutical composition comprises about 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45 %w/w of the oily phase vehicle, or within a range of any of the preceding values.
  • the oily phase vehicle is selected from medium-chain triglycerides, glycerin, propylene glycol, polyethylene glycol, olive oil, soybean oil, corn oil, and transcutol. In some embodiments, the oily phase vehicle is medium-chain triglycerides. In some embodiments, the medium-chain triglycerides are Labrafac TM Lipophile WL1349.
  • the medium-chain triglycerides are Miglyol 812N.
  • An emulsifying agent is a compound or substance that acts as a stabilizer for emulsions.
  • the pharmaceutical composition comprises about 10 %w/w to about 30 %w/w of the emulsifying agent. In some embodiments, the pharmaceutical composition comprises about 15 %w/w to about 25 %w/w of the emulsifying agent. In some embodiments, the pharmaceutical composition comprises about 20 %w/w of the emulsifying agent.
  • 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/w of the emulsifying agent, or within a range of any of the preceding values.
  • the emulsifying agent is selected from medium-chain triglycerides, propylene glycol dicaprylate/dicaprate, glycerin, propylene glycol, polyethylene glycol, olive oil, soybean oil, corn oil, and transcutol.
  • the emulsifying agent is propylene glycol dicaprylate/dicaprate.
  • the propylene glycol dicaprylate/dicaprate is Labrafac TM PG.
  • a nonionic surfactant is a substance with a hydrophilic head and a hydrophobic tail that has no charge that is a formulation component added to improve solubility or emulsion properties.
  • the pharmaceutical composition comprises about 10 %w/w to about 30 %w/w of the nonionic surfactant. In some embodiments, the pharmaceutical composition comprises about 15 %w/w to about 25 %w/w of the nonionic surfactant. In some embodiments, the pharmaceutical composition comprises about 19 %w/w of the nonionic surfactant.
  • 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/w of the nonionic surfactant, or within a range of any of the preceding values.
  • the nonionic surfactant is selected from oleoyl polyoxyl- 6 glycerides, linoleoyl polyoxyl-6 glycerides, Polysorbate 80, Polysorbate 20, Gelucire, lauroyl polyoxyl-32 glycerides, Poloxamer, PEG-32 stearate, and PEG-32 hydrogenated palm glycerides.
  • the nonionic surfactant is lauroyl polyoxyl-32 glycerides.
  • the lauroyl polyoxyl-32 glycerides are Gelucire® 44/14.
  • a solubilizing agent is a solvent that assists with solubilizing the 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4- methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition comprises about 1 %w/w to about 20 %w/w of the solubilizing agent. In some embodiments, the pharmaceutical composition comprises about 5 %w/w to about 15 %w/w of the solubilizing agent. In some embodiments, the pharmaceutical composition comprises about 11 %w/w of the solubilizing agent. In some embodiments, the pharmaceutical composition comprises about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 %w/w of the solubilizing agent, or within a range of any of the preceding values.
  • the solubilizing agent 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, and Poloxamer.
  • the solubilizing agent is vitamin E polyethylene glycol succinate.
  • the vitamin E polyethylene glycol succinate is Kolliphor® TPGS.
  • the vitamin E polyethylene glycol succinate is Vitamin E/TPGS 260.
  • the pharmaceutical composition comprises: a.
  • the pharmaceutical composition comprises: a. about 5 %w/w to about 20 %w/w of 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5- methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-2- propyn-1-yl (crinecerfont) as a freebase; b.
  • the pharmaceutical composition comprises 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3- fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont) as a free base.
  • the pharmaceutical composition comprising 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3- fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof, is in capsule form.
  • the capsule is a soft gelatin capsule.
  • the capsule comprises 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3- fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof, in an amount of 25 mg, 50 mg, or 100 mg, based on the weight of the free base.
  • the capsule comprises 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2- cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof, in an amount of 25 mg based on the weight of the free base.
  • the capsule comprises 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3- fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof, in an amount of 50 mg based on the weight of the free base.
  • the capsule comprises 2 ⁇ thiazolamine, 4-(2-chloro- 4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]- 5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof, in an amount of 100 mg based on the weight of the free base.
  • Oral solution dosage formulations of crinecerfont [0141] Provided herein (e.g., for use in the methods disclosed herein) is an oral solution dosage formulation comprising: a.
  • the oral solution dosage formulation comprises about 4 %w/v to about 6 % w/v of 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N- [(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof, based on the weight of the free base.
  • the oral solution dosage formulation comprises about 4 %w/v, about 4.1 %w/v, about 4.2 %w/v, about 4.3 %w/v, about 4.4 %w/v, about 4.5 %w/v, about 4.6 %w/v, about 4.7 %w/v, about 4.8 %w/v, about 4.9 %w/v, about 5 %w/v, about 5.1 %w/v, about 5.2 %w/v, about 5.3 %w/v, about 5.4 %w/v, about 5.5 %w/v, about 5.6 %w/v, about 5.7 %w/v, about 5.8 %w/v, about 5.9 %w/v, about 6 %w/v of 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3- fluoro-4-methylphenyl)ethy
  • the oral solution dosage formulation comprises about 5 %w/v of 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3- fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof, based on the weight of the free base.
  • the oral solution dosage formulation comprises about 5 %w/v of 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3- fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont) as a free base.
  • 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.
  • the pharmaceutical composition comprises about 0.1 w/v% to about 0.5 w/v% of the sweetener.
  • 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 yorkame. In some embodiments, the sweetener is saccharin.
  • An anti-oxidant is a formulation component included to improve stability by preventing oxidation.
  • 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. In some embodiments, 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.
  • a flavor is a formulation component added to mask taste through aromatics. In some embodiments, 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.
  • 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. In some embodiments, the flavor is FONA orange flavor.
  • a liquid vehicle is a solvent capable of dissolving or partially dissolving the 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3- fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof, for the purposes of delivery as an oral dosing solution.
  • 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.
  • 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. In some embodiments, the liquid vehicle is medium-chain triglycerides.
  • the medium-chain triglycerides is Labrafac 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.
  • the pharmaceutical composition comprises about 20 w/v% of the surfactant.
  • 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. In some embodiments, the oleoyl polyoxyl-6 glycerides is LABRAFIL M 1944 CS. [0153] In some embodiments, 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.
  • 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 Lipophile WL1349.
  • the oral solution dosage formulation comprises: a. about 4 %w/v to about 6 %w/v of 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5- methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-2- propyn-1-yl (crinecerfont), 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.
  • the oral solution dosage formulation comprises: a.
  • the oral solution dosage formulation comprises: a.
  • the oral solution dosage formulation comprises: a.
  • the pharmaceutical composition comprises 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3- fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont) as a freebase.
  • the oral solution dosage formulation comprises 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3- fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof, in an amount of 50 mg/mL, based on the weight of the freebase.
  • Spray-dried dispersions of crinecerfont may comprise administering a spray-dried dispersion (SDD) of 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5- methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N- 2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof, and to the use of the SDDs in the treatment of congenital adrenal hyperplasia (CAH).
  • SDD spray-dried dispersion
  • CAH congenital adrenal hyperplasia
  • concentration and bioavailability enhancement in an aqueous environment of a low-solubility drug in a spray-dried dispersion is achieved if the SDD exhibits one or more properties, including, for example: (1) the solid dispersion is substantially homogeneous; (2) the drug is substantially amorphous; (3) the SDD has a relatively high drug loading; and (4) the SDD has a low residual solvent content.
  • the dispersion when administered to an aqueous environment, provides at least a temporary dissolved drug concentration in the aqueous environment that is greater than the solubility of the crystalline form of the drug in the same environment.
  • the aqueous environment can be, for example, an in vitro environment, such as a dissolution test media (e.g., phosphate buffered saline (PBS) solution), or an in vivo environment, such as the gastrointestinal (GI) tract of an animal, for example, a human.
  • a dissolution test media e.g., phosphate buffered saline (PBS) solution
  • PBS phosphate buffered saline
  • GI gastrointestinal
  • the aqueous environment is the lower GI tract, such as the small intestine and large intestine.
  • 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5- methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N- 2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof, in the spray- dried dispersion is substantially amorphous.
  • substantially amorphous means that the amount of 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N- [(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof, in amorphous form is at least 60 %w/w and that the amount of crystalline form present does not exceed 20 %w/w.
  • 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N- [(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof, in the dispersion is “almost completely amorphous,” meaning that at least 90 %w/w of the drug is amorphous, or that the amount of 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2- cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof, in the crystalline form does not exceed 10 %w/w.
  • Amounts of crystalline drug can be measured by powder X-ray diffraction (PXRD), scanning electron microscope (SEM) analysis, differential scanning calorimetry (DSC), polarized light microscopy (PLM), or any other standard quantitative or qualitative measurement used to detect crystalline material.
  • PXRD powder X-ray diffraction
  • SEM scanning electron microscope
  • DSC differential scanning calorimetry
  • PLM polarized light microscopy
  • the amorphous, or non-crystalline form, in combination with the polymer leads to greater ease of dissolution and absorption in the desired location, for example, the intestines, resulting in enhanced bioavailability as compared to a crystalline form of 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5- methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N- 2-propyn-1-yl (crinecerfont) without polymer.
  • the spray-dried dispersion comprises: 2 ⁇ thiazolamine, 4- (2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4- methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont) , or a pharmaceutically acceptable salt thereof; and a polymer that is a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate having the structure: H H , wherein the value of n of m and the copolymer comprises 1-vinyl-2-pyrrolidone and vinyl acetate at a ratio of about 60:40 by weight; and wherein the weight ratio of 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5-methylphenyl)-N- [(1S)-2-cyclopropyl-1-(3-fluoro-4-methylpheny
  • the pharmaceutical composition comprises: a. the spray-dried dispersion comprising 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5- methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-2- p ropyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof, and a polymer; b. a glidant; c. a filler; and d. a disintegrant. [0166] In some embodiments, the pharmaceutical composition includes a filler.
  • the filler is selected from among binders, diluents, disintegrants, glidants, surfactants, and combinations thereof.
  • Binders include agents that hold the active pharmaceutical ingredient and inactive ingredients together in a cohesive mix. Suitable diluents include, but are not limited to, lactose, mannitol, isomalt, sucrose, dextrose, and sorbitol. Disintegrants include any agent that promotes breakup of the formulation in an aqueous environment, for example, to promote more rapid release of the active pharmaceutical ingredient. Glidants can be used to improve the flowability of a powder or granules or both.
  • a surfactant is a formulation component added to improve solubility or emulsion properties.
  • the pharmaceutical composition includes a lubricant.
  • Lubricants are agents added to pharmaceutical formulations to reduce friction during processing and prevent ingredients from clumping together.
  • Additional excipients can be included in the pharmaceutical formulations of the present disclosure. Further examples of excipients include, but are not limited to, pigments, colorants, flavoring agents, preservatives, and sweeteners. Flavors and colors can be added to improve the taste or appearance of a formulation.
  • preservatives used in pharmaceutical compositions are aromatic alcohols, such as benzyl or phenol alcohol, antioxidants such as vitamin A, vitamin E, vitamin C, and selenium, amino acids such as cysteine and methionine, citric acid and sodium citrate, or synthetic preservatives such as methyl paraben and propyl paraben.
  • Sweeteners can be added to make the ingredients more palatable, especially in chewable tablets or liquids like syrups.
  • Multi-layer oral pharmaceutical composition of hydrocortisone [ 0170] Provided herein (e.g., for use in the methods disclosed herein) are multi -layer oral pharmaceutical compositions of hydrocortisone.
  • the multi-layer oral pharmaceutical composition may be a delayed release oral pharmaceutical composition of hydrocortisone.
  • the multi-layer oral pharmaceutical composition may be an i mmediate release oral pharmaceutical composition of hydrocortisone.
  • Delayed release oral pharmaceutical composition of hydrocortisone [0171] Provided herein (e.g., for use in the methods disclosed herein) is a delayed release oral pharmaceutical composition of hydrocortisone.
  • the delayed release oral pharmaceutical composition provides a delay in the release of hydrocortisone of from about 2 hours to about 5 hours from the administering of the delayed release oral pharmaceutical composition of hydrocortisone.
  • the delayed release oral pharmaceutical composition provides a peak cortisol level (Cmax) at about 6 hours to about 14 hours after the administering of the delayed release oral pharmaceutical composition of hydrocortisone.
  • Cmax peak cortisol level
  • the delayed release oral pharmaceutical composition is an oral pharmaceutical composition comprising: a. a core comprising hydrocortisone and a carrier; and b. a layer comprising a delayed release polymer, wherein the layer comprising a delayed release polymer is in contact with said core and is adapted to delay release of hydrocortisone from said core.
  • the delayed release oral pharmaceutical composition is an oral pharmaceutical composition comprising: a. a core comprising hydrocortisone, a binding agent, and a carrier; and b.
  • the delayed release polymer is an enteric polymer wherein the dissolution of said enteric polymer is between pH 5.5 and 7.0; preferably between pH 6.0 and 6.8.
  • the delayed release polymer is selected from the group consisting of: acrylic and/or poly [methyl] acrylic polymers, cellulose acetate succinate, or polyvinylacetate phthalate.
  • the delayed release oral pharmaceutical composition is an oral pharmaceutical composition comprising: a.
  • a core comprising hydrocortisone, a binding agent, and a carrier
  • a layer comprising a delayed release polymer, talc, and a plasticizer, wherein the layer comprising a delayed release polymer is in contact with said core
  • said delayed release polymer is a mixture of (i) poly(methacrylic acid, methyl methacrylate) in a ratio of 1:1 and (ii) poly(methacrylic acid, methyl methacrylate) in a ratio of 1:2, wherein (i) and (ii) are at a ratio of 1:4 and at 6% to 7% w/w of the composition which is adapted to delay release of hydrocortisone from said core, wherein the hydrocortisone is at a concentration of 5-8% w/w of the composition, wherein the binding agent comprises povidone at a concentration of 0.5-4.0% w/w of the composition, wherein the carrier comprises microcrystalline cellulose particles, and wherein the carrier is 75-85% w/w of
  • the delayed release oral pharmaceutical composition is an oral pharmaceutical composition consisting of: a. a core comprising hydrocortisone, a binding agent, and a carrier; and b. a layer comprising a delayed release polymer, talc, and a plasticizer, wherein the layer comprising a delayed release polymer is in contact with said core, wherein said delayed release polymer is a mixture of (i) poly(methacrylic acid, methyl methacrylate) in a ratio of 1:1 and (ii) poly(methacrylic acid, methyl methacrylate) in a ra tio of 1:2, wherein (i) and (ii) are at a ratio of 1:4 and at 6% to 7% w/w of the composition which is adapted to delay release of hydrocortisone from said core, wherein the hydrocortisone is at a concentration of 5-8% w/w of the composition, wherein the binding agent comprises povidone at a concentration of 0.5-4.0%
  • the delayed release oral pharmaceutical composition is in capsule form.
  • the capsule is a hard capsule.
  • the capsule is a hard capsule containing granules.
  • the delayed release oral pharmaceutical composition is an oral pharmaceutical composition as set out in Table 1 below: [ 0181] Table 1: delayed release oral pharmaceutical compositions of hydrocortisone.
  • the delayed release oral pharmaceutical composition of hydrocortisone is in capsule form.
  • the capsule is a hard capsule.
  • the capsule is a hard capsule containing granules.
  • the capsule comprises hydrocortisone in an amount of 5 mg, 10 mg or 20 mg. In some embodiments, the capsule comprises hydrocortisone in an amount of 5 mg.
  • the capsule comprises hydrocortisone in an amount of 10 mg. In some embodiments, the capsule comprises hydrocortisone in an amount of 20 mg.
  • Immediate release pharmaceutical composition of hydrocortisone [0183] Provided herein (e.g., for use in the methods disclosed herein) is an immediate release oral pharmaceutical composition of hydrocortisone. [0184] In some embodiments, hydrocortisone contained in the immediate-release immediate release oral pharmaceutical composition is not released before about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, or about 5 minutes in aqueous conditions in the mouth of the subject.
  • hydrocortisone contained in the immediate-release immediate release oral pharmaceutical composition is not r eleased before about 5 minutes in aqueous conditions in the mouth of the subject.
  • the immediate release oral pharmaceutical composition provides release of hydrocortisone after swallowing.
  • at least 70% of hydrocortisone contained in the immediate release oral pharmaceutical composition is released within 15 minutes of swallowing.
  • at least 90% of hydrocortisone contained in the immediate release oral pharmaceutical composition is released within 60 minutes of swallowing.
  • the immediate release oral pharmaceutical composition comprises: a. a micro-particulate carrier; b . a drug layer comprising hydrocortisone and a binding agent; c.
  • the immediate release oral pharmaceutical composition comprises: a. a micro-particulate carrier; b . a drug layer comprising hydrocortisone and a binding agent; c. a taste-masking polymer layer comprising 0.14-0.16% w/w hydroxypropyl methylcellulose and 0.58-0.62% w/w ethyl cellulose; and d.
  • the immediate release oral pharmaceutical composition comprises: a . a micro-particulate carrier comprising at least 60% w/w microcrystalline cellulose; b. a drug layer comprising at least 0.60% w/w hydrocortisone and a binding agent comprising at least 0.60% w/w hydroxypropyl methylcellulose, wherein the drug layer is in contact with the carrier; c.
  • the immediate release oral pharmaceutical composition comprises: a. a micro-particulate carrier comprising 63-65% w/w microcrystalline cellulose; b.
  • a drug layer comprising 0.64-0.66% w/w hydrocortisone and a binding agent comprising 0.64-0.66% w/w hydroxypropyl methylcellulose, wherein the drug layer is in contact with the carrier; c. a sealing layer comprising 29-31% w/w hydroxypropyl methylcellulose and 2.9-3.1% w/w magnesium stearate, wherein the sealing layer is in contact with the drug layer; and d.
  • the immediate release oral pharmaceutical composition is an oral pharmaceutical composition as set out in Table 2 below: [ 0191] Table 2: immediate release oral pharmaceutical composition of hydrocortisone. Quantity per dose (mg) Quantity ) Quantity per dose (mg) Quantity (%w/w) q y p [0192] In some embodiments, the immediate release oral pharmaceutical composition comprises: a.
  • micro-particulate carrier comprising 80-81% w/w microcrystalline cellulose, wherein said microcrystalline cellulose micro-particulates have an average diameter of 350-500 ⁇ m; b. a drug layer comprising 0.64-0.66% w/w hydrocortisone and 0.64-0.66% w/w h ydroxypropyl methylcellulose, in contact with the carrier; c. a sealing layer consisting of 14-16% w/w hydroxypropyl methylcellulose and 1-2% w/w magnesium stearate, in contact with the drug layer; and d.
  • the immediate release oral pharmaceutical composition comprises: a. a micro-particulate carrier comprising 81% w/w microcrystalline cellulose, wherein said microcrystalline cellulose micro-particulates have an average diameter of 350-500 ⁇ m; b. a drug layer consisting of 0.66% w/w hydrocortisone and 0.66% w/w hydroxypropyl methylcellulose, in contact with the carrier; c.
  • the immediate release oral pharmaceutical composition is an oral pharmaceutical composition as set out in Table 3 below: [0195] Table 3: alternative immediate release oral pharmaceutical composition of hydrocortisone. Ingredient Function Quantity (%w/w) [0196] In some embodiments, the immediate release oral pharmaceutical composition is in capsule form.
  • the capsule is a capsule for opening, the capsule for opening comprising granules.
  • the capsule for opening comprises hydrocortisone in an amount of 0.5 mg, 1 mg, 2 mg, or 5 mg. In some embodiments, the capsule for opening comprises hydrocortisone in an amount of 0.5 mg. In some embodiments, the capsule for opening comprises hydrocortisone in an amount of 1 mg. In some embodiments, the capsule for opening comprises hydrocortisone in an amount of 2 mg. In some embodiments, the capsule for opening comprises hydrocortisone in an amount of 5 mg.
  • Oral liquid formulation of hydrocortisone Provided herein (e.g., for use in the methods disclosed herein) is an oral liquid formulation of hydrocortisone.
  • Oral liquid formulations include, but are not limited to, solutions (both aqueous and non-aqueous), suspensions, emulsions, syrups, slurries, juices, elixirs, dispersions, and the like. It is envisioned that solution/suspensions are also included where certain components described herein are in solution.
  • the oral liquid formulation is an oral solution formulation.
  • the oral liquid formulation of hydrocortisone is as described in WO 2024/107653 A1, which is hereby incorporated herein by reference in its entirety.
  • the oral liquid formulation comprises: h ydrocortisone, or a pharmaceutically acceptable salt thereof; a non-aqueous liquid carrier; and a preservative.
  • the oral liquid formulation comprises hydrocortisone, or a pharmaceutically acceptable salt thereof, in an amount of about 0.01 % to about 10 % weight by volume (w/v).
  • the oral liquid formulation comprises hydrocortisone, or a pharmaceutically acceptable salt thereof, in an amount of about 0.01 % to about 8 %, about 0.01 % to about 5 %, or about 0.01 % to about 2 % w/v. In some embodiments, the oral liquid formulation comprises hydrocortisone, or a pharmaceutically acceptable salt thereof, in an amount of about 0.01 % to about 2 % w/v. In some embodiments, the oral liquid formulation comprises hydrocortisone, or a pharmaceutically acceptable salt thereof, in an amount of about 0.1 % w/v. In some embodiments, the oral liquid formulation comprises hydrocortisone, or a pharmaceutically acceptable salt thereof, in an amount of about 0.2 % w/v.
  • the oral liquid formulation comprises hydrocortisone, or a pharmaceutically acceptable salt thereof, in an amount of about 0.5 % w/v.
  • the hydrocortisone used in the oral liquid formulations described herein is a hydrocortisone free base.
  • the hydrocortisone used in the oral liquid formulations described herein is a hydrocortisone salt.
  • the hydrocortisone salt is hydrocortisone acetate.
  • the hydrocortisone salt is hydrocortisone sodium succinate.
  • the hydrocortisone salt is hydrocortisone sodium phosphate.
  • the hydrocortisone salt is in the form of hydrocortisone acetate or hydrocortisone sodium succinate.
  • the oral liquid formulation of hydrocortisone comprises the non-aqueous liquid carrier in an amount of about 25 % w/v to about 120 % w/v. In some embodiments, the oral liquid formulation of hydrocortisone comprises the non- aqueous liquid carrier in an amount of about 80 % w/v to about 110 % w/v. In some embodiments, the oral liquid formulation of hydrocortisone comprises the non-aqueous liquid carrier in an amount of about 100 % w/v to about 120 % w/v.
  • the oral liquid formulation of hydrocortisone comprises the non-aqueous liquid carrier in an amount of about 110 % w/v to about 120 % w/v.
  • the nonaqueous liquid carrier comprises edible vegetable oils (e.g., soybean oil, partially hydrogenated soybean oil, corn oil, sunflower oil, or peanut oil), synthetic edible oils (e.g., triglycerides of the C8-C10 fatty acids of fractionated coconut oil; e.g., triglyceride of capric and caprylic acids with glycerol, sold under the trade name Miglyol®), propylene glycol, glycerin, polypropylene glycol, polyethylene glycol (PEG), alcohol (e.g., ethanol), polyoxylglycerides (e.g., caprylocaproyl polyoxyl -8 glycerides, sold under the trade name Labrasol®).or any combinations thereof.
  • edible vegetable oils e.g., soybean oil, partially hydrogenated soybean oil, corn oil,
  • the nonaqueous liquid carrier comprises propylene glycol, glycerin, PEG, or a combination thereof. In some embodiments, the nonaqueous liquid carrier comprises propylene glycol. In some embodiments, the nonaqueous liquid carrier comprises glycerin. In some embodiments, the nonaqueous liquid carrier comprises PEG. In some embodiments, the nonaqueous liquid carrier is propylene glycol, glycerin, and PEG 400. [0202] In some embodiments, the oral liquid formulation of hydrocortisone comprises PEG in an amount of about 20 % to about 80 % w/v.
  • the oral liquid formulation of hydrocortisone comprises PEG in an amount of about 40 % to about 60 % w/v. In some embodiments, the oral liquid formulation of hydrocortisone comprises PEG in an amount of about 45 % to about 55 % w/v. In some embodiments, the oral liquid formulation of hydrocortisone comprises PEG in an amount of about 40 % w/v. In some embodiments, the oral liquid formulation of hydrocortisone comprises PEG in an amount of about 50 % w/v. In some embodiments, the PEG is PEG 400. In some embodiments, the oral liquid formulation of hydrocortisone comprises PEG 400 in an amount of about 50 % w/v.
  • the oral liquid formulation of hydrocortisone comprises propylene glycol in an amount of about 0.1 % to about 20 % w/v. In some embodiments, the oral liquid formulation of hydrocortisone comprises propylene glycol in an amount of about 2 % to about 8 % w/v. In some embodiments, the oral liquid formulation of hydrocortisone comprises propylene glycol in an amount of about 5 % w/v. [0204] In some embodiments, the oral liquid formulation of hydrocortisone comprises glycerin in an amount of about 20 % to about 90 % w/v.
  • the oral liquid formulation of hydrocortisone comprises glycerin in an amount of about 30 % to about 80 % wt. In some embodiments, the oral liquid formulation of hydrocortisone comprises glycerin in an amount of about 50 % to about 70 % wt. In some embodiments, the oral liquid formulation of hydrocortisone comprises glycerin in an amount of about 50 % wt. In some embodiments, the oral liquid formulation of hydrocortisone comprises glycerin in an amount of about 52.3 % wt. In some embodiments, the oral liquid formulation of hydrocortisone comprises glycerin in an amount of about 60 % wt.
  • the oral liquid formulation of hydrocortisone comprises glycerin in an amount of about 65 % wt. [0205] In some embodiments, the oral liquid formulation of hydrocortisone comprises: glycerin in an amount of about 43.5 % w/v; propylene glycol in an amount of about 5 % w/v; and PEG 400 in an amount of about 50 % w/v.N [0206] In some embodiments, the oral liquid formulation of hydrocortisone comprises water.
  • the oral liquid formulation of hydrocortisone comprises less than 20 % wt, less than 15 % wt, less than 10 % wt, less than 9 % wt, less than 8 % wt, less than 7 % wt, less than 6 % wt, less than 5 % wt, less than 4 % wt, less than 3 % wt, less than 2 % wt, or less than 1 % wt of water.
  • the oral liquid formulation of hydrocortisone comprises about 5 % wt of water or less.
  • the oral liquid formulation of hydrocortisone comprises less than 0.1 % wt of water.
  • the oral liquid formulation of hydrocortisone comprises less than 0.01 % wt of water. In some embodiments, the oral liquid formulation does not comprise water. In some embodiments, the oral liquid formulation is nonaqueous.
  • the preservative comprises an antioxidant, an antimicrobial agent, or a combination thereof. In some embodiments, the preservative comprises an antioxidant. In some embodiments, the preservative comprises an antimicrobial agent. In some embodiments, the preservative comprises an antioxidant and an antimicrobial agent. In some embodiments, the preservative comprises a chelating agent.
  • the oral liquid formulation of hydrocortisone comprises the antioxidant in an amount of about 0.005 % to about 0.05 % w/v. In some embodiments, the oral liquid formulation of hydrocortisone comprises the antioxidant in an amount of about 0.02 % w/v. In some embodiments, the oral liquid formulation of hydrocortisone comprises the antioxidant in an amount of about 0.01 % w/v. In some embodiments, the antioxidant comprises vitamin A, monothioglycerol, ascorbic acid, sodium bisulfite, sodium sulfite, ⁇ -tocopherol acetate (vitamin E), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), or a combination thereof.
  • the antioxidant comprises butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), or a combination thereof.
  • the antioxidant comprises BHA.
  • the antioxidant comprises BHT.
  • the antioxidant is BHA and BHT.
  • the antioxidant is BHA.
  • the antioxidant is BHT.
  • the oral liquid formulation of hydrocortisone comprises the antimicrobial agent in an amount of about 0.05 % to about 0.5 % w/v. In some embodiments, the oral liquid formulation of hydrocortisone comprises the antimicrobial agent in an amount of about 0.2 % w/v.
  • the antimicrobial agent comprises methyl paraben, ethyl paraben, propyl paraben, benzoic acid or a pharmaceutically acceptable salt thereof (e.g., sodium benzoate), sorbic acid or a pharmaceutically acceptable salt thereof, phenoxyethanol, benzyl alcohol, propionic acid, or a combination thereof.
  • the antimicrobial agent comprises parabens.
  • the parabens comprise methyl paraben, propyl paraben, or a combination thereof.
  • the antimicrobial agent comprises methyl paraben.
  • the antimicrobial agent comprises propyl paraben.
  • the antimicrobial agent comprises methyl paraben and propyl paraben.
  • the oral liquid formulation of hydrocortisone comprises the chelating agent in an amount of about 0.001 % w/v to about 5 % w/v. In some embodiments, the oral liquid formulation of hydrocortisone comprises the chelating agent in an amount of about 0.05 % w/v to about 0.2 % w/v. In some embodiments, the oral liquid formulation of hydrocortisone comprises the chelating agent in an amount of about 0.1 % w/v.
  • the chelating agent comprises disodium ethylenediaminetetraacetic acid, polyphosphates, citric acid, calcium disodium edetate, ethylenediaminetetraacetic acid (EDTA), or a combination thereof. In some embodiments, the chelating agent is EDTA.
  • the oral liquid formulation of hydrocortisone comprises a sweetener. In some embodiments, the oral liquid formulation of hydrocortisone comprises a sweetener in an amount of about 0.1 % w/v to about 5 % w/v.
  • the oral liquid formulation of hydrocortisone comprises a sweetener in an amount of about 0.5 % w/v to about 2 % w/v. In some embodiments, the oral liquid formulation of hydrocortisone comprises a sweetener in an amount of about 1 % w/v.
  • the sweetener comprises glucose, fructose, sucrose, lactose, maltose, xylitol, tagatose, sucralose, maltitol, isomaltulose, hydrogenated isomaltulose, lactitol, sorbitol, erythritol, trehalose, maltodextrin, polydextrose, acesulfame or a pharmaceutically acceptable salt thereof (e.g., acesulfame potassium), alitame, aspartame, neotame, sodium cyclamate, saccharin or a pharmaceutically acceptable salt thereof (e.g., saccharin sodium or saccharin calcium), neohesperidin dihydrochalcone, stevioside, thaumatin, or a combination thereof.
  • acesulfame potassium a pharmaceutically acceptable salt thereof
  • the sweetener comprises sucralose, maltose, or a combination thereof. In some embodiments, the sweetener is sucralose. In some embodiments, the sweetener is maltose. In some embodiments, the sweetener is sucralose and maltose. In some embodiments, the oral liquid formulation of hydrocortisone comprises a sucralose in an amount of about 1 % w/v. [0212] In some embodiments, the oral liquid formulation of hydrocortisone comprises a flavoring agent. In some embodiments, the oral liquid formulation of hydrocortisone comprises a flavoring agent in an amount of about 0.005 % w/v to about 0.5 % w/v.
  • the oral liquid formulation of hydrocortisone comprises a flavoring agent in an amount of about 0.2 % w/v to about 0.5 % w/v. In some embodiments, the oral liquid formulation of hydrocortisone comprises a flavoring agent in an amount of about 0.4 % w/v.
  • pharmaceutically acceptable flavors such as (4-hydroxy-3-methoxybenzaldehyde (vanillin), methyl anthranilate (grape flavor), 3,5- Dimethyl-1,2-Cyclopentadione (caramel flavor), maltol, 4-(4-Hydroxyphenyl)butan-2- one (raspberry flavor), ethyl maltol, ethyl propionate (fruity flavor) and berry flavor
  • vanillin methyl anthranilate
  • carbamel flavor 3,5- Dimethyl-1,2-Cyclopentadione
  • maltol 4-(4-Hydroxyphenyl)butan-2- one
  • raspberry flavor 4-(4-Hydroxyphenyl)butan-2- one
  • ethyl maltol ethyl propionate
  • berry flavor ethyl maltol
  • fruity flavor ethyl propionate
  • berry flavor can be used to improve the
  • the flavoring agent comprises vanillin, grape flavor, caramel flavor, maltol, raspberry flavor, fruity flavor, berry flavor, 4-hydroxy- 3-methoxybenzaldehyde, methyl anthranilate, 3,5-dimethyl-1,2-cyclopentadione, 4-(4- hydroxyphenyl_butan-2-one, ethyl maltol, ethyl propionate, or a combination thereof.
  • the flavoring agent comprises berry flavor, ethyl maltol, or a combination thereof.
  • the flavoring agent is berry flavor (e.g., Berry Mixed Flavor WONF, WS Natural 13.17579).
  • the flavoring agent is ethyl maltol. In some embodiments, the flavoring agent is berry flavor and ethyl maltol. In some embodiments, the oral liquid formulation of hydrocortisone comprises berry flavor in an amount of about 0.2 % w/v. In some embodiments, the oral liquid formulation of hydrocortisone comprises ethyl maltol in an amount of about 0.2 % w/v. In some embodiments, the oral liquid formulation of hydrocortisone comprises ethyl maltol in an amount of about 0.1 % w/v. [0213] In some embodiments, the oral liquid formulation of hydrocortisone described herein do not contain monothioglycerol.
  • the oral liquid formulations of hydrocortisone described herein do not contain monobasic sodium phosphate.
  • the oral liquid formulation of hydrocortisone described herein comprises additional excipients including, but not limited to coloring agents and thickeners. Additional excipients such as bulking agents and tonicity agents are within the scope of the embodiments.
  • the oral liquid formulation of hydrocortisone is an oral liquid formulation according to any one of formulations F-I to F-XXVVII (as set out in Tables A-I, below). In some embodiments, the oral liquid formulation of hydrocortisone is an oral liquid formulation according to F-I or F-II (as set out in Table A, below).
  • the oral liquid formulation of hydrocortisone is an oral liquid formulation according to F-III, F-IV, F-V, F-VI, F-VII, or F-VIII (as set out in Table B, below). In some embodiments, the oral liquid formulation of hydrocortisone is an oral liquid formulation according to F-VIII (as set out in Table B, below). In some embodiments, the oral liquid formulation of hydrocortisone is an oral liquid formulation according to F-IX, F-X, F-XI, F-XIII, F-XIV, F-XV, or F-XVI (as set out in Tables C and D, below).
  • the oral liquid formulation of hydrocort isone is an oral liquid formulation according to F-XVII, F-XVIII, F-XIX, F-XX, F-XXI, F-XXII, F-XXIII, or F-XXIV (as set out in Tables E and F, below).
  • the oral liquid formulation of hydrocortisone is an oral liquid formulation according to F- XXV, F-XXVI, F-XXVII, F-XXVIII, F-XXVIV, F-XXVV, F-XXVVI, F-XXVVII, F-XXVVII, F- XXVVII (as set out in Tables G, H, and I, below).
  • Table A oral liquid formulations of hydrocortisone with water.
  • Quantity %w/v Ingredient Table B oral liquid formulations of hydrocortisone without water.
  • Quantity %w/v Ingredient FIII FIV FV FVI FVII FVIII Table C oral liquid formulations of hydrocortisone with varied preservatives, sweeteners, and flavoring agents.
  • Quantity %w/v Ingredient e a L Table F: oral liquid formulations of hydrocortisone with varied preservatives.
  • Quantity %w/v In redient Quantity %w/v Ingredient F XXVIII F XXVIV F XXVV L Table I: or al liquid formulations of hydrocortisone with varied non-aqueous liquid carriers. Quantity %w/v Ingredient L Fixed dose combination [0216] Also provided herein (e.g., for use in the methods disclosed herein) is a fixed dose combination product comprising 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5- methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N- 2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof, and hydrocortisone in a fixed ratio and in a single dosage form.
  • the fixed dose combination product further comprises at least one pharmaceutically acceptable carrier, diluent, or excipient.
  • the fixed dose combination product comprises the hydrocortisone in a delayed release oral pharmaceutical composition.
  • Kits and Twin Packs [0218] Also provided herein are kits, including twin packs.
  • a kit or twin pack includes two or more pharmaceutical compositions as described herein, e.g., a pharmaceutical composition containing 2 ⁇ thiazolamine, 4-(2-chloro-4-methoxy-5- methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N- 2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing hydrocortisone.
  • a pharmaceutical composition containing 2 ⁇ thiazolamine 4-(2-chloro-4-methoxy-5- methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N- 2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing hydrocortisone.
  • kits or twin pack can include one or more delivery systems, e.g., for delivering or administering the pharmaceutical composition as provided herein, and directions for use of the kit (e.g., instructions for treating a subject).
  • the kit or twin pack can include a pharmaceutical composition as described herein and a label that indicates that the contents are to be administered to a subject with congenital adrenal hyperplasia (e.g., classic congenital adrenal hyperplasia). The actual dose of the compound in each composition depends on the specific formulation, the weight of the patient, and on the condition to be treated. Medical uses and manufacture of medicaments [0219] Also provided herein are compounds and compositions for use in any of the methods described herein.
  • 2 ⁇ thiazolamine 4-(2-chloro-4-methoxy-5-methylphenyl)-N- [(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt or solvate thereof, for use in combination with a delayed release oral pharmaceutical composition of hydrocortisone in a method of treating described herein.
  • a delayed release oral pharmaceutical composition of h ydrocortisone for use in a method of treating described herein.
  • Example 1 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Crinecerfont in Adult Subjects with Classic Congenital Adrenal Hyperplasia, followeded by Open-Label Treatment (I) Objectives ⁇ To evaluate the efficacy of crinecerfont, (100 mg twice daily [i.e., BID] based on the free base), compared with placebo, in reducing daily glucocorticoid dosage while maintaining adrenal androgen control. ⁇ To evaluate the efficacy of crinecerfont, compared with placebo, in reducing adrenal steroid levels following an initial 4-week treatment period.
  • A Screening period (Weeks -4 up to Day -1) [0228] All subjects must have provided signed and witnessed informed consent prior to the conduct of any study-related procedures. Subjects underwent screening for up to 4 weeks (Weeks -4 to Day -1) to determine eligibility. There was a second visit (optional at home) during the screening period to collect a blood sample (for hormone measurements). Subjects must be on a supraphysiologic glucocorticoid regimen defined as >14 mg/m 2 /day in hydrocortisone dose equivalents adjusted for body surface area (BSA) that has been stable at least 1 month leading up to screening.
  • BSA body surface area
  • the glucocorticoid regimen was optimized by the treating physician to achieve control of adrenal androgen levels and minimization of glucocorticoid dosage to the extent appropriate for the subject’s individual medical needs and treatment goals.
  • Rescreening was permitted if a subject did not meet all eligibility requirements and returned to be rescreened. A subject that has failed screening twice may not be rescreened again without prior permission.
  • Randomization was stratified by total daily glucocorticoid dose, glucocorticoid type, and sex. Beginning on Day 1 (baseline), the study drug or placebo in the form of one or more capsules were administered at home with the subject’s evening meal; thereafter, the capsule(s) were administered BID with the subject’s breakfast and evening meal (doses separated by approximately 12 hours).
  • Subjects had study visits at Weeks 6 (optional at home), 9 (optional at home), and 12 for study assessments, including collection of blood samples to assess hormone levels and routine safety assessments.
  • the investigator instructed the subject on the second step of the glucocorticoid dose reduction and arranged to contact the subject by telephone within a week of the study visit to assess how the subject was tolerating the glucocorticoid dose reduction.
  • the investigator contacted the subject at approximately Week 8 to advise on t he third step of glucocorticoid dose reduction (if applicable).
  • the investigator assessed whether the subject was tolerating the third glucocorticoid dose reduction.
  • glucocorticoid dose reduction (if applicable).
  • the subject experienced any of the following signs or symptoms at any time during the glucocorticoid dose reduction process, the glucocorticoid dose was NOT reduced further but returned to the previous dose that was tolerated. However, before the glucocorticoid dose reduction was stopped for symptoms or signs of orthostatic hypotension, volume status was optimized (e.g., with additional dietary salt, salt tablets, intravenous saline).
  • the glucocorticoid dose was reduced by approximately 10% to 20% at each visit (Months 7, 8, and 9), as long as androstenedione levels were within control (i.e., androstenedione ⁇ 120% of the subject’s baseline or ⁇ ULN for age and sex) and the subject was not experiencing any signs or symptoms suggestive of clinically relevant glucocorticoid insufficiency or unacceptable symptoms of hyperandrogenism.
  • the glucocorticoid dose reduction did not require dose reduction below 8 mg/m 2 /day hydrocortisone equivalents.
  • the site contacted the subject by telephone (within a week) to assess how the subject was tolerating the glucocorticoid dose reduction.
  • Subjects had study visits at Months 8, 9, and 10 for study assessments including collection of blood samples for hormone levels.
  • 2-Month Glucocorticoid Maintenance Period (Month 10 up to Month 12)
  • Subjects returned to the study site at Months 10 and 12 for study assessments as outlined in the Schedule of Assessments.
  • glucocorticoid regimen was adjusted due to sick-day guidelines, the subject resumed their glucocorticoid dosing regimen for at least 3 days before their next scheduled hormone panel assessment, and this 3-day window superseded all other visit windows.
  • An independent Data and Safety Monitoring Board (DSMB) periodically reviewed ongoing clinical safety data to ensure the safety and well-being of study subjects.
  • Study Population Approximately 165 female and male subjects, at least 18 years of age, with a documented medical diagnosis of classic CAH due to 21-hydroxylase deficiency were enrolled into this study. [0256] Study participants met the following criteria: 1. Subjects must provide written informed consent. 2. Be a female or male at least 18 years of age. 3.
  • Subjects who are on dexamethasone alone must be receiving ⁇ 0.5 mg/day. 5. If treated with fludrocortisone, dose should be stable for at least 1 month prior to screening with an upright plasma renin activity (PRA) during screening within the normal range on the subject’s usual sodium intake. If PRA is not within the normal range, the subject must have systolic blood pressure >100 mmHg, without orthostatic hypotension, and with serum sodium and potassium in the normal range. 6. Female subjects of childbearing potential must agree to use contraception consistently from screening until the final study visit or 30 days after the last dose of study drug, whichever is longer.
  • PRA upright plasma renin activity
  • a female who is not of childbearing potential must meet 1 of the following: o Postmenopausal, defined as no menses for 12 months without an alternative medical cause and confirmed by elevated follicle-stimulating hormone (FSH) consistent with a postmenopausal range o Permanent sterilization procedure, such as hysterectomy, bilateral salpingectomy, or bilateral oophorectomy 1.
  • FSH follicle-stimulating hormone
  • Male subjects must agree to use contraception consistently from screening until 90 days after the last dose of study drug.
  • the acceptable method of contraception for male subjects is condom with spermicide (cream, spray, foam, gel, suppository, or polymer film).
  • Crinecerfont was administered at 100 mg BID (200 mg total daily dose), based on the free base, in oral capsule form with subjects’ breakfast and evening meal (doses separated by approximately 12 hours). The dose may have been adjusted to 50 mg qAM and 150 mg qPM at Month 12. Each administration comprised one or more capsules containing 50 mg of crinecerfont.
  • Subjects took the capsule(s) by mouth beginning with the evening meal on Day 1, and then with breakfast and the evening meal (doses separated by approximately 12 hours) for the remainder of the treatment period. Each meal should have been completed within 30 minutes of taking the capsule(s).
  • 17-hydroxyprogesterone (serum; ng/dL), androstenedione (serum; ng/dL), testosterone (serum; ng/dL), adrenocorticotropic hormone (ACTH) (plasma; pg/mL), cortisol (serum; ⁇ g/dL), luteinizing hormone (LH) (serum; IU/L), follicle stimulating hormone (FSH; IU/L), progesterone (serum; ng/mL), plasma renin activity (measured upright) (ng/mL/hr).
  • THP 17-hydroxyprogesterone
  • Urine androgen metabolite levels (androsterone and etiocholanolone).
  • Metabolic assessments (fasting lipid panel, homeostatic model assessment of insulin resistance [HOMA-IR] based on fasting glucose and insulin levels, glycated hemoglobin [HbA1c], glucose tolerance test).
  • DXA Dual-energy X-ray absorptiometry
  • Hirsutism and Acne Scales (female subjects only).
  • Testicular ultrasounds to detect adrenal rest tissue) (male subjects only).
  • Menstrual Cycle Questionnaire (only in female subjects of childbearing potential who are not on hormonal or intrauterine device contraceptives).
  • Bone markers serum osteocalcin, serum bone-specific alkaline phosphatase, serum C-terminal telopeptide, urine N-terminal telopeptide.
  • B Patient-Reported Outcomes: [0269] 36-Item Short Form Health Survey (SF-36), EuroQol 5 Dimensions 5 Levels (EQ-5D-5L), Multidimensional Assessment of Fatigue (MAF), Psychological General Well-Being Index (PGWBI), and Medical Outcomes Study 12-Item Sleep Scale (MOS- 12).
  • the primary analysis of the primary endpoint was p erformed using an analysis of covariance (ANCOVA) model.
  • the first key secondary endpoint was the change from baseline in serum androstenedione at Week 4, which was analyzed using an ANCOVA model.
  • the second key secondary endpoint is the achievement of a reduction in glucocorticoid daily dose to physiologic levels ( ⁇ 11 mg/m2/day in hydrocortisone equivalent adjusted for BSA) at Week 24 while maintaining androstenedione levels (as defined above in the primary endpoint), which was analyzed using a Cochran-Mantel- Haenszel (CMH) test.
  • CMH Cochran-Mantel- Haenszel
  • Example 2 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Crinecerfont in Pediatric Subjects with Classic Congenital Adrenal Hyperplasia, followeded by Open- Label Treatment (I) Objectives ⁇ To evaluate the efficacy of crinecerfont compared with placebo, in reducing adrenal androgen and precursor levels during a glucocorticoid-stable period.
  • Eligible subjects were randomly assigned in a 2:1 ratio (active : placebo) to either crinecerfont (25 mg BID oral liquid for subjects 10 to ⁇ 20 kg, 50 mg BID oral liquid for subjects 20 to ⁇ 55 kg, or 100 mg BID oral capsule for subjects ⁇ 55 kg) or matching placebo (oral liquid placebo for subjects ⁇ 55 kg and oral capsule placebo for subjects ⁇ 55 kg).
  • crinecerfont 25 mg BID oral liquid for subjects 10 to ⁇ 20 kg, 50 mg BID oral liquid for subjects 20 to ⁇ 55 kg, or 100 mg BID oral capsule for subjects ⁇ 55 kg
  • placebo oral liquid placebo for subjects ⁇ 55 kg and oral capsule placebo for subjects ⁇ 55 kg
  • Blood samples were obtained serially over approximately 3.5 hours (at 0830, 0900, 1000, 1100, and 1200 hours), with the morning glucocorticoid dose administered after the 0900 hour sample is collected.
  • Subjects ⁇ 6 years of age or ⁇ 20 kg body weight took their morning glucocorticoid dose at home and have a single blood sample collected at the site, timed to be approximately 2 hours after the morning glucocorticoid dose.
  • Salivary samples for adrenal androgens and precursors were collected. [0281] Subjects were randomized on Day 1 in a 2:1 ratio (active : placebo). Randomization was stratified by pubertal stage (Tanner stage 1 or 2 vs.3, 4 or 5) and sex within each dose group.
  • the oral liquid or capsule(s) was administered at home with the subject’s evening meal; thereafter, the oral liquid or capsule(s) was administered BID with the subject’s breakfast and evening meals (doses separated by approximately 12 hours).
  • subjects maintained a stable glucocorticoid regimen to the extent possible, except for sick-day guidelines. Sick-day dosing may follow alternate guidelines or can be based on guidance provided by the investigator or the subject’s treating physician.
  • (b) Glucocorticoid Adjustment Period [0283] At the Week 4 visit, subjects ⁇ 6 years of age and ⁇ 20 kg body weight held their morning glucocorticoid and oral liquid or capsule(s) and brought it with them to the study site, arriving to the site by approximately 0800 hours. Blood samples were obtained serially over approximately 6.5 hours (at 0830, 0900, 1000, 1100, 1200, 1300, and 1500 hours). The morning glucocorticoid dose and oral liquid or capsule(s) was administered after the 0900 hours sample was collected.
  • Glucocorticoid dose adjustments could 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.
  • the target glucocorticoid dose was within the range of 8 to 10 mg/m 2 /day to the extent possible, but could be lower than this range depending on practical issues considered in clinical practice related to available dosage strengths.
  • the investigator evaluated the subject for any symptoms suggestive of glucocorticoid insufficiency using a standardized checklist and arranged for follow-up if needed after the dose reduction.
  • the first glucocorticoid dose adjustment step was guided by the change in androstenedione (A4) at Week 4 from baseline.
  • a suggested guideline is provided in the table below, but the exact amount adjusted may have differed from this guideline based on practical issues considered in clinical practice related to available dosage strengths.
  • the investigator contacted the subject once the Week 4 lab results were available in order to provide guidance on the amount of the first glucocorticoid dose adjustment.
  • Table 4 Percent Change from Baseline in GC Dose Adjustment Step #1 (approximately d [ eek 8 (at home or the study site).
  • the target amount of glucocorticoid dose reduction at each step was approximately 1 to 4 mg/m 2 /day but was guided by the androstenedione level at the preceding blood test as well as on practical issues considered in clinical practice related to available dosage strengths.
  • Table 5 Blood Test Glucocorticoid Dose Adjustment Step d [02 essments as outl ined in the Schedule of Assessments. Prior to the Week 16 and Week 28 visits, subjects held their morning oral liquid or capsule(s) and brought it with them to the study site, but took their morning glucocorticoid dose at home, with blood sample collection timed to be approximately 2 hours later.
  • a suggested guideline is provided below but the exact amount adjusted may have differed from this guideline based on practical issues considered in clinical practice related to available dosage strengths.
  • the investigator contacted the subject once the Week 32 lab results were available in order to provide guidance on the amount of the first glucocorticoid dose adjustment (if needed) during the open-label period.
  • Table 6 Percent Change from Week 28 in GC Dose Adjustment Step #1 (approximately Week 34) Androstenedione at Week 32 [ ollow-up blood test was arranged approximately 2 weeks later at Week 36 (at home or the study site).
  • glucocorticoid dose adjustments occurred at approximately Week 38 and Week 42 (or when lab results are available) with follow-up blood tests at Week 40 (at the study site) and Week 44 (at home or the study site, and only if the glucocorticoid dose was modified at Week 42).
  • the target amount of glucocorticoid dose reduction at each step was approximately 1 to 4 mg/m 2 /day but was guided by the androstenedione level at the preceding blood test as well as practical issues considered in clinical practice related to available dosage strengths. Table 7.
  • Blood Test GC dose adjustment step Blood Test GC dose adjustment step e ts as sits, subjects held their morning oral liquid or capsule(s) and brought it with them to the study site, but took their morning glucocorticoid dose at home, with blood sample collection timed to be approximately 2 hours later. [0299] For the Week 52 visit, subjects ⁇ 12 years of age fasted after midnight the night before until the first blood sample was collected at the site, after which they were provided breakfast. Subjects were encouraged to drink water during the fasting period to avoid any hypovolemic status. Subjects ⁇ 12 years of age did not need to fast. (D) Study Assessments and Study Visit Scheduling [0300] Efficacy, safety, and PK were assessed at scheduled times throughout the study.
  • glucocorticoid dose regimen (defined as >12 mg/m 2/day in hydrocortisone dose equivalents) that has been above this threshold for at least 6 months and at a stable dose for at least 1 month prior to screening, is intended for chronic use, and consists of 1 or more of the following glucocorticoids: hydrocortisone (except sustained release), prednisone, prednisolone, methylprednisolone, or dexamethasone. Subjects must be on a morning dose of glucocorticoid. 5.
  • a female subject of childbearing potential is defined as a female capable of becoming pregnant, which includes subjects who have had their first menstrual cycle (i.e., menarche) and are not surgically sterile (i.e., bilateral oophorectomy, hysterectomy or bilateral tubal ligation for at least 3 months prior to screening).
  • a male subject of childbearing potential is defined as a subject who has reached spermarche and has not been vasectomized for at least 3 months prior to screening.
  • Crinecerfont 25 mg BID oral liquid for subjects 10 to ⁇ 20 kg, 50 mg BID oral liquid for subjects 20 to ⁇ 55 kg, or 100 mg BID oral capsule for subjects ⁇ 55 kg was administered with subjects’ breakfast and evening meals (doses separated by approximately 12 hours). Each oral capsule contained 50 mg crinecerfont (free base).
  • the oral liquid contained 50 mg of crinecerfont (free base) per 1 mL and was administered via a calibrated oral dosing syringe.
  • V Criteria for evaluation
  • A Efficacy ⁇ Hormone measurements: Androstenedione (A4; serum and saliva), 17- hydroxyprogesterone (17-OHP; serum and saliva), adrenocorticotropic hormone (ACTH; plasma), luteinizing hormone (LH; serum), testosterone (serum), plasma renin activity (measured upright).
  • ACTH adrenocorticotropic hormone
  • LH luteinizing hormone
  • testosterone serum
  • plasma renin activity measured upright.
  • BSA body surface area
  • ⁇ Growth (assessed as height velocity). ⁇ Bone age based on X-ray (only for subjects not at adult height and not with fused phalangeal epiphyses on X-ray). ⁇ Metabolic assessments (only in subjects ⁇ 12 years of age; fasting lipid panel and homeostatic model assessment of insulin resistance [HOMA-IR] based on fasting glucose and insulin levels). ⁇ Menstrual cycle questionnaire (only in female subjects who have undergone menarche and are not on hormonal or intrauterine device contraceptives). ⁇ Hirsutism (only for female subjects) and acne scales. ⁇ Testicular ultrasounds (to detect adrenal rest tissue; only in male subjects).
  • the first key secondary endpoint was the change from baseline to Week 4 in serum 17-OHP (average across all values obtained from 0830 to 1200 hours).
  • the second key secondary endpoint was the percent change from baseline to Week 28 in glucocorticoid daily dose (in hydrocortisone equivalents adjusted for BSA [mg/m 2 /day]), while Week 28 androstenedione was less than or equal to the baseline value.
  • One secondary endpoint was the achievement of a reduction in glucocorticoid daily dose to physiologic levels ( ⁇ 11 mg/m 2 /day in hydrocortisone equivalent adjusted for BSA) at Week 28, while Week 28 androstenedione was less than or equal to the baseline value.
  • Additional secondary endpoints include change from baseline in body mass index standard deviation score (SDS) at Week 28 and change in height velocity at Week 28 (restricted to subset of subjects not at adult height).
  • SDS body mass index standard deviation score
  • the continuous endpoints were analyzed using an analysis of covariance (ANCOVA) model and included treatment group (crinecerfont v. placebo), stratification factors used in the randomization and, as appropriate, baseline value.
  • the binary endpoint was compared by treatment group (crinecerfont vs. placebo) using a Cochran- Mantel-Haenszel (CMH) test stratified by factors used in the randomization.
  • CSH Cochran- Mantel-Haenszel
  • the overall Type I error of 0.05 was controlled by testing the primary, first key secondary, and second key secondary endpoints sequentially in this order.

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Abstract

La présente invention concerne de manière générale le traitement d'un dysfonctionnement surrénal (tel que l'hyperplasie surrénale congénitale) avec une combinaison de 2‑thiazolamine, 4-(2-chloro-4-méthoxy-5-méthylphényl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-méthylphényl)éthyl]-5-méthyl-N-2-propyn-1-yle (crinecerfont) et de certaines compositions pharmaceutiques d'hydrocortisone (telle qu'une composition pharmaceutique d'hydrocortisone à administration par voie orale à libération retardée).
PCT/US2025/029344 2024-05-15 2025-05-14 Traitement combiné Pending WO2025240605A1 (fr)

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