Combination treatment

Abstract

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).

Description

COMBINATION TREATMENT TECHNICAL FIELD

[0001] 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). DESCRIPTION OF RELATED TECHNOLOGY

[0002] 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. The compound of Formula (I) can be prepared according to the methods described in U.S. Patent Nos.6,586,456 and 8,314,249, each of which is hereby incorporated by reference in its entirety.

[0004] One clinical manifestation of the absence of cortisol that occurs in congenital adrenal hyperplasia (CAH) is the lack of feedback inhibition of pituitary adrenocorticotropic hormone (ACTH) secretion. Increased ACTH levels cause adrenal hyperplasia and the enzyme block causes a shunting of cortisol precursor steroids to alternate pathways. Most notably, the shunting to androgens leads to virilization and other developmental complications in females, and the elevated ACTH levels are associated with the formation of testicular adrenal rest tumors in males. In addition, since the same enzyme (21-hydroxylase) is used in the pathway for the biosynthesis of themineralocorticoids, a number of these patients suffer from aldosterone deficiency which can result in dehydration and death due to salt-wasting.

[0005] While survival is properly ensured through steroid replacement strategies based on physiologic dosing of glucocorticoids (e.g., hydrocortisone) and mineralocorticoids (e.g., fludrocortisone), these doses are often inadequate to suppress the overproduction of ACTH, progestogens, and androgens (e.g., 17-hydroxyprogesterone [17-OHP], androstenedione, and testosterone). 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 patientswith Addison’s disease). This increased exposure to glucocorticoids can lead to weigh tgain, 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. 2006 Mar; 91(3):865-9; Migeon and Wisniewski, Endocrinol Metab Clin North Am. 2001 Mar; 30(1):193-206).

[0006] 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, may be administered in various compositions of formulations to patients with CAH. In certain cases, 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.

[0007] Hydrocortisone may be administered in various compositions or formulations to patients with CAH. In certain cases, 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. In other cases, the hydrocortisone formulation may be an immediate release formulation, such as those described in U.S. Patent Nos. 9,649,280 and 9,675,559, each of which is hereby incorporated by reference in its entirety. In other cases, the 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.

[0008] 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. Therefore, compounds that block CRF1 receptors have the potential to directly inhibit the excessive ACTH release that occurs in CAH and thereby allow for normalization of androgen production while using lower, more physiologic doses 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, or a pharmaceutically acceptable salt thereof, may provide an important therapeutic approach to treat patients with CAH. SUMMARY

[0009] Provided herein are methods related to treating adrenal dysfunction (such ascongenital 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). Also provided herein are 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.

[0010] Provided herein is 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 delayedrelease oral pharmaceutical composition of hydrocortisone.

[0011] Provided herein is a kit 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 delayed release oral pharmaceutical composition of hydrocortisone;packaged together; optionally further comprising instructions for their administration.

[0012] Provided herein is a 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 delayed release oral pharmaceutical composition of hydrocortisone;optionally further comprising instructions for their administration.

[0013] Provided herein is 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 at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0014] Provided 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 or solvate thereof; and adelayed release oral pharmaceutical composition of hydrocortisone.

[0015] Provided herein is 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 instructing the subject to administer to themselves a delayed release oral pharmaceutical composition of hydrocortisone.

[0016] Provided herein is 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.

[0017] Provided herein is 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 instructing 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.

[0018] Provided herein is 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; instructing 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 instructing 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 consistent with 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 .

[0019] Provided herein is a method of treating adrenal dysfunction (for example, 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.

[0020] Provided herein is 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 a delayed release oral pharmaceutical composition of hydrocortisone.

[0021] Provided herein is 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 solvate thereof; and administering to the subject a therapeutically effective amount of the delayed release oral pharmaceutical composition of hydrocortisone.

[0022] Provided herein is a delayed release oral pharmaceutical composition of hydrocortisone 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 delayed release oral pharmaceutical composition of hydrocortisone; andadministering 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.

[0023] Provided herein is 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-methyl-N-2-propyn-1-yl (crinecerfont), or pharmaceutically acceptable salt or solvate thereof.

[0024] Provided herein is use 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, in the manufacture of a medicament 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 a delayed release oral pharmaceutical composition of hydrocortisone.

[0025] Provided herein is use of hydrocortisone in the manufacture of a delayed release oral pharmaceutical composition 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 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.

[0026] In some embodiments, the congenital adrenal hyperplasia is classic congenital adrenal hyperplasia.

[0027] In some embodiments, 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.

[0028] In some embodiments, 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, methylmethacrylate) in a ratio of 1:1 and (ii) poly(methacrylic acid, methyl methacrylate) in a ratioof 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 composition, and wherein the plasticizer comprises dibutyl sebacate at 0.5-1.0% w / w of the composition.

[0029] Other features and advantages of the methods, processes, formulations, and uses provided herein will be apparent from the following detailed description and from the claims. DETAILED DESCRIPTION

[0030] Newborn screening for CAH is performed by immunoassay to measure 17-OHP levels in heel-stick capillary blood specimens obtained within the first 72 hours of life. The blood sample is analyzed for 17-OHP by commercially available dissociation- enhanced lanthanide fluoroimmunoassay (DELFIA; PerkinElmer, Waltham Massachusetts) (White et al., J. Pediatr. 163:10-12 (2013)). Second-tier screening tests utilizing biochemical and molecular genetic testing methods, performed between 8 and14 days of life, 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., Speiser et al., Int. J. Pediatr. Endocrinol. 2010:494173, 2010). The genetic screen looks for CYP21A2 mutations that are associated with CAH. While not widely employed in the U.S., the addition of a second screening could potentially improve the sensitivity of the overall screening process, where sensitivity of the first screen alone is approximately 72%.

[0031] In absence of results from the newborn screening, female infants with classicalCAH are typically identified due to the presence of ambiguous genitalia. Males havenormal genitalia at birth and therefore are not diagnosed unless newborn screening is conducted or other medical complications come to attention. Infants who are not initially diagnosed with CAH and suffer from the salt-wasting form of the disease are later diagnosed in the setting of poor weight gain, vomiting, hyperkalemia and hyponatremia within the first few weeks of life.

[0032] 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 levelsfrom the pituitary, which drives increased androgen production. Unlike the treatment ofAddison’s disease (adrenal insufficiency), in which cortisol replacement is sufficient, the treatment of CAH must also reduce ACTH production, to control the subsequent androgen excess as well. Thus, the goals of glucocorticoid treatment include 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 regularblood pressure, electrolyte balance, and volume status in those patients with the salt -wasting form of CAH.

[0033] 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). Careful monitoring is also necessary to avoid the development of iatrogenic Cushing’s syndrome due toglucocorticoid overtreatment in an effort to adequately suppress androgen production, or Addisonian syndrome due to under-treatment.

[0034] Overtreatment with mineralocorticoids may cause hypertension while under- treatment may lead to low blood pressure, salt loss, fatigue and increased requirements for glucocorticoids. Typical laboratory tests for monitoring treatment efficacy include measurement of plasma concentrations of 17-OHP, androstenedione, testosterone, renin activity, and electrolytes.

[0035] Adult patients with CAH have an increased prevalence of risk factors for cardiovascular disease including obesity, hypertension, and insulin resistance (see, e.g., Kim et al., Semin. Reprod.Med. 27(4):316-21 (2009)). A study of a large cohort of pediatric and adult CAH patients (n=244) demonstrated that patients are prescribed a variety of glucocorticoid treatment regimens yet frequently suffer from poor hormonal control and the aforementioned adverse outcomes (see, e.g., Finkielstain et al., J. Clin. Endocrinol Metab. 97(12):4429-38 (2012)).

[0036] Treatment of CAH includes efforts to normalize the cortisol deficiency with glucocorticoids (usually hydrocortisone in children but often more potent agents withnarrow therapeutic indices, such as dexamethasone, in adults) and, if necessary for salt -wasting, mineralocorticoids (usually fludrocortisone). The glucocorticoid doses required to achieve sufficient suppression of excess androgens, however, are usually well above the normal physiologic dose used for cortisol replacement alone as in patients with Addison’s disease. This increased exposure to glucocorticoids can lead to iatrogenic Cushing’s syndrome, increased cardiovascular risk factors, glucose intolerance, and decreased bone mineral density in CAH patients (see, e.g., Elnecave et al., J. Pediatr. Endocrinol. Metab. 21:1155-62 (2008); King et al., J. Clin. Endocrinol. Metab. 91(3):8656-59 (2006); Migeon et al., Endocrinol. Metab. Clin. North Am. 30:193-206 (2001)). Recently, best practices for the clinical management of congenital adrenalhyperplasia were published in the Journal of Clinical Endocrinology and Metabolism(Speiser, P.W., et al. J. Clin. Endocrinol. Metab. November 2018, 103(11): 1-46). This article is incorporated by reference in its entirety.

[0037] Corticotropin-releasing factor (CRF) 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). Secretion of CRF causes release of ACTH from corticotrophs in the anterior pituitary via binding to the CRF1receptor, a member of the class B family of G-protein coupled receptors.

[0038] Due to the physiological significance of CRF, the development of biologically- active small molecules having significant CRF1receptor binding activity and which are capable of antagonizing the CRF1 receptor remains a desirable goal and has been the subject of ongoing research and development for the treatment of anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, and substance abuse.

[0039] The pituitary hormone ACTH, under the control of hypothalamic corticotropin- releasing factor (CRF), stimulates uptake of cholesterol and drives the synthesis of pregnenolone initiating steroidogenesis in the adrenal gland. The adrenal cortex is comprised of three zones, which produce distinct classes of hormones many of which are driven by ACTH mobilizing cholesterol through this pathway. Deficiencies in these enzymes as a result of mutation or deletion cause the substrate concentrations to increase. In the most common form of CAH resulting from mutations or deletions in the 21- hydroxylase gene (CYP21A2), potent androgens are produced by the adrenal because of the accumulation of the steroid precursors, progesterone and 17-hydroxyprogesterone (17-OHP). Plasma levels of 17-OHP can reach 10-1000 times the normal concentration in these cases. These increases result in the overproduction of androgens, specifically androstenedione, testosterone, and dihydroxytestosterone causing virilization in females. In addition, 21-hydroxylase deficiency in CAH causes insufficient biosynthesis of glucocorticoids and mineralocorticoids, specifically cortisol and aldosterone. 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 ACTHstimulation causes hypertrophy of the zona fasciculata and zona reticularis resulting inadrenal hyperplasia. Definitions

[0040] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Methods and materials are described herein for use in the present disclosure; other, suitable methods and materials known in the art can also be used. Thematerials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0041] As 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 having the Formula (I): or a pharmaceutically CRF1 receptor antagonistthat has been found to be effective in treating congenital adrenal hyperplasia. Specifically, the compound of Formula (I) has been found to effectively reduce several biomarkers associated with congenital adrenal hyperplasia. As used herein, the term “crinecerfont” refers to the compound of Formula (I) and includes any pharmaceutically acceptable salts and / or polymorphs thereof. In addition to the chemical name disclosed above, 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. 32, No. 4, 2018). 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”.

[0042] The term “about” preceding a stated value includes the stated value and also includes ±20% of the stated value, and includes more specifically values of ±10%, ±5%, ±2%, and ±1% of the stated value.

[0043] To provide a more concise description, some of the quantitative expressions herein are recited as a range from about amount X to about amount Y. It is understood that when a range is recited, the range is not limited to the recited upper and lowerbounds, but rather includes the full range from about amount X through about amount Y, or any range therein.

[0044] “Spray-drying” refers to the method of producing a dry powder from a solution or slurry. The solution or slurry is atomized or rapidly dried with a hot gas, e.g., air ornitrogen, that causes the solvent to evaporate quickly and uniformly. A “spray -drieddispersion” refers to the powder obtained from the spray-drying process.

[0045] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, co-solvents, complexing agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, which are not biologically or otherwise undesirable. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic formulations is contemplated. Supplementary active ingredients can also be incorporated into the formulations. In addition, various excipients, such as are commonly used in the art, can be included. These and other such compounds are described in the literature, e.g., in the Merck Index, Merck & Company, Rahway, NJ. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., in Gilman et al. (Eds.) (2010); Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 12th Ed., The McGraw-Hill Companies.

[0046] “Subject,” as used herein, 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. In some embodiments, the subject is a human.

[0047] In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented. In some embodiments, the subject has been identified or diagnosed as having congenital adrenal hyperplasia (CAH). In some embodiments, the subject is suspected of having CAH. In some embodiments, 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 thecompositions provided herein). In some embodiments, the subject is a pediatric subject.

[0048] 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 dividedinto various subpopulations including: neonates (from birth through the first month oflife); infants (1 month up to two years of age); children (two years of age up to 12 yearsof 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. Philadelphia: W.B. Saunders Company, 1996; Rudolph et al., Rudolph’s Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery et al., Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In some embodiments, 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). In some embodiments, apediatric subject is from birth through the first 28 days of life, from 29 days of age toless 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 ofage, or from 15 years of age to less than 22 years of age.

[0049] As used herein, the terms “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 ascompared to expected survival if not receiving treatment.

[0050] 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.

[0051] 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 thepharmaceutical formulation, the site of the disease, and the severity of the disease.

[0052] The term “therapeutically effective amount” as used herein, is an amount of a compound (e.g., crinecerfont, or a pharmaceutically acceptable salt or solvate thereof, orhydrocortisone) 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).

[0053] The term “pharmaceutically acceptable” as used herein, 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 inmedicine, 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. Also, pharmaceutically-acceptable salts can be preparedas alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts.

[0054] As used herein, “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.

[0055] As used herein, “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.

[0056] 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 900mL of media adjusted to pH 7.2 (via the addition of pre-warmed 50 mL of 0.23M trisodium ortho phosphate dodecahydrate buffer).

[0057] As used herein, “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.

[0058] As used herein, “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.

[0059] As used herein, the terms “multi-particulate” and “micro-particulate” areinterchangeable 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 μm 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.

[0060] As used herein, "delayed release polymer" refers to a pH sensitive entericpolymer and is adapted to delay release of hydrocortisone from said core.

[0061] As used herein, “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.

[0062] As used herein, “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.

[0063] As used herein in respect of pharmaceutical compositions and formulations 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. For example, 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%).

[0064] As used herein, the term “fed state,” refers to administration to a subject of a medicament from about 1 hour before consumption of food or a nutritional compositionto 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 or a nutritional composition and administration to a subject of a medicament.Methods

[0065] Provided herein is a method of treating adrenal dysfunction (for example, 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 multi -layer oralpharmaceutical composition of hydrocortisone.

[0066] In some embodiments, the multi-layer oral pharmaceutical composition is a delayed release oral pharmaceutical composition of hydrocortisone as described herein.

[0067] Also provided herein is a method of treating adrenal dysfunction (for example, 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 an oral liquid formulation of hydrocortisone.

[0068] In some embodiments, 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.

[0069] In some embodiments, 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.

[0070] In some embodiments, the adrenal dysfunction is congenital adrenal hyperplasia (CAH) or adrenal insufficiency.

[0071] In some embodiments, the adrenal dysfunction is congenital adrenal hyperplasia (CAH). In some embodiments, the CAH is classic CAH. In some embodiments the classic CAH is due to 21-hydroxylase deficiency. In some embodiments 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 11β-hydroxylase gene CYP11B1 (11β-OH CAH).

[0072] In some embodiments, 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.

[0073] In some embodiments, the method is 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.

[0074] Also provided herein is 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 instructing the subject to administer to themselves a delayed release oralpharmaceutical composition of hydrocortisone, as described herein.

[0075] Also provided herein is 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 instructing 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

[0076] In some embodiments, the method comprises measuring a subject characteristic at a first time point. In some embodiments, 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.

[0077] In some embodiments, 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.

[0078] In some embodiments, at a first time point 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). In some embodiments, 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. As used herein, 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] In some embodiments, 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. In some embodiments, the 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. In some embodiments, 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. In some embodiments, the bodymass 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.

[0080] In some embodiments, the method comprises determining body mass index (BMI) of the subject at a first time point. In some embodiments, 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 / m2and 10 kg / m2less than the body mass index (BMI) of the subject at the first time point. In some embodiments, the body mass index (BMI) of the subject at the second time point is at least about 0.1 kg / m2, about 0.2 kg / m2, about 0.3 kg / m2, about 0.4 kg / m2, about 0.5 kg / m2, about 0.6 kg / m2, about 0.7 kg / m2, about 0.8 kg / m2, about 0.9 kg / m2, about 1 kg / m2, about 1.1 kg / m2, about 1.2 kg / m2, about 1.3 kg / m2, about 1.4 kg / m2, about 1.5 kg / m2, about 1.6 kg / m2, about 1.7 kg / m2, about 1.8 kg / m2, about 1.9 kg / m2, about 2 kg / m2, about 2.1 kg / m2, about 2.2 kg / m2, about 2.3 kg / m2, about 2.4 kg / m2, about 2.5 kg / m2, about 2.6 kg / m2, about 2.7 kg / m2, about 2.8 kg / m2, about 2.9 kg / m2, about 3 kg / m2, about 3.1 kg / m2, about 3.2 kg / m2, about 3.3 kg / m2, about 3.4 kg / m2, about 3.5 kg / m2, about 3.6 kg / m2, about 3.7 kg / m2, about 3.8 kg / m2, about 3.9 kg / m2, about 4 kg / m2, about 4.1 kg / m2, about 4.2 kg / m2, about 4.3 kg / m2, about 4.4 kg / m2, about 4.5 kg / m2, about 4.6 kg / m2, about 4.7 kg / m2, about 4.8 kg / m2, about 4.9 kg / m2, about 5 kg / m2, about 5.5 kg / m2, about 6 kg / m2, about 6.5 kg / m2, about 7 kg / m2, about 7.5 kg / m2, about 8 kg / m2, about 8.5 kg / m2, about 9 kg / m2, about 9.5 kg / m2, or about 10 kg / m2less than the body mass index (BMI) of the subject at the first time point. Body mass index is determined by the subject's weight in kilograms (kg) divided by the square of their height in meters (m).

[0081] In some embodiments, 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 thesecond time point is between 1 cm and 30 cm less than the waist circumference of the subject at the first time point. In some embodiments, 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).

[0082] In some embodiments, the method comprises measuring body fat percentage of the subject at a first time point. In some embodiments, 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. In some embodiments, 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. 5, pages 76-90; DOI: 10.1080 / 00913847.1985.11708790, which is hereby incorporated by reference in its entirety).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. In some embodiments, 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.

[0084] In some embodiments, the biomarkers are selected from (a) 17- hydroxyprogesterone (17-OHP); (b) adrenocorticotropic hormone (ACTH); and (c) androstenedione in the subject.

[0085] In some embodiments, the change in level of any of the biomarkers (e.g., any of 17-OHP, ACTH, and androstenedione) 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. In some embodiments, the change in level of any of the biomarkers (e.g., any of 17-OHP, ACTH, and androstenedione) 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. A day prior to administering applies to a subject that has not previously been administered 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, within at least the past 24 hours.

[0086] In some embodiments, the circadian release of biomarkers associated with CAH occurs between the hours of 2 a.m. and 10 a.m. In other embodiments, the circadian release of biomarkers associated with CAH occurs between the hours of 6 a.m. and 10 a.m.

[0087] In some embodiments, 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 someembodiments, 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. In some embodiments, 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. In some embodiments, 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 subjectwithout CAH, i.e., less than 1,000 ng / dL or less than 200 ng / dL.

[0089] In some embodiments, 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. In some embodiments, 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. In some embodiments, the blood plasma level of adrenocorticotropic hormone is reduced by at least 10% at the second time point ascompared 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.

[0091] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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 monthbefore beginning the administering of a method described herein to 1 week after beginning the administering of a method described herein. In some embodiments, 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. In some embodiments, 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. In some embodiments, the 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. Side effects of glucocorticoid treatment

[0096] 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.

[0097] 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. In some embodiments, the glucocorticoid is selected from cortisol (hydrocortisone), cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone, fludrocortisone acetate, and deoxycorticosterone acetate. In some embodiments, the glucocorticoid is cortisol (hydrocortisone). In some embodiments, the glucocorticoid is cortisone. In some embodiments, the glucocorticoid is prednisone. In some embodiments, the glucocorticoid is dexamethasone.

[0098] In some embodiments, 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. (2016): Long-term effect of glucocorticoids, Expert Opinion on Drug Safety. DOI: 10.1517 / 14740338.2016.1140743, which is hereby incorporated by reference in its entirety). Such side effects are associated with every biological system, e.g., 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, easy bruising, acne, hirsutism, and hair loss), neuropsychiatric (e.g., mood changes, depression, euphoria, mood lability, irritability, akathisia, anxiety, cognitive impairment, psychosis, dementia, and delirium), ophthalmologic (e.g., cataract, glaucoma, ptosis, mydriasis, opportunistic ocular infections, and central serous chorioretinopathy), and immunologic (e.g., suppression of cell-mediated immunity, predisposition to infections, and reactivation of latent infections).

[0100] Accordingly, In some embodiments, 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, opportunistic ocular infections, central serous chorioretinopathy, suppression of cell-mediated immunity, predisposition to infections, reactivation of latent infections, and any combination thereof.

[0101] In some embodiments, the side effects of glucocorticoid treatment are selected from hyperglycemia, diabetes mellitus, dyslipidemia, weight gain, Cushing syndrome, Cushingoid features, growth suppression, and adrenal suppression.

[0102] In some embodiments, the side effect of glucocorticoid treatment is weight gain.

[0103] In some embodiments, 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.

[0104] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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 thatcomparative 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. In some embodiments, 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 someembodiments, the adult subject is over twenty one years old.

[0108] In some embodiments, the subject is female. In some embodiments, the subject is male.

[0109] In some embodiments, the subject has a body mass index (BMI) of at least about 25 kg / m2before 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 / m2before beginning the administering of a method described herein. Amount and timing of dosing

[0111] 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 initialdoses applied, higher doses (or effectively higher doses) may be employed to the extent that patient tolerance permits.

[0112] In some embodiments, 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.

[0113] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.

[0114] In some embodiments, 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 FDA has provided draft guidelines regarding high fat and low fat meals (“Assessing the Effects of Food on Drugs in INDs and NDAs – Clinical Pharmacology Considerations Guidance for Industry,” U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), February 2019, Clinical Pharmacology).

[0115] In some embodiments, the therapeutically effective amount of crinecerfont, or pharmaceutically acceptable salt or solvate thereof, is administered twice daily in a firstdaily dose and a second daily dose. In some embodiments, the therapeutically effectiveamount 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. In some embodiments, the first daily dose of crinecerfont, or pharmaceutically acceptable salt or solvate thereof, is administered in the morning. In some embodiments, 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. In some embodiments, the first 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 first 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 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. In some embodiments, 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.

[0116] In some embodiments, the administering of hydrocortisone (e.g., in a delayed release oral pharmaceutical composition) is daily.

[0117] In some embodiments, the therapeutically effective amount of the multi -layeroral 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 doseof from 7.5 mg to 40 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 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.

[0118] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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 pharmaceuticalcomposition 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. 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 1:1.05 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 oralpharmaceutical 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. In some embodiments, the second daily dose of the delayed release oral pharmaceutical composition of hydrocortisone is administered in the evening. In some embodiments, the subject is in a fasted state on the administering of the delayed release oral pharmaceutical composition of hydrocortisone. In some embodiments, 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. In some embodiments, the second daily dose is of the delayed release oral pharmaceutical composition of hydrocortisone is administered in the evening, atleast 2 hours after the previous meal and at least one hour before the next meal.

[0121] In some embodiments, 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. In some embodiments, 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, andthe administering of the delayed release oral pharmaceutical composition of hydrocortisone is sequential. 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 simultaneous.

[0124] In some embodiments, the crinecerfont, or pharmaceutically acceptable salt or solvate thereof, is administered twice daily in a first daily dose and a second daily dose, and the delayed release oral pharmaceutical composition of hydrocortisone is administered twice daily in a first daily dose and a second daily dose.

[0125] In some embodiments, 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.

[0126] In some embodiments, 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 or solvate thereof, is administered to the subject in a fed state in the evening.Lipidic semi-solid formulations of crinecerfont

[0127] Provided herein (e.g., for use in the methods disclosed herein) is 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; b. an oily phase vehicle; c. an emulsifying agent; d. a nonionic surfactant; and e. a solubilizing agent.

[0128] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.

[0129] An oily phase vehicle is a solvent that is poorly miscible with water. In some embodiments, the pharmaceutical composition comprises about 20 %w / w to about 50 %w / w of the oily phase vehicle. In some embodiments, the pharmaceutical composition comprises about 35 %w / w to about 45 %w / w of the oily phase vehicle. In some embodiments, 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.

[0130] In some embodiments, 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. In some embodiments, the medium-chain triglycerides are Miglyol 812N.

[0131] An emulsifying agent is a compound or substance that acts as a stabilizer for emulsions. In some embodiments, 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. In some embodiments, the pharmaceutical composition comprises about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 %w / w of the emulsifying agent, or within a range of any of the preceding values.

[0132] In some embodiments, 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. In some embodiments, the emulsifying agent is propylene glycol dicaprylate / dicaprate. In some embodiments, the propylene glycol dicaprylate / dicaprate is Labrafac TM PG.

[0133] 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. In some embodiments, 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. In some embodiments, the pharmaceutical composition comprises about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 %w / w of the nonionic surfactant, or within a range of any of the preceding values.

[0134] In some embodiments, 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. In some embodiments, the nonionic surfactant is lauroyl polyoxyl-32glycerides. In some embodiments, the lauroyl polyoxyl-32 glycerides are Gelucire® 44 / 14.

[0135] 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. In some embodiments, 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.

[0136] In some embodiments, 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. In some embodiments, the solubilizing agent is vitamin E polyethylene glycol succinate. In some embodiments, the vitamin E polyethylene glycol succinate is Kolliphor® TPGS. In some embodiments, the vitamin E polyethylene glycol succinate is Vitamin E / TPGS 260.

[0137] In some embodiments, 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), or a pharmaceutically acceptable salt thereof, based on the weight of the free base;b. about 35 %w / w to about 45 %w / w of an oily phase vehicle;c. about 15 %w / w to about 25 %w / w of an emulsifying agent; d. about 15 %w / w to about 25 %w / w of a nonionic surfactant; and e. about 5 %w / w to about 15 %w / w of a solubilizing agent.

[0138] In some embodiments, 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. about 35 %w / w to about 45 %w / w of medium-chain triglycerides;c. about 15 %w / w to about 25 %w / w of propylene glycol dicaprylate / dicaprate;d. about 15 %w / w to about 25 %w / w of lauroyl polyoxyl-32 glycerides; and e. about 5 %w / w to about 15 %w / w of vitamin E polyethylene glycol succinate.

[0139] In some embodiments, 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.

[0140] In some embodiments, 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. In some embodiments, the capsule is a soft gelatin capsule. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. 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; b. a sweetener;c. an anti-oxidant; d. a flavor; and e. a liquid vehicle.

[0142] In some embodiments, 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. In some embodiments, 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)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof, based on the weight of the free base. In some embodiments, 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. In some embodiments, 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.

[0143] A sweetener is a formulation component added to improve taste. In some embodiments, the pharmaceutical composition comprises about 0.01 %w / v to about 1.5 %w / v of the sweetener. In some embodiments, the pharmaceutical composition comprises about 0.1 w / v% to about 0.5 w / v% of the sweetener. In some embodiments, the pharmaceutical composition comprises about 0.15 w / v% of the sweetener. In some embodiments, the pharmaceutical composition comprises about 0.1, 0.2, 0.3, 0.4, or 0.5 w / v% of the sweetener, or within a range of any of the preceding values.

[0144] In some embodiments, the sweetener is selected from saccharin, sucrose, sucralose, aspartame, dextrose, fructose, maltitol, mannitol, sorbitol, and avantame. In some embodiments, the sweetener is saccharin.

[0145] An anti-oxidant is a formulation component included to improve stability by preventing oxidation. In some embodiments, the pharmaceutical composition comprisesabout 0.01 %w / v to about 1.5 %w / v of the anti-oxidant. In some embodiments, thepharmaceutical 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.

[0146] In some embodiments, the anti-oxidant is selected from butylatedhydroxytoluene, vitamin E TPGS, butylated hydroxyanisole, ascorbic acid, lecithin, tert -butylhydroquinone, and citric acid. In some embodiments, the anti-oxidant is butylated hydroxytoluene.

[0147] 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. In some embodiments, the pharmaceutical composition comprises about 0.10 w / v% of the flavor. In some embodiments, the pharmaceutical composition comprises about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19 or 0.2 w / v% of the flavor, or within a range of any of the preceding values.

[0148] In some embodiments, 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.

[0149] 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. In some embodiments, the pharmaceutical composition comprises about 90 %w / v to about 99 %w / v of the liquid vehicle. In some embodiments, the pharmaceutical composition comprises about 92 %w / v to about 97 %w / v of the liquid vehicle. In some embodiments, the pharmaceutical composition comprises about 94.6 %w / v of the liquid vehicle. In some embodiments, the pharmaceutical composition comprises about 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 %w / v of the liquid vehicle, or within a range of any of the preceding values.

[0150] In some embodiments, 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. In some embodiments, the medium-chain triglycerides is Labrafac Lipophile WL1349.

[0151] In some embodiments, the pharmaceutical composition further comprises a surfactant. A surfactant is a formulation component added to improve solubility or emulsion properties. In some embodiments, the pharmaceutical composition comprises about 1 w / v% to about 50 w / v% of the surfactant. In some embodiments, the pharmaceutical composition comprises about 10 w / v% to about 30 w / v% of the surfactant. In some embodiments, the pharmaceutical composition comprises about 20 w / v% of the surfactant. In some embodiments, the pharmaceutical composition comprises about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29 or 30 w / v% of the surfactant, or within a range of any of the preceding values.

[0152] In some embodiments, 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. In some embodiments, 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. In some embodiments, the pharmaceutical composition comprises about 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 w / v% of the liquid vehicle, or within a range of any of the preceding values.

[0154] In some embodiments, 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. In some embodiments, the medium-chain triglycerides is Labrafac Lipophile WL1349.

[0155] In some embodiments, 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. about 0.1 %w / v to about 0.2 %w / v of an anti-oxidant; d. about 0.05 %w / v to about 0.2 %w / v of a flavor; and e. about 92 %w / v to about 97 %w / v of a liquid vehicle.

[0156] In some embodiments, 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 saccharin;c. about 0.1 %w / v to about 0.2 %w / v of butylated hydroxytoluene;d. about 0.05 %w / v to about 0.2 %w / v of FONA orange flavor; and e. about 92 %w / v to about 97 %w / v of medium-chain triglycerides.

[0157] In some embodiments, 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 saccharin;c. about 0.1 %w / v to about 0.2 %w / v of butylated hydroxytoluene;d. about 0.05 %w / v to about 0.2 %w / v of FONA orange flavor; e. about 15 %w / v to about 25 %w / v of oleoyl polyoxyl-6 glycerides; and f. about 70 %w / v to about 80 %w / v of medium-chain triglycerides.

[0158] In some embodiments, the oral solution dosage formulation comprises: a. 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), based on the weight of the free base; b. about 0.15 %w / v of saccharin; c. about 0.17 %w / v of butylated hydroxytoluene; d. about 0.1 %w / v of FONA orange flavor;e. about 20 %w / v of oleoyl polyoxyl-6 glycerides; and f. about 75 %w / v of medium-chain triglycerides.

[0159] In some embodiments, 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.

[0160] In some embodiments, 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

[0161] The methods and uses of the present disclosure 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).

[0162] In some embodiments, 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. In some embodiments, 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. In some embodiments, the aqueous environment is the lower GI tract, such as the small intestine and large intestine.

[0163] In some embodiments, 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. As used herein, “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. In some embodiments, 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. Without wishing to be bound by any theory, it is believed that 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.

[0164] In some embodiments, 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 nof 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-methylphenyl)ethyl]-5-methyl-N-2-propyn-1-yl (crinecerfont), or a pharmaceutically acceptable salt thereof, to the copolymer is from about 1:1 to about 1:9, based on the weight of the freebase.

[0165] In some embodiments, 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- propyn-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. In some embodiments, the filler is selected from among binders, diluents, disintegrants, glidants, surfactants, and combinations thereof.

[0167] 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.

[0168] In some embodiments, the pharmaceutical composition includes a lubricant. Lubricants are agents added to pharmaceutical formulations to reduce friction during processing and prevent ingredients from clumping together.

[0169] 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. Examples of 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 -layeroral 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 immediate 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.

[0172] In some embodiments, 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. In some embodiments, 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.

[0173] In some embodiments, 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 coreand is adapted to delay release of hydrocortisone from said core.

[0174] In some embodiments, 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. a layer comprising a delayed release polymer, talc, and a plasticizer, wherein the layer comprising a delayed release polymer is in contact with said coreand is adapted to delay release of hydrocortisone from said core.

[0175] In some embodiments, 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.

[0176] In some embodiments, the delayed release polymer is selected from the group consisting of: acrylic and / or poly [methyl] acrylic polymers, cellulose acetate succinate, or polyvinylacetate phthalate.

[0177] In some embodiments, 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. 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, methylmethacrylate) in a ratio of 1:1 and (ii) poly(methacrylic acid, methyl methacrylate) in a ratioof 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 composition, and wherein the plasticizer comprises dibutyl sebacate at 0.5-1.0% w / w of the composition.

[0178] In some embodiments, 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, methylmethacrylate) in a ratio of 1:1 and (ii) poly(methacrylic acid, methyl methacrylate) in a ra tioof 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 composition, andwherein the plasticizer comprises dibutyl sebacate at 0.5-1.0% w / w of the composition.

[0179] In some embodiments, the delayed release oral pharmaceutical composition is in capsule form. In some embodiments, the capsule is a hard capsule. In some embodiments, the capsule is a hard capsule containing granules.

[0180] In some embodiments, 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.Quantity (mg / capsule) Quantity( ) - Removed during processing, does not appear in the final product, required quantity shown in parenthesis 1 Talc included in the coating formulation as anti-sticking agent 2 Talc included extra-granularly as anti-sticking agent and is removed in the manufacturing process

[0182] In some embodiments, the delayed release oral pharmaceutical composition of hydrocortisone is in capsule form. In some embodiments, the capsule is a hard capsule. In some embodiments, the capsule is a hard capsule containing granules. In some embodiments, 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. In some embodiments, 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. In some embodiments, hydrocortisone contained in the immediate-release immediate release oral pharmaceutical composition is not released before about 5 minutes in aqueous conditions in the mouth of the subject.

[0185] In some embodiments, the immediate release oral pharmaceutical composition provides release of hydrocortisone after swallowing. In some embodiments, at least 70% of hydrocortisone contained in the immediate release oral pharmaceutical composition is released within 15 minutes of swallowing. In some embodiments, at least 90% of hydrocortisone contained in the immediate release oral pharmaceutical composition is released within 60 minutes of swallowing.

[0186] In some embodiments, 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; andd. a sealing polymer layer that separates the drug layer and the taste masking polymer layer; wherein the drug layer is in contact with the micro-particulate carrier and with the sealing polymer layer.

[0187] In some embodiments, 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. a sealing polymer layer that separates the drug layer and the taste masking polymer layer, wherein the sealing polymer layer consists of 14-16% w / w hydroxypropyl methylcellulose and 1-2% w / w magnesium stearate; wherein the drug layer is in contact with the micro-particulate carrier and with the sealing polymer layer.

[0188] In some embodiments, 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. a sealing layer comprising at least 20% w / w hydroxypropyl methylcellulose and at least 2% w / w magnesium stearate, wherein the sealing layer is in contact with the drug layer; and d. a taste masking layer comprising at least 0.25% w / w hydroxypropyl methylcellulose, at least 1% w / w ethyl cellulose, and at least 0.4% w / w magnesium stearate, wherein the taste masking layer is in contact with the sealing layer.

[0189] In some embodiments, 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. a taste masking layer comprising 0.29-0.31-% w / w hydroxypropyl methylcellulose, 1.1-1.3% w / w ethyl cellulose, and at least 0.4-0.5% w / w magnesium stearate, wherein the taste masking layer is in contact with the sealing layer.

[0190] In some embodiments, 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. a micro-particulate carrier comprising 80-81% w / w microcrystalline cellulose, wherein said microcrystalline cellulose micro-particulates have an average diameter of 350-500 µm; b. a drug layer comprising 0.64-0.66% w / w hydrocortisone and 0.64-0.66% w / w hydroxypropyl 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. a taste masking layer comprising 0.14-0.16% w / w hydroxypropyl methylcellulose, 0.58-0.62% w / w ethyl cellulose, and 0.20-0.25% w / w magnesium stearate, in contact with the sealing layer.

[0193] In some embodiments, 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 µm; b. a drug layer consisting of 0.66% w / w hydrocortisone and 0.66% w / w hydroxypropyl methylcellulose, in contact with the carrier;c. a sealing layer consisting of 15% w / w hydroxypropyl methylcellulose and 1.5% w / w magnesium stearate, in contact with the drug layer; and d. a taste masking layer consisting of 0.15% w / w hydroxypropyl methylcellulose, 0.61% w / w ethyl cellulose, and 0.23% w / w magnesium stearate, in contact with the sealing layer.

[0194] In some embodiments, 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. In some embodiments, the capsule is a capsule for opening, the capsule for opening comprising granules. In some embodiments, 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

[0197] 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. In some embodiments, the oral liquid formulation is an oral solution formulation. In someembodiments, the oral liquid formulation of hydrocortisone is as described in WO 2024 / 107653 A1, which is hereby incorporated herein by reference in its entirety.

[0198] In some embodiments, the oral liquid formulation comprises: hydrocortisone, or a pharmaceutically acceptable salt thereof;a non-aqueous liquid carrier; and a preservative.

[0199] In some embodiments, 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). In some embodiments, 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. In some embodiments, the oral liquid formulation comprises hydrocortisone, or a pharmaceutically acceptable salt thereof, in an amount of about 0.5 % w / v.

[0200] In some embodiments, the hydrocortisone used in the oral liquid formulations described herein is a hydrocortisone free base. In some embodiments, the hydrocortisone used in the oral liquid formulations described herein is a hydrocortisonesalt. In some instances, the hydrocortisone salt is hydrocortisone acetate. In some instances, the hydrocortisone salt is hydrocortisone sodium succinate. In some instances, the hydrocortisone salt is hydrocortisone sodium phosphate. In other instances, the hydrocortisone salt is in the form of hydrocortisone acetate or hydrocortisone sodium succinate.

[0201] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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 -8glycerides, sold under the trade name Labrasol®).or any combinations thereof. In someembodiments, 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. In some embodiments, 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. Insome embodiments, the oral liquid formulation of hydrocortisone comprises PEG 400 in an amount of about 50 % w / v.

[0203] In some embodiments, 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. In some embodiments, 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. In some embodiments, the oral liquid formulation ofhydrocortisone 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. In some embodiments, 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. In some embodiments, the oral liquid formulation of hydrocortisone comprises about 5 % wt of water or less. In some embodiments, the oral liquid formulation of hydrocortisone comprises less than 0.1 % wt of water. In some embodiments, the oral liquid formulation of hydrocortisone comprises less than 0.01 % wt of water. In some embodiments, the oral liquid formulationdoes not comprise water. In some embodiments, the oral liquid formulation is nonaqueous.

[0207] In some embodiments, 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.

[0208] In some embodiments, 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, α-tocopherol acetate (vitamin E), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), or a combination thereof. In some embodiments, the antioxidant comprises butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), or a combination thereof. In some embodiments, theantioxidant comprises BHA. In some embodiments, the antioxidant comprises BHT. Insome embodiments, the antioxidant is BHA and BHT. In some embodiments, the antioxidant is BHA. In some embodiments, the antioxidant is BHT.

[0209] In some embodiments, 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. In some embodiments, 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. In some embodiments, the antimicrobial agent comprises parabens. In some embodiments, the parabens comprise methyl paraben, propyl paraben, or a combination thereof. In some embodiments, the antimicrobial agent comprises methyl paraben. In some embodiments, the antimicrobial agent comprises propyl paraben. In some embodiments, the antimicrobial agent comprises methyl paraben and propyl paraben.

[0210] In some embodiments, 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. In some embodiments, 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.

[0211] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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, can be used to improve the flavor of hydrocortisone and other excipients in the formulation, and to enhance palatability and thus compliance in a range of patient populations. In some embodiments, 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. In some embodiments, the flavoring agent comprises berry flavor, ethyl maltol, or a combination thereof. In some embodiments, the flavoring agent is berry flavor (e.g., Berry Mixed Flavor WONF, WS Natural 13.17579). In some embodiments, 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 ofhydrocortisone 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. In some embodiments, the oral liquid formulations of hydrocortisone described herein do not contain monobasic sodium phosphate.

[0214] In further embodiments, 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.

[0215] In some 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). In some embodiments, 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 someembodiments, the oral liquid formulation of hydrocortisone is an oral liquid formulation according to F-IX, F-X, F-XI, F-XII, F-XIII, F-XIV, F-XV, or F-XVI (as set out in Tables Cand D, below). In some embodiments, the oral liquid formulation of hydrocort isone isan 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). In some embodiments, 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 (as set out in Tables G, H, and I, below).Table A: oral liquid formulations of hydrocortisone with water.Quantity %w / v IngredientTable B: oral liquid formulations of hydrocortisone without water.Quantity %w / v IQuantity %w / v Ingredient FIII FIV FV FVI FVII FVIIITable C: oral liquid formulations of hydrocortisone with varied preservatives, sweeteners, and flavoring agents. Quantity %w / v Ingredient , ,Quantity %w / v Ingredient F IX F X F XI F XII - L Table D: oral liquid formulations of hydrocortisone with varied preservatives, sweeteners, and flavoring agents. Quantity %w / v Ingredient , , -Quantity %w / v Ingredient FXIII FXIV FXV FXVI LTaq y p .Quantity %w / v Ingredient e, a LTable F: oral liquid formulations of hydrocortisone with varied preservatives. Quantity %w / v Ingredient F XXI F XXII F XXIII F XXIV e, a LTable G: oral liquid formulations of hydrocortisone with varied non-aqueous liquid carriers. Quantity %w / vQuantity %w / v Ingredient FXXV FXXVI FXXVII LTable H: oral liquid formulations of hydrocortisone with varied non-aqueous liquid carriers. Quantity %w / v In redientQuantity %w / v Ingredient F XXVIII F XXVIV F XXVV L Table I: oral liquid formulations of hydrocortisone with varied non-aqueous liquid carriers. Quantity %w / v Ingredient LFixed 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. In some embodiments, thefixed dose combination product further comprises at least one pharmaceutically acceptable carrier, diluent, or excipient.

[0217] In some embodiments, the fixed dose combination product comprises thehydrocortisone in a delayed release oral pharmaceutical composition.Kits and Twin Packs

[0218] Also provided herein are kits, including twin packs. Typically, 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. In certain embodiments, a kit 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). In some embodiments, 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. Also provided herein is the use of compounds in themanufacture of medicaments for use in any of the methods described herein.

[0220] Provided herein is 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 described herein.

[0221] Provided herein is 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.

[0222] Provided herein is a delayed release oral pharmaceutical composition of hydrocortisone for use in a method of treating described herein.

[0223] Provided herein is 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 described herein.

[0224] Provided herein is use 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, in the manufacture of a medicament for use in a method of treating described herein.

[0225] Provided herein is use of hydrocortisone in the manufacture of a delayed release oral pharmaceutical composition for use in a method of treating described herein.EXAMPLES

[0226] Example 1: Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Crinecerfont in Adult Subjects with Classic Congenital Adrenal Hyperplasia, Followed 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. · To evaluate the effect of crinecerfont compared with placebo, on clinical endpoints associated with supraphysiologic glucocorticoid dosing.· To evaluate plasma concentrations of crinecerfont and metabolites.· To assess the safety and tolerability of crinecerfont. · To evaluate an alternate dosing regimen of crinecerfont in subjects who have not reduced their glucocorticoid dose by Month 12. o Unexplained hyponatremia (serum sodium <135 mmol / L) (II) Methodology:

[0227] This is a Phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, and tolerability of crinecerfont, versus placebo administeredBID with breakfast and the evening meal (doses separated by approximately 12 hours) for 24 weeks in approximately 165 adult subjects with classic CAH due to 21- hydroxylase deficiency. Eligible subjects were randomly assigned in a 2:1 ratio (active : placebo) to 2 treatment groups: crinecerfont, 100 mg BID or placebo. After the 24-week randomized treatment period, there was a 6 month, open-label treatment period, during which all subjects received crinecerfont at 100 mg BID. At Month 12, subjects who did not reduced their glucocorticoid dose to ≤11 mg / m2 / day were re-randomized (2:1) to receive 50 mg every morning (qAM) and 150 mg every evening (qPM) or to continue 100 mg BID, in a blinded fashion. Subjects who did reduced their glucocorticoid dose to ≤11 mg / m2 / day continued to receive 100 mg BID in an open label fashion. A final studyvisit was conducted approximately 4 weeks after the Month 18 visit.(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 / m2 / day in hydrocortisone dose equivalents adjusted for body surface area (BSA) that has been stable at least 1 month leading up to screening. 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 thesubject’s individual medical needs and treatment goals.

[0229] 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. (B) Randomized, Double-Blind, Placebo-Controlled Treatment Period (Day 1 up to Week 24) (a) 4-Week Glucocorticoid Stable Period (Day 1 up to Week 4)

[0230] During the first 4 weeks of the study, subjects maintained their stable glucocorticoid regimen, except for sick-day guidelines (e.g., based on guidance provided by the investigator or their treating physician).

[0231] On Day 1 (baseline), subjects collected a urine sample (all voids from midnight the night before the study visit to the first morning void after awakening for the day) at home in the morning and brought it to the site for measurement of androgen metabolite levels. They held their morning glucocorticoid dose and brought it with them to the study site, a blood sample was then obtained prior to taking the morning glucocorticoid dose; subjects then took their morning dose of glucocorticoid at the study site, and another blood sample was taken approximately 2 hours post dose in order to establish the baseline pre- and post-glucocorticoid hormone levels. Subjects fasted from the night before so that fasting blood tests and an oral glucose tolerance test could be performed, but subjectswere encouraged to drink water to avoid any hypovolemic status.

[0232] Subjects were randomized on Day 1 in a 2:1 ratio (active : placebo). 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). (b) 8-Week Glucocorticoid Reduction Period (Week 4 up to Week 12)

[0233] During this period, subjects underwent a down-titration (in 4 or fewer steps) oftheir glucocorticoid dose with the goal to reach a target dose of 8 to 10 mg / m 2 / day(hydrocortisone equivalents adjusted for body surface area (BSA)) by Week 12, unless the subject exhibited any signs or symptoms suggestive of clinically relevant glucocorticoid insufficiency or unacceptable symptoms of hyperandrogenism.

[0234] At the week 4 visit, a similar procedure was followed as for Day 1 to obtain a more detailed assessment of androgen status, with collection of a urine sample at home and collection of blood samples prior to and approximately 2 hours after dosing of morning glucocorticoid and capsule(s) at the study site. At this visit, the investigator instructed the subject on the first 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. During the follow-up telephone contact, if the investigator felt that a clinical assessment and / or laboratory tests were needed, these were performed as an unscheduled visit.

[0235] 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.

[0236] At the Week 6 visit, 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 the third step of glucocorticoid dose reduction (if applicable).

[0237] At the Week 9 study visit, the investigator assessed whether the subject was tolerating the third glucocorticoid dose reduction. The investigator contacted the subject at approximately Week 10 to advise on the fourth step of glucocorticoid dose reduction (if applicable).

[0238] If 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). · Orthostatic hypotension with decrease in systolic blood pressure >20 mmHg or in diastolic blood pressure >10 mmHg after standing (from a seated position) after approximately 2 minutes, or severe symptoms of dizziness or lightheadedness upon standing · Severe nausea, food aversion, vomiting · Unacceptable symptoms of hyperandrogenism (e.g., hirsutism, acne, amenorrhea)

[0239] Glucocorticoid dose reductions during Weeks 4 to 12 should proceed even if androstenedione levels increased transiently, provided that the increase is asymptomatic and tolerated by the subject.

[0240] At the Week 12 visit, based on review of the subject’s hormone levels collected up to that visit as well as based on clinical assessment, the investigator determined the appropriate dose of glucocorticoid to continue past Week 12 (the reduced dose if tolerated, or a prior [higher] dose) in order to achieve adequate control of androgen levels (i.e., androstenedione ≤120% of the subject’s baseline or ≤upper limit of normal [ULN] for age and sex). (c) 12-Week Glucocorticoid Optimization Period (Week 12 up to Week 24)

[0241] Subjects continued on the glucocorticoid regimen as instructed by the investigator at Week 12 and returned to the study site at Week 16 (optional at home),Week 20 (optional at home), and Week 24 during the glucocorticoid optimization period. At these visits, the investigator reviewed the laboratory results from the preceding study visit and determined if the glucocorticoid regimen required adjustment in order to achieve adequate control of androgen levels (i.e., androstenedione ≤120% of thesubject’s baseline or ≤ULN for age and sex).

[0242] At the Week 24 visit, subjects followed a similar procedure as Day 1 for additional androgen assessments with collection of a urine sample at home and collection of blood samples prior to and approximately 2 hours after dosing of morning glucocorticoid and study drug at the study site. Subjects fasted from the night before, but were encouraged to drink water to avoid any hypovolemic status, and a glucose tolerancetest was performed (with study drug taken with the glucose load rather than a meal).(C) Open-Label Treatment Period (Week 24 up to Month 12)

[0243] For the purpose of this study, months are defined as 4 week intervals.

[0244] Starting the evening of the Week 24 visit (after all Week 24 assessments had been performed), all subjects received capsule(s) comprising active study drug (crinecerfont) at 100 mg BID with breakfast and evening meals. Subjects continued the glucocorticoid regimen specified by the investigator at Week 24. Subjects and investigators remained blinded to subjects’ treatment group assignment from the double- blind period. (a) 1-Month Glucocorticoid Stable Period (Week 24 up to Month 7)

[0245] During the first month of open-label treatment with crinecerfont, subjects maintained a stable glucocorticoid regimen (except for sick-day guidelines). (b) 3-Month Glucocorticoid Reduction Period (Month 7 up to Month 10)

[0246] At Months 7 (optional at home), 8, and 9 (optional at home), investigators decreased glucocorticoid doses in those subjects whose glucocorticoid dose was still greater than 11 mg / m2 / day at Month 7 (unless there was a safety concern with regard to glucocorticoid insufficiency), with the goal to achieve a target physiologic dose of 8 to 10 mg / m2 / day by Month 10. 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 / m2 / day hydrocortisone equivalents.

[0247] After each of the glucocorticoid dose reduction steps, 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 studyassessments including collection of blood samples for hormone levels.(c) 2-Month Glucocorticoid Maintenance Period (Month 10 up to Month 12)

[0248] Subjects returned to the study site at Months 10 and 12 for study assessments as outlined in the Schedule of Assessments. During this period, the goal was to maintain stable glucocorticoid doses; however, the dose could have been adjusted according to standard of care (e.g., to achieve the control of androgen levels appropriate to the treatment targets for each subject).

[0249] At the Month 12 visit, subjects had additional androgen assessments with collection of a urine sample at home and blood sample collection before and approximately 2 hours after dosing of morning glucocorticoid and study drug at the study site. Subjects should have fasted from the night before (subjects were encouraged to drink water to avoid any hypovolemic status). A glucose tolerance test was performed (withcapsule(s) taken with the glucose load rather than a meal) at the Month 12 visit.(D) Open-Label or Double-Blind Active-Controlled Treatment (Month 12 to Month 18) (a) 6-Month Glucocorticoid Maintenance Period (Month 12 to Month 18) for Subjects with Month 12 Glucocorticoid Dose ≤11 mg / m2 / day

[0250] Subjects with glucocorticoid dose ≤11 mg / m2 / day at Month 12 continued on active study drug at 100 mg BID until Month 18 with study visits at Months 14, 16, and 18. The goal during this period was to maintain stable glucocorticoid doses while androstenedione levels were within control (i.e., androstenedione ≤120% of the subject’s baseline or ≤ULN for age and sex), although the dose could have been adjusted according to standard of care.

[0251] At the Month 18 visit, subjects had additional androgen assessments with collection of a urine sample at home and blood sample collection before and approximately 2 hours after dosing of morning glucocorticoid and capsule(s) administration at the study site. Subjects should have fasted from the night before(subjects were encouraged to drink water to avoid any hypovolemic status).(E) Follow-Up Period (Month 19)

[0252] A final post-treatment visit was conducted at Month 19, 1 month after subjects’ final dose of capsule(s). (F) Study Assessments and Study Visit Scheduling

[0253] Efficacy, safety, and PK were assessed at scheduled times throughout the study. As much as possible, all study visits (including baseline and follow-up) should occurred at approximately the same time in the morning to standardize time of day for assessment of efficacy, safety, and drug exposure.

[0254] In the double-blind, placebo-controlled portion of the study, all visits during the glucocorticoid stable period and glucocorticoid reduction period had a visit window of +5 days, and all visits during the glucocorticoid optimization period had a visit window of ±5 days. In the open-label treatment period, visits from Month 7 to Month 10 had a visit window of ±5 days and visits from Month 12 to Month 19 had a visit window of ±7 days. If a subject’s 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. (III) Study Population

[0255] 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. Have a medically confirmed diagnosis of classic 21-hydroxylase deficiency CAH based on standard medically accepted criteria such as elevated 17-OHP level, confirmed CYP21A2 genotype, positive newborn screening with confirmatory second-tier testing, or cosyntropin stimulation. 4. Be on a stable, supraphysiologic glucocorticoid dose regimen (defined as >14 mg / m2 / day in hydrocortisone dose equivalents) that has been stable for at least 1 month prior to screening, is intended for chronic use, and consists of 1 or more of the followingglucocorticoids: hydrocortisone (except sustained release), prednisone, prednisolone, methylprednisolone, or dexamethasone. 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 normalrange on the subject’s usual sodium intake. If PRA is not within the normal range, thesubject 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. 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. 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). o Adverse events (including glucocorticoid-related events) (IV) Investigational product, dosage and mode of administration:

[0257] 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.

[0258] 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).

[0259] If a subject forgot or was unable to take the capsule(s), the subject was recommended take his or her dose of study drug as soon as possible, as long as thesubject’s next dose would have been at least 8 hours later. The subject would have needed to skip the dose if he or she was unable to take the study drug at least 8 hours prior to the next dose. (V) Criteria for Evaluation: (A) Efficacy:

[0260] Daily glucocorticoid regimen expressed in hydrocortisone equivalents adjusted for body surface area (BSA) (mg / m2 / day).

[0261] Hormone measurements: 17-hydroxyprogesterone (17-OHP) (serum; ng / dL), androstenedione (serum; ng / dL), testosterone (serum; ng / dL), adrenocorticotropic hormone (ACTH) (plasma; pg / mL), cortisol (serum; μg / 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).

[0262] Urine androgen metabolite levels (androsterone and etiocholanolone).

[0263] 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).

[0264] Dual-energy X-ray absorptiometry (DXA) scan (bone mineral density and body composition). Blood pressure.

[0265] Hirsutism and Acne Scales (female subjects only).

[0266] Testicular ultrasounds (to detect adrenal rest tissue) (male subjects only).

[0267] Menstrual Cycle Questionnaire (only in female subjects of childbearingpotential who are not on hormonal or intrauterine device contraceptives).

[0268] 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). (C) Pharmacokinetics:

[0270] Blood samples to evaluate plasma concentrations of crinecerfont and metabolites were collected throughout the study.(D) Safety:

[0271] Safety and tolerability were monitored throughout the study and included the following assessments: · Clinical laboratory tests · Vital signs · Weight / body mass index (BMI), and waist circumference · Physical examinations · 12-lead electrocardiograms · Brief Psychiatric Rating Scale (BPRS) · Columbia-Suicide Severity Rating Scale (C-SSRS) (VI) Study Endpoints:

[0272] The primary endpoint was the percent change from baseline in glucocorticoid daily dose (in hydrocortisone equivalents adjusted for BSA [mg / m2 / day]) at Week 24, while Week 24 androstenedione is adequately controlled at ≤120% of baseline or ≤upper limit of normal for age and sex. The primary analysis of the primary endpoint was performed using an analysis of covariance (ANCOVA) model.

[0273] The first key secondary endpoint was the change from baseline in serum androstenedione at Week 4, which was analyzed using an ANCOVA model.

[0274] 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.

[0275] Additional key secondary endpoints are the changes from baseline in HOMA- IR, weight, and fat mass at Week 24, which were analyzed using an ANCOVA model.

[0276] Example 2: Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Crinecerfont in Pediatric Subjects with Classic Congenital Adrenal Hyperplasia, Followed 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. · To evaluate the efficacy of crinecerfont compared with placebo, in reducing dailyglucocorticoid dosage while maintaining adrenal androgen control.· To evaluate plasma concentrations of crinecerfont and metabolites.· To assess the safety and tolerability of crinecerfont. (II) Methodology

[0277] This was a Phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, and tolerability of crinecerfont versus placebo administered twice daily (BID) with breakfast and evening meals for 28 weeks in 81 pediatric subjects with classic CAH due to 21-hydroxylase deficiency. 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). After the 28 -week placebo-controlled treatment period, there was a 24-week, open-label treatment period, during which all subjects received crinecerfont at the same doses as administered during the placebo-controlled treatment period. A final study visit was conducted approximately 4 weeks after the Week 52 visit. (A) Screening Period (Weeks -4 up to Day -1)

[0278] Parental or legal guardian informed consent with signed and witnessed study subject assent (as required by the governing institutional review board or ethics committee and according to local laws and regulations) was obtained prior to any study- related procedures. Subjects underwent screening for up to 4 weeks (Weeks -4 to Day - 1) to determine eligibility. Rescreening was permitted if a subject did not meet all eligibility requirements and returned to be rescreened. A subject that failed screening twice was not rescreened again without prior permission. (B) Randomized, Double-Blind, Placebo-Controlled Treatment Period (Day 1 up to Week 28) (a) Glucocorticoid-Stable Period

[0279] On Day 1, subjects ≥12 years of age should have been fasting after midnight the night before until the first blood sample was collected at the site, after which they were provided breakfast. They were encouraged to drink water during the fasting period to avoid any hypovolemic status. Subjects <12 years of age did not need to fast.

[0280] On Day 1 (baseline), subjects ≥6 years of age and ≥20 kg body weight held their morning glucocorticoid dose and brought it with them to the study site, arriving to the site by approximately 0800 hours. Blood samples were obtained serially overapproximately 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. Beginning on Day 1 (baseline), 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).

[0282] From Day 1 until Week 4, 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. Subjects <6 years of age or <20 kg body weight took their morning glucocorticoid dose at home (at approximately the same time as on Day 1) but held their morning oral liquid or capsule(s) and had a single blood sample collected at the site, timed to be approximately 2 hours after the morning glucocorticoid dose.

[0284] Salivary samples for adrenal androgens and precursors were collected.

[0285] From Week 4 until Week 28, the subject’s glucocorticoid dose was adjusted according to their androstenedione levels, with the goal to reach a dose of approximately 8 to 10 mg / m2 / day at Week 28, if androstenedione was maintained ≤baseline levels. 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 eachstep. The target glucocorticoid dose was within the range of 8 to 10 mg / m2 / 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. Before any glucocorticoid dose reduction was implemented, 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.

[0286] 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 orderto 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 (athome or the study site).

[0288] For all blood tests after the Week 4 visit, subjects took their morning glucocorticoid dose at home with blood sample collection timed approximately 2 hours after the glucocorticoid dose.

[0289] If needed, subsequent glucocorticoid dose adjustment steps occurred when lab results were available (at approximately Week 10, Week 14, and Week 18) with follow- up blood tests at Week 12 (at home or the study site, and only if the glucocorticoid dose was modified at Week 10), Week 16 (at the study site), and Week 20 (at home or the study site).

[0290] The target amount of glucocorticoid dose reduction at each step was approximately 1 to 4 mg / m2 / day but was guided by the androstenedione level at thepreceding 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 outlined 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.

[0292] For the Week 28 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 hypovolemic status. Subjects <12 years of age did not need to fast. (C) Open-Label Treatment Period (Week 28 to Week 52)

[0293] Starting the evening of the Week 28 visit (after all Week 28 assessments have been performed), all subjects received crinecerfont (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) with breakfast and evening meals. Subjects and investigators remained blinded to subjects’ treatment group assignment during the placebo-controlled treatment period.

[0294] For subjects who were still on greater than 10 mg / m2 / day glucocorticoid dose at Week 28, further adjustments in glucocorticoid dose were made following the guidelines used during the placebo-controlled period, and a blood sample was collected at Week 32 (at home or the study site).

[0295] The first glucocorticoid dose adjustment step (if done) was guided by the androstenedione change at Week 32 (compared with Week 28), after all subjects had been on open-label active study drug for 4 weeks. 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-upblood test was arranged approximately 2 weeks later at Week 36 (at home or the study site).

[0297] If needed, subsequent 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 / m2 / 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 stepBlood Test GC dose adjustment step e ts assits, 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. As much as possible, all study visits (including baseline, during the study, and follow- up) occurred at approximately the same time in the morning to standardize time of day for assessment of efficacy, safety, and drug exposure.

[0301] The Week 4 visit had a visit window of ±5 days, and subsequent visits had a visit window of ±7 days. If a subject’s 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 lab test, and this 3-day window superseded all other visit windows.

[0302] An independent Data Monitoring Committee periodically reviewed unblinded study data to ensure the safety and well-being of study subjects and to confirm observed exposures were consistent with expected target exposures. (III) Study Population

[0303] Approximately 81 female and male subjects, 2 to 17 years of age, with a documented medical diagnosis of classic CAH due to 21-hydroxylase deficiency were enrolled into this study.

[0304] The study participants met the following criteria: 1. Have documentation of witnessed written or oral pediatric assent from the subject deemed capable of providing assent, and written informed consent from the subject’sparent(s) or legal guardian in accordance with the governing institutional review board orethics committee and according to local laws and regulations.2. Be a female or male at least 2 years of age and less than 18 years of age and a body weight of at least 10 kg. 3. Have a medically confirmed diagnosis of classic 21-hydroxylase deficiency CAH based on standard medically accepted criteria such as elevated 17-OHP level, confirmed CYP21A2 genotype, positive newborn screening with confirmatory second-tier testing, or cosyntropin stimulation.4. Be on a supraphysiologic glucocorticoid dose regimen (defined as >12 mg / m 2 / day inhydrocortisone 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. Have an androstenedione level (prior to the morning glucocorticoid dose) greater thanupper limit of normal (according to age, sex, and / or pubertal stage).6. Have a 17-hydroxyprogesterone level (prior to the morning glucocorticoid dose) greater than 800 ng / dL. 7. 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 normalrange on the subject’s usual sodium intake. If PRA is not within the normal range, thesubject must have systolic blood pressure >100 mmHg, without orthostatic hypotension, and with serum sodium and potassium in the normal range. 8. Female subjects of childbearing potential who are sexually active 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. 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. Male subjects of childbearing potential who are sexually active must agree to use effective barrier contraception consistently from screening until 90 days after the lastdose of study drug. The acceptable method of contraception for male subjects is condomwith spermicide (cream, spray, foam, gel, suppository, or polymer film).(IV) Investigational product, dosage and mode of administration

[0305] 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). · Daily glucocorticoid regimen expressed in hydrocortisone equivalents adjusted for body surface area (BSA) (mg / m2 / day). · Body weight and body mass index. · 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 menarcheand 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).(B) Patient and Caregiver Reported Outcomes · EuroQol (European Quality of Life)-5 Dimensions-Youth (EQ-5D-Y) · Pediatric Quality of Life Instrument (Peds-QL) · Peds-QL Family Impact(C) Pharmacokinetics · Blood samples to evaluate plasma concentrations of crinecerfont and metabolites were collected throughout the study. (D) Other · Palatability assessment o Adverse events (including glucocorticoid-related events) (E) Safety· Clinical laboratory tests (chemistry, hematology, coagulation, urinalysis)· Vital signs · Physical examinations, including height, weight, and Tanner stage · 6- or 12-lead electrocardiograms · Brief Psychiatric Rating Scale, Children’s Version (BPRS-C) o Columbia-Suicide Severity Rating Scale (C-SSRS) Children’s Version (only for subjects ≥6 years of age) (VI) Study Endpoints and Statistical Analysis

[0306] The primary endpoint was the change from baseline to Week 4 in serum androstenedione (average across all values obtained from 0830 to 1200 hours). 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 / m2 / day]), while Week 28 androstenedione was less than or equal to the baseline value.

[0307] One secondary endpoint was the achievement of a reduction in glucocorticoid daily dose to physiologic levels (≤11 mg / m2 / 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).

[0308] 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. The overallType I error of 0.05 was controlled by testing the primary, first key secondary, andsecond key secondary endpoints sequentially in this order.OTHER EMBODIMENTS

[0309] It is to be understood that the foregoing description is intended to illustrate and not limit the scope of the disclosure, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

CLAIMS What is claimed is:

1. 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.

2. The method of claim 1, wherein the congenital adrenal hyperplasia is classic congenital adrenal hyperplasia.

3. The method of claim 1, wherein 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.

4. The method of claim 2, wherein 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.

5. The method of claim 1, wherein the method comprises measuring body mass of the subject at a first time point.

6. The method of claim 5, wherein the method comprises measuring body mass of the subject at a second time point.

7. The method of claim 6, wherein the body mass of the subject at the second time point isbetween 1% and 25% less than the body mass of the subject at the first time point.

8. The method of claim 6, wherein the 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%, about23%, about 24%, or about 25% less than the body mass of the subject at the first time point.

9. The method of claim 7 or 8, wherein the congenital adrenal hyperplasia is classic congenital adrenal hyperplasia.

10. The method of claim 7 or 8, wherein 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.

11. The method of claim 9, wherein 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.

12. The method of claim 6, wherein 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.

13. The method of claim 6, wherein 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.

14. The method of claim 12 or 13, wherein the congenital adrenal hyperplasia is classic congenital adrenal hyperplasia.

15. The method of claim 12 or 13, wherein 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.

16. The method of claim 14, wherein 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.

17. The method of claim 1, wherein the method further comprises determining the body mass index (BMI) of the subject at a first time point.

18. The method of claim 17, wherein the method further comprises determining the bodymass index (BMI) of the subject at a second time point.

19. The method of claim 18, wherein the BMI of the subject at the second time point is between 0.1 kg / m2and 10 kg / m2less than the body mass index (BMI) of the subject at the first time point.

20. The method of claim 18, wherein the body mass index (BMI) of the subject at the second time point is at least about 0.1 kg / m2, about 0.2 kg / m2, about 0.3 kg / m2, about 0.4 kg / m2, about 0.5 kg / m2, about 0.6 kg / m2, about 0.7 kg / m2, about 0.8 kg / m2, about 0.9 kg / m2, about 1 kg / m2, about 1.1 kg / m2, about 1.2 kg / m2, about 1.3 kg / m2, about 1.4 kg / m2, about 1.5 kg / m2, about 1.6 kg / m2, about 1.7 kg / m2, about 1.8 kg / m2, about 1.9 kg / m2, about 2 kg / m2, about 2.1 kg / m2, about 2.2 kg / m2, about 2.3 kg / m2, about 2.4 kg / m2, about 2.5 kg / m2, about 2.6 kg / m2, about 2.7 kg / m2, about 2.8 kg / m2, about 2.9 kg / m2, about 3 kg / m2, about 3.1 kg / m2, about 3.2 kg / m2, about 3.3 kg / m2, about 3.4 kg / m2, about 3.5 kg / m2, about 3.6 kg / m2, about 3.7 kg / m2, about 3.8 kg / m2, about 3.9 kg / m2, about 4 kg / m2, about 4.1 kg / m2, about 4.2 kg / m2, about 4.3 kg / m2, about 4.4 kg / m2, about 4.5 kg / m2, about 4.6 kg / m2, about 4.7 kg / m2, about 4.8 kg / m2, about 4.9 kg / m2, about 5 kg / m2, about 5.5 kg / m2, about 6 kg / m2, about 6.5 kg / m2, about 7 kg / m2, about 7.5 kg / m2, about 8 kg / m2, about 8.5 kg / m2, about 9 kg / m2, about 9.5 kg / m2, or about10 kg / m2 less than the BMI of the subject at the first time point.

21. The method of claim 19 or 20, wherein the congenital adrenal hyperplasia is classic congenital adrenal hyperplasia.

22. The method of claim 19 or 20, wherein 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.

23. The method of claim 21, wherein 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.

24. The method of claim 1, wherein the method comprises measuring the waist circumference of the subject at a first time point.

25. The method of claim 24, wherein the method comprises measuring the waist circumference of the subject at a second time point.

26. The method of claim 25, wherein 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.

27. The method of claim 25, wherein 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.

28. The method of claim 26 or 27, wherein the congenital adrenal hyperplasia is classic congenital adrenal hyperplasia.

29. The method of claim 26 or 27, wherein 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.

30. The method of claim 28, wherein 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.

31. The method of claim 1, wherein the method comprises measuring the body fat percentage of the subject at a first time point.

32. The method of claim 31, wherein the method comprises measuring the body fat percentage of the subject at a second time point.

33. The method of claim 32, wherein 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.

34. The method of claim 32, wherein 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.

35. The method of claim 33 or 34, wherein the congenital adrenal hyperplasia is classic congenital adrenal hyperplasia.

36. The method of claim 33 or 34, wherein 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.

37. The method of claim 35, wherein 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.

38. The method of claim 1, wherein the method comprises measuring the level of one or more biomarkers of congenital adrenal hyperplasia in the subject at a first time point and a second time point; wherein the one or more biomarkers are selected from: (i) blood serum level of 17-hydroxyprogesterone, (ii) blood plasma level of adrenocorticotropic hormone, and (iii) blood serum androstenedione.

39. The method of claim 38, wherein 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.

40. The method of claim 39, wherein the congenital adrenal hyperplasia is classic congenital adrenal hyperplasia.

41. The method of claim 39, wherein 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.

42. The method of claim 40, wherein 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.

43. The method of claim 38, wherein 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.

44. The method of claim 43, wherein the congenital adrenal hyperplasia is classic congenital adrenal hyperplasia.

45. The method of claim 43, wherein 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.

46. The method of claim 44, wherein 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.

47. The method of claim 38, wherein 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.

48. The method of claim 47, wherein the congenital adrenal hyperplasia is classic congenital adrenal hyperplasia.

49. The method of claim 47, wherein 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.

50. The method of claim 48, wherein 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.

51. The method of any one of claims 6 to 50, wherein each first time point is independently from 1 month before beginning the administering of crinecerfont, or a pharmaceutically acceptable salt or solvate thereof, and the delayed release oral pharmaceutical composition of hydrocortisone to 1 month after beginning the administering of crinecerfont, or a pharmaceutically acceptable salt or solvate thereof, and the delayed release oral pharmaceutical composition of hydrocortisone.

52. The method of any one of claims 6 to 51, wherein each second time point is independently about 1 month, about 2 months, about 3 months, about 6 months, about 9 months, about 1 year, or more after beginning the administering of crinecerfont, or a pharmaceutically acceptable salt or solvate thereof, and the delayed release oral pharmaceutical composition of hydrocortisone.

53. The method of claim 1, wherein 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, methylmethacrylate) in a ratio of 1:1 and (ii) poly(methacrylic acid, methyl methacrylate) in aratio 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 composition, and wherein the plasticizer comprises dibutyl sebacate at 0.5-1.0% w / w of the composition.

54. The method of claim 53, wherein the congenital adrenal hyperplasia is classic congenital adrenal hyperplasia.

55. The method of claim 53, wherein 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.

56. The method of claim 54, wherein 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.

57. The method of claim 53, wherein the method comprises measuring body mass of the subject at a first time point.

58. The method of claim 57, wherein the method comprises measuring body mass of the subject at a second time point.

59. The method of claim 58, wherein the body mass of the subject at the second time pointis between 1% and 25% less than the body mass of the subject at the first time point.

60. The method of claim 58, wherein the 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%, about23%, about 24%, or about 25% less than the body mass of the subject at the first time point.

61. The method of claim 59 or 60, wherein the congenital adrenal hyperplasia is classic congenital adrenal hyperplasia.

62. The method of claim 59 or 60, wherein 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.

63. The method of claim 61, wherein 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.

64. The method of claim 58, wherein 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.

65. The method of claim 58, wherein 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.

66. The method of claim 64 or 65, wherein the congenital adrenal hyperplasia is classic congenital adrenal hyperplasia.

67. The method of claim 64 or 65, wherein 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.

68. The method of claim 66, wherein 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.

69. The method of claim 53, wherein the method further comprises determining the body mass index (BMI) of the subject at a first time point.

70. The method of claim 69, wherein the method further comprises determining the bodymass index (BMI) of the subject at a second time point.

71. The method of claim 70, wherein the BMI of the subject at the second time point is between 0.1 kg / m2and 10 kg / m2less than the body mass index (BMI) of the subject at the first time point.

72. The method of claim 70, wherein the body mass index (BMI) of the subject at the second time point is at least about 0.1 kg / m2, about 0.2 kg / m2, about 0.3 kg / m2, about 0.4 kg / m2, about 0.5 kg / m2, about 0.6 kg / m2, about 0.7 kg / m2, about 0.8 kg / m2, about 0.9 kg / m2, about 1 kg / m2, about 1.1 kg / m2, about 1.2 kg / m2, about 1.3 kg / m2, about 1.4 kg / m2, about 1.5 kg / m2, about 1.6 kg / m2, about 1.7 kg / m2, about 1.8 kg / m2, about 1.9 kg / m2, about 2 kg / m2, about 2.1 kg / m2, about 2.2 kg / m2, about 2.3 kg / m2, about 2.4 kg / m2, about 2.5 kg / m2, about 2.6 kg / m2, about 2.7 kg / m2, about 2.8 kg / m2, about 2.9 kg / m2, about 3 kg / m2, about 3.1 kg / m2, about 3.2 kg / m2, about 3.3 kg / m2, about 3.4 kg / m2, about 3.5 kg / m2, about 3.6 kg / m2, about 3.7 kg / m2, about 3.8 kg / m2, about 3.9 kg / m2, about 4 kg / m2, about 4.1 kg / m2, about 4.2 kg / m2, about 4.3 kg / m2, about 4.4 kg / m2, about 4.5 kg / m2, about 4.6 kg / m2, about 4.7 kg / m2, about 4.8 kg / m2, about 4.9 kg / m2, about 5 kg / m2, about 5.5 kg / m2, about 6 kg / m2, about 6.5 kg / m2, about 7 kg / m2,about 7.5 kg / m2, about 8 kg / m2, about 8.5 kg / m2, about 9 kg / m2, about 9.5 kg / m2, or about10 kg / m2 less than the BMI of the subject at the first time point.

73. The method of claim 71 or 72, wherein the congenital adrenal hyperplasia is classic congenital adrenal hyperplasia.

74. The method of claim 71 or 72, wherein 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.

75. The method of claim 73, wherein 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.

76. The method of claim 53, wherein the method comprises measuring the waist circumference of the subject at a first time point.

77. The method of claim 76, wherein the method comprises measuring the waist circumference of the subject at a second time point.

78. The method of claim 77, wherein 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.

79. The method of claim 77, wherein 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.

80. The method of claim 78 or 79, wherein the congenital adrenal hyperplasia is classic congenital adrenal hyperplasia.

81. The method of claim 78 or 79, wherein 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.

82. The method of claim 80, wherein 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.

83. The method of claim 53, wherein the method comprises measuring the body fat percentage of the subject at a first time point.

84. The method of claim 83, wherein the method comprises measuring the body fat percentage of the subject at a second time point.

85. The method of claim 84, wherein 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.

86. The method of claim 84, wherein 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.

87. The method of claim 85 or 86, wherein the congenital adrenal hyperplasia is classic congenital adrenal hyperplasia.

88. The method of claim 85 or 86, wherein 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.

89. The method of claim 87, wherein 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.

90. The method of claim 53, wherein the method comprises measuring the level of one or more biomarkers of congenital adrenal hyperplasia in the subject at a first time point and a second time point; wherein the one or more biomarkers are selected from: (i) blood serum level of 17-hydroxyprogesterone, (ii) blood plasma level of adrenocorticotropic hormone, and(iii) blood serum level of androstenedione.

91. The method of claim 90, wherein 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.

92. The method of claim 91, wherein the congenital adrenal hyperplasia is classic congenital adrenal hyperplasia.

93. The method of claim 91, wherein 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.

94. The method of claim 92, wherein 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.

95. The method of claim 90, wherein 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.

96. The method of claim 95, wherein the congenital adrenal hyperplasia is classic congenital adrenal hyperplasia.

97. The method of claim 95, wherein 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.

98. The method of claim 96, wherein 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.

99. The method of claim 90, wherein 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.

100. The method of claim 99, wherein the congenital adrenal hyperplasia is classic congenital adrenal hyperplasia.

101. The method of claim 99, wherein 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.

102. The method of claim 100, wherein 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.

103. The method of any one of claims 58 to 102, wherein each first time point is independently from 1 month before beginning the administering of crinecerfont, or a pharmaceutically acceptable salt or solvate thereof, and the delayed release oral pharmaceutical composition of hydrocortisone to 1 month after beginning the administering of crinecerfont, or a pharmaceutically acceptable salt or solvate thereof, and the delayedrelease oral pharmaceutical composition of hydrocortisone.

104. The method of any one of claims 58 to 103, wherein each second time point is independently about 1 month, about 2 months, about 3 months, about 6 months, about 9 months, about 1 year, or more after beginning the administering of crinecerfont, or a pharmaceutically acceptable salt or solvate thereof, and the delayed release oral pharmaceutical composition of hydrocortisone.

105. A kit 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 delayed release oral pharmaceutical composition of hydrocortisone;packaged together; optionally further comprising instructions for their administration.

106. A 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 delayed release oral pharmaceutical composition of hydrocortisone;optionally further comprising instructions for their administration.

107. 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 at least one pharmaceutically acceptable carrier, diluent, or excipient.

108. The kit of claim 105, twin pack of claim 106, or pharmaceutical composition of claim 107, wherein the hydrocortisone is in the form of a 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, wherein the carrier comprises microcrystalline cellulose particles, and wherein the carrier is 75-85% w / w of the composition, and wherein the plasticizer comprises dibutyl sebacate at 0.5-1.0% w / w of the composition.

109. 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 adelayed release oral pharmaceutical composition of hydrocortisone.

110. The fixed dose combination product of claim 109, wherein the delayed release oral pharmaceutical composition 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, methylmethacrylate) in a ratio of 1:1 and (ii) poly(methacrylic acid, methyl methacrylate) in aratio 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 composition, and wherein the plasticizer comprises dibutyl sebacate at 0.5-1.0% w / w of the composition.

111. 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 instructing the subject to administer to themselves a delayed release oral pharmaceutical composition of hydrocortisone.

112. The method of claim 111, wherein the delayed release oral pharmaceutical composition 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, methylmethacrylate) in a ratio of 1:1 and (ii) poly(methacrylic acid, methyl methacrylate) in aratio 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 composition, and wherein the plasticizer comprises dibutyl sebacate at 0.5-1.0% w / w of the composition.

113. 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 instructing 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.

114. The method of claim 113, wherein the delayed release oral pharmaceutical composition 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, methylmethacrylate) in a ratio of 1:1 and (ii) poly(methacrylic acid, methyl methacrylate) in aratio 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 composition, and wherein the plasticizer comprises dibutyl sebacate at 0.5-1.0% w / w of the composition.

115. A method of treating adrenal dysfunction 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.

116. 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 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 a delayed release oral pharmaceutical composition of hydrocortisone.

117. 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 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 the delayedrelease oral pharmaceutical composition of hydrocortisone.

118. A delayed release oral pharmaceutical composition of hydrocortisone for use in amethod of treating adrenal dysfunction 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.

119. 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 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-methyl-N-2-propyn-1-yl (crinecerfont), or pharmaceutically acceptable salt or solvate thereof.

120. Use 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, in the manufacture of a medicamentfor use in a method of treating adrenal dysfunction 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 a delayed release oral pharmaceutical composition of hydrocortisone.

121. Use of hydrocortisone in the manufacture of a delayed release oral pharmaceutical composition for use in a method of treating adrenal dysfunction 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.

122. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 121; wherein the adrenal dysfunction is congenital adrenal hyperplasia (CAH).

123. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 122; wherein the congenital adrenal hyperplasia is classic congenital adrenal hyperplasia.

124. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 122; wherein the classic CAH is due to 21-hydroxylase deficiency.

125. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 122; wherein the subject has a mutation in the CYP21A2 gene located on chromosome 6p21.

126. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 122; wherein the subject does not have a mutation of the 11β-hydroxylase gene CYP11B1 (11β-OH CAH).

127. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 121; wherein the adrenal dysfunction is adrenal insufficiency.

128. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 127; wherein the adrenal insufficiency is primary adrenal insufficiency.

129. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 127; wherein the adrenal insufficiency is secondary adrenal insufficiency.

130. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 127; wherein the adrenal insufficiency is tertiary adrenal insufficiency.

131. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 130; wherein the method comprises measuring the body mass of the subject at a first time point.

132. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 131; wherein the method comprises measuring the body mass of the subject at a second time point.

133. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 132; wherein the body mass of the subject at the second time point is between 1% and25% less than the body mass of the subject at the first time point.

134. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 132; wherein the 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 about25% less than the body mass of the subject at the first time point.

135. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 132; wherein 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.

136. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 132; wherein 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.

137. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 136; wherein the method further comprises determining the body mass index (BMI) of the subject at a first time point.

138. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 137; wherein the method further comprises determining the body mass index (BMI) of the subject at a second time point.

139. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 138; wherein the BMI of the subject at the second time point is between 0.1 kg / m2 and10 kg / m2 less than the body mass index (BMI) of the subject at the first time point.

140. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 138; wherein the body mass index (BMI) of the subject at the second time point is at least about 0.1 kg / m2, about 0.2 kg / m2, about 0.3 kg / m2, about 0.4 kg / m2, about 0.5 kg / m2, about 0.6 kg / m2, about 0.7 kg / m2, about 0.8 kg / m2, about 0.9 kg / m2, about 1 kg / m2, about 1.1 kg / m2, about 1.2 kg / m2, about 1.3 kg / m2, about 1.4 kg / m2, about 1.5 kg / m2, about 1.6 kg / m2, about 1.7 kg / m2, about 1.8 kg / m2, about 1.9 kg / m2, about 2 kg / m2, about 2.1 kg / m2, about 2.2 kg / m2, about 2.3 kg / m2, about 2.4 kg / m2, about 2.5 kg / m2, about 2.6 kg / m2, about 2.7 kg / m2, about 2.8 kg / m2, about 2.9 kg / m2, about 3 kg / m2, about 3.1 kg / m2, about 3.2 kg / m2, about 3.3 kg / m2, about 3.4 kg / m2, about 3.5 kg / m2, about 3.6 kg / m2, about 3.7 kg / m2, about 3.8 kg / m2, about 3.9 kg / m2, about 4 kg / m2, about 4.1 kg / m2, about 4.2 kg / m2, about 4.3 kg / m2, about 4.4 kg / m2, about 4.5 kg / m2, about 4.6 kg / m2, about 4.7 kg / m2, about 4.8 kg / m2, about 4.9 kg / m2, about 5 kg / m2, about 5.5 kg / m2, about 6 kg / m2, about 6.5 kg / m2, about 7 kg / m2, about 7.5 kg / m2, about 8 kg / m2, about 8.5 kg / m2, about 9 kg / m2, about 9.5 kg / m2, or about 10 kg / m2less than the BMI of the subject at the first time point.

141. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 140; wherein the method comprises measuring the waist circumference of the subject at a first time point.

142. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 141; wherein the method comprises measuring the waist circumference of the subject at a second time point.

143. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 142; wherein the waist circumference of the subject at the second time point is between1 cm and 30 cm less than the waist circumference of the subject at the first time point.

144. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 142; wherein 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.

145. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 144; wherein the method comprises measuring the body fat percentage of the subject at a first time point.

146. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 145; wherein the method comprises measuring the body fat percentage of the subject at a second time point.

147. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 146; wherein the body fat percentage of the subject at the second time point is between1% and 25% less than the body fat percentage of the subject at the first time point.

148. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 146; wherein 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%, about24%, or about 25% less than the body fat percentage of the subject at the first time point.

149. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 148; wherein the method comprises measuring the level of one or more biomarkers of congenital adrenal hyperplasia in the subject at a first time point and a second time point; wherein the one or more biomarkers are selected from: (i) blood serum level of 17-hydroxyprogesterone, (ii) blood plasma level of adrenocorticotropic hormone, and (iii) blood serum level of androstenedione.

150. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 149; wherein, 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.

151. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 149; wherein, 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.

152. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 149; wherein, 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.

153. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 152; wherein at a first time point, the subject is on a stable dose of hydrocortisone or hydrocortisone equivalents; and at a second time point, the dose of hydrocortisone orhydrocortisone equivalents is reduced with respect to the first time point.

154. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 132 to 153; wherein each first time point is independently from 1 month before beginning the administering of crinecerfont, or a pharmaceutically acceptable salt or solvate thereof, and the delayed release oral pharmaceutical composition of hydrocortisone to 1 month after beginning the administering of crinecerfont, or a pharmaceutically acceptable salt or solvatethereof, and the delayed release oral pharmaceutical composition of hydrocortisone.

155. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 132 to 153; wherein each first time point is independently from 1 week before beginning the administering of crinecerfont, or a pharmaceutically acceptable salt or solvate thereof, and the delayed release oral pharmaceutical composition of hydrocortisone to 1 week after beginning the administering of crinecerfont, or a pharmaceutically acceptable salt or solvatethereof, and the delayed release oral pharmaceutical composition of hydrocortisone.

156. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 132 to 153; wherein each first time point is independently from 1 month before beginning the administering of crinecerfont, or a pharmaceutically acceptable salt or solvate thereof, andthe delayed release oral pharmaceutical composition of hydrocortisone to 1 week af terbeginning the administering of crinecerfont, or a pharmaceutically acceptable salt or solvatethereof, and the delayed release oral pharmaceutical composition of hydrocortisone.

157. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 132 to 153; wherein each first time point is independently from 1 week before beginning the administering of crinecerfont, or a pharmaceutically acceptable salt or solvate thereof, andthe delayed release oral pharmaceutical composition of hydrocortisone to 1 day afte rbeginning the administering of crinecerfont, or a pharmaceutically acceptable salt or solvatethereof, and the delayed release oral pharmaceutical composition of hydrocortisone.

158. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 132 to 153; wherein each first time point is the same day as beginning the administering of crinecerfont, or a pharmaceutically acceptable salt or solvate thereof, and the delayedrelease oral pharmaceutical composition of hydrocortisone.

159. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 154 to 158; wherein each second time point is independently at least one month after beginning the administering of crinecerfont, or a pharmaceutically acceptable salt or solvate thereof,and the delayed release oral pharmaceutical composition of hydrocortisone.

160. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 154 to 158; wherein each second time point is independently about 1 month, about 2 months, about 3 months, about 6 months, about 9 months, about 1 year after beginning the administering of crinecerfont, or a pharmaceutically acceptable salt or solvate thereof, andthe delayed release oral pharmaceutical composition of hydrocortisone.

161. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 160; wherein the subject is a mammal.

162. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 160; wherein the subject is a human subject.

163. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 162;wherein the human subject is an adult human subject.

164. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 162; wherein the human subject is a pediatric human subject.

165. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 162 to 164; wherein the subject has a BMI of at least about 25 before beginning the administering of crinecerfont, or a pharmaceutically acceptable salt or solvate thereof, andthe delayed release oral pharmaceutical composition of hydrocortisone.

166. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 162 to 164; wherein the subject has a BMI of at least about 30 before beginning the administering of crinecerfont, or a pharmaceutically acceptable salt or solvate thereof, andthe delayed release oral pharmaceutical composition of hydrocortisone.

167. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 166; wherein 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.

168. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 167; wherein the delayed release oral pharmaceutical composition provides a peak cortisol level (Cmax) at about 6 hours to about 14 hours after the administering of thedelayed release oral pharmaceutical composition of hydrocortisone.

169. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 167 or 168; wherein the delayed release oral pharmaceutical composition is an oral pharmaceutical composition comprising: a core comprising hydrocortisone and a carrier; and a layer comprising a delayed release polymer, wherein the layer comprising a delayed release polymer is in contact with said coreand is adapted to delay release of hydrocortisone from said core.

170. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 167 or 168; wherein the delayed release oral pharmaceutical composition 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 coreand is adapted to delay release of hydrocortisone from said core.

171. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 167 or 168; wherein the delayed release oral pharmaceutical composition 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, wherein the carrier comprises microcrystalline cellulose particles, and wherein the carrier is 75-85% w / w of the composition, andwherein the plasticizer comprises dibutyl sebacate at 0.5-1.0% w / w of the composition.

172. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 167 or 168; wherein the delayed release oral pharmaceutical composition is an oral pharmaceutical composition consisting of: 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, methylmethacrylate) in a ratio of 1:1 and (ii) poly(methacrylic acid, methyl methacrylate) in aratio 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 composition, and wherein the plasticizer comprises dibutyl sebacate at 0.5-1.0% w / w of the composition.

173. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 167 to 172; wherein the delayed release oral pharmaceutical composition is in capsule form.

174. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 173; wherein the capsule is a hard capsule.

175. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 173; wherein the capsule is a hard capsule containing granules.

176. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 173 to 175; wherein the capsule comprises hydrocortisone in an amount of 5 mg, 10 mg or 20 mg.

177. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 176; wherein the crinecerfont, or pharmaceutically acceptable salt or solvate thereof, is administered in a pharmaceutical composition comprising: (a) crinecerfont, or a pharmaceutically acceptable salt thereof;(b) an oily phase vehicle; (c) an emulsifying agent; (d) a nonionic surfactant; and (e) a solubilizing agent.

178. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 176; wherein the crinecerfont, or pharmaceutically acceptable salt or solvate thereof, is administered in a pharmaceutical composition comprising: (a) about 5 %w / w to about 20 %w / w of crinecerfont, or a pharmaceutically acceptable salt thereof, based on the weight of the freebase; (b) about 35 %w / w to about 45 %w / w of an oily phase vehicle;(c) about 15 %w / w to about 25 %w / w of an emulsifying agent; (d) about 15 %w / w to about 25 %w / w of a nonionic surfactant; and (e) about 5 %w / w to about 15 %w / w of a solubilizing agent.

179. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 177 or 178; wherein the oily phase vehicle is a medium-chain triglycerides component.

180. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 177 to 179; wherein the emulsifying agent is a propylene glycol dicaprylate / dicaprate component.

181. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 177 to 180; wherein the nonionic surfactant is a lauroyl polyoxyl-32 glycerides component.

182. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 177 to 181; wherein the solubilizing agent is a vitamin E polyethylene glycol succinate component.

183. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 177 to 182; wherein the pharmaceutical composition comprising crinecerfont, or a pharmaceutically acceptable salt thereof, is in capsule form.

184. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 183; wherein capsule is a soft gelatin capsule.

185. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 183 or 184; wherein the capsule comprises crinecerfont, or a pharmaceutically acceptable salt thereof, in an amount of 25 mg, 50 mg, or 100 mg, based on the weight of the freebase.

186. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 176; wherein the crinecerfont, or pharmaceutically acceptable salt or solvate thereof, isadministered in an oral solution dosage formulation comprising:(a) crinecerfont, or a pharmaceutically acceptable salt thereof;(b) a sweetener; (c) an anti-oxidant; (d) a flavor; and (e) a surfactant; (f) a liquid vehicle.

187. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 176; wherein the crinecerfont, or pharmaceutically acceptable salt or solvate thereof, isadministered in an oral solution dosage formulation comprising:(a) about 4 %w / v to about 6 %w / v of crinecerfont, or a pharmaceutically acceptable salt thereof, based on the weight of the freebase; (b) about 0.1 %w / v to about 0.2 %w / v of a sweetener; (c) about 0.1 %w / v to about 0.2 %w / v of an anti-oxidant; (d) about 0.05 %w / v to about 0.2 %w / v of a flavor; (e) about 15 %w / v to about 25 %w / v of a surfactant; and (f) about 70 %w / v to about 80 %w / v of a liquid vehicle.

188. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 186 or 187; wherein the sweetener is saccharin.

189. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 186 to 188; wherein the anti-oxidant is butylated hydroxytoluene.

190. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 186 to 189; wherein the flavor is orange flavor.

191. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 186 to 190; wherein the surfactant is PEG-5 oleate.

192. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 186 to 191; wherein the liquid vehicle is medium-chain triglycerides.

193. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 186 to 192; wherein the oral solution dosage formulation comprises crinecerfont, or a pharmaceutically acceptable salt thereof, in an amount of 50 mg / mL, based on the weight of the freebase.

194. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 193; wherein 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.

195. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 194; wherein 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.

196. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 194; wherein 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.

197. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 195 or 196; wherein 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.

198. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 197; wherein the daily dose of crinecerfont, or pharmaceutically acceptable salt or solvatethereof, is equally divided between the first daily dose and the second daily dose.

199. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 197 or 198; wherein the first daily dose of crinecerfont, or pharmaceutically acceptable salt or solvate thereof, is administered in the morning.

200. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 197 to 199; wherein the second daily dose of crinecerfont, or pharmaceutically acceptable salt or solvate thereof, is administered in the evening.

201. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 197 to 200; wherein the first daily dose of crinecerfont, or pharmaceutically acceptable salt or solvate thereof, is selected 25 mg, 50 mg 100 mg, and 200 mg of crinecerfont, or apharmaceutically acceptable salt or solvate thereof, based on the weight of the free base.

202. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 197 to 201; wherein the second daily dose of crinecerfont, or pharmaceutically acceptable salt or solvate thereof, is selected 25 mg, 50 mg 100 mg, and 200 mg of crinecerfont, or apharmaceutically acceptable salt or solvate thereof, based on the weight of the free base.

203. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 197 to 202; wherein the subject is in a fed state on the administering of crinecerfont, or pharmaceutically acceptable salt or solvate thereof.

204. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 203; wherein the therapeutically effective amount of the delayed release oral pharmaceutical composition of hydrocortisone is a total daily dose of from 2.5 mg to 80 mg of hydrocortisone.

205. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 203; wherein the therapeutically effective amount of the delayed release oral pharmaceutical composition of hydrocortisone is a total daily dose of from 7.5 mg to 40 mg of hydrocortisone.

206. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 203;wherein 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.

207. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 203; wherein the therapeutically effective amount of the delayed 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, 20 mg, 25 mg. 30 mg, 35 mg, or 40 mg hydrocortisone.

208. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 203; wherein the therapeutically effective amount of the delayed 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.

209. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 203; wherein 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.

210. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 204 to 209; wherein 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.

211. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 210; wherein the second daily dose of the delayed release oral pharmaceutical composition of hydrocortisone delivers a greater amount of hydrocortisone than the firstdaily dose of the delayed release oral pharmaceutical composition of hydrocortisone.

212. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 210;wherein 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.

213. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 210; wherein 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.

214. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 210; wherein 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.

215. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 210 to 214; wherein the first daily dose of the delayed release oral pharmaceutical composition of hydrocortisone is administered in the morning.

216. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 215; wherein the first daily dose of the delayed release oral pharmaceutical composition of hydrocortisone administered in the morning, at least 1 hour before a meal and at least 2 hours after the previous meal.

217. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 210 to 216; wherein the second daily dose of the delayed release oral pharmaceuticalcomposition of hydrocortisone is administered in the evening.

218. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 217; wherein the second daily dose is of the delayed release oral pharmaceutical composition of hydrocortisone administered in the evening, at least 2 hours after theprevious meal and at least one hour before the next meal.

219. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 218; wherein the subject is in a fasted state on the administering of the delayed release oral pharmaceutical composition of hydrocortisone.

220. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 219; wherein 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.

221. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 219; wherein 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.

222. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 219; wherein the administering of crinecerfont, or pharmaceutically acceptable salt or solvate thereof, and the administering of the delayed release oral pharmaceutical composition of hydrocortisone; is simultaneous.

223. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to any one of claims 115 to 222; wherein the crinecerfont, or pharmaceutically acceptable salt or solvate thereof, is administered twice daily in a first daily dose and a second daily dose; and the delayed release oral pharmaceutical composition of hydrocortisone isadministered twice daily in a first daily dose and a second daily dose.

224. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 223; wherein 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.

225. The method; the crinecerfont, salt, or solvate for use; the pharmaceutical composition for use; or the use according to claim 223; wherein 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 or solvate thereof, is administered to the subject in a fed state in the evening.

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