Methods and compositions for treating polycystic ovary syndrome

Abstract

Polycystic ovary syndrome (PCOS) is characterized by elevated levels of androgens, cysts in the ovaries, and irregular periods. Women with PCOS present with additional symptoms, including hirsutism, alopecia, acne, infertility, weight gain, fatigue, depression and mood changes. The present disclosure provides new compounds, salts, compositions and uses thereof in the treatment of PCOS due to elevated adrenal androgens. Further, the present disclosure provides methods for treating PCOS due to elevated adrenal androgens.

Description

METHODS AND COMPOSITIONS FOR TREATING POLYCYSTIC OVARYSYNDROMECROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 532,319 filed August 11, 2023, which is incorporated herein by reference in its entirety.BACKGROUND

[0002] Polycystic ovary syndrome (PCOS) is a common endocrine disorder that affects up to 12% of reproductive aged women in the U.S. and is the most frequent cause of female infertility. Heterogeneous in nature, PCOS commonly presents with hyperandrogenism (e.g., hirsutism), acne, and irregular menses with underlying ovulatory dysfunction resulting in subfertility or infertility. Hyperandrogenemia may be predominantly ovarian or adrenal in source; however, overlap is not uncommon.

[0003] Though the pathophysiology of PCOS has not been fully elucidated, evidence suggests that while elevated levels and sensitivity to luteinizing hormone (LH) drives increased ovarian androgen production, adrenal androgen production results from hyperresponsiveness of the adrenal gland zona reticularis region to the adrenocorticotropic hormone (ACTH) signal from the anterior pituitary. In up to approximately 40% of patients with PCOS, adrenal hyperandrogenism is present, with or without ovarian hyperandrogenism. Dehydroepiandrosterone sulfate (DHEAS) is an adrenal androgen that can serve as a biochemical marker for adrenal androgen overproduction. Thus, DHEAS may be an important biomarker for assessing the treatment of PCOS.SUMMARY

[0004] Provided herein, in some embodiments, is a method of treating polycystic ovary syndrome (PCOS) in a subject in need thereof, comprising administering a pharmaceutical composition comprising a CRF1 antagonist or pharmaceutically acceptable salt thereof, wherein said subject has chronic anovulation, a dehydroepiandrosterone sulfate (DHEAS) level that is greater than an upper limit of normal of a reference range of said DHEAS level, or a combination thereof, wherein the pharmaceutical composition comprises: a CRF1 antagonist in an amount of about 20% to about 30% by weight of a total weight of the pharmaceutical composition; one or more diluents in a total amount of about 60% to about 70% by weight of the pharmaceutical composition; a binder; a surfactant; a disintegrant; aglidant; a lubricant; and a film former. Provided herein, in some embodiments, is a method of treating polycystic ovary syndrome (PCOS) in a subject in need thereof, comprising administering a pharmaceutical composition comprising a CRF1 antagonist or pharmaceutically acceptable salt thereof, wherein said subject has chronic anovulation, a dehydroepiandrosterone sulfate (DHEAS) level that is greater than an upper limit of normal of a reference range of said DHEAS level, or a combination thereof. In some embodiments, said subject is administered said CRF1 antagonist or pharmaceutically acceptable salt thereof in an amount of 50 mg for a first time period, said subject is administered said CRF1 antagonist or pharmaceutically acceptable salt thereof in an amount of 100 mg for a second time period, and wherein said subject is administered said CRF1 antagonist or pharmaceutically acceptable salt thereof in an amount of 200 mg for a third time period. In some embodiments, said first time period is about four weeks. In some embodiments, said second time period is about four weeks. In some embodiments, said third time period is at least about four weeks. In some embodiments, said CRF1 antagonist or pharmaceutically acceptable saltthereof is administered once daily. In some embodiments, said subject further has hyperandrogenism. In some embodiments, said subject has chronic anovulation. In some embodiments, said chronic anovulation is less than eight menstrual cycles in twelve months. In some embodiments, said subject has hyperandrogenism and chronic anovulation. In some embodiments, said subject has said DHEAS level that is greater than an upper limit of normal of a reference range of said DHEAS level. In some embodiments, said upper limit of said reference range of said DHEAS level is an age-matched referenced upper limit of said DHEAS level. In some embodiments, said administering reduces said DHEAS level from baseline. In some embodiments, said DHEAS level is greater than 1 .2 times said upper limit of said DHEAS level. In some embodiments, said DHEAS level is reduced by at least about 10 pg / dL from baseline. In some embodiments, said DHEAS level is reduced by at least about 20 pg / dL from baseline. In some embodiments, said reduction is at about 12 weeks after said administering. In some embodiments, said administering is a first administration of said pharmaceutical composition. In some embodiments, said administering occurs once daily for about 12 weeks. In some embodiments, said DHEAS level is reduced by at least about 30 pg / dL from baseline. In some embodiments, said DHEAS level is reduced by at least about 35 pg / dL from baseline. In some embodiments, said DHEAS level is reduced by at least about 40 pg / dL from baseline. In some embodiments, said reduction is at about 8 weeks after said administering. In some embodiments, said subject has any 2 or more of hyperandrogenism, chronic anovulation, and said DHEAS level that is greater than an upperlimit of normal of a reference range of said DHEAS level. In some embodiments, said subject has hyperandrogenism, chronic anovulation, and said DHEAS level that is greater than an upper limit of normal of a reference range of said DHEAS level. In some embodiments, said DHEAS is reduced by at least about 5% from baseline. In some embodiments, said DHEAS reduction is at eight weeks or twelve weeks after said administering. In some embodiments, said administering reduces a dehydroepiandrosterone (DHEA) level from baseline. In some embodiments, said DHEA level is reduced by at least about 0.75% from baseline. In some embodiments, said DHEA level is reduced by at least about 7% from baseline. In some embodiments, said DHEA level is reduced by at least about 0.3 ng / mL from baseline. In some embodiments, said DHEA level is reduced by at least about 0.7 ng / mL from baseline. In some embodiments, said DHEA reduction is at four weeks after said administering. In some embodiments, said DHEA level is reduced by at least about 5% from baseline. In some embodiments, said DHEA level is reduced by at least about 10% from baseline. In some embodiments, said DHEA reduction is at eight weeks after said administering. In some embodiments, said administering reduces a level of a second hormone. In some embodiments, the second hormone comprises adrenocorticotropic hormone (ACTH), 17- hydroxyprogesterone (17-OHP), androstenedione (A4), testosterone, or a combination thereof. In some embodiments, said second hormone is reduced compared to a corresponding administering of a pharmaceutical composition that does not contain a CRF1 antagonist or pharmaceutically acceptable salt thereof. In some embodiments, said administering reduces a low-density lipoprotein cholesterol (LDL) level from baseline. In some embodiments, said LDL level is reduced by atleast about 5%, at least about 10%, at least about 15%, or at least about 20%. In some embodiments, said administering reduces a total cholesterol level from baseline. In some embodiments, said total cholesterol level is reduced by at least about 10%, at least about 15%, at least about 20%. In some embodiments, the endocrine disorder is polycystic ovary syndrome with functional ovarian hyperandrogenism and functional adrenal hyperandrogenism (PCOS-FOH + FAH) or polycystic ovary syndrome with functional adrenal hyperandrogenism (PCOS-FAH).

[0005] Further provided herein, in some embodiments, is a method of treating polycystic ovary syndrome (PCOS) in a subject in need thereof, comprising administering a pharmaceutical composition comprising a CRF1 antagonist or pharmaceutically acceptable salt thereof, wherein said subject has chronic anovulation, a dehydroepiandrosterone sulfate (DHEAS) level that is less than 1 .2 times an upper limit of normal of a reference range of said DHEAS level, or a combination thereof, wherein the pharmaceutical compositioncomprises: a CRF1 antagonist in an amount of about20% to about 30% by weight of a total weight of the pharmaceutical composition; one or more diluents in a total amount of about 60% to about 70% by weight of the pharmaceutical composition; a binder; a surfactant; a disintegrant; a glidant; a lubricant; and a film former. In some embodiments, provided herein is a method of treating polycystic ovary syndrome (PCOS) in a subject in need thereof, comprising administering a pharmaceutical composition comprising a CRF1 antagonist or pharmaceutically acceptable salt thereof, wherein said subject has chronic anovulation, a dehydroepiandrosterone sulfate (DHEAS) level that is less than 1.2 times an upper limit of normal of a reference range of said DHEAS level, or a combination thereof. In some embodiments, DHEAS is less than 1.2 times the upper limit of normal of said reference range of said DHEAS level. In some embodiments, said DHEAS is less than one times the upper limit of normal of said reference range of said DHEAS level. In some embodiments, said DHEAS level is reduced by at least about 25 pg / dL from baseline. In some embodiments, a DHEAS level is reduced by at least about 30 pg / dL from baseline. In some embodiments, said reduction is at 8 weeks after said administering. In some embodiments, a DHEAS level is reduced by at least about 35 pg / dL from baseline administering. In some embodiments, a DHEAS level is reduced by at least about 40 pg / dL from baseline administering. In some embodiments, a DHEAS level is reduced by at least about 45 pg / dL from baseline administering.

[0006] In some embodiments, the CRF1 antagonist is a compound of Formula (I), or a pharmaceutically acceptable salt thereof:Formula (I) wherein: RAis Ci-C6alkyl, Ci-C6alkenyl, Ci-C6alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted 5- to 12- membered heterocyclyl, optionally Ce-Cnaryl, or optionally substituted 5- to 12- membered heteroaryl, wherein the optionally substituted C3- C6cycloalkyl, 5- to 12- membered heterocyclyl, C6-Ci2aryl, and 5- to 12- membered heteroaryl is optionally substituted with Ci.Cealkyl; RBis hydrogen, halogen, Ci-Cealkyl, Ci- C6alkenyl, Ci-C6alkynyl, Ci-C6alkoxy, optionally substituted C3-C12 cycloalkyl, optionally substituted 5- to 12- membered heterocyclyl, optionally Ce-Ci2aryl, or optionally substituted 5- to 12- membered heteroaryl, wherein the optionally substituted C3-C6cycloalkyl, 5- to 12-membered heterocyclyl, C6-Ci2aryl, and 5- to 12- membered heteroaryl is optionally substituted with halogen, Ci-Cealkyl, or Ci-Ce alkoxy; R4is hydrogen, halogen, Ci-Cealkyl, - NR4aR4b,-NHC(O)Ci-C6alkyl, -Ci-C6alkylene-O-Ci-C6alkyl, optionally substituted 5- to 6- membered heterocyclyl, or optionally substituted 5- to 6- membered heteroaryl, wherein the optionally substituted 5- to 6- membered heterocyclyl and 5- to 6- membered heteroaryl is optionally substituted with Ci-C6alkyl; and R4aand R4bare independently hydrogen, optionally substituted Ci-Cealkyl, optionally substituted Ci-Cealkenyl, optionally substituted Ci-C6alkynyl, wherein the optionally substituted Ci-C6alkyl, Ci-C6alkenyl, and Ci-C6alkynyl is optionally substituted with one or more amine, -C(O)Ci-C6alkyl, -C(O)OCi-C6alkyl, optionally substituted Cs-Cecycloalkyl, optionally substituted 5- to 12- membered heterocyclyl, optionally C6-Ci2aryl, or optionally substituted 5- to 12- membered heteroaryl, wherein the optionally substituted C3-C6cycloalkyl, 5- to 12- membered heterocyclyl, C6- Ci2aryl, and 5- to 12- membered heteroaryl is optionally substituted with halogen or Ci- C6alkyl.

[0007] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (II):Formula (II) wherein: R1and R2are independently ethyl or / / -propyl; R3is hydrogen, F, Cl, Br, methyl, trifluoromethyl, or methoxy; R4is hydrogen, Br, -NR4aR4b, methoxymethyl, / / -butyl, acetamido, pyridin-4-yl, morpholin-4-yl,are independently hydrogen, optionally substituted Ci-Cealkyl, optionally substituted Ci-C6alkenyl, optionally substituted Ci-C6alkynyl, wherein the optionally substituted Ci-C6alkyl, Ci-C6alkenyl, and Ci-C6alkynyl is optionally substitutedwith one or more amine, -C(O)Ci-C6alkyl, -C(O)OCi-C6alkyl, C3-C6cycloalkyl, 5- to 12- membered heterocyclyl, Ce-Cnaryl, or 5- to 12- membered heteroaryl, wherein the optionally substituted C3-C6cycloalkyl, 5- to 12- membered heterocyclyl, C6-Ci2aryl, and 5- to 12- membered heteroaryl is optionally substituted with halogen or Ci-C6alkyl. In some embodiments, R3is F, Cl, Br, methyl, or trifluoromethyl. In some embodiments, R3is Cl orCH3Br. In some embodiments, R4is -NRaRb, pyridin-4-yl, morpholin-4-yl,In some embodiments, R4is morpholin-some embodiments, R4is -NRaRb, andRaand Rbare independently Ci-C3alkyl. In some embodiments, the CRF1 antagonist is:pharmaceutically acceptable salt thereof. In some embodiments, the CRF1 antagonist is:pharmaceutically acceptable salt thereof. In some embodiments, the CRF1 antagonist is Compound I:(Compound I), or a pharmaceutically acceptable salt thereof.Compound I may be referred to as “tildacerfont”. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (III):Formula (III) wherein: RAis Ci-C6alkyl, Ci-C6alkenyl, Ci-C6alkynyl, RB1is halogen, Ci.C6alkyl, or Ci-C6alkoxy; R4aand R4bare independently optionally substituted Ci-Cealkyl, optionally substituted Ci-C6alkenyl, optionally substituted Ci-C6alkynyl, wherein the optionally substituted Ci-Cealkyl, Ci-Cealkenyl, and Ci-Cealkynyl is optionally substituted with one or more amine, -C(O)Ci-C6alkyl, -C(O)OCi-C6alkyl, C3-C6cycloalkyl, 5- to 12- membered heterocyclyl, C6-Ci2aryl, or 5- to 12- membered heteroaryl, wherein the optionally substituted Cs-Cecycloalkyl, 5- to 12- membered heterocyclyl, Ce-Cnaryl, and 5- to 12- membered heteroaryl is optionally substituted with halogen or Ci-C6alkyl; and n is 0 to 5. In some embodiments, RAis Ci-Ce alkyl. In some embodiments, RAis methyl. In some embodiments, eachRB1is independently Cl, Br, methyl, ethyl, methoxy, or ethoxy. In some embodiments, each RB1is independently Cl, methyl, or methoxy. In some embodiments, n is 1 to 3. In some embodiments, n is 3. In some embodiments, the CRF1 antagonist ispharmaceutically acceptable salt thereof.

[0008] In some embodiments, the CRF1 antagonist or pharmaceutically acceptable salt thereof is administered as a dose of about 50 mg to about 1000 mg per day. In some embodiments, CRF1 antagonist or pharmaceutically acceptable saltthereof is administered as a dose of about 50 mg per day. In some embodiments, CRF1 antagonist or pharmaceutically acceptable salt thereof is administered as a dose of about 100 mg per day. In some embodiments, CRF1 antagonist or pharmaceutically acceptable saltthereof is administered as a dose of about 200 mg per day. In some embodiments, CRF1 antagonist or pharmaceutically acceptable saltthereof is administered as a dose of about 50 mg per day for four weeks. In some embodiments, CRF1 antagonist or pharmaceutically acceptable salt thereof isadministered as a dose of about 100 mg per day for four weeks. In some embodiments, CRF1 antagonist or pharmaceutically acceptable salt thereof is administered as a dose of about 200 mg per day for four weeks. In some embodiments, said CRF1 antagonist or pharmaceutically acceptable salt thereof is administered as a dose of about 50 mg for a first period of four weeks. In some embodiments, after said first period of four weeks, said CRF1 antagonist or pharmaceutically acceptable salt thereof is administered as a dose of about 100 mg for a second period of four weeks. In some embodiments, after said second period of four weeks, said CRF1 antagonist or pharmaceutically acceptable salt thereof is administered as a dose of about 200 mg for a third period of four weeks. In some embodiments, said subject is a pediatric subject. In some embodiments, said subject is an adult subject. In some embodiments, said adult subject is 18 to 40 years old.

[0009] In some embodiments, said administering reduces a symptom of PCOS. In some embodiments, said symptom of PCOS is reduced compared to a corresponding administering of a pharmaceutical composition that does not contain a CRF1 antagonist or pharmaceutically acceptable salt thereof. In some embodiments, said symptom comprises sleep apnea syndrome, fatigue, a skin disorder, a psychiatric disorder, or a combination thereof. In some embodiments, said skin disorder comprises acne. In some embodiments, said psychiatric disorder comprises anxiety or mood swings. In some embodiments, said pharmaceutical composition further comprises a diluent. In some embodiments, said diluent comprises lactose monohydrate, microcrystalline cellulose, or a combination thereof. In some embodiments, said pharmaceutical composition further comprises a binder. In some embodiments, said binder comprises hydroxypropylcellulose. In some embodiments, said pharmaceutical composition further comprises a surfactant. In some embodiments, said surfactant comprises sodium lauryl sulfate. In some embodiments, said pharmaceutical composition further comprises a disintegrant. In some embodiments, said disintegrant comprises croscarmellose sodium. In some embodiments, said pharmaceutical composition further comprises a glidant. In some embodiments, said glidant comprises silicon dioxide. In some embodiments, said silicon dioxide comprises colloidal silicon dioxide. In some embodiments, said pharmaceutical composition further comprises a lubricant. In some embodiments, said lubricant comprises magnesium stearate. In some embodiments, said pharmaceutical composition further comprises a film former. In some embodiments, said film former comprises opadry II yellow.BRIEF DESCRIPTION OF THE DRAWINGS

[0010] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0011] FIG. 1 depicts an overview of a study design for analyzing the effect of administration of a CRF1 antagonist (e.g., Compound I) to subjects having polycystic ovary syndrome (PCOS).

[0012] FIG. 2A depicts the geometric mean levels of dehydroepiandrosterone sulfate (DHEAS) (ug / dL) in treatment group receiving Compound I (“Treatment Group”) as compared to subjects receiving placebo (“Placebo Group”) over 12 weeks.

[0013] FIG. 2B depicts the mean and standard error (SE) of change from baseline of DHEAS (ug / dL) in Treatment Group compared to Placebo Group over 12 weeks.

[0014] FIG. 3A depicts the geometric mean of DHEAS (ug / dL) in Treatment Group compared to Placebo Group over 12 weeks wherein subjects had a DHEAS level that is greater than an upper limit of normal of a reference range of DHEAS at the screening visit.

[0015] FIG. 3B depicts the mean and standard error (SE) of change from baseline of DHEAS (ug / dL) in Treatment Group compared to Placebo Group over 12 weeks wherein the subjects had a DHEAS level is greater than an upper limit of normal of a reference range of DHEAS at the screening visit.

[0016] FIG. 4A depicts the geometric mean of DHEAS (ug / dL) in Treatment Group compared to Placebo Group over 12 weeks wherein the subjects did not have a DHEAS level is greater than an upper limit of normal of a reference range of DHEAS at the screening visit.

[0017] FIG. 4B depicts the mean and standard error (SE) of change from baseline of DHEAS (ug / dL) in Treatment Group compared to Placebo Group over 12 weeks wherein the subjects did not have a DHEAS level is greater than an upper limit of normal of a reference range of DHEAS at the screening visit.

[0018] FIG. 5 A depicts the geometric mean of DHEAS (ug / dL) in Treatment Group compared to Placebo Group over 12 weeks wherein the subjects had a screening DHEAS value < 1.2 x upper limit of normal (ULN) of a reference range of DHEAS.

[0019] FIG. 5B depicts the mean and standard error (SE) of change from baseline of DHEAS (ug / dL) in Treatment Group compared to Placebo Group and over 12 weeks whereinthe subjects had a screening DHEAS value < 1.2 x upper limit of normal (ULN) of a reference range of DHEAS.

[0020] FIG. 6 A depicts the geometric mean of DHEAS (ug / dL) in Treatment Group compared to Placebo Group over 12 weeks wherein the subjects had a screening DHEAS value > 1.2 x ULN of a reference range of DHEAS.

[0021] FIG. 6B depicts the mean and standard error (SE) of change from baseline of DHEAS (ug / dL) in Treatment Group compared to Placebo Group over 12 weeks wherein the subjects had a screening DHEAS value > 1.2 x ULN of a reference range of DHEAS.

[0022] FIG. 7A depicts the percent of subjects in Treatment Group and Placebo Group with > 30% reduction in DHEAS.

[0023] FIG. 7B depicts the percent of subjects in Treatment Group and Placebo Group with > 25% reduction in DHEAS.

[0024] FIG. 8 depicts the geometric mean of ACTH (pg / mL) in Treatment Group and Placebo Group over 12 weeks.DETAILED DESCRIPTION

[0025] Polycystic ovary syndrome (PCOS) is a heterogeneous disorder with multiple phenotypes and is one of the most common endocrine metabolic disorders in reproductive aged women. PCOS was first diagnosed and described as a syndrome of oligo-amenorrhea and polycystic ovaries that was variably accompanied by hirsutism, acne, and obesity. There are various diagnostic criteria for adolescent and adult patients considering the core diagnostic features, such as hyperandrogenism, persistent ovulatory dysfunction, and polycystic ovary morphology (PCOM). Exemplary diagnostic criteria for the diagnosis of PCOS include the modified National Institutes of Health (NIH) 1990 criteria, which may be supplemented with evidence of adrenal-based hyperandrogenemia. The NIH diagnostic criteria state that patients must satisfy both of the following criteria: clinical and / or biochemical signs of hyperandrogenism and menstrual irregularity due to oligo- or anovulation. Other disorders causing hyperandrogenism and anovulations must be excluded.

[0026] The exact etiology of PCOS is not entirely clear, however, both genetic and environmental factors seem to play roles in causing the disorder. Generally, PCOS presents as a phenotype reflecting a self-perpetuating vicious cycle involving neuroendocrine, metabolic, and ovarian dysfunction and is characterized by excessive ovarian and / or adrenal androgen secretion. For example, intrinsic ovarian factors such as altered steroidogenesis and factors external to the ovary such as hyperinsulinemia may contribute to the excessiveovarian androgen production. The classic ovarian phenotype of enlarged ovaries with string- of-pearl morphology and theca interstitial hyperplasia reflects androgen exposure; this morphology has also been observed in women with congenital adrenal hyperplasia (CAH).

[0027] In order to attempt to understand the pathophysiology of PCOS, it is important to understand the molecular basis of steroidogenesis and androgen source, production and physiology. Under normal circumstances in women, the ovaries and adrenal glands contribute about equally to testosterone production. Approximately half of testosterone originates from direct testosterone secretion by the ovaries and adrenal glands, whereas half is produced by peripheral conversion of circulating androstenedione, which itself arises from approximately equal ovarian and adrenal secretion. Androgen production is not normally under direct negative feedback regulation by the neuroendocrine system in females, as is the case for estradiol and cortisol secretion. Androgens may be secreted by both the ovaries and adrenal glands in response to their respective tropic hormones, LH and ACTH. The zona reticularis of the adrenal gland resembles the theca cell compartment of the ovary in its expression of the core enzymatic pattern for androgen production.Corticotropin Releasing Factor

[0028] Currently, no single universal treatment for PCOS is available. As a result, current treatments tend to be individualized and adapted to the actual needs of the individual patient. Furthermore, treatment may be symptom-oriented. For example, targets for pharmacological treatment may include androgen excess. For PCOS patients with elevated adrenal androgens, FOH+FAH and PCOS-FAH patients, in some embodiments, pharmacological treatment, such as corticotropin releasing factor (CRF) receptor antagonist targeting ACTH production may be useful.

[0029] Corticotropin releasing factor (CRF) is a 41 amino acid peptide that is the primary physiological regulator of proopiomelanocortin (POMC) derived peptide secretion from the anterior pituitary gland. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in the brain. There is also evidence that CRF plays a significant role in integrating the response in the immune system to physiological, psychological, and immunological stressors.

[0030] CRF has been implicated in psychiatric disorders and neurological diseases including depression and anxiety, as well as the following: Alzheimer's disease, Huntington's disease, progressive supranuclear palsy, amyotrophic lateral sclerosis, Parkinson's disease, epilepsy, migraine, alcohol and substance abuse and associated withdrawal symptoms, obesity, metabolic syndrome, congenital adrenal hyperplasia (CAH), Cushing's disease, hypertension, stroke, irritable bowel syndrome, stress-induced gastric ulceration, premenstrual syndrome, sexual dysfunction, premature labor, inflammatory disorders, allergies, multiple sclerosis, visceral pain, sleep disorders, pituitary tumors or ectopic pituitary derived tumors, chronic fatigue syndrome, and fibromyalgia.

[0031] CRF is believed to be the major physiological regulator of the basal and stress- induced release of adrenocorticotropic hormone ("ACTH"), P-endorphin, and other proopiomelanocortin ("POMC")-derived peptides from the anterior pituitary. Secretion of CRF may cause release of ACTH from corticotrophs in the anterior pituitary via binding to the CRF1 receptor, a member of the class B family of G-protein coupled receptors.

[0032] Due to the physiological significance of CRF1, the development of biologically - active small molecules having significant CRF receptor 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, and congenital adrenal hyperplasia.

[0033] The pituitary hormone ACTH, under the control of hypothalamic corticotropinreleasing factor (CRF), may stimulate 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. The middle layer, the zona reticularis is responsible for the production of androgens such as DHEA, DHEAS and androstenedione, (A4) the precursor to testosterone (T) and dihydrotestosterone (DHT). This layer is also responsible for the production of the 11 -oxy androgens, 1 ip-hydroxyandrostenedione (110HA4) and 1 ip-hydroxy testosterone (11OHT), which are major bioactive androgens, particularly in women. Due to an unknown cause in PCOS patients with elevated androgens, the zone reticularis displays a hyperresponsiveness to ACTH resulting excessive levels of DHEA, DHEAS, 110HA4, 11OHT and A4. The excessive ACTH stimulation causes hypertrophy of the zona reticularis resulting in adrenal hyperplasia and clinically manifests with physical features typical of PCOS and hyperandrogenism. Reducing the stimulatoryeffect on the pituitary’s ACTH secretion by inhibiting the CRF1 receptor is expected is reduce excessive androgen synthesis from the ACTH responsive zone of the adrenal gland in PCOS. The normalization of elevated androgen levels in the shortterm would be expected to ameliorate cardinal features of PCOS - hirsutism, acne and menstrual irregularities - over the longterm. CRF1 antagonists may be useful in lowering hormones, such as DHEAS, DHEA, ACTH, 17-OHP, 110HA4, 110HT and A4. As such, CRF1 antagonists, such as tildacerfont.Certain Definitions

[0034] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments described herein, certain preferred methods, devices, and materials are now described.

[0035] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, reference to “an excipient” is a reference to one or more excipients and equivalents thereof known to those skilled in the art, and so forth.

[0036] The term “about” is used to indicate that a value includes 10% level of error for the device or method being employed to determine the value.

[0037] The use of the term “or” in the claims is used to mean “and / or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and to “and / or.”

[0038] “Alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to five carbon atoms (i.e. Cl-C5alkyl). In some embodiments, an alkyl comprises one to four carbon atoms (i.e., Cl-C4alkyl). In some embodiments, an alkyl comprises one to three carbon atoms (i.e., C1-C3 alkyl). In some embodiments, an alkyl comprises one to two carbon atoms (i.e., Cl-C2alkyl). In some embodiments, an alkyl comprises one carbon atom (i.e., Cl alkyl). In certain embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl (n-propyl), 1 -methylethyl (iso-propyl), 1 -butyl (n-butyl), 1 -methylpropyl (sec-butyl), 2- methylpropyl (isobutyl), 1 , 1 -dimethylethyl (tert-butyl), or 1 -pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more substituents such as those described herein.

[0039] The terms “comprise,” “have” and “include” are open-ended linking verbs. Any forms or tenses of one or more of these verbs, such as “comprises,” “comprising,” “has,” “having,” “includes” and “including,” are also open-ended. For example, any method that “comprises,” “has” or “includes” one or more steps is not limited to possessing only those one or more steps and also covers other unlisted steps.

[0040] “Administering” when used in conjunction with a therapeutic means to administer a therapeutic systemically or locally, as directly into or onto a target tissue, or to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted. “Administering” a pharmaceutical composition may be accomplished by injection, topical administration, and oral administration or by other methods alone or in combination with other known techniques.

[0041] By “pharmaceutically acceptable”, it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

[0042] The term “pharmaceutical composition” means a composition comprising at least one active ingredient, such as a steroid or a pharmaceutically acceptable salt thereof or a CRF1 antagonist or a pharmaceutically acceptable salt thereof, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human). Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.

[0043] A “therapeutically effective amount” or “effective amount” as used herein refers to the amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and / or symptomatology), and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology).

[0044] The terms “treat,” “treated,” “treatment,” or “treating” as used herein refers to both therapeutic treatment in some embodiments and prophylactic or preventative measures in other embodiments, wherein the object is to prevent or slow (lessen) an undesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results. For the purposes described herein, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. A prophylactic benefit of treatment includes prevention of a condition, retarding the progress of a condition, stabilization of a condition, or decreasing the likelihood of occurrence of a condition. As used herein, “treat,” “treated,” “treatment,” or “treating” includes prophylaxis in some embodiments.Methods of treating polycystic ovary syndrome

[0045] Provided herein, in some embodiments, is a method of treating polycystic ovary syndrome (PCOS) in a subject in need thereof, comprising administering a pharmaceutical composition comprising a CRF1 antagonist or pharmaceutically acceptable salt thereof, wherein said subject has chronic anovulation, a dehydroepiandrosterone sulfate (DHEAS) level that is greater than an upper limit of normal of a reference range of said DHEAS level, or a combination thereof, wherein the pharmaceutical composition comprises: a CRF1 antagonist in an amount of about 20% to about 30% by weight of a total weight of the pharmaceutical composition; one or more diluents in a total amount of about 60% to about 70% by weight of the pharmaceutical composition; a binder; a surfactant; a disintegrant; a glidant; a lubricant; and a film former. Provided herein, in some embodiments, is a method of treating polycystic ovary syndrome (PCOS) in a subject in need thereof, comprising administering a pharmaceutical composition comprising a CRF1 antagonist or pharmaceutically acceptable salt thereof, wherein said subject has chronic anovulation, a dehydroepiandrosterone sulfate (DHEAS) level that is greater than an upper limit of normal of a reference range of said DHEAS level, or a combination thereof. In some embodiments, described herein is a method of treating polycystic ovary syndrome (PCOS) in a subject inneed thereof, comprising administering a pharmaceutical composition comprising Compound I or pharmaceutically acceptable salt thereof, wherein said subject has chronic anovulation, a dehydroepiandrosterone sulfate (DHEAS) level that is greater than an upper limit of normal of a reference range of said DHEAS level, or a combination thereof, wherein the pharmaceutical composition comprises: Compound I in an amount of about 20% to about 30% by weight of a total weight of the pharmaceutical composition; one or more diluents in a total amount of about 60% to about 70% by weight of the pharmaceutical composition; a binder; a surfactant; a disintegrant; a glidant; a lubricant; and a film former. In some embodiments, described herein is a method of treating polycystic ovary syndrome (PCOS) in a subject in need thereof, comprising administering a pharmaceutical composition comprising Compound I or pharmaceutically acceptable salt thereof, wherein said subject has chronic anovulation, a dehydroepiandrosterone sulfate (DHEAS) level that is greater than an upper limit of normal of a reference range of said DHEAS level, or a combination thereof.CRF1 Antagonists

[0046] CRF1 antagonists are compounds that bind to the corticotropin-releasing factor (CRF) type-1 (CRF1) receptor. Compound I is an oral small-molecule CRF1 receptor antagonist. In vitro studies show that Compound I binds to CRF1 receptors with high affinity and specificity and blocks CRF-stimulated receptor function.

[0047] Compound I has demonstrated the ability to reduce the levels of ACTH and downstream adrenal androgen production (17-hydroxyprogesterone [17-OHP] and androstenedione [A4]) in adult patients with CAH. While the etiology of adrenal androgen excess in PCOS is not fully understood, one hypothesis is that adrenal hyperandrogenemia is due to adrenal hyper-responsiveness to ACTH. Thus, Compound I’s mechanism of action is well-suited to potentially reduce elevated adrenal androgen levels in PCOS patients who are biochemically hyperresponsive to ACTH by reducing ACTH and as a result, possibly improve clinical manifestations such as hirsutism, acne, irregular menses, and anovulation.

[0048] In some embodiments, the CRF1 antagonist is a compound of Formula (I), or a pharmaceutically acceptable salt thereof:Formula (I) wherein:RAis Ci-C6alkyl, Ci-C6alkenyl, Ci-C6alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted 5- to 12- membered heterocyclyl, optionally C&- Ci2aryl, or optionally substituted 5- to 12- membered heteroaryl, wherein the optionally substituted C3-C6cycloalkyl, 5- to 12- membered heterocyclyl, C6-Ci2aryl, and 5- to 12- membered heteroaryl is optionally substituted with Ci.C6alkyl;RBis hydrogen, halogen, Ci-C6alkyl, Ci-C6alkenyl, Ci-C6alkynyl, Ci-C6alkoxy, optionally substituted C3-Ci2cycloalkyl, optionally substituted 5- to 12- membered heterocyclyl, optionally C6-Ci2aryl, or optionally substituted 5- to 12- membered heteroaryl, wherein the optionally substituted C3-C6cycloalkyl, 5- to 12- membered heterocyclyl, Ce-Ci2aryl, and 5- to 12- membered heteroaryl is optionally substituted with halogen, Ci.C6alkyl, or Ci-C6alkoxy;R4is hydrogen, halogen, Ci-C6alkyl, -NR4aR4b,-NHC(O)Ci-C6alkyl, -Ci- C6alkylene-O-Ci-C6alkyl, optionally substituted 5- to 6- membered heterocyclyl, or optionally substituted 5- to 6- membered heteroaryl, wherein the optionally substituted 5- to 6- membered heterocyclyl and 5- to 6- membered heteroaryl is optionally substituted with Ci-C6alkyl; andR4aand R4bare independently hydrogen, optionally substituted Ci-C6alkyl, optionally substituted Ci-Cealkenyl, optionally substituted Ci-Cealkynyl, wherein the optionally substituted Ci-C6alkyl, Ci-C6alkenyl, and Ci-C6alkynyl is optionally substituted with one or more amine, -C(O)Ci-C6alkyl, -C(O)OCi-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 5- to 12- membered heterocyclyl, optionally C6-Ci2aryl, or optionally substituted 5- to 12- membered heteroaryl, wherein the optionally substituted C3-C6cycloalkyl, 5- to 12- membered heterocyclyl, C6-Ci2aryl, and 5- to 12- membered heteroaryl is optionally substituted with halogen or Ci-C6alkyl.

[0049] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (II):Formula (II)wherein:R1and R2are independently ethyl or w-propyl;R3is hydrogen, F, Cl, Br, methyl, trifluoromethyl, or methoxy;R4is hydrogen, Br, -NR4aR4b, methoxymethyl, w-butyl, acetamido, pyridin-4- yi, morpholin-4-yl,R4aand R4bare independently hydrogen, optionally substituted Ci-C6alkyl, optionally substituted Ci-Cealkenyl, optionally substituted Ci-Cealkynyl, wherein the optionally substituted Ci-C6alkyl, Ci-C6alkenyl, and Ci-C6alkynyl is optionally substituted with one or more amine, -C(O)Ci-C6alkyl, -C(O)OCi-C6alkyl, C3-C6cycloalkyl, 5- to 12- membered heterocyclyl, Ce-Cnaryl, or 5- to 12- membered heteroaryl, wherein the optionally substituted C3-C6cycloalkyl, 5- to 12- membered heterocyclyl, C6-Ci2aryl, and 5- to 12- membered heteroaryl is optionally substituted with halogen or Ci-C6alkyl.

[0050] In some embodiments, R3is F, Cl, Br, methyl, or trifluoromethyl. In some embodiments, R3is methyl or trifluoromethyl. In some embodiments, R3is methyl. In some embodiments, R3is trifluoromethyl. In some embodiments, R3is Cl or Br. In some embodiments, R3is Cl. In some embodiments, R3is Br.

[0051] In some embodiments, R4is -NRaRb, pyridin-4-yl, morpholin-4-yl, orIn some embodiments, R4is morpholin-some embodiments, R4is -NRaRb, and Raand Rbare independently Ci-C3alkyl.

[0052] In some embodiments, the CRF1 antagonist is:pharmaceutically acceptable salt thereof.

[0053] In some embodiments, the CRF1 antagonist is:pharmaceutically acceptable salt thereof.

[0054] In some embodiments, the CRF1 antagonist is Compound I:(Compound I), or a pharmaceutically acceptable salt thereof.Compound I may also be referred to as Tildacerfont.

[0055] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (III):Formula (III) wherein:RAis Ci-C6alkyl, Ci-C6alkenyl, Ci-C6alkynyl,RB1is halogen, Ci.Cealkyl, or Ci-Ce alkoxy;R4aand R4bare independently optionally substituted Ci-C6alkyl, optionally substituted Ci-C6alkenyl, optionally substituted Ci-C6alkynyl, wherein the optionally substituted Ci-Cealkyl, Ci-Cealkenyl, and Ci-Cealkynyl is optionally substituted with one or more amine, -C(O)Ci-C6alkyl, -C(O)OCi-C6alkyl, C3-C6cycloalkyl, 5- to 12- membered heterocyclyl, Ce-Cnaryl, or 5- to 12- membered heteroaryl, wherein the optionally substituted C3-C6cycloalkyl, 5- to 12- membered heterocyclyl, C6-Ci2aryl, and 5- to 12- membered heteroaryl is optionally substituted with halogen or Ci- Cealkyl; and n is 0 to 5.

[0056] In some embodiments, RAis Ci-C6alkyl. In some embodiments, RAis Ci-C3alkyl. In some embodiments, RAis methyl. In some embodiments, RAis ethyl.

[0057] In some embodiments, eachRB1is independently Cl, Br, methyl, ethyl, methoxy, or ethoxy. In some embodiments, eachRB1is independently Cl, methyl, or methoxy. In some embodiments, each RB1is independently Cl. In some embodiments, each RB1is independently methyl. In some embodiments, each RB1is independently methoxy.

[0058] In some embodiments, n is 1 to 3. In some embodiments, n is 3. In some embodiments, n is 2. In some embodiments, n is 1.

[0059] In some embodiments, the CRF1 antagonistpharmaceutically acceptable salt thereof.

[0060] In some embodiments, the CRF1 antagonist is:(Compoundpharmaceutically acceptable salt thereof.

[0061] In some embodiments, said subject is administered said CRF1 antagonist or pharmaceutically acceptable salt thereof in an amount of 50 mg for a first time period, said subject is administered said CRF1 antagonist or pharmaceutically acceptable salt thereof in an amount of lOOmgfor a second time period, and wherein said subject is administered said CRF1 antagonist or pharmaceutically acceptable salt thereof in an amount of 200 mg for a third time period.

[0062] In some embodiments, said first time period is about four weeks. In some embodiments, said second time period is about four weeks. In some embodiments, said third time period is at least about four weeks.

[0063] In some embodiments, said CRF1 antagonist or pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, said CRF1 antagonist or pharmaceutically acceptable saltthereof is administered twice daily. In some embodiments, said CRF1 antagonist or pharmaceutically acceptable salt thereof is administered thrice daily.

[0064] In some embodiments, CRF1 antagonist or pharmaceutically acceptable salt thereof is administered as a dose of about 50 mg to about 1000 mg per day. In some embodiments, CRF1 antagonist or pharmaceutically acceptable saltthereof is administered as a dose of about 50 mg per day. In some embodiments, CRF1 antagonist or pharmaceutically acceptable salt thereof is administered as a dose of about 100 mg per day. In some embodiments, CRF1 antagonist or pharmaceutically acceptable saltthereof is administered as a dose of about 200 mg per day. In some embodiments, the CRF1 antagonist or pharmaceutically acceptable saltthereof is administered as a dose of about 50 mg, about 100 mg, about 150 mg, about200 mg, about250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg per day. In some embodiments, the CRF1 antagonist or pharmaceutically acceptable salt thereof is administered as a dose of at least 50 mg, at least 100 mg, at least 150 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 350 mg, at least 400 mg, at least 450 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, or at least 1000 mg per day. In some embodiments, the CRF1 antagonist or pharmaceutically acceptable saltthereof is administered as a dose of at most 50 mg, at most 100 mg, at most 150 mg, at most200 mg, at most 250 mg, at most 300 mg, at most 350 mg, at most 400 mg, at most 450 mg, at most 500 mg, at most 600 mg, at most 700 mg, at most 800 mg, at most 900 mg, or at most 1000 mg per day.

[0065] In some embodiments, CRF1 antagonist or pharmaceutically acceptable salt thereof is administered as a dose of about 50 mg per day for four weeks. In some embodiments, CRF1 antagonist or pharmaceutically acceptable saltthereof is administered as a dose of about 100 mg per day for four weeks. In some embodiments, CRF1 antagonist or pharmaceutically acceptable salt thereof is administered as a dose of about 200 mg per day for four weeks. In some embodiments, CRF1 antagonist or pharmaceutically acceptable salt thereof is administered as a dose of about 50 mg, about lOO mg, about 150 mg, about200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg,about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg per day for four weeks. In some embodiments, CRF1 antagonist or pharmaceutically acceptable salt thereof is administered as a dose of at least 50 mg, at least 100 mg, at least 150 mg, at least 200 mg, at least 250 mg, at least 300 mg, at least 350 mg, at least 400 mg, at least 450 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, or at least 1000 mg per day for four weeks. In some embodiments, CRF1 antagonist or pharmaceutically acceptable salt thereof is administered as a dose of at most 50 mg, at most 100 mg, at most 150 mg, at most 200 mg, at most 250 mg, at most 300 mg, at most 350 mg, at most 400 mg, at most 450 mg, at most 500 mg, at most 600 mg, at most 700 mg, at most 800 mg, at most 900 mg, or at most 1000 mg per day for four weeks.

[0066] In some embodiments, said CRF1 antagonist or pharmaceutically acceptable salt thereof is administered as a dose of about 50 mg for a first period of four weeks. In some embodiments, said first period is about 1 to 10 weeks. In some embodiments, said first period is about 1 to 8 weeks. In some embodiments, said first period is about 1 to 6 weeks. In some embodiments, said first period is about 1 to 4 weeks. In some embodiments, said first period is about 1, about2, about 3, about 4, about 5, or about 6 weeks. In some embodiments, said first period is at least 1, at least 2, at least 3, at least 4, at least 5, or at least 6 weeks. In some embodiments, said first period is at most 1, at most 2, at most 3, at most 4, at most 5, or at most 6 weeks.

[0067] In some embodiments, after said first period of four weeks, said CRF1 antagonist or pharmaceutically acceptable salt thereof is administered as a dose of about 100 mg for a second period of four weeks. In some embodiments, said second period is about 1 to about 10 weeks. In some embodiments, said second period is about 1 to about 8 weeks. In some embodiments, said second period is about 1 to about 6 weeks. In some embodiments, said second period is about 1 to about 4 weeks. In some embodiments, said second period is about 1, about 2, about 3, about 4, about 5, or about 6 weeks. In some embodiments, said second period is at least 1, at least 2, at least 3, at least 4, at least 5, or at least 6 weeks. In some embodiments, said second period is at most 1, at most 2, at most 3, at most 4, at most 5, or at most 6 weeks.

[0068] In some embodiments, after said second period of four weeks, said CRF1 antagonist or pharmaceutically acceptable salt thereof is administered as a dose of about 200 mg for a third period of four weeks. In some embodiments, said third period is about 1 to about 10 weeks. In some embodiments, said third period is about 1 to about 8 weeks. In some embodiments, said third period is about 1 to about 6 weeks. In some embodiments, said thirdperiod is about 1 to about 4 weeks. In some embodiments, said third period is about 1, about 2, about 3, about4, about 5, or about 6 weeks. In some embodiments, said third period is at least 1, at least 2, at least 3, at least 4, at least 5, or at least 6 weeks. In some embodiments, said third period is at most 1, at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, or at most 10 weeks.Hyperandrogenism

[0069] In some embodiments, said subject further has hyperandrogenism.Hyperandrogenism is a condition characterized by high levels of androgens is often a defining sign of PCOS. Common signs and symptoms of hyperandrogenism include seborrhea, acne, hirsutism, a deepened voice, male pattern balding, irregular menstruation, infertility, and obesity. Often, hyperandrogenism is biochemically demonstrated as the high concentration of testosterone and other calculated parameters of androgen excess like free testosterone (FT) and free androgen index (FAI). Accordingly, there is a need to treat or prevent hyperandrogenism in subject with PCOS.Anovulation

[0070] In some embodiments, said subject has chronic anovulation. Anovulation is the lack or absence of ovulation (the release of an egg). About 70% of subjects with PCOS suffer from anovulation, which is a common cause of infertility. Chronic anovulation may occur when anovulation persists for long periods of time (e.g., 12 months). In some embodiments, said chronic anovulation is less than eight menstrual cycles in twelve months. In some embodiments, said chronic anovulation is less than eight menstrual cycles in twelve months In some embodiments, said subject has hyperandrogenism and chronic anovulation.Dehydroepiandrosterone sulfate (DHEAS) and DHEA

[0071] DHEAS is secreted by the adrenal glands and is the most abundant circulating steroid hormone in humans. In females, moderately high levels of DHEAS can cause symptoms of hyperandrogenism, one of the primary symptoms of PCOS. Some studies have indicated that elevated levels of DHEAS occur in nearly 48-52% of subjects with PCOS. Furthermore, PCOS is often associated with psychosocial stress, which increases cortisol release in response to ACTH. As, dehydroepiandrosterone (DHEA) and its sulphated form (DHEAS) are also released from adrenals in response to ACTH. Accordingly, there is a need for the treatment of PCOS that lowers a level of DHEAS or DHEA.

[0072] CRF1 receptor antagonist, such as Compound I, may help lower levels of DHEAS in subjects with PCOS. In some embodiments, said subject has said DHEAS level that is greater than an upper limit of normal of a reference range of said DHEAS level. In someembodiments, said upper limit of said reference range of said DHEAS level is an age- matched referenced upper limit of said DHEAS level. Levels of DHEAS may vary by age and gender; however, normal levels of DHEAS in females may present as follows:18- and 19-year-olds: 145 to 395 micrograms per deciliter (mcg / dL) 20s: 65 and 380 mcg / dL 30s: 45 to 270 mcg / dL 40s: 32 to 240 mcg / dL 50s: 26 to 200 mcg / dL 60s: 13 to 130 mcg / dL After age 69: 17 to 90 mcg / dL

[0073] In some embodiments, said administering (e.g., of said CRF1 antagonist or salt thereof) reduces said DHEAS level from baseline. In some embodiments, said DHEAS level is greater than 1.2 times said upper limit of said DHEAS level. In some embodiments, said DHEAS level is reduced by at least about 10 pg / dL from baseline. In some embodiments, said DHEAS level is reduced by at least about 20 pg / dL from baseline. In some embodiments, said DHEAS level is reduced by at least about 5 pg / dL, at least about 10 pg / dL, at least about 15 pg / dL, at least about 20 pg / dL, at least about 25 pg / dL, at least about 30 pg / dL, at least about 35 pg / dL, at least about 40 pg / dL, at least about 45 pg / dL, at least about 50 pg / dL from baseline.

[0074] In some embodiments, said reduction in a DHEAS level is at about 12 weeks after said administering. In some embodiments, said reduction in a DHEAS level is at about 8 weeks after said administering. In some embodiments, said reduction in a DHEAS level is at about 4 weeks, about 6 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks after said administering. In some embodiments, said reduction in a DHEAS level occurs about 4 to about 12 weeks (e.g., 4 weeks, 8 weeks, or 12 weeks) after a first administration. In some embodiments, said reduction in DHEAS level occurs after daily administrations of said CRF1 antagonist for 4 weeks. In some embodiments, said reduction in DHEAS level occurs after daily administrations of said CRF1 antagonist for 8 weeks. In some embodiments, said reduction in DHEAS level occurs after daily administrations of said CRF1 antagonist for 12 weeks.

[0075] In some embodiments, said DHEAS level is reduced by at least about 30 pg / dL from baseline. In some embodiments, said DHEAS level is reduced by at least about 35 pg / dL from baseline. In some embodiments, said DHEAS level is reduced by at least about 40 pg / dL from baseline. In some embodiments, said DHEAS level is reduced by at leastabout 45 pg / dL from baseline. In some embodiments, said DHEAS level is reduced by at least about 50 pg / dL from baseline.

[0076] In some embodiments, said reduction is at about 8 weeks after said administering. In some embodiments, after said administering may be after a first administration of the CRF1 antagonist and may occur after said CRF1 antagonist is administered for about 4 to about 12 weeks.

[0077] In some embodiments, said subject has any 2 or more of the following: hyperandrogenism, chronic anovulation, and said DHEAS level that is greater than an upper limit of normal of a reference range of a DHEAS level. In some embodiments, said subject has hyperandrogenism, chronic anovulation, and a DHEAS level that is greater than an upper limit of normal of a reference range of said DHEAS level.

[0078] In some embodiments, said DHEAS is reduced by at least about 5% from baseline. In some embodiments, said DHEAS is reduced by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30% from baseline. In some embodiments, said DHEAS is reduced by about 5% to about 30%, about 5% to about 25% , about 5% to about 20%, about 5% to about 15%, about 5% to about 10%, about 10% to about 30% from baseline.

[0079] In some embodiments, said DHEAS reduction is at eight weeks or twelve weeks after said administering. In some embodiments, said DHEAS reduction is at eight weeks after said administering. In some embodiments, said DHEAS reduction is at eight weeks, nine weeks, ten weeks, eleven weeks, or twelve weeks after said administering. In some embodiments, after said administering may be after a first administration of the CRF1 antagonist and may occur after said CRF1 antagonist is administered for about 4 to about 12 weeks.

[0080] CRF1 receptor antagonist, such as Compound I, may help lower levels of DHEA in subjects with PCOS. In some embodiments, said administering reduces a dehydroepiandrosterone (DHEA) level from baseline. In some embodiments, said DHEA level is reduced by at least about 0.75% from baseline. In some embodiments, said DHEA level is reduced by at least about 7% from baseline. In some embodiments, said DHEA level is reduced by at least about 0.75%, at least about 1%, at least about 1.5%, at least about 2%, at least about 2.5%, at least about 3%, at least about 4 %, at least about 4.5 %, at least about 5 %, at least about 5.5 %, at least about 6 %, at least about 6.5 %, or at least about 7 % frombaseline. In some embodiments, said DHEA level is reduced by about 0.75% to about 7%, about 0.75% to about 6.5%, about 0.75% to about 6%, about 0.75% to about 5.5%, about 0.75% to about 5%, about 0.75%to about 4.5%, about O.75% to about 4%, about O.75% to about 3.5%, about O.75% to about 3%, about 0.75%to about 2.5%, or about 0.75% to about 2% from baseline.

[0081] In some embodiments, said DHEA level is reduced by at least about 0.3 ng / mL from baseline. In some embodiments, said DHEA level is reduced by at least about 0.7 ng / mL from baseline. In some embodiments, said DHEA level is reduced by at least about 0.2 ng / mL, at least about 0.25 ng / mL, at least about 0.3 ng / mL, at least about 0.35 ng / mL, at least about 0.4 ng / mL, at least about 0.45 ng / mL, at least about 0.5 ng / mL, at least about 0.55 ng / mL, at least about 0.6 ng / mL, at least about 0.65 ng / mL, or at least about 0.7 ng / mL from baseline. In some embodiments, said DHEA level is reducedby about 0.3 ng / mL to about 0.7 ng / mL, about 0.3 ng / mL to about 0.65 ng / mL, about 0.3 ng / mL to about 0.6 ng / mL, about 0.3 ng / mL to about 0.55 ng / mL, about 0.3 ng / mL to about 0.5 ng / mL, about 0.3 ng / mL to about 0.45 ng / mL, or about 0.3 ng / mL to about 0.4 ng / mL from baseline.

[0082] In some embodiments, said DHEA reduction is at four weeks after said administering. In some embodiments, said DHEA reduction is at eight weeks after said administering. In some embodiments, said DHEA reduction is at twelve weeks after said administering. In some embodiments, said DHEA reduction is at about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, about 13 weeks, about 14 weeks, or about 15 weeks after said administering.

[0083] In some embodiments, said DHEA level is reduced by at least about 5% from baseline. In some embodiments, said DHEA level is reduced by at least about 10% from baseline. In some embodiments, said DHEA level is reduced by at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9%, or at least about 10% from baseline. In some embodiments, said DHEA level is reduced by about 2% to about 10%, about 3% to about 10%, about 4% to about 10%, about 5% to about 10%, about 3% to about 9%, about 3% to about 8%, about 3% to about 7%, about 3% to about 6%, about 4% to about 10%, about 4% to about 9%, about 4% to about 8%, about 4% to about 7%, about 4% to about 6%, about 5% to about 9%, about 5% to about 8%, or about 5% to about 7% from baseline. In some embodiments, said DHEA reduction is at eight weeks after said administering. In some embodiments, after said administering may be after a first administration of the CRF1 antagonist and may occur aftersaid CRFl antagonist is administered for about 4 to about 12 weeks. In some embodiments, said administering reduces a level of a second hormone. In some embodiments, the second hormone comprises adrenocorticotropic hormone (ACTH), 17-hydroxy progesterone (17- OHP), androstenedione (A4), testosterone, or a combination thereof.

[0084] In some embodiments, said second hormone is reduced compared to a corresponding administering of a pharmaceutical composition that does not contain a CRF1 antagonist or pharmaceutically acceptable salt thereof.

[0085] In some embodiments, said administering increases a level of a second hormone. In some embodiments, the second hormone comprises serum sex hormone binding globulin (SHBG). In some embodiments, said second hormone is increased compared to a corresponding administering of a pharmaceutical composition that does not contain a CRF1 antagonist or pharmaceutically acceptable salt thereof.Cholesterol Levels

[0086] In some embodiments, said administering reduces a low-density lipoprotein cholesterol (LDL) level from baseline. In some embodiments, said LDL level is reduced by at least about 5%, at least about 10%, at least about 15%, or at least about 20%. In some embodiments, said LDL level is reduced by at least about 2%, at least about 7%, at least about 12%, or at least about 17% from baseline. In some embodiments, said LDL level is reduced by about 5% to about 20%, about 5% to about 15%, about 5% to about 10%, about 2% to about 20%, about 2% to about 15%, or about 2% to about 10% from baseline.

[0087] In some embodiments, said administering reduces a total cholesterol level from baseline. In some embodiments, said total cholesterol level is reduced by at least about 10%, at least about 15%, at least about 20%. In some embodiments, said total cholesterol level is reduced by about 5%, about 10%, about 15%, or about 20% from baseline. In some embodiments, said total cholesterol level is reduced by about 5% to about 20%, about 5% to about 15%, or about 5% to about 10% from baseline.

[0088] In some embodiments, the endocrine disorder is polycystic ovary syndrome with functional ovarian hyperandrogenism and functional adrenal hyperandrogenism (PCOS-FOH + FAH) or polycystic ovary syndrome with functional adrenal hyperandrogenism (PCOS- FAH).

[0089] An aspect of the present disclosure is a method of treating polycystic ovary syndrome (PCOS) in a subject in need thereof, comprising administering a pharmaceutical composition comprising a CRF1 antagonist or pharmaceutically acceptable salt thereof,wherein said subject has chronic anovulation, a dehydroepiandrosterone sulfate (DHEAS) level that is less than 1.2 times an upper limit of normal of a reference range of said DHEAS level, or a combination thereof, wherein the pharmaceutical composition comprises: a CRF1 antagonist in an amount of about 20% to about 30% by weight of a total weight of the pharmaceutical composition; one or more diluents in a total amount of about 60% to about 70% by weight of the pharmaceutical composition; a binder; a surfactant; a disintegrant; a glidant; a lubricant; and a film former. Another aspect of the present disclosure is a method of treating polycystic ovary syndrome (PCOS) in a subject in need thereof, comprising administering a pharmaceutical composition comprising a CRF1 antagonist or pharmaceutically acceptable salt thereof, wherein said subject has chronic anovulation, a dehydroepiandrosterone sulfate (DHEAS) level that is less than 1.2 times an upper limit of normal of a reference range of said DHEAS level, or a combination thereof. In some embodiments, described herein is a method of treating polycystic ovary syndrome (PCOS) in a subject in need thereof, comprising administering a pharmaceutical composition comprising Compound I or pharmaceutically acceptable salt thereof, wherein said subject has chronic anovulation, a dehydroepiandrosterone sulfate (DHEAS) level that is less than 1.2 times an upper limit of normal of a reference range of said DHEAS level, or a combination thereof, wherein the pharmaceutical composition comprises: Compound I in an amount of about 20% to about 30% by weight of a total weight of the pharmaceutical composition; one or more diluents in a total amount of about 60% to about 70% by weight of the pharmaceutical composition; a binder; a surfactant; a disintegrant; a glidant; a lubricant; and a film former. In some embodiments, described herein is a method of treating polycystic ovary syndrome (PCOS) in a subject in need thereof, comprising administering a pharmaceutical composition comprising Compound I or pharmaceutically acceptable salt thereof, wherein said subject has chronic anovulation, a dehydroepiandrosterone sulfate (DHEAS) level that is less than 1.2 times an upper limit of normal of a reference range of said DHEAS level, or a combination thereof.

[0090] In some embodiments, said DHEAS is less than 1.2 times the upper limit of normal of said reference range of said DHEAS level. In some embodiments, said DHEAS is less than 1.1 times the upper limit of normal of said reference range of said DHEAS level. In some embodiments, said DHEAS is less than one times the upper limit of normal of said reference range of said DHEAS level.

[0091] In some embodiments, said DHEAS level is reduced by at least about 25 pg / dL from baseline. In some embodiments, a DHEAS level is reduced by at least about 30 pg / dLfrom baseline. In some embodiments, a DHEAS level is reduced by at least about 5 pg / dL, at least about 10 pg / dL, at least about 15 pg / dL, at least about 20 pg / dL, at least about 25 pg / dL, at least about 30 pg / dL, at least about 35 pg / dL, at least about 40 pg / dL from baseline. In some embodiments, said reduction is at 8 weeks after said administering. In some embodiments, after said administering may be after a first administration of the CRF1 antagonist and may occur after said CRF1 antagonist is administered for about 4 to about 12 weeks.

[0092] In some embodiments, a DHEAS level is reduced by at least about 35 pg / dL from baseline administering. In some embodiments, a DHEAS level is reduced by at least about 40 pg / dL from baseline administering. In some embodiments, a DHEAS level is reduced by at least about 45 pg / dL from baseline administering. In some embodiments, a DHEAS level is reduced by at least about 5 pg / dL, at least about 10 pg / dL, at least about 15 pg / dL, at least about 20 pg / dL, at least about 25 pg / dL, at least about 30 pg / dL, at least about 35 pg / dL, at least about 40 pg / dL, at least about 45 pg / dL, at least about 50 pg / dL from baseline administering. In some embodiments, a DHEAS level is reduced by about 5 ug / dL to about 50 ug / dL, about 5 ug / dL to about 40 ug / dL, about 5 ug / dL to about 35 ug / dL, about 5 ug / dL to about 30 ug / dL, about 5 ug / dL to about 25 ug / dL, about 5 ug / dL to about 20 ug / dL, about 5 ug / dL to about 15 ug / dL, about 10 ug / dL to about 50 ug / dL, about 10 ug / dL to about 45 ug / dL, about 10 ug / dL to about 40 ug / dL, about 10 ug / dL to about 35 ug / dL, about 10 ug / dL to about 30 ug / dL, about 10 ug / dL to about 25 ug / dL, or about 10 ug / dL to about 20 ug / dL from baseline administering.Symptoms of PCOS

[0093] PCOS is often associated with multiple symptoms, such as missed periods, seborrhea, acne, hirsutism, a deepened voice, male pattern balding, irregular menstruation, infertility, obesity, acne, and psychiatric disorders, to name a few. These symptoms can interfere with family planning, social interactions, and quality of life. As such, there is a need for treatments of PCOS that help decrease the symptom(s) associated therewith.

[0094] In some embodiments, said administering reduces a symptom of PCOS. In some embodiments, said symptom of PCOS is reduced compared to a corresponding administering of a pharmaceutical composition that does not contain a CRF1 antagonist or pharmaceutically acceptable salt thereof.

[0095] In some embodiments, said symptom comprises sleep apnea syndrome, fatigue, a skin disorder, a psychiatric disorder, or a combination thereof. In some embodiments, saidskin disorder comprises acne. In some embodiments, said psychiatric disorder comprises anxiety or mood swings. In some embodiments, said psychiatric disorder comprises anxiety. In some embodiments, said psychiatric disorder comprises mood swings. In some embodiments, said symptom comprises acne and anxiety. In some embodiments, said symptom comprises acne and mood swings.Pharmaceutical Compositions

[0096] In some embodiments, said pharmaceutical composition comprises a CRF1 antagonist (e.g., Compound I) or pharmaceutically acceptable salt thereof. In some embodiments, said pharmaceutical composition further comprises a diluent. In some embodiments, said diluent comprises calcium carbonate, microcrystalline cellulose, calcium phosphate, starch, pregelatinized starch, sodium carbonate, mannitol, lactose, or a combination thereof. In some embodiments, said diluent comprises lactose monohydrate, microcrystalline cellulose, or a combination thereof. In some embodiments, said diluent comprises lactose monohydrate. In some embodiments, said diluent comprises microcrystalline cellulose.

[0097] In some embodiments, said pharmaceutical composition further comprises a binder. In some embodiments, said binder comprises starches (e.g., corn starch and potato starch), gelatin, sucrose, hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), hydroxypropyl methyl cellulose (HPMC), or a combination thereof. In some embodiments, said binder comprises hydroxypropylcellulose.

[0098] In some embodiments, said pharmaceutical composition further comprises a surfactant. In some embodiments, said surfactant comprises sodium lauryl sulfate.

[0099] In some embodiments, said pharmaceutical composition further comprises a disintegrant. In some embodiments, said disintegrant comprises ac-di-sol, croscarmellose sodium, starch, sodium starch glycolate, alginic acid, crospovidone, or a combination thereof. In some embodiments, said disintegrant comprises croscarmellose sodium.

[0100] In some embodiments, said pharmaceutical composition further comprises a glidant. In some embodiments, said glidant comprises silicon dioxide. In some embodiments, said silicon dioxide comprises colloidal silicon dioxide.

[0101] In some embodiments, said pharmaceutical composition further comprises a lubricant. In some embodiments, said lubricant comprises talc, stearic acid, magnesium stearate, sodium stearyl fumarate, or a combination thereof. In some embodiments, said lubricant comprises magnesium stearate.

[0102] In some embodiments, said pharmaceutical composition further comprises a film former. In some embodiments, said film former comprises opadry II yellow.

[0103] In some embodiments, a pharmaceutical composition disclosed herein comprises Compound I, lactose monohydrate, hydroxypropylcellulose, sodium lauryl sulfate, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, opadry II yellow, and purified water.

[0104] An exemplary pharmaceutical composition is set forth in Table 1.Table 1: Example formulation of Compound I as a 50 mg strength tabletDefinitions

[0105] Unless defined otherwise, all terms of art, notations and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should notnecessarily be construed to represent a substantial difference over what is generally understood in the art.

[0106] Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0107] As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unlessthe context clearly dictates otherwise. For example, the term “a sample” includes a plurality of samples, including mixtures thereof.

[0108] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.EXAMPLES

[0109] The following examples further illustrate the invention but should not be construed as in any way limiting its scope. In particular, the processing conditions are merely exemplary and can be readily varied by one of ordinary skill in the art.

[0110] All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. Unless defined otherwise, technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.Example 1. Evaluation of the safety and efficacy of a CRF1 antagonist in adult subjects with Polycystic Ovary Syndrome and elevated adrenal androgens

[0111] Compound I (also referred to as “tildacerfont”) was studied in a randomized, placebo-controlled, dose escalation study to evaluate the safety and efficacy of Compound I in adult subjects with Polycystic Ovary Syndrome (PCOS) and elevated adrenal androgens.Subjects randomized to the Compound I group received 3 escalating dose levels of Compound I with each dose level administered for a period of time (e.g., 4 weeks). All placebo subjects remained on placebo over the full treatment period (e.g., 12 weeks). Subjects who continue to meet all eligibility criteria will be randomized to either dose escalation with Compound I or matching placebo in a 2: 1 ratio of Compound I to placebo.

[0112] Objectives of the study were to i) evaluate the effect of tildacerfont in reducing dehydroepiandrosterone sulfate (DHEAS) in subjects with PCOS and elevated adrenal androgens, ii) evaluate the effect of tildacerfont in achieving target reduction in DHEAS in subjects with PCOS and elevated adrenal androgens, iii) evaluate the safety of tildacerfont in subjects with PCOS and elevated adrenal androgens, and (iv) evaluate the effect of tildacerfont in reducing key serum hormones and androgens in subjects with PCOS and elevated adrenal androgens.

[0113] This randomized, placebo-controlled dose escalation study evaluated the safety and efficacy of 3 Compound I dose levels (e.g., 50 mg, 100 mg, and 200 mg QD) compared to placebo for up to the length of the study period (e.g., 12 weeks) in subjects with PCOS and elevated adrenal androgens at baseline. The study was planned as a 3-period study with a duration (e.g., 4 weeks) for each period. Subjects diagnosed with PCOS per the 1990 NIH criteria (Zawadski and Dunaif, 1992) were screened to determine eligibility for the study over up to 2 screening visits. For subjects with unknown DHEAS elevations (within 6 months of target randomization date), an optional DHEAS Screening Visit was optionally used to test DHEAS level prior to further screening evaluations. In order to qualify for the study, a subject’ s DHEAS value must exceed the age-matched, reference ULN threshold. Screening sisit assessments included safety laboratories and assessments. Subjects meeting all eligibility criteria were randomized to either dose escalation with Compound I or matching placebo.

[0114] Subjects were randomized to the Compound I group initiated treatment with a first period of 4 weeks at a first dose of 50 mg QD, then proceeded to a second period of 4 weeks at a second dose of 100 mg QD, and completed the study with a third period of 4 weeks at a third dose of 200 mg QD. All placebo subjects remained on placebo over the full treatment period.

[0115] If signs, symptoms, or biochemical evidence of adrenal insufficiency were noted, study drug was be suspended until adrenal function maybe fully evaluated for relationship to clinical findings. If adrenal insufficiency is confirmed, study drug was to be permanently discontinued.

[0116] Study drug was administered at home during each period with an evening meal (e.g., containing approximately <50% fat content between 6 P.M. and midnight).Efficacy Assessments:

[0117] Blood samples were collected at every clinic visit for measurement of serum DHEAS levels. The primary efficacy assessment is measurement of serum DHEAS levels. Exploratory efficacy assessments included assessment of various serum hormone levels: ACTH, DHEA, T, A4, 17-OHP, 110HA4, 11OHT, 11KA4, 11KT, LH, FSH, SHBG, and estradiol.Safety Assessments:

[0118] Safety assessments included monitoring and recording all AEs (including SAEs, AEs leading to discontinuation / withdrawal, and AESIs), physical examination, vital signs assessment, ECGs, clinical laboratories, including serum cortisol, and monitoring for suicide risk using the Columbia-Suicide Severity Rating Scale (C-SSRS).Pharmacokinetics (PK) Assessments:

[0119] PK assessments were conducted at specified timepoints (e.g., weeks 4, 8, and 12) and consisted of a single sample (e.g., 8 A.M. ± 1 hour).Study Conduct

[0120] Each subject’s course consisted of the following visits:Clinic VisitsClinic visits occurred at the following times:• Optional DHEAS Screening Visit• Screening Visit (Safety labs and assessments, inclusion / exclusion criteria evaluation, medical history, and concomitant medications)Treatment Period:• Period 1 : At Day 1 and Day 28• Period 2: Day 56• Period 3: Day 84Follow-up: At 30 days after the last dose of study drug

[0121] Clinic visits were scheduled for the early morning, to accommodate morning laboratory assessments (approximately 8 A.M. ± 1 hour). DHEAS is expected to peak in the morning after overnight ACTH surge, so morning draws are optimal for the DHEAS Screening Visit. However, any previously documented DHEAS elevation confirmed eligibility during the optional pre-screening visit.

[0122] Duration of Subject Participation: Approximately 25 weeks, inclusive of up to 30 days of optional DHEAS screening, 30 days of screening, 12 weeks of treatment, and 30 day follow up.

[0123] Planned Sample Size and Number of Sites: This study enrolled approximately 40 subjects at approximately 15 investigative sites within North America. A sample size of 33 subjects with 2 : 1 randomization provided at least 80% power to detect a difference of 164 mcg / dL in mean DHEAS between at least one dose of Compound I and placebo assuming a standard deviation of 154 mcg / dL and a two-sided alpha of 0.05. Accounting for a 15% drop out, the final sample size is N=39 (n=26 for Compound I group and n=13 for placebo).Subjects were randomized using the strata of Screening DHEAS (<1 ,2x ULN, >1 ,2x ULN).

[0124] Study Drug and Route of Administration: Compound I, an oral small-molecule corticotropin-releasing factor type-1 (CRFi) receptor antagonist was supplied as 50 mg tablets (e.g., as a formulation shown in Table 1). Placebo was supplied as tablets that look identical to drug product but contain no drug substance.

[0125] Subject Population: Female subjects 18 to 40 years old with PCOS and screening DHEAS levels that exceed the age-matched reference ULN threshold.Treatment Administration: All subjects were treated with 3 doses of oral Compound I (50 mg, 100 mg, or 200 mg QD), or placebo for 12 weeks.Inclusion and Exclusion Criteria:Inclusion Criteria:• Female subjects 18 to 40 years old, inclusive, at the screening visit• Diagnosis of PCOS (either historical or during screening) according to the NIH (1990) criteria (both (a) and (b) are necessary and other disorders causing hyperandrogenism and anovulation must be excluded):• Presence of clinical and / or biochemical hyperandrogenism• Chronic anovulation (defined as <8 menstrual cycles in the previous 12 months)• DHEAS level > age matched reference ULN at ScreeningDHEAS upper limit of normal is defined for the following inclusive age ranges as: 377 pg / dL for women 18 - 30 years old; 295 pg / dL for women 31 - 40 years old; 240 pg / dL for women 41 - 50 years old• Agrees to follow contraception guidelines. Subjects must be postmenopausal, have documentation of hysterectomy, bilateral salpingectomy, or bilateral oophorectomy, be sexually abstinent, have a male sexual partner who is vasectomized, or agree to use a highly effective contraceptive method from at least 1 month before Screening until 30 days after the last dose of study drug.• Is able to understand all study procedures and risks involved and provides written informed consent indicating willingness to comply with all aspects of the protocolExclusion Criteria:• Evidence of any of the following: o History of congenital adrenal hyperplasia, Cushing’s syndrome, pituitary or adrenal disease o Clinically significant hyperprolactinemia o Thyroid stimulating hormone (TSH) <0.1 mU / mL or >4.5 mU / mL at screening■ Subjects receiving concomitant treatment for thyroid disease must be on stable medication for at least 6 weeks o Cortisol levels concerning for adrenal insufficiency (A.M. basal cortisol level <6.2 pg / dL at Screening) o Any other findings suggestive of a secondary cause for anovulation and / or hyperandrogenemia• Total testosterone levels >140 ng / dL, DHEAS >650 mcg / dL, virilization or other signs or symptoms concerning for ovarian hyperthecosis or androgen-secreting tumors• Medical conditions that require glucocorticoid treatment within 30 days of screening and throughout the duration of the study• Prior hysterectomy or bilateral oophorectomy• History of allergy or hypersensitivity to Compound I, any of its excipients, or any other CRFi receptor antagonist• A clinically significant unstable medical condition, medically significant illness, or chronic disease occurring during or within 30 days of screening, including but not limited to: o An ongoing malignancy or <3 years of remission history from any malignancy, other than successfully treated localized skin cancero Estimated glomerular filtration rate (eGFR) of <45 mL / min / 1.73 m2o Current or history of liver disease (except Gilbert’s syndrome) o History of alcohol or substance abuse within the last year, or any significant history of alcohol or substance abuse that would likely prevent the subject from reliably participating in the study, based on the opinion of the Investigator o Active hepatitis B, hepatitis C, human immunodeficiency virus (HIV) at screening or other condition / therapy rendering a subject immunosuppressed during screening or throughout the duration of the study o Subjects who plan to undergo bariatric surgery during the study are excluded.• Psychiatric conditions including, but not limited to bipolar, schizophrenia, or schizoaffective disorders that are not effectively controlled on medication and may, in the opinion of the Investigator, have adverse impact on study compliance. Symptoms of hallucinations, delusions and psychosis are exclusionary. Additionally: o Increased risk of suicide based on the Investigator’s judgment or the results of the Columbia- Suicide Severity Rating Scale (C-SSRS) conducted at screening (eg, C- SSRS Type 3, 4, or 5 ideation within the past 6 months or any suicidal behavior within the past 12 months)• Has clinically significant abnormal electrocardiogram (ECG) or clinical laboratory results during screening. Abnormal results that must be reviewed and discussed with the Medical Monitor to determine eligibility include but are not limited to: o Any clinically meaningful abnormal ECG results, including Fridericia-corrected QT interval (QTcF) >470 ms o Alanine aminotransferase (ALT) >2x ULN o Total bilirubin >1 ,5x ULN o Total bile acids >5x ULN• Is pregnant or nursing, or plans to become pregnant from screening until 30 days after the last dose of study drug• Use of any other investigational drug or device from 30 days or 5 half-lives (whichever is longer) before screening to the end of the studyUse of the following drugs or devices from 30 days or 5 half-lives (whichever is longer) before Day 1 to the end of the study: o Any medication for the treatment of PCOS including but not limited to antiandrogens, metformin, GnRH agonists, or other therapy or supplement that could impact subject safety or confound study data o Drugs which are or contain:■ Moderate to strong inhibitors and / or inducers of cytochrome P450 3 A4 (CYP3A4)■ Sensitive substrates or narrow-therapeutic-range substrates of CYP3 A4 (except hormonal contraception containing <35 pg ethinyl estradiol)■ Sensitive substrates or narrow-therapeutic-range substrates of breast cancer resistance protein (BCRP) other than those which can be administered once-daily in the morning (separated by approximately 10 hours from study drug evening administration)• Donation or receipt of blood from 90 days before screening to the end of the study; or donation or receipt of platelets, white blood cells, or plasma from 30 days prior to screening to the end of the study.

[0126] Efficacy Analyses: All efficacy analyses were conducted on modified intent-to- treat (mITT) Population using a 2-sided alpha of 0.05. The modified ITT (mITT) Analysis Set includes all randomized subjects who receive at least 1 dose of study drug (Compound I or placebo), have a baseline DHEAS assessment, and have at least one post-baseline DHEAS assessment. No adjustment for multiplicity is planned. The primary endpoint, the change from baseline in DHEAS, was used to evaluate the preliminary efficacy of Compound I therapy relative to placebo and was summarized using an analysis of covariance (ANCOVA) model with baseline DHEAS as a covariate and randomization strata and dose level as independent variables. Baseline values are defined as the last non-missing assessment prior to the first dose of randomized, double-blind study drug. Each Treatment Period’s final DHEAS assessment (ie, Week 4, Week 8, and Week 12) is the dependent variable. Additional covariates may be added in the statistical analysis plan (SAP).The proportion of subjects meeting specific DHEAS thresholds was summarized using exact tests through logistic regression using a similar variable structure as the primary endpoint:• DHEAS >30% reduction from baseline vs <30% reduction from baseline• DHEAS <ULN vs >ULN.

[0127] Additional covariates may be added in the SAP. Missing values for proportion endpoints were not imputed and weren’t assumed to be failures.

[0128] Exploratory hormone and androgen endpoints were summarized using an ANCOVA model using a similar variable structure as the primary endpoint. Additional endpoints may be specified in the SAP.Results

[0129] The percent of subjects with >30% reduction in DHEAS was measured by treatment group and timepoint in a mITT analysis set (FIG. 7A). At week 8, it was found that 6% of subjects in the Compound I study group demonstrated >30% reduction in DHEAS. At week 12, it was found that 6% of subjects in the Compound I study group demonstrated >30% reduction in DHEAS. At week 8 and week 12, none of the subjects in the placebo study group demonstrated >30% reduction in DHEAS.

[0130] The percent of subjects with >25% reduction in DHEAS was measured by treatment group and timepoint in a mITT analysis set (FIG. 7B). At week 4, the percentage of subjects with >25% reduction in DHEAS was 6% and 10% for Compound I study group and placebo study group, respectively. At week 8, the percentage of subjects with >25% reduction in DHEAS was 19% and 10% for Compound I study group and placebo study group, respectively. At week 12, the percentage of subjects with >25% reduction in DHEAS was 13% and 0% for Compound I study group and placebo study group, respectively.

[0131] Table 2 and FIGs. 2A-2B show the change in DHEAS (pg / dL) from baseline in the group receiving Compound I (also referred to as “tildacerfont”) compared to the group receiving placebo. Measurements are shown at 4 weeks, 8 weeks, and 12 weeks.Table 2: Change in DHEAS (pg / dL) from baseline using modified Intent-to-Treat analysis

[0132] Table 3 and FIGs. 3A-3B show the change in DHEAS (pg / dL) from baseline in subjects having a DHEAS level that is greater than an upper limit of normal of a reference range of DHEAS at the screening visit (“Inclusion Criteria #3) the group receiving Compound I compared to the group receiving placebo. Measurements are shown at 4 weeks, 8 weeks, and 12 weeks.Table 3: Change in DHEAS (pg / dL) from baseline Using a modified Intent-to-TreatAnalysis Set, where subjects met Inclusion Criteria #3.

[0133] Table 4 and FIGs. 4A-4B show the change in DHEAS (pg / dL) from baseline in subjects not having a DHEAS level that is greater than an upper limit of normal of a reference range of DHEAS at the screening visit (“Inclusion Criteria #3) the group receiving Compound I compared to the group receiving placebo. Measurements are shown at 4 weeks, 8 weeks, and 12 weeks.Table 4: Change in DHEAS (pg / dL) from baseline using a modified Intent-to-TreatAnalysis Set, wherein subjects did not meet Inclusion Criteria #3

[0134] Table 5 and FIGs. 5A-5B show the change in DHEAS (pg / dL) from baseline in subjects that had screening DHEAS < 1.2 x ULN in the group receiving Compound I compared to the group receiving placebo. Measurements are shown at 4 weeks, 8 weeks, and 12 weeks.Table 5: Change in DHEAS (pg / dL) from baseline using a modified Intent-to-TreatAnalysis Set with subjects that had screening DHEAS < 1.2 ULN.

[0135] Table 6 and FIGs. 6A-6B show the change in DHEAS (pg / dL) from baseline in subjects that had screening DHEAS > 1 .2 x ULN in the group receiving Compound I compared to the group receiving placebo. Measurements are shown at 4 weeks, 8 weeks, and 12 weeks.Table 6: Change in DHEAS (pg / dL) from baseline. Modified Intent-to-Treat Analysis Set wherein subjects had screening DHEAS > 1.2 x ULN. Data is illustrated in FIGS.6A-6B.

[0136] As an example, Table 7 shows a summary of DHEA levels in the group receiving Compound I compared to the group receiving placebo. Measurements are shown at 4 weeks, 8 weeks, and 12 weeks.Table 7: Summary of DHEA levels by Post-Baseline Visit using a modified intent-to- treat analysis set

[0137] Table 8 shows a summary of adrenocorticotropic hormone (ACTH) levels in the group receiving Compound I compared to the group receiving placebo. Measurements are shown at 4 weeks, 8 weeks, and 12 weeks.Table 8: Summary of Adrenocorticotropic Hormone by Post-Baseline Visit of a modified intent-to-treat analysis set.Mm, Max 3, 50

[0138] Table 9 shows a summary of 17-Hydroxyprogesterone (17-OHP) levels in the group receiving Compound I compared to the group receiving placebo. Measurements are shown at 4 weeks, 8 weeks, and 12 weeks.Table 9: Summary of 17-Hydroxyprogesterone by Post-Baseline Visit of a modified intent-to-treat analysis set.

[0139] Table 10 shows a summary of Androstenedione (A4) levels in the group receiving Compound I compared to the group receiving placebo. Measurements are shown at 4 weeks, 8 weeks, and 12 weeks.Table 10: Summary of Androstenedione by Post-Baseline Visit of a modified intent-to- treat analysis set.

[0140] Table 11 shows a summary of testosterone levels in the group receivingCompound I compared to the group receiving placebo. Measurements are shown at 4 weeks, 8 weeks, and 12 weeks.Table 11 : Summary of Testosterone by Post-Baseline Visit of a modified intent-to-treat analysis set.

[0141] Table 12 shows a summary of Dehydroepiandrosterone Sulfate (DHEAS) levels in the group receiving Compound I compared to the group receiving placebo. Measurements are shown at 4 weeks, 8 weeks, and 12 weeks.Table 12: Summary of DHEAS levels by Post-Baseline Visit of a modified intent-to-treat analysis set.

[0142] Table 13 shows a summary of adverse events experienced in subjects receiving Compound I as compared to subjects receiving placebo treatment.Table 13: Summary of Study Drug-Related Treatment-Emergent Adverse Events by System Organ Class and Preferred Term Safety Analysis Set

[0143] Table 14 shows a summary of serious adverse events in the group receiving Compound I and the group receiving placebo.Table 14: Summary of serious treatment-emergent adverse events by system organ class and preferred term safety analysis set

[0144] Table 15 shows an overall summary of adverse events in the group receiving Compound I and the group receiving placebo.Table 15: Overall Summary of Adverse Events Safety Analysis Set

[0145] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMSWhat is claimed is:1 . A method of treating polycystic ovary syndrome (PCOS) in a subject in need thereof, comprising administering a pharmaceutical composition comprising a CRF1 antagonist or pharmaceutically acceptable salt thereof, wherein said subject has chronic anovulation, a dehydroepiandrosterone sulfate(DHEAS) level that is greater than an upper limit of normal of a reference range of said DHEAS level, or a combination thereof, wherein the pharmaceutical composition comprises: a CRF1 antagonist in an amount of about 20% to about 30% by weight of a total weight of the pharmaceutical composition; one or more diluents in a total amount of about 60% to about 70% by weight of the pharmaceutical composition; a binder; a surfactant; a disintegrant; a glidant; a lubricant; and a film former.

2. The method of claim 1, wherein said subject is administered said CRF1 antagonist or pharmaceutically acceptable salt thereof in an amount of 50 mg for a first time period, said subject is administered said CRF1 antagonist or pharmaceutically acceptable salt thereof in an amount of 100 mg for a second time period, and wherein said subject is administered said CRF1 antagonist or pharmaceutically acceptable salt thereof in an amount of 200 mg for a third time period.

3. The method of claim 1, wherein said first time period is about four weeks.

4. The method of claim 1 or 2, wherein said second time period is about four weeks.

5. The method of any one of claims 1 -4, wherein said third time period is at least about four weeks.

6. The method of claim 1, wherein said CRF1 antagonist or pharmaceutically acceptable salt thereof is administered once daily.

7. The method of claim 1, wherein said subject further has hyperandrogenism.

8. The method of claim 1-7, wherein said subject has chronic anovulation.

9. The method of claim 8, wherein said chronic anovulation is less than eight menstrual cycles in twelve months.

10. The method of claim 1, wherein said subject has hyperandrogenism and chronic anovulation.

11. The method of any one of claims 1-10, wherein said subject has said DHEAS level that is greater than an upper limit of normal of a reference range of said DHEAS level.

12. The method of claim 11, wherein said upper limit of said reference range of said DHEAS level is an age-matched referenced upper limit of said DHEAS level.

13. The method of any one of claims 1-12, wherein said administering reduces said DHEAS level from baseline.

14. The method of claim 1-13, wherein said DHEAS level is greater than 1.2 times said upper limit of said DHEAS level.

15. The method of claim 14, wherein said DHEAS level is reduced by at least about 10 pg / dL from baseline.

16. The method of claim 14, wherein said DHEAS level is reduced by at least about 20 pg / dL from baseline.

17. The method of any one of claims 13-16, wherein said reduction is at about 12 weeks after said administering.

18. The method of claim 17, wherein said administering is a first administration of said pharmaceutical composition.

19. The method of claim 18, wherein said administering occurs once daily for about 12 weeks.

20. The method of claim 14, wherein said DHEAS level is reduced by at least about 30 pg / dL from baseline.

21. The method of claim 14, wherein said DHEAS level is reduced by at least about 35 pg / dL from baseline.

22. The method of claim 14, wherein said DHEAS level is reduced by at least about 40 pg / dL from baseline.

23. The method of any one of claims 13-16 or 20-22, wherein said reduction is at about 8 weeks after said administering.

24. The method of any one of claims 1-23, wherein said subject has any 2 or more of hyperandrogenism, chronic anovulation, and said DHEAS level that is greater than an upper limit of normal of a reference range of said DHEAS level.

25. The method of any one of claims 1-24, wherein said subject has hyperandrogenism, chronic anovulation, and said DHEAS level that is greater than an upper limit of normal of a reference range of said DHEAS level.

26. The method of any one of claims 1-25, wherein said DHEAS is reduced by at least about 5% from baseline.

27. The method of claim 26, wherein said DHEAS reduction is at eight weeks or twelve weeks after said administering.

28. The method of any one of claims 1-27, wherein said administering reduces a dehydroepiandrosterone (DHEA) level from baseline.

29. The method of claim 28, wherein said DHEA level is reduced by at least about 0.75% from baseline.

30. The method of claim 28, wherein said DHEA level is reduced by at least about 7% from baseline.

31. The method of claim 28, wherein said DHEA level is reduced by at least about 0.3 ng / mL from baseline.

32. The method of claim 28, wherein said DHEA level is reduced by at least about 0.7 ng / mL from baseline.

33. The method of any one of claims 28-32, wherein said DHEA reduction is at four weeks after said administering.

34. The method of claim 28, wherein said DHEA level is reduced by at least about 5% from baseline.

35. The method of claim 28, wherein said DHEA level is reduced by at least about 10% from baseline.

36. The method of claim 34 or 35, wherein said DHEA reduction is at eight weeks after said administering.

37. The method of any one of claims 1-36, wherein said administering reduces a level of a second hormone.

38. The method of claim 37, wherein the second hormone comprises adrenocorticotropic hormone (ACTH), 17-hydroxy progesterone (17-OHP), androstenedione (A4), testosterone, or a combination thereof.

39. The method of claim 37 or 38, wherein said second hormone is reduced compared to a corresponding administering of a pharmaceutical composition that does not contain a CRF1 antagonist or pharmaceutically acceptable salt thereof.

40. The method of any one of claims 1-39, wherein said administering reduces a low-density lipoprotein cholesterol (LDL) level from baseline.

41. The method of claim 40, wherein said LDL level is reduced by at least about 5%, at least about 10%, at least about 15%, or at least about 20%.

42. The method of any one of claims 1-41, wherein said administering reduces a total cholesterol level from baseline.

43. The method of claim 42, wherein said total cholesterol level is reduced by at least about 10%, at least about 15%, at least about 20%.

44. The method of any one of claims 1-43, wherein the endocrine disorder is polycystic ovary syndrome with functional ovarian hyperandrogenism and functional adrenal hyperandrogenism (PCOS-FOH + FAH) or polycystic ovary syndrome with functional adrenal hyperandrogenism (PCOS-FAH).

45. A method of treating polycystic ovary syndrome (PCOS) in a subject in need thereof, comprising administering a pharmaceutical composition comprising a CRF1 antagonist or pharmaceutically acceptable salt thereof, wherein said subject has chronic anovulation, a dehydroepiandrosterone sulfate (DHEAS) level that is less than 1.2 times an upper limit of normal of a reference range of said DHEAS level, or a combination thereof, wherein the pharmaceutical composition comprises: a CRF1 antagonist in an amount of about 20% to about 30% by weight of a total weight of the pharmaceutical composition; one or more diluents in a total amount of about 60% to about 70% by weight of the pharmaceutical composition; a binder; a surfactant; a disintegrant; a glidant; a lubricant; and a film former.

46. The method of claim 45, wherein said DHEAS is less than 1.2 times the upper limit of normal of said reference range of said DHEAS level.

47. The method of claim 45, wherein said DHEAS is less than one times the upper limit of normal of said reference range of said DHEAS level.

48. The method of any one of claims 45-47, wherein said DHEAS level is reduced by at least about 25 pg / dL from baseline.

49. The method of any one of claims 45-48, wherein a DHEAS level is reduced by at least about 30 pg / dL from baseline.

50. The method of claim 48 or 49, wherein said reduction is at 8 weeks after said administering.

51. The method of any one of claims 45-49, wherein a DHEAS level is reduced by at least about 35 pg / dL from baseline administering.

52. The method of any one of claims 45-49 or 51, wherein a DHEAS level is reduced by at least about 40 pg / dL from baseline administering.

53. The method of any one of claims 45-49, 51, or 52, wherein a DHEAS level is reduced by at least about 45 pg / dL from baseline administering.

54. The method of any one of claims 1-53, wherein the CRF1 antagonist is a compound of Formula (I), or a pharmaceutically acceptable salt thereof:Formula (I) wherein:RAis Ci-Cealkyl, Ci-Cealkenyl, Ci-Cealkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted 5- to 12- membered heterocyclyl, optionally C6- Ci2aryl, or optionally substituted 5- to 12- membered heteroaryl, wherein the optionally substituted Cs-Cecycloalkyl, 5- to 12- membered heterocyclyl, Ce-Cnaryl, and 5- to 12- membered heteroaryl is optionally substituted with Ci.C6alkyl;RBis hydrogen, halogen, Ci-C6alkyl, Ci-C6alkenyl, Ci-C6alkynyl, Ci-C6alkoxy, optionally substituted C3-C12 cycloalkyl, optionally substituted 5- to 12- membered heterocyclyl, optionally C6-Ci2aryl, or optionally substituted 5- to 12- membered heteroaryl, wherein the optionally substituted Cs-Cecycloalkyl, 5- to 12- membered heterocyclyl, C6-Ci2aryl, and 5- to 12- membered heteroaryl is optionally substituted with halogen, Ci.C6alkyl, or Ci-C6alkoxy;R4is hydrogen, halogen, Ci-Cealkyl, -NR4aR4b,-NHC(O)Ci-Cealkyl, -Ci- C6alkylene-O-Ci-C6alkyl, optionally substituted 5- to 6- membered heterocyclyl, or optionally substituted 5- to 6- membered heteroaryl, wherein the optionally substituted 5- to 6- membered heterocyclyl and 5- to 6- membered heteroaryl is optionally substituted with Ci-C6alkyl; andR4aand R4bare independently hydrogen, optionally substituted Ci-Cealkyl, optionally substituted Ci-C6alkenyl, optionally substituted Ci-C6alkynyl, wherein the optionally substituted Ci-C6alkyl, Ci-C6alkenyl, and Ci-C6alkynyl is optionally substituted with one or more amine, -C(O)Ci-Cealkyl, -C(O)OCi-Cealkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 5- to 12- membered heterocyclyl, optionally C6-Ci2aryl, or optionally substituted 5- to 12- membered heteroaryl, wherein the optionally substituted Cs-Cecycloalkyl, 5- to 12- membered heterocyclyl, C6-Ci2aryl, and 5- to 12- membered heteroaryl is optionally substituted with halogen or Ci-Cealkyl.

55. The method of claim 54, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (II):Formula (II) wherein:R1and R2are independently ethyl or w-propyl;R3is hydrogen, F, Cl, Br, methyl, trifluoromethyl, or methoxy;R4is hydrogen, Br, -NR4aR4b, methoxymethyl, w-butyl, acetamido, pyridin-4- yi, morpholin-4-yl,R4aand R4bare independently hydrogen, optionally substituted Ci-C6alkyl, optionally substituted Ci-Cealkenyl, optionally substituted Ci-Cealkynyl, wherein the optionally substituted Ci-C6alkyl, Ci-C6alkenyl, and Ci-C6alkynyl is optionally substituted with one or more amine, -C(O)Ci-C6alkyl, -C(O)OCi-C6alkyl, C3- Cecycloalkyl, 5- to 12- membered heterocyclyl, Ce-Cnaryl, or 5- to 12- membered heteroaryl, wherein the optionally substituted C3-C6cycloalkyl, 5- to 12- membered heterocyclyl, C6-Ci2aryl, and 5- to 12- membered heteroaryl is optionally substituted with halogen or Ci-Cealkyl.

56. The method of claim 55, wherein R3is F, Cl, Br, methyl, or trifluoromethyl.

57. The method of claim 56, wherein R3is Cl or Br.

58. The method of any one of claims 55-57, wherein R4is -NRaRb, pyridin-4-yl, morpholin-4-yl,59. The method of claim 58, wherein R4is morpholin-60. The method of claim 58, wherein R4is -NRaRb, and Raand Rbare independently Ci-C3alkyl.

61. The method of any one of claims 1-60, wherein the CRF1 antagonist is:or a pharmaceutically acceptable salt thereof.

62. The method of any one of claims 1-60, wherein the CRF1 antagonist is:or a pharmaceutically acceptable salt thereof.

63. The method of any one of claims 1-60, wherein the CRF1 antagonist is Compound I:or a pharmaceutically acceptable salt thereof.

64. The method of claim 54, wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof is a compound of Formula (III):Formula (III) wherein:RAis Ci-Cealkyl, Ci-Cealkenyl, Ci-Cealkynyl,RB1is halogen, Ci.C6alkyl, or Ci-C6alkoxy;R4aand R4bare independently optionally substituted Ci-Cealkyl, optionally substituted Ci-C6alkenyl, optionally substituted Ci-C6alkynyl, wherein the optionally substituted Ci-C6alkyl, Ci-C6alkenyl, and Ci-C6alkynyl is optionally substituted with one or more amine, -C(O)Ci-Cealkyl, -C(O)OCi-Cealkyl, Cs-Cecycloalkyl, 5- to 12- membered heterocyclyl, C6-Ci2aryl, or 5- to 12- membered heteroaryl, wherein the optionally substituted C3-C6cycloalkyl, 5- to 12- membered heterocyclyl, C6-Ci2aryl, and 5- to 12- membered heteroaryl is optionally substituted with halogen or Ci- C6alkyl; and n is 0 to 5.

65. The method of claim 64, wherein RAis Ci-Ce alkyl.

66. The method of claim 65, wherein RAis methyl.

67. The method of any one of claims 64-66, wherein eachRB1is independently Cl, Br, methyl, ethyl, methoxy, or ethoxy.

68. The method of claim 67, wherein each RB1is independently Cl, methyl, or methoxy.

69. The method of any one of claims 64-68, wherein n is 1 to 3.

70. The method of any one of claims 64-68, wherein n is 3.

71. The method of any one of claims 64-70, wherein the CRF1 antagonist isor a pharmaceutically acceptable salt thereof.

72. The method of any one of claims 1-71, wherein CRF1 antagonist or pharmaceutically acceptable salt thereof is administered as a dose of about 50 mg to aboutlOOO mg per day.

73. The method of any one of claims 1-71, wherein CRF1 antagonist or pharmaceutically acceptable salt thereof is administered as a dose of about 50 mg per day.

74. The method of any one of claims 1-71, wherein CRF1 antagonist or pharmaceutically acceptable salt thereof is administered as a dose of about 100 mg per day.

75. The method of any one of claims 1-71, wherein CRF1 antagonist or pharmaceutically acceptable salt thereof is administered as a dose of about 200 mg per day.

76. The method of any one of claims 1-71, wherein CRF1 antagonist or pharmaceutically acceptable salt thereof is administered as a dose of about 50 mg per day for four weeks.

77. The method of any one of claims 1-71 or 76, wherein CRF1 antagonist or pharmaceutically acceptable salt thereof is administered as a dose of about 100 mg per day for four weeks.

78. The method of any one of claims 1-71 or 76-77, wherein CRF1 antagonist or pharmaceutically acceptable salt thereof is administered as a dose of about 200 mg per day for four weeks.

79. The method of any one of claims 1-71, wherein said CRF1 antagonist or pharmaceutically acceptable salt thereof is administered as a dose of about 50 mg for a first period of four weeks.

80. The method of claim 79, wherein after said first period of four weeks, said CRF1 antagonist or pharmaceutically acceptable salt thereof is administered as a dose of about 100 mg for a second period of four weeks.

81. The method of claim 80, wherein after said second period of four weeks, said CRF1 antagonist or pharmaceutically acceptable salt thereof is administered as a dose of about 200 mg for a third period of four weeks.

82. The method of any one of claims 1-81, wherein said subject is a pediatric subject.

83. The method of any one of claims 1-81, wherein said subject is an adult subject.

84. The method of claim 83, wherein said adult subject is 18 to 40 years old.

85. The method of any one of claims 1-84, wherein said administering reduces a symptom of PCOS.

86. The method of claim 85, wherein said symptom of PCO S is reduced compared to a corresponding administering of a pharmaceutical composition that does not contain a CRF1 antagonist or pharmaceutically acceptable salt thereof.

87. The method of claim 85 or 86, wherein said symptom comprises sleep apnea syndrome, fatigue, a skin disorder, a psychiatric disorder, or a combination thereof.

88. The method of claim 87, wherein said skin disorder comprises acne.

89. The method of claim 87, wherein said psychiatric disorder comprises anxiety or mood swings.

90. The method of any one of claims 1 -89, wherein said diluent comprises lactose monohydrate, microcrystalline cellulose, or a combination thereof.

91. The method of any one of claims 1-89, wherein said binder comprises hydroxypropylcellulose.

92. The method of any one of claims 1-91, wherein said surfactant comprises sodium lauryl sulfate.

93. The method of any one of claims 1-92, wherein said disintegrant comprises croscarmellose sodium.

94. The method of claim 93, wherein said glidant comprises silicon dioxide.

95. The method of claim 94, wherein said silicon dioxide comprises colloidal silicon dioxide.

96. The method of any one of claims 1-95, wherein said lubricant comprises magnesium stearate.

97. The method of any one of claims 1-96, wherein said film former comprises opadry II yellow.

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