CROSS-REFERENCE

[0001] This application claims benefit of U.S. Provisional Patent Application No. 63/313,199 filed on February 23, 2022, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[0002] The instant disclosure relates to medical therapy, particularly the treatment of congenital adrenal hyperplasia (CAH) and polycystic ovary syndrome (PCOS).

BACKGROUND OF THE INVENTION

[0003] CAH is an autosomal recessive disease of the adrenal glands due to mutations in key enzymes involved in adrenal steroidogenesis, which result in impaired cortisol synthesis. The lack of cortisol removes the negative feedback at the pituitary and the hypothalamus, resulting in elevated corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) secretion, respectively, which drives adrenal steroid synthesis to produce excess steroids and precursors, particularly adrenal androgens. This steroid precursor oversecretion is associated with a variety of effects including improper gonadal development, hyperandrogenism, and a potential life-threatening mineralocorticoid deficiency. Because of the need for life-long exogenous glucocorticoid therapy, often at high doses in order to control adrenal hyperandrogenism, CAH patients have a two-fold risk of bone fractures compared to the general population and commonly suffer from hypercholesterolemia, insulin resistance, and hypertension.

[0004] The most common cause of CAH is defects in 21 -hydroxylase (also known as CYP21 A2), accounting for over 90% of cases of CAH. Different mutations in the gene responsible for 21 -hydroxylase result in different levels and/or activity of the enzyme, producing a spectrum of effects. CAH due to defects in 21 -hydroxylase is commonly broken down into two subcategories: classical CAH and non-classical CAH (NCCAH).

[0005] Forms of classical CAH include “simple virilizing CAH,” in which some 21- hydroxylase function remains, and the salt-losing form in which a complete loss of 21- hydroxylase activity results in a lack of both cortisol and aldosterone production, the latter of which causes the salt-wasting adrenal crises. Although cortisol production may be sufficient to avoid adrenal crisis in simple virilizing CAH, the reduced negative feedback and resultant ACTH-driven excess androgen production requiring life-long suppression from exogenous glucocorticoids also leads to significant morbidity in these patients.

[0006] Patients with NCCAH typically have 20-70% residual 21 -hydroxylase enzyme activity, which results in a less severe phenotype than classical CAH. The majority of patients with NCCAH have increased levels of cortisol precursors and androgens, including 17-hydroxyprogesterone, androstenedione, and testosterone. Symptoms of androgen excess may start during childhood or later in life, with premature adrenarche most common, along with other findings including acne, hirsutism, androgen alopecia, clitoromegaly, infertility, irregular menstruation, or even primary amenorrhoea.

[0007] Current treatment of CAH centers on replacing deficient adrenal hormones (e.g., cortisol and aldosterone) and suppressing excess androgen production. Glucocorticoid therapy is used not only to replace the deficiency, but also to provide sufficient feedback inhibition to decrease ACTH production and reduce resultant androgen production.

However, the doses of glucocorticoids required to suppress ACTH-driven androgen production in 21 -hydroxylase deficient CAH patients are often higher than physiologic replacement levels and can result in iatrogenic Cushing’s syndrome (CS) and its associated comorbidities.

[0008] The inability to precisely dose glucocorticoids can often lead to cycles of over- or undertreatment. Undertreatment fails to address clinical symptoms, potentially resulting in adrenal crisis, while overtreatment with exogenous glucocorticoids and/or mineralocorticoids results in serious, undesirable side effects, and comorbidities affecting multiple body systems. The complexity of achieving treatment balance with available therapies demonstrates the unsatisfactory nature of current treatment options for patients with CAH. Therefore, a need exists for improved therapies for the treatment of CAH.

[0009] Polycystic ovary syndrome (PCOS) is a hormonal disorder in women of reproductive age. Infrequent, irregular or prolonged menstrual cycles are the most common sign of PCOS. Women with PCOS may have elevated androgen levels (hyperandrogenism), resulting in physical signs, such as excess facial and body hair, severe acne, and male-pattern baldness. Women with PCOS may also have polycystic ovaries, which are enlarged ovaries with cysts that may fail to function properly. Complications of PCOS include infertility, miscarriage, premature birth, diabetes, metabolic syndrome, nonalcoholic steatohepatitis, and high blood pressure. No cure for PCOS exists, and thus, treatments typically address the related symptoms. Treatments include birth control pills, diabetes medications, diet alterations, medications that cause ovulation, and medications that help reduce hair growth or acne. A need exists for improved therapies for the treatment of PCOS.

SUMMARY OF THE INVENTION

[0010] Solutions for the above-described needs are provided herein.

[0011] In some embodiments, the instant disclosure provides a method of treating congenital adrenal hyperplasia (CAH) comprising coadministering an effective amount of an melanocortin receptor 2 (MC2 receptor) antagonist and an effective amount of a corticotropin-releasing factor receptor 1 (CRFi receptor) antagonist to a human in need thereof. In some embodiments, the effective amount of the MC2 receptor antagonist and/or the effective amount of the CRFi receptor antagonist is less than the amount of the MC2 receptor antagonist and/or the amount of the CRFi receptor antagonist that is effective to treat CAH when administered individually to the human.

[0012] In some embodiments, the human has a mutation in the gene encoding 21- hydroxylase, 1 ip-hydroxylase, 17a-hydroxylase, 3 P-hydroxy steroid dehydrogenase, p450 oxidoreductase, or a combination thereof.

[0013] In some embodiments, treating CAH comprises reducing levels of androstenedione (A4), 17-hydroxyprogesterone (17-OHP), aldosterone, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), 11 -oxygenated androgens, or a combination thereof, in the human. In certain specific embodiments, treating CAH comprises reducing levels of A4, 17-OHP, 11 -oxygenated androgens, or a combination thereof, in the human. [0014] In some embodiments, the instant disclosure provides a method of reducing androgen levels in a human in need thereof comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of a CRFi receptor antagonist to the human. In some embodiments, the effective amount of the MC2 receptor antagonist and/or the effective amount of the CRFi receptor antagonist is less than the amount of the MC2 receptor antagonist and/or the amount of the CRFi receptor antagonist that is effective for reducing androgen levels when administered individually to the human. In some embodiments, the human has CAH. In some embodiments, the human has PCOS.

[0015] In some embodiments, the androgens are selected from the group consisting of A4, 17-OHP, aldosterone, DHEAS, DHEA, 11 -oxygenated androgens, and combinations thereof. In certain embodiments, the androgens are selected from the group consisting of A4, 17- OHP, 11 -oxygenated androgens, and combinations thereof. [0016] In some embodiments, the instant disclosure provides a method of reducing glucocorticoid dose requirements for a human with CAH comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of a CRFi receptor antagonist to the human. In some embodiments, the effective amount of the MC2 receptor antagonist and/or the effective amount of the CRFi receptor antagonist is less than the amount of the MC2 receptor antagonist and/or the amount of the CRFi receptor antagonist that is effective for reducing glucocorticoid dose requirements when administered individually to the human.

[0017] In some embodiments, the instant disclosure provides a method of treating polycystic ovary syndrome (PCOS) comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of a CRFi receptor antagonist to a human in need thereof. In some embodiments, the effective amount of the MC2 receptor antagonist and/or the effective amount of the CRFi receptor antagonist is less than the amount of the MC2 receptor antagonist and/or the amount of the CRFi receptor antagonist that is effective to treat PCOS when administered individually to the human. In some embodiments, treating PCOS comprises reducing androgen levels in the human.

[0018] In some embodiments, the instant disclosure provides a pharmaceutical composition comprising an effective amount of an MC2 receptor antagonist and an effective amount of a CRFi receptor antagonist. In some embodiments, the effective amount of the MC2 receptor antagonist and/or the effective amount of the CRFi receptor antagonist is less than the amount of the MC2 receptor antagonist and/or the amount of the CRFi receptor antagonist that is effective to treat CAH and/or PCOS individually.

[0019] In some embodiments, the MC2 receptor antagonist is Compound 1, or a pharmaceutically acceptable salt thereof: (Compound 1).

[0020] In some embodiments, the CRFi receptor antagonist is Compound 3, or a pharmaceutically acceptable salt thereof: (Compound 3).

BRIEF DESCRIPTION OF THE DRAWINGS

[0021] FIG. 1 depicts the effect of administration of Compound 1, crinecerfont, and Compound 1 in combination with crinecerfont on (A) CRF-stimulated production of ACTH and (B) CRF-stimulated production of corticosterone (i.e. CORT) in an in vivo rat model.

[0022] FIG. 2 depicts the percentage change of the (A) ACTH response and (B) CORT response to CRF stimulation following administration of Compound 1, crinecerfont, and Compound 1 in combination with crinecerfont in an in vivo rat model.

DETAILED DESCRIPTION OF THE INVENTION

MC2 Receptor Antagonists

[0023] ACTH is a 39 amino acid peptide synthesized by anterior pituitary corti cotrophic cells by proteolytic cleavage of the proopiomelanocortin hormone (POMC). ACTH is the primary regulator of adrenal glucocorticoid (cortisol in humans and most other species; corticosterone in rodents) synthesis and secretion. As the central actor in this hypothalamic- pituitary-adrenal (HP A) axis, ACTH is secreted by the pituitary in response to stressful stimuli and acts at the adrenal gland to stimulate the synthesis and secretion of cortisol. This stimulation is mediated through a highly specific G protein-coupled receptor (GPCR) which is expressed almost uniquely in the adrenal cortex. The receptor is the melanocortin receptor 2 (MC2 receptor), and, along with ACTH, is part of the larger melanocortin system.

[0024] As used herein, an “MC2 receptor antagonist” is a compound that blocks the activation of the MC2 receptor by ACTH. In some embodiments, an MC2 receptor antagonist blocks activation of the MC2 receptor by binding to the MC2 receptor, ACTH, or a combination thereof. The term “MC2 receptor antagonist” encompasses small molecule therapeutics, including pharmaceutically acceptable salts of the active ingredients, as well as large molecule therapeutics or biologies, e.g., antibodies.

[0025] In some embodiments, the MC2 receptor antagonist used in the methods and compositions disclosed herein is Compound 1. Compound 1 refers to 6-(2-ethoxyphenyl)-3- ((R)-2-ethyl-4-(l-(trifluoromethyl)cyclobutane-l-carbonyl)pi perazin-l-yl)-N-((S)- quinuclidin-3-yl)picolinamide, which has the following chemical structure: (Compound 1).

[0026] Compound 1 is also referred to as N-[(3S)-l-azabicyclo[2.2.2]octan-3-yl]-6-(2- ethoxyphenyl)-3 -[(2R)-2-ethyl-4-[ 1 -(trifluoromethyl)cyclobutanecarbonyl]piperazin- 1 - yl]pyridine-2-carboxamide.

[0027] Properties of Compound 1 and a method for preparing Compound 1 are described in International Publication No. WO 2019/236699, the contents of which are fully incorporated by reference.

[0028] In some embodiments, the MC2 receptor antagonist used in the methods and compositions disclosed herein is a solvate, polymorph, metabolite, or prodrug of Compound

1.

[0029] In some embodiments, the MC2 receptor antagonist used in the methods and compositions disclosed herein is a compound or pharmaceutically acceptable salt thereof disclosed in International Publication No. WO 2019/236699, International Publication No. WO 2021/091788, International Publication No. WO 2021/126693, or International Publication No. WO 2021/133563, of which the contents of each are fully incorporated by reference.

CRFi Receptor Antagonists

[0030] Corticotropin-releasing factor (CRF) was isolated from ovine hypothalami and identified as a 41 -amino acid peptide. CRF has been found to produce alterations in endocrine, nervous, and immune system function. CRF is believed to be the major physiological regulator of the basal and stress-induced release of ACTH, B-endorphin, and other POMC-derived peptides from the anterior pituitary. Secretion of CRF causes release of ACTH from corticotrophs in the anterior pituitary via binding to the corticotropin-releasing factor receptor 1 (CRFi receptor), a member of the class B family of G-protein coupled receptors.

[0031] As used herein, a “CRFi receptor antagonist” is a compound that blocks the activation of the CRFi receptor by CRF. In some embodiments, a CRFi receptor antagonist blocks activation of the CRFi receptor by binding to the CRFi receptor, CRF, or a combination thereof. The term “CRFi receptor antagonist” encompasses small molecule therapeutics, including pharmaceutically acceptable salts of the active ingredients, as well as large molecule therapeutics or biologies, e.g., antibodies.

[0032] In some embodiments, the CRFi receptor antagonist used in the methods and compositions disclosed herein is Compound 2. Compound 2 refers to 4-(4-chloro-5-(2,5- dimethyl-7-(pentan-3-yl)pyrazolo[l,5-a]pyrimidin-3-yl)thiazo l-2-yl)morpholine, which has the following chemical structure: (Compound 2).

[0033] Compound 2 is also referred to as 3-(4-chloro-2-(morpholin-4-yl)thiazol-5-yl)-7-(l- ethylpropyl)-2,5-dimethylpyrazolo[l,5-a]pyrimidine. Compound 2 is also known by its nonproprietary name tildacerfont.

[0034] Properties of Compound 2 and a method for preparing Compound 2 are described in International Publication No. WO 2008/036579.

[0035] In some embodiments, the CRFi receptor antagonist used in the methods and compositions disclosed herein is a solvate, polymorph, metabolite, or prodrug of Compound 2.

[0036] In some embodiments, the CRFi receptor antagonist used in the methods and compositions disclosed herein is Compound 3. Compound 3 refers to (5)-4-(2-chloro-4- methoxy-5-methylphenyl)-7V-(2-cyclopropyl-l-(3-fluoro-4-meth ylphenyl)ethyl)-5-methyl-7V- (prop-2-yn-l-yl)thiazol-2-amine, which has the following chemical structure: (Compound 3).

[0037] Compound 3 is also known by its nonproprietary name crinecerfont. [0038] Properties of Compound 3 and a method for its preparation are described in U.S. Patent No. 6,586,456.

[0039] In some embodiments, the CRFi receptor antagonist used in the methods and compositions disclosed herein is a solvate, polymorph, metabolite, or prodrug of Compound 3.

[0040] In some embodiments, the CRFi receptor antagonist is selected from the group consisting of NBI-27914, CP-316,311, NBI-462000, DMP696, pexacerfont, NBI-35965, ONO-2333Ms, antalarmin, NBI-34041, DMP904, NBI-30775, SSR125543, NBI-77860, GSK876008, CRA5626/JNJ19567470/R317573, NBI-76169, verucerfont, and CP-154,526. Methods of Treatment

[0041] In some embodiments, the instant disclosure provides a method of treating CAH comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of a CRFi receptor antagonist to a subject in need thereof. In some embodiments, the instant disclosure provides a method of treating CAH comprising coadministering an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and an effective amount of a CRFi receptor antagonist to a subject in need thereof. In some embodiments, the instant disclosure provides a method of treating CAH comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of Compound 2, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the instant disclosure provides a method of treating CAH comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of Compound 3, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the instant disclosure provides a method of treating CAH comprising coadministering an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and an effective amount of Compound 2, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the instant disclosure provides a method of treating CAH comprising coadministering an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and an effective amount of Compound 3, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the effective amount of the MC2 receptor antagonist, e.g., Compound 1 or a pharmaceutically salt thereof, and/or the effective amount of the CRFi receptor antagonist, e.g., Compound 2 or a pharmaceutically acceptable salt thereof, or Compound 3 or a pharmaceutically acceptable salt thereof, is less than the amount of the MC2 receptor antagonist and/or the amount of the CRFi receptor antagonist that is effective to treat CAH when administered individually to the subject.

[0042] In some embodiments, the subject is a human with CAH. In some embodiments, the CAH is classical CAH. In some embodiments, classical CAH comprises salt-losing CAH or simple-virilizing CAH. In some embodiments, the CAH is non-classical CAH.

[0043] In some embodiments, the instant disclosure provides a method of treating PCOS comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of a CRFi receptor antagonist to a subject in need thereof. In some embodiments, the instant disclosure provides a method of treating PCOS comprising coadministering an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and an effective amount of a CRFi receptor antagonist to a subject in need thereof. In some embodiments, the instant disclosure provides a method of treating PCOS comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of Compound 2, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the instant disclosure provides a method of treating PCOS comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of Compound 3, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the instant disclosure provides a method of treating PCOS comprising coadministering an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and an effective amount of Compound 2, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the instant disclosure provides a method of treating PCOS comprising coadministering an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and an effective amount of Compound 3, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the effective amount of the MC2 receptor antagonist, e.g., Compound 1 or a pharmaceutically salt thereof, and/or the effective amount of the CRFi receptor antagonist, e.g., Compound 2 or a pharmaceutically acceptable salt thereof, or Compound 3 or a pharmaceutically acceptable salt thereof, is less than the amount of the MC2 receptor antagonist and/or the amount of the CRFi receptor antagonist that is effective to treat PCOS when administered individually to the subject. In some embodiments, the subject is a human with PCOS. In some embodiments, the subject is a female human with PCOS.

[0044] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, inhibiting the disease or condition, arresting the development of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition. [0045] In some aspects, treating CAH or PCOS comprises reducing levels of androstenedione (A4), 17-hydroxyprogesterone (17-OHP), aldosterone, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), 11 -oxygenated androgens, or a combination thereof, in the subject. In certain embodiments, treating CAH or PCOS comprises reducing levels of A4, 17-OHP, 11 -oxygenated androgens, or a combination thereof, in the subject. In certain specific embodiments, treating CAH or PCOS comprises reducing levels of A4, 17-OHP, or a combination thereof, in the subject.

[0046] In some embodiments, treating CAH or PCOS comprises reducing secretion of androgens in the subject. In some embodiments, treating CAH or PCOS comprises reducing levels of ACTH-stimulated androgens or cortisol precursors in the subject. In some embodiments the androgens are selected from A4, 17-OHP, aldosterone, DHEAS, DHEA, 11 -oxygenated androgens, and combinations thereof.

[0047] In some embodiments, treating CAH comprises improvement in at least one pharmacodynamic biomarker of CAH. In some embodiments, the at least one pharmacodynamic biomarker of CAH comprises serum levels of cortisol, ACTH, A4, 17- OHP, aldosterone, DHEAS, DHEA, or combinations thereof.

[0048] In some embodiments, treating CAH comprises reducing improper gonadal development, hyperandrogenism, and replacement of mineralocorticoids. In some embodiments, treating CAH comprises reducing improper gonadal development. In some embodiments, treating CAH comprises reducing hyperandrogenism. In some embodiments, treating CAH comprises reducing replacement of mineralocorticoids. In some embodiments, treating CAH comprises reducing the development of or clinical effects of testicular adrenal rest tumors.

[0049] In some embodiments, treating PCOS comprises reducing hyperandrogenism. In some embodiments, treating PCOS comprises reducing functional adrenal hyperandrogenism. [0050] The terms “coadminister,” “coadministration” or the like, as used herein, are meant to encompass administration of the therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different routes of administration, and at the same or different times.

[0051] The terms “administer,” “administering,” “administration,” and the like, as used herein, refer to the methods that may be used to deliver compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), and topical administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0052] In some embodiments, the instant disclosure provides a method of reducing androgen levels in a subject in need thereof comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of a CRFi receptor antagonist to the subject. In some embodiments, the instant disclosure provides a method of reducing androgen levels in a subject in need thereof comprising coadministering an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and an effective amount of a CRFi receptor antagonist to the subject. In some embodiments, the instant disclosure provides a method of reducing androgen levels in a subject in need thereof comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of Compound 2, or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the instant disclosure provides a method of reducing androgen levels in a subject in need thereof comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of Compound 3, or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the instant disclosure provides a method of reducing androgen levels in a subject in need thereof comprising coadministering an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and an effective amount of Compound 2, or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the instant disclosure provides a method of reducing androgen levels in a subject in need thereof comprising coadministering an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and an effective amount of Compound 3, or a pharmaceutically acceptable salt thereof, to the subject. In certain embodiments, the effective amount of the MC2 receptor antagonist, e.g. Compound 1 or a pharmaceutically acceptable salt thereof and/or the effective amount of the CRFi receptor antagonist, e.g., Compound 2 or a pharmaceutically acceptable salt thereof, or Compound 3 or a pharmaceutically acceptable salt thereof, is less than the amount of the MC2 receptor antagonist and/or the amount of the CRFi receptor antagonist that is effective for reducing androgen levels when administered individually to the subject.

[0053] In some embodiments, the subject is a human with CAH. In some embodiments, the subject is a human with PCOS. In some embodiments, the subject is a human with functional adrenal hyperandrogenism. In some aspects, the androgens are selected from the group consisting of A4, 17-OHP, aldosterone, DHEAS, DHEA, 11 -oxygenated androgens, and combinations thereof. In certain embodiments, the androgens are selected from the group consisting of A4, 17-OHP, 11 -oxygenated androgens, and combinations thereof. In certain specific embodiments, the androgens are selected from the group consisting of A4, 17-OHP, and combinations thereof.

[0054] In some embodiments, the instant disclosure provides a method of normalizing androgen levels in a subject in need thereof comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of a CRFi receptor antagonist to the subject. In some embodiments, the instant disclosure provides a method of normalizing androgen levels in a subject in need thereof comprising coadministering an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and an effective amount of a CRFi receptor antagonist to the subject. In some embodiments, the instant disclosure provides a method of normalizing androgen levels in a subject in need thereof comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of Compound 2, or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the instant disclosure provides a method of normalizing androgen levels in a subject in need thereof comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of Compound 3, or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the instant disclosure provides a method of normalizing androgen levels in a subject in need thereof comprising coadministering an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and an effective amount of Compound 2, or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the instant disclosure provides a method of normalizing androgen levels in a subject in need thereof comprising coadministering an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and an effective amount of Compound 3, or a pharmaceutically acceptable salt thereof, to the subject. In certain embodiments, the effective amount of the MC2 receptor antagonist, e.g. Compound 1 or a pharmaceutically acceptable salt thereof and/or the effective amount of the CRFi receptor antagonist, e.g., Compound 2 or a pharmaceutically acceptable salt thereof, or Compound 3 or a pharmaceutically acceptable salt thereof, is less than the amount of the MC2 receptor antagonist and/or the amount of the CRFi receptor antagonist that is effective for normalizing androgen levels when administered individually to the subject. [0055] In some embodiments, the subject is a human with CAH. In some embodiments, the subject is a human with PCOS. In some embodiments, the subject is a human with functional adrenal hyperandrogenism. In some aspects, the androgens are selected from the group consisting of A4, 17-OHP, aldosterone, DHEAS, DHEA, 11 -oxygenated androgens, and combinations thereof. In certain embodiments, the androgens are selected from the group consisting of A4, 17-OHP, 11 -oxygenated androgens, and combinations thereof. In certain specific embodiments, the androgens are selected from the group consisting of A4, 17-OHP, and combinations thereof.

[0056] In some embodiments, disclosed herein is a method of reducing endogenous adrenal steroid hormone levels in a subject in need thereof comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of a CRFi receptor antagonist to the subject. In some embodiments, disclosed herein is a method of reducing endogenous adrenal steroid hormone levels in a subject in need thereof comprising coadministering an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and an effective amount of a CRFi receptor antagonist to the subject. In some embodiments, disclosed herein is a method of reducing endogenous adrenal steroid hormone levels in a subject in need thereof comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of Compound 2, or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, disclosed herein is a method of reducing endogenous adrenal steroid hormone levels in a subject in need thereof comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of Compound 3, or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, disclosed herein is a method of reducing endogenous adrenal steroid hormone levels in a subject in need thereof comprising coadministering an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and an effective amount of Compound 2, or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, disclosed herein is a method of reducing endogenous adrenal steroid hormone levels in a subject in need thereof comprising coadministering an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and an effective amount of Compound 3, or a pharmaceutically acceptable salt thereof, to the subject. In certain embodiments, the effective amount of the MC2 receptor antagonist, e.g. Compound 1 or a pharmaceutically acceptable salt thereof and/or the effective amount of the CRFi receptor antagonist, e.g., Compound 2 or a pharmaceutically acceptable salt thereof, or Compound 3 or a pharmaceutically acceptable salt thereof, is less than the amount of the MC2 receptor antagonist and/or the amount of the CRFi receptor antagonist that is effective for reducing endogenous adrenal steroid hormone levels when administered individually to the subject. In some embodiments, the subject is a human with CAH. In some embodiments, the subject is a human with PCOS.

[0057] In some aspects, disclosed herein is a method of inhibiting adrenal androgen secretion in a subject in need thereof comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of a CRFi receptor antagonist to the subject. In some embodiments, disclosed herein is a method of inhibiting adrenal androgen secretion in a subject in need thereof comprising coadministering an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and an effective amount of a CRFi receptor antagonist to the subject. In some embodiments, disclosed herein is a method of inhibiting adrenal androgen secretion in a subject in need thereof comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of Compound 2, or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, disclosed herein is a method of inhibiting adrenal androgen secretion in a subject in need thereof comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of Compound 3, or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, disclosed herein is a method of inhibiting adrenal androgen secretion in a subject in need thereof comprising coadministering an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and an effective amount of Compound 2, or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, disclosed herein is a method of inhibiting adrenal androgen secretion in a subject in need thereof comprising coadministering an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and an effective amount of Compound 3, or a pharmaceutically acceptable salt thereof, to the subject. In certain embodiments, the effective amount of the MC2 receptor antagonist, e.g. Compound 1 or a pharmaceutically acceptable salt thereof and/or the effective amount of the CRFi receptor antagonist, e.g., Compound 2 or a pharmaceutically acceptable salt thereof, or Compound 3 or a pharmaceutically acceptable salt thereof, is less than the amount of the MC2 receptor antagonist and/or the amount of the CRFi receptor antagonist that is effective for inhibiting adrenal androgen secretion when administered individually to the subject. In some embodiments, the subject is a human with CAH. In some embodiments, the androgen A4. In some embodiments, the subject is a human with PCOS. [0058] In still other aspects, disclosed herein is a method of inhibiting production of cortisol precursors in a subject in need thereof comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of a CRFi receptor antagonist to the subject. In some embodiments, disclosed herein is a method of inhibiting production of cortisol precursors in a subject in need thereof comprising coadministering an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and an effective amount of a CRFi receptor antagonist to the subject. In some embodiments, disclosed herein is a method of inhibiting production of cortisol precursors in a subject in need thereof comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of Compound 2, or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, disclosed herein is a method of inhibiting production of cortisol precursors in a subject in need thereof comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of Compound 3, or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, disclosed herein is a method of inhibiting production of cortisol precursors in a subject in need thereof comprising coadministering an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and an effective amount of Compound 2, or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, disclosed herein is a method of inhibiting production of cortisol precursors in a subject in need thereof comprising coadministering an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and an effective amount of Compound 3, or a pharmaceutically acceptable salt thereof, to the subject. In certain embodiments, the effective amount of the MC2 receptor antagonist, e.g. Compound 1 or a pharmaceutically acceptable salt thereof and/or the effective amount of the CRFi receptor antagonist, e.g., Compound 2 or a pharmaceutically acceptable salt thereof, or Compound 3 or a pharmaceutically acceptable salt thereof, is less than the amount of the MC2 receptor antagonist and/or the amount of the CRFi receptor antagonist that is effective for inhibiting production of cortisol precursors when administered individually to the subject. In some embodiments, the subject is a human with CAH. In some embodiments, the cortisol precursor is 17-OHP.

[0059] In some embodiments, disclosed herein is a method of reducing glucocorticoid dose requirements for a subject with CAH comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of a CRFi receptor antagonist to the subject. In some embodiments, disclosed herein is a method of reducing glucocorticoid dose requirements for a subject with CAH comprising coadministering an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and an effective amount of a CRFi receptor antagonist to the subject. In some embodiments, disclosed herein is a method of reducing glucocorticoid dose requirements for a subject with CAH comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of Compound 2, or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, disclosed herein is a method of reducing glucocorticoid dose requirements for a subject with CAH comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of Compound 3, or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, disclosed herein is a method of reducing glucocorticoid dose requirements for a subject with CAH comprising coadministering an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and an effective amount of Compound 2, or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, disclosed herein is a method of reducing glucocorticoid dose requirements for a subject with CAH comprising coadministering an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and an effective amount of Compound 3, or a pharmaceutically acceptable salt thereof, to the subject. In certain embodiments, the effective amount of the MC2 receptor antagonist and/or the effective amount of the CRFi receptor antagonist is less than the amount of the MC2 receptor antagonist and/or the amount of the CRFi receptor antagonist that is effective for reducing glucocorticoid dose requirements when administered individually to the subject. In some embodiments, reducing glucocorticoid dose requirements for a subject with CAH provides a steroid sparing effect. In some embodiments, the subject is a human with CAH.

[0060] In some embodiments, disclosed herein is a method of reducing or eliminating the need for administration of supraphysiologic doses of glucocorticoids to a subject with CAH comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of a CRFi receptor antagonist to the subject. As used herein, a “supraphysiologic dose of glucocorticoids” refers to a dose of glucocorticoids that is higher than physiologic replacement levels. In some embodiments, disclosed herein is a method of reducing or eliminating the need for administration of supraphysiologic doses of glucocorticoids to a subject with CAH comprising coadministering an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and an effective amount of a CRFi receptor antagonist to the subject. In some embodiments, disclosed herein is a method of reducing or eliminating the need for administration of supraphysiologic doses of glucocorticoids to a subject with CAH comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of Compound 2, or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, disclosed herein is a method of reducing or eliminating the need for administration of supraphysiologic doses of glucocorticoids to a subject with CAH comprising coadministering an effective amount of an MC2 receptor antagonist and an effective amount of Compound 3, or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, disclosed herein is a method of reducing or eliminating the need for administration of supraphysiologic doses of glucocorticoids to a subject with CAH comprising coadministering an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and an effective amount of Compound 2, or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, disclosed herein is a method of reducing or eliminating the need for administration of supraphysiologic doses of glucocorticoids to a subject with CAH comprising coadministering an effective amount of Compound 1, or a pharmaceutically acceptable salt thereof, and an effective amount of Compound 3, or a pharmaceutically acceptable salt thereof, to the subject. In certain embodiments, the effective amount of the MC2 receptor antagonist and/or the effective amount of the CRFi receptor antagonist is less than the amount of the MC2 receptor antagonist and/or the amount of the CRFi receptor antagonist that is effective for reducing or eliminating the need for administration of supraphysiologic doses of glucocorticoids to a subject with CAH when administered individually to the subject. In some embodiments, the subject is a human with CAH.

[0061] In some embodiments, coadministration of an effective amount of an MC2 receptor antagonist and an effective amount of an CRFi receptor antagonist provides additive benefit of the two therapeutic agents. In some embodiments, coadministration of an effective amount of an MC2 receptor antagonist and an effective amount of an CRFi receptor antagonist provides a synergistic benefit of the two therapeutic agents. In some embodiments, providing a synergistic benefit means that lower amounts of the MC2 receptor antagonist and/or the CRFi receptor antagonist are required to achieve the desired therapeutic benefit or effect when the agents are coadministered according to the instant disclosure versus when the agents are administered individually for the same therapeutic benefit or effect. In some embodiments, coadministration of an effective amount of an MC2 receptor antagonist and an effective amount of an CRFi receptor antagonist potentiates the activity of the MC2 receptor antagonist or the CRFi receptor antagonist, whereby the therapeutic benefit or effect of one of the active agents is enhanced by coadministration with the second active agent, but the therapeutic benefit or effect of the second active agent is not affected when coadministered with the first active agent.

[0062] In some embodiments, coadministration of an effective amount of an MC2 receptor antagonist and an effective amount of an CRFi receptor antagonist mitigates, minimizes, and/or reduces hyperpigmentation associated with the administration of MC2 receptor antagonists. In some embodiments, coadministration of an effective amount of an MC2 receptor antagonist and an effective amount of an CRFi receptor antagonist mitigates, minimizes and/or reduces enlargement of the pituitary gland associated with the administration of MC2 receptor antagonists.

Subjects

[0063] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human. In some embodiments, the human is 18 years or older. In some embodiments, the human is under 18 years old. In some embodiments, the human is 2 years old to 17 years old.

[0064] In some embodiments, the subject has a mutation in the gene encoding 21- hydroxylase, 1 ip-hydroxylase, 17a-hydroxylase, 3 P-hydroxy steroid dehydrogenase, or a combination thereof. In some embodiments, the subject has congenital lipoid adrenal hyperplasia or p450 oxidoreductase deficiency.

[0065] In some embodiments, a subject with CAH produces excess ACTH. In some embodiments, the subject has a pituitary adenoma or corticotroph adenoma. In some embodiments, the subject has an ectopic ACTH-secreting tumor.

[0066] In some embodiments, a subject with PCOS has elevated androgen levels. In some embodiments, a subject with PCOS has hyperandrogenism. In some embodiments, a subject with PCOS has functional adrenal hyperandrogenism.

Dosage and Administration

[0067] In some embodiments, the methods described herein involve coadministration of separate pharmaceutical compositions that include an effective amount of an MC2 receptor antagonist and an effective amount of a CRFi receptor antagonist to a subject. In some embodiments, the methods described herein involve administration of a single pharmaceutical composition that includes an effective amount of an MC2 receptor antagonist and an effective amount of a CRFi receptor antagonist to a subject.

[0068] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of the active agent being administered to achieve the desired result, e.g. treat the disease or condition being treated, or any other desired alteration of biological activity. The “effective amounts” or “therapeutically effective amounts” of specific MC2 receptor antagonists and CRFi receptor antagonists vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or subject in need of treatment, and are determined according to the particular circumstances surrounding the case, including, e.g., the specific compound being administered, the route of administration, the condition being treated, and the subject being treated.

[0069] In some embodiments, the MC2 receptor antagonist and the CRFi receptor antagonist are administered once a day, twice a day, three times a day, once a week, twice a week, three times a week, four times a week, five times a week, six times a week, or seven times a week. In some embodiments, daily administration is once a day. In some embodiments, daily administration is twice a day. In some embodiments, daily administration is three times a day.

[0070] In general, the desired doses of the MC2 receptor antagonist and CRFi receptor antagonist are presented in a single dose or in divided doses administered simultaneously or at appropriate intervals, for example as two, three, four or more sub-doses per day.

[0071] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount equivalent to about 5 mg to about 300 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount equivalent to about 5 mg to about 250 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount equivalent to about 10 mg to about 250 mg of Compound 1. [0072] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in amount equivalent to about: 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg,

150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, or 300 mg of Compound 1.

[0073] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount equivalent to less than about 80 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount equivalent to less than about 120 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount equivalent to less than about 160 mg of Compound 1.

[0074] In some embodiments, Compound 2, or a pharmaceutically acceptable salt thereof, is administered in an amount equivalent to about 50 mg to about 1,000 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt thereof, is administered in an amount equivalent to about 200 mg to about 1,000 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt thereof, is administered in an amount equivalent to about 200 mg to about 600 mg of Compound 2. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount equivalent to about 600 mg to about 1,000 mg of Compound 2. [0075] In some embodiments, Compound 2, or a pharmaceutically acceptable salt thereof, is administered in amount equivalent to about: 200 mg, 600 mg, or 1,000 mg, of Compound 2.

[0076] In some embodiments, Compound 2, or a pharmaceutically acceptable salt thereof, is administered in an amount equivalent to less than about 200 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt thereof, is administered in an amount equivalent to less than about 600 mg of Compound 2. In some embodiments, Compound 2, or a pharmaceutically acceptable salt thereof, is administered in an amount equivalent to less than about 1,000 mg of Compound 2.

[0077] In some embodiments, Compound 2, or a pharmaceutically acceptable salt thereof, is administered in amount equivalent to about: 50 mg/day, 100 mg/day, 150 mg/day, or 200 mg/day of Compound 2.

[0078] In some embodiments, Compound 3, or a pharmaceutically acceptable salt thereof, is administered in an amount equivalent to about 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, or 200 mg. In some embodiments, Compound 3, or a pharmaceutically acceptable salt thereof, is administered in an amount equivalent to about 50 mg to about 200 mg of Compound 3. In some embodiments, Compound 3, or a pharmaceutically acceptable salt thereof, is administered in an amount equivalent to about 50 mg/day, about 100 mg/day, about 150 mg/day or about 200 mg/day of Compound 3. In some embodiments, Compound 3, or a pharmaceutically acceptable salt thereof, is administered in an amount equivalent to about 50 mg once a day, about 100 mg once a day, or about 100 mg twice a day of Compound 3. In some embodiments, Compound 3, or a pharmaceutically acceptable salt thereof, is administered in an amount equivalent to about 25 mg twice a day, 50 mg twice a day, or 100 mg twice a day of Compound 3. In some embodiments, Compound 3, or a pharmaceutically acceptable salt thereof, is administered in an amount equivalent to about 100 mg twice a day of Compound 3.

[0079] In certain instances, an effective amount of an MC2 receptor antagonist and an effective amount of a CRFi receptor antagonist are coadministered with one or more additional therapeutic agents. In some embodiments, the MC2 receptor antagonist and the CRFI receptor antagonist are coadministered with one or more additional therapeutic agents selected from glucocorticoids, mineralocorticoids, and combinations thereof. Example glucocorticoids contemplated for coadministration include, but are not limited to, beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, ethamethasoneb, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, or the like. In some embodiments, hydrocortisone is administered in an oral modified release formulation, e.g., CHRONOCORT®. Example mineralocorticoids contemplated for coadministration include, but are not limited to, fludrocortisone and the like.

[0080] In some embodiments, the one or more additional therapeutic agents are selected from contraceptive pills, intrauterine systems, diabetes medications, e.g. metformin, medicines to control unwanted hair growth, e.g. cyproterone acetate, spironolactone, flutamide, and finasteride, weight-loss medications, e.g. orlistat, cholesterol-lowering medications, e.g. statins, and acne treatments.

[0081] The dosages of the one or more additional therapeutic agents varies depending on the on the specific drug employed, on the disease severity, and so forth. When coadministered with an MC2 receptor antagonist and a CRFi receptor antagonist, the one or more additional therapeutic agents may be administered either simultaneously or sequentially.

[0082] The dosage regimen for methods described herein may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the therapy to elicit a response in the subject. While certain embodiments described herein may not be effective in treating every subject, they provide a statistically significant treatment across a number of subjects. Pharmaceutical Compositions

[0083] In some embodiments, the MC2 receptor antagonists and the CRFi receptor antagonists are formulated in pharmaceutical compositions for administration according to the methods described herein. Pharmaceutical compositions are formulated in a manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.

[0084] In some embodiments, an effective amount of an MC2 receptor antagonist and an effective amount of a CRFi receptor antagonist are formulated in separate pharmaceutical compositions for administration according to the methods described herein. In some embodiments, an effective amount of an MC2 receptor antagonist and an effective amount of a CRFi receptor antagonist are formulated together in a single pharmaceutical composition for administration according to the methods described herein.

[0085] Pharmaceutical compositions for the administration of Compound 1 according to the methods described herein are provided in International Publication No. WO 2019/236699. Pharmaceutical compositions for the administration of Compound 2 according to the methods described herein are provided in International Publication No. WO 2019/036472.

Pharmaceutical compositions for the administration of Compound 3 according to the methods described herein are provided in International Publication No. WO 2020/115555, the entire contents of which are incorporated by reference.

Certain Terminology

[0086] Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0087] As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a sample” includes a plurality of samples, including mixtures thereof.

[0088] As used herein, the term “about” in reference to a number refers to that number plus or minus 10% of that number. The term “about” a range refers to that range minus 10% of its lowest value and plus 10% of its greatest value. [0089] The term “pharmaceutically acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0090] 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.

[0091] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

EXAMPLE

[0092] The following example is included for illustrative purposes only and is not intended to limit the scope of the invention.

Example 1: Suppression of CRF-Stimulated ACTH and Corticosterone (i.e. CORT) Production in a Preclinical Model

[0093] The following experimental protocol is used to evaluate the efficacy of MC2 receptor antagonists and CRFi receptor antagonists in reducing androgen production and treating CAH in a preclinical model. Specifically, the dose responses of Compound 1 and Compound 3 are independently evaluated to identify the pharmacologically effective doses of each compound for suppressing CRF-stimulated ACTH and corticosterone production in rats. The efficacy of combinations of MC2 receptor antagonists and CRFi receptor antagonists, i.e., Compound 1 and Compound 3, respectively, are measured using sub-maximal doses of the active agents to determine whether the combination of agents elicits a greater suppression of CRF-stimulated corticosterone production than administration of either active agent alone.

[0094] CRF-stimulated ACTH and CORT in rats. Two to four days before the start of the experiment, rats are habituated to a remote sampling chamber and the procedure room for approximately 2 hours by placing them in opaque, open-topped chambers with white noise on in the room. Food and water are removed during habituation. On the day before the start of the experiment, the habituation procedure is repeated. On the day of the experiment, 13” of PE-50 tubing line with a metal connector and silastic tubing sheath over the connection point is attached to the end of the jugular vein catheter of each animal for remote blood sampling. The open end of the PE-50 tubing is connected to a 1 mL syringe filled with heparinized saline (5 parts/mL). Rats are habituated to the procedure room in an opaque, open-topped chamber with white noise on and the remote sampling tubing hanging outside of the chamber for approximately two hours prior to the start of the CRF stimulation test. Food and water are removed during habituation and for the duration of the experiment. All intravenous infusions and blood collections are done by remote sampling via the jugular vein catheter. The CRFi receptor antagonist (10 mg/kg) or vehicle is administered by oral gavage 90 min prior to intravenous CRF (t= -90 min). The MC2R antagonist (3 mg/kg) or vehicle is administered by oral gavage 60 min prior to intravenous CRF (t= -60 min) Room temperature CRF is infused intravenously through the jugular vein catheter at t = 0 min at a dose of 10 pg/kg and a dosing volume of 1 mL/kg. Blood for measurement of ACTH (pg/mL), CORT (ng/mL), and test article exposure (300 pL) is collected via the jugular vein catheter with a 23G blunt tip 1 mL syringe at -120 min, -30 min, 20 min, 40 min, 80 min, and 120 min relative to CRF administration (see FIG. 1). Following each blood collection, 300 pL of saline is returned to the animal followed by 150 pL of heparinized saline to fill the remote sampling line. Blood is collected into K2EDTA tubes for ACTH, CORT, and test article analysis. Tubes containing the blood samples are inverted several times to mix and immediately placed on ice until processing. Blood samples are centrifuged at 4 °C at 11,000 rpm for 6 min to isolate the plasma. The plasma samples are frozen on dry ice and stored at -80 °C until analysis. Plasma concentrations of ACTH are measured using xMAP™ (Luminex) technology with the MILLIPLEX® MAP rat stress hormone magnetic bead panel kit. Plasma concentrations of corticosterone are measured using liquid chromatography-mass spectrometry (LC-MS). Plasma concentrations of test articles are also measured using LC-MS.

[0095] Results. A single oral dose of crinecerfont (10 mg/kg) suppressed CRF-stimulated production of ACTH, while a single oral dose of Compound 1 (3 mg/kg) slightly increased production of ACTH. Administration Compound 1 in combination with crinecerfont had a neutral or slightly decreased effect on ACTH levels (see FIG. 1 A). A single oral dose of Compound 1 (3 mg/kg), crinecerfont (10 mg/kg), or Compound 1 (3 mg/kg) in combination with crinecerfont (10 mg/kg) suppressed CRF-stimulated production of CORT (see FIG. IB). Crinecerfont decreased ACTH by 52% (see FIG. 2A). CORT was suppressed by 27%, 32%, and 54% by Compound 1, crinecerfont, and the combination thereof, respectively (see FIG. 2B). The combination of Compound 1 with crinecerfont showed greater suppression of CRF- stimulated production of CORT than either agent alone while simultaneously minimizing the potential effect of Compound 1 on ACTH levels (see FIG. 1 and 2).

[0096] Conclusions. MC2R antagonists can cause ACTH levels to rise. Increased ACTH levels can boost melanin production, leading to skin pigmentation, including hyperpigmentation. Additional possible complications arising from increased ACTH levels include pituitary hyperplasia or hypertrophy, which can lead to enlargement of the pituitary gland. The presently claimed invention can successfully mitigate these issues by combining a CRFi receptor antagonist with a MC2R antagonist. Further, by using a CRFi receptor antagonist in combination with a MC2R antagonist, one can minimize the dosages thereof to further minimize the occurrence of any other potential side effects associated with the active agents.

[0097] Therefore, it is advantageous for patients in need of treatment with a MC2R antagonist, such as those with CAH or PCOS, to be treated with a MC2R antagonist in combination with a CRFi receptor antagonist.

[0098] 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.