Compositions and methods for the treatment of congenital adrenal hyperplasia

Abstract

The present invention relates to compositions and methods of treating congenital adrenal hyperplasia (CAH), and hyperandrogenism in a subject with CAH, in a subject on glucocorticoid (GC) therapy comprising administering to the subject an adrenocorticotropic hormone (ACTH) antagonist; wherein the subject is > 18 years of age; wherein GC therapy comprises administering to the subject a dose of a GC; and wherein the dose of the GC is reduced following administration of the ACTH antagonist, wherein the preferred ACTH antagonist is atumelnant.

Description

Docket No. P00044-WO COMPOSITIONS AND METHODS FOR THE TREATMENT OF CONGENITAL ADRENAL HYPERPLASIACROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of U.S. Provisional Patent Application No. 63 / 777,855, filed on March 26, 2025; U.S. Provisional Patent Application No. 63 / 837,240, filed on July 2, 2025; U.S. Provisional Patent Application No. 63 / 945,219, filed on December 19, 2025; and U.S. Provisional Patent Application No. 63 / 957.146, filed on January 9, 2026; each of which is incorporated herein by reference in its entirety.FIELD

[0002] Provided herein are compositions and methods for the treatment of congenital adrenal hyperplasia (CAH).BACKGROUND

[0003] Congenital adrenal hyperplasia (CAH) is a series of rare autosomal recessive diseases of the adrenal glands due to mutations in key enzy mes involved in adrenal steroidogenesis.

[0004] The only currently available treatment for CAH in the United States is glucocorticoid therapy. However, the doses of glucocorticoids required to sufficiently suppress androgen production to effectively treat classic CAH are often higher than required for physiologic replacement. These high dosages result in the well-documented side-effect of chronic supraphysiologic glucocorticoid exposure, which is essentially an iatrogenic state of Cushing’s syndrome (CS). Thus, there is a delicate balance between under- and over-treatment as patients with CAH often suffer chronically from various degrees of hyperandrogenism caused by the disease along with the manifold complications of chronic supraphysiologic glucocorticoid therapy7used to treat the disease.

[0005] Under-replacement of glucocorticoids in CAH patients can result in low blood pressure, hyponatremia, and hyperkalemia due to absent mineralocorticoid; hypoglycemia due to decreased gluconeogenesis; reduced final adult height due to early epiphyseal closure due to increased adrenal androgens and increased bone mass; weight loss; and muscle weakness and myalgia. Over-replacement of glucocorticoids in CAH patients can result in high blood pressure, volume retention, edema, hypernatremia, and hypokalemia; hyperglycemia, hypertriglyceridemia due to increased gluconeogenesis and lipolysis; osteopenia, osteoporosis due to glucocorticoid-induced inhibition of osteoclast function, and vitamin D antagonism; increased fat mass (i. e. ,Docket No. P00044-WO adrenocortical obesity) and predominantly of centripetal distribution; and muscle atrophy and myopathy.

[0006] As described above, the consequences of under- or over-replacement of glucocorticoids have serious implications on a multitude of bodily systems, including cardiovascular, liver, bone, adipose tissue, and muscle systems. As such, there remains an unmet need for new compositions and methods useful for the treatment of CAH that circumvent the drawbacks associated with glucocorticoid therapy. The present disclosure fulfills these and other needs, evident in reference to the following disclosure.BRIEF SUMMARY

[0007] Provided is a method of treating congenital adrenal hyperplasia (CAH) in a subject on glucocorticoid (GC) therapy which includes administering to the subject an adrenocorticotropic hormone (ACTH) antagonist; wherein GC therapy includes administering to the subject a dose of a GC; and wherein the dose of the GC is reduced following administration of the ACTH antagonist

[0008] Also provided is a method of treating hyperandrogemsm in a subject with CAH on glucocorticoid (GC) therapy which includes administering to the subject an adrenocorticotropic hormone (ACTH) antagonist; wherein GC therapy includes administering to the subject a dose of a GC; and wherein the dose of the GC is reduced following administration of the ACTH antagonist.

[0009] In some embodiments, the ACTH antagonist is an insurmountable ACTH antagonist.

[0010] In some embodiments, the ACTH antagonist is atumelnant, or a pharmaceutically acceptable salt thereof.

[0011] Also provided is a method of treating congenital adrenal hyperplasia (CAH) in a subject on glucocorticoid (GC) therapy which includes administering to the subject atumelnant, or a pharmaceutically acceptable salt thereof; wherein GC therapy includes administering to the subject a dose of a GC; and wherein the dose of the GC is reduced following administration of atumelnant, or a pharmaceutically acceptable salt thereof.

[0012] Also provided is a method of treating hyperandrogenism in a subject with CAH on glucocorticoid (GC) therapy which includes administering to the subject atumelnant, or a pharmaceutically acceptable salt thereof; wherein GC therapy includes administering to the subject a dose of a GC; and wherein the dose of the GC is reduced following administration of atumelnant, or a pharmaceutically acceptable salt thereof.Docket No. P00044-WO

[0013] In some embodiments, the dose of the GC is > 11 mg / m2 / day prior to administration of atumelnant or a pharmaceutically acceptable salt thereof. In some embodiments, the dose of the GC is > 14 mg / m2 / day prior to administration of atumelnant or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the dose of the GC is reduced following administration of atumelnant, or a pharmaceutically acceptable salt thereof, via one or more reductions of the dose of the GC. In some embodiments, a reduction of the dose of the GC is donefollowing administration of atumelnant, or a pharmaceutically acceptable salt thereof, for at least 2 weeks, for at least 5 weeks, for at least 8 weeks, or for at least 12 weeks.

[0015] In some embodiments, the dose of the GC is reduced to a minimum amount to be therapeutically effective following administration of atumelnant, or a pharmaceutically acceptable salt thereof, for at least 16 weeks, for at least 28 weeks, or for at least 32 weeks.

[0016] In some embodiments, the dose of the GC is reduced to a physiologic dose following administration of atumelnant or a pharmaceutically acceptable salt thereof . In some embodiments, the physiologic dose of the GC is < 11 mg / m2 / day.

[0017] In some embodiments, the GC is selected from the group consisting of hydrocortisone, prednisolone, prednisone, and methylprednisolone.

[0018] In some embodiments, treating includes reducing the subject’s serum level of androstenedione (A4) from baseline. In some embodiments, the subject’s serum level of A4 is reduced from baseline to < upper limit of normal (ULN).

[0019] In some embodiments, the subject’s serum level of A4 is reduced by > 25% from baseline, by > 50% from baseline, or by > 75% from baseline.

[0020] In some embodiments, the subject’s serum level of A4 is reduced to < 120% of baseline.

[0021] In some embodiments, the subject’s serum level of A4 is a morning serum level of A4.

[0022] In some embodiments, treating includes reducing the subject’s serum level of 17-hydroxyprogesterone (17-OHP) from baseline. In some embodiments, the subject’s serum level of 17-OHP is reduced by > 25% from baseline, by > 50% from baseline, or by > 75% from baseline.

[0023] In some embodiments, the subject’s serum level of 17-OHP is a morning serum level of 17-OHP.

[0024] In some embodiments, treating includes reducing the subject’s serum levels of one or more of 11 -deoxycorticosterone (11-DOC), 1 ip-hydroxy androstenedione (11-OHA4), 11-Docket No. P00044-WO ketoandrostenedione (11 -ketoA4). 1 ip-hydroxytestosterone ( 11 -OHT). and 11 -ketotestosterone (11-ketoT) from baseline.

[0025] In some embodiments, treating includes reducing the subject’s serum levels of one or more of testosterone and progesterone from baseline.

[0026] In some embodiments, treating includes reducing the subject’s serum levels of one or more of cortisol and 21-deoxycortisol from baseline.

[0027] In some embodiments, treating includes reducing the subject’s serum level of one or more of renin and aldosterone from baseline.

[0028] In some embodiments, treating includes reducing the aldosterone / renin ratio from baseline.

[0029] In some embodiments, treating includes reducing the luteinizing hormone (LH) / follicle-stimulating hormone (FSH) ratio from baseline.

[0030] In some embodiments, the subject has acne. In some embodiments, the subject reports their acne has improved following administration of atumelnant, or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, treating includes reducing the subject’s adrenal gland size from baseline.

[0032] In some embodiments, treating includes reducing the subject’s waist circumference from baseline. In some embodiments, treating includes reducing the subject’s body mass index (BMI) from baseline.

[0033] In some embodiments, treating includes reducing the subject’s serum level of hemoglobin A1C (HbAlC) from baseline.

[0034] In some embodiments, treating includes reducing the subject’s blood pressure from baseline.

[0035] In some embodiments, treating includes reducing the subject’s lipid levels from baseline. In some embodiments, the lipids are selected from one or more of total cholesterol, triglycerides, high-density lipoprotein, and low-density lipoprotein.

[0036] In some embodiments, treating includes increasing the subject's bone mineral density (BMD) from baseline.Docket No. P00044-WO

[0037] In some embodiments, treating includes increasing the subject’s markers of bone resorption from baseline. In some embodiments, the markers of bone resorption are selected from N-telopeptide (NTX), C-telopeptide (CTX), and pyridinoline cross-links.

[0038] In some embodiments, treating includes increasing the subject’s markers of bone formation from baseline. In some embodiments, the markers of bone formation are selected from bone-specific alkaline phosphatase (BSAP), osteocalcin, and serum procollagen type 1 N-terminal propeptide (P1NP).

[0039] In some embodiments, treating includes decreasing bone turnover (osteocalcin) from baseline.

[0040] In some embodiments, the subject’s reproductive function improves.

[0041] In some embodiments, the subject is male. In some embodiments, treating includes reducing the subject’s serum ratio of A4 / testosterone from baseline. In some embodiments, the subject has a testicular adrenal rests tumor (TART). In some embodiments, the subject’s TART has reduced in size from baseline. In some embodiments, the subject’s sperm count improves from baseline.

[0042] In some embodiments, the subject is female. In some embodiments, the subject has hirsutism. In some embodiments, the subject reports their hirsutism has improved following administration of atumelnant, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject has menstrual dysfunction. In some embodiments, the subject reports their menstrual dysfunction has improved following administration of atumelnant, or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, the subject is female and treating includes reducing the subject’s level of progesterone from baseline. In some embodiments, the subject’s level of progesterone is sufficiently reduced to improve the subject’s fertility. In some embodiments, the subject begins menstruating normally following administration of atumelnant, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is not using contraception. In some embodiments, the contraception is selected from hormonal and an intrauterine device.

[0044] In some embodiments, atumelnant, or a pharmaceutically acceptable salt thereof, is administered as a daily dose. In some embodiments, the daily dose of atumelnant is equivalent to 80 mg of atumelnant free base. In some embodiments, the daily dose of atumelnant, or a pharmaceutically acceptable salt thereof, is increased by an amount equivalent to 40 mg of atumelnant free base. In some embodiments, the daily dose of atumelnant, or a pharmaceutically acceptable salt thereof, is equivalent to 120 mg of atumelnant free base.Docket No. P00044-WO

[0045] In some embodiments, atumelnant. or a pharmaceutically acceptable salt thereof, is administered as a single daily dose. In some embodiments, the atumelnant is a pharmaceutically acceptable salt of atumelnant. In some embodiments, the pharmaceutically acceptable salt of atumelnant is atumelnant maleate.

[0046] In some embodiments, the subject has hyperandrogenism.

[0047] In some embodiments, the subject has polycythemia. In some embodiments, treating includes resolving the subject’s polycythemia. In some embodiments, treating includes improving the subject’s polycythemia.

[0048] In some embodiments, the dose of the GC is a daily dose of GC.

[0049] In some embodiments, the subject is > 18 years of age.

[0050] Also provided is a pharmaceutical composition for use in treating a subject with congenital adrenal hyperplasia (CAH) on a physiologic dose of a glucocorticoid (GC), wherein the composition includes an adrenocorticotropic hormone (ACTH) antagonist.

[0051] Also provided is use of an adrenocorticotropic hormone (ACTH) antagonist in the manufacture of a medicament for treating a subject with congenital adrenal hyperplasia (CAH) on a physiologic dose of a glucocorticoid (GC).

[0052] Also provided is a pharmaceutical composition for use in treating a subject with congenital adrenal hyperplasia (CAH) on a physiologic dose of a glucocorticoid (GC), wherein the composition includes atumelnant, or a pharmaceutically acceptable salt thereof.

[0053] Also provided is use of atumelnant, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a subject with congenital adrenal hyperplasia (CAH) on a physiologic dose of a glucocorticoid (GC).BRIEF DESCRIPTION OF THE DRAWINGS

[0054] FIG. 1 shows the study schema.

[0055] FIG. 2 shows the inability to produce cortisol leads to loss of negative feedback and excess adrenocorticotropic hormone in those with congenital adrenal hyperplasia.

[0056] FIG. 3 shows the change From Baseline in Total Adrenal Volume Per Patient from a phase 2 study.DETAILED DESCRIPTION

[0057] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understandDocket No. P00044-WO that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the w ord “comprise"’ and variations thereof, such as “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0058] References throughout this specification to “one embodiment” or “an embodiment” or “some embodiments” or “a certain embodiment"’ means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” or “in some embodiments” or “in a certain embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0059] Also, as used in this specification and the appended claims, the singular forms "a." "an," and "the" include plural referents unless the content clearly dictates otherwise.

[0060] As used herein, “about"’ means ±10% of the stated value, and includes more specifically values of ±5%, ±2%, and ±1% of the stated value.

[0061] As used herein, “administering to a patient” refers to the process of introducing a composition or dosage form into the patient via an art-recognized means of introduction.

[0062] As used herein the term “disorder” is intended to be generally synonymous, and is used interchangeably, with the terms “disease,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, and is ty pically manifested by distinguishing signs and symptoms.

[0063] As used herein, the term “adrenocorticotropic hormone antagonist” or “ACTH antagonist” refers to an antagonist of the adrenocorticotropic hormone (ACTH) receptor that inhibits ACTH signaling, resulting in steroid hormone production inhibitory activity.

[0064] As used herein, the term “insurmountable ACTH antagonist” refers to a drug that can effectively block the effects of adrenocorticotropic hormone (ACTH) even at high ACTH concentrations.Docket No. P00044-WO

[0065] As used herein, atumelnant refers to a compound having the structure of Formula (I) shown below:Formula (I).

[0066] Atumelnant is also known as CRN04894, CRN04894 free base, A-[(3S)-1-Azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2f?)-2-ethyl-4-[l-(trifluoromethyl)cyclobutanecarbonyl]-piperazin-l-yl]pyridine-2-carboxamide (IUPAC name), A-[(3S)-l-Azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(27?)-2-ethyl-4-[l- (trifluoromethyl)cyclobutanecarbonyl]-piperazin-l-yl]pyridine-2-carboxamide free base, 6-(2-Ethoxy pheny 1 )-3-(( / ?)-2-ethy l-4-( 1 -(tri fl uoromethy 1 jcyclobutane- 1 -carbonyljpiperazin- 1 -y 1)-N-((S)-quinuclidin-3-yl)picolinamide, and 6-(2-Ethoxyphenyl)-3-((7?)-2-ethyl-4-(l- (tnfl uoromethy l)cyclobutane-l -carbonyljpiperazin- l-yl)-N-(fS')-quinuclidin-3-yl)picolinamide free base.

[0067] As used herein, a “dose” means the measured quantity of an active agent to be taken at one time by a patient. In certain embodiments, wherein the active agent is not the free base of the compound of Formula (I), the quantity is the molar equivalent to the corresponding amount of the free base of the compound of Formula (I). For example, often a drug is packaged in a pharmaceutically acceptable salt form, such as the maleate salt of the compound of Formula (I), and the dosage form strength refers to the mass of the molar equivalent of the corresponding free base. As an example, 47.56 mg of the maleate salt of the compound of Formula (I) is the molar equivalent of 40.00 mg of the free base of the compound of Formula (I).

[0068] As used herein, “effective amount” and “therapeutically effective amount” of an agent, compound, drug, or composition is an amount which is nontoxic and effective for producing some desired therapeutic effect upon administration to a subject or patient (e.g., a human subject or patient).

[0069] As used herein, “patient” or “individual” or “subject” means a mammal, including a human, for whom or which therapy is desired, and generally refers to the recipient of the therapy. In some embodiments, the subject is an adult subject (i.e., > 18 years of age).Docket No. P00044-WO

[0070] As used herein, “pharmaceutically acceptable’7refers to a material that is not biologically or otherwise undesirable, i.e., the material may be incorporated into a pharmaceutical composition to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. When the term “pharmaceutically acceptable” is used to refer to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration. “Pharmacologically active” (or simply “active”) as in a “pharmacologically active” (or “active”) derivative or analog, refers to a derivative or analog having the same type of pharmacological activity as the parent compound and approximately equivalent in degree. The term “pharmaceutically acceptable salts” include acid addition salts which are formed with suitable inorganic acids, inorganic bases, or organic bases.

[0071] As used herein, “risk” means the probability or chance of adverse reaction, injury, or other undesirable outcome arising from a medical treatment. An “acceptable risk” means a measure of the risk of harm, injury, or disease arising from a medical treatment that will be tolerated by an individual or group. Whether a risk is “acceptable” will depend upon the advantages that the individual or group perceives to be obtainable in return for taking the risk, whether they accept whatever scientific and other advice is offered about the magnitude of the risk, and numerous other factors, both political and social. An “acceptable risk” of an adverse reaction means that an individual or a group in society is willing to take or be subjected to the risk that the adverse reaction might occur since the adverse reaction is one whose probability of occurrence is small, or whose consequences are so slight, or the benefits (perceived or real) of the active agent are so great. An “unacceptable risk” of an adverse reaction means that an individual or a group in society is unwilling to take or be subjected to the risk that the adverse reaction might occur upon weighing the probability of occurrence of the adverse reaction, the consequences of the adverse reaction, and the benefits (perceived or real) of the active agent. “At risk” means in a state or condition marked by a high level of risk or susceptibility. Risk assessment consists of identifying and characterizing the nature, frequency, and severity of the risks associated with the use of a product.

[0072] As used herein, “safety” means the incidence or severity’ of adverse events associated with administration of an active agent, including adverse effects associated with patient-related factors (e.g., age, gender, ethnicity, race, target illness, abnormalities of renal or hepatic function,Docket No. P00044-WO co-morbid illnesses, genetic characteristics such as metabolic status, or environment) and active agent-related factors (e.g., dose, plasma level, duration of exposure, or concomitant medication).

[0073] As used herein, "treating" or '‘treatment’’ refers to therapeutic applications to slow or stop progression of a disorder, and / or alleviate symptoms thereof.

[0074] Methods of Treatment

[0075] Disclosed herein is a method of treating congenital adrenal hyperplasia (CAH) in a subject on glucocorticoid (GC) therapy comprising administering to the subject an adrenocorticotropic hormone (ACTH) antagonist; wherein GC therapy comprises administering to the subject a dose of a GC; and wherein the dose of the GC is reduced following administration of the ACTH antagonist.

[0076] Also disclosed herein is a method of treating hyperandrogenism in a subject with CAH on glucocorticoid (GC) therapy comprising administering to the subject an adrenocorticotropic hormone (ACTH) antagonist; wherein GC therapy comprises administering to the subject a dose of a GC; and wherein the dose of the GC is reduced following administration of the ACTH antagonist.

[0077] In certain embodiments, the GC is reduced via one or more reductions of the dose of the GC

[0078] In certain embodiments, a reduction of the dose of the GC is done following administration of the ACTH antagonist for at least 2 weeks. In certain embodiments, one or more reductions of the dose of the GC are done following administration of the ACTH antagonist for at least 5 weeks. In certain embodiments, one or more reductions of the dose of the GC are done following administration of the ACTH antagonist for at least 8 weeks. In certain embodiments, one or more reductions of the dose of the GC are done following administration of the ACTH antagonist for at least 12 weeks.

[0079] In certain embodiments, the dose of the GC is reduced to a minimum amount to be therapeutically effective following administration of the ACTH antagonist for at least 16 weeks. In certain embodiments, the dose of the GC is reduced to a minimum amount to be therapeutically effective following administration of the ACTH antagonist for at least 28 weeks. In certain embodiments, the dose of the GC is reduced to a physiologic dose following administration of the ACTH antagonist for at least 32 weeks.

[0080] In certain embodiments, the ACTH antagonist is an insurmountable ACTH antagonist.Docket No. P00044-WO

[0081] In certain embodiments, the ACTH antagonist is atumelnant, or a pharmaceutically acceptable salt thereof.

[0082] Also disclosed herein is a method of treating congenital adrenal hyperplasia (CAH) in a subject on glucocorticoid (GC) therapy comprising administering to the subject atumelnant, or a pharmaceutically acceptable salt thereof; wherein GC therapy comprises administering to the subject a dose of a GC; and wherein the dose of the GC is reduced following administration of atumelnant, or a pharmaceutically acceptable salt thereof.

[0083] Also disclosed herein is a method of treating hyperandrogenism in a subject with CAH on glucocorticoid (GC) therapy comprising administering to the subject atumelnant, or a pharmaceutically acceptable salt thereof; wherein GC therapy comprises administering to the subject a dose of a GC; and wherein the dose of the GC is reduced following administration of atumelnant, or a pharmaceutically acceptable salt thereof.

[0084] In certain embodiments, the GC is reduced via one or more GC dose reductions.

[0085] In certain embodiments, a GC dose reduction is done following administration of atumelnant, or a pharmaceutically acceptable salt thereof, for at least 2 weeks. In certain embodiments, one or more GC dose reductions are done following administration of atumelnant, or a pharmaceutically acceptable salt thereof, for at least 5 weeks. In certain embodiments, one or more GC dose reductions are done following administration of atumelnant, or a pharmaceutically acceptable salt thereof, for at least 8 w eeks. In certain embodiments, one or more GC dose reductions are done following administration of atumelnant. or a pharmaceutically acceptable salt thereof, for at least 12 weeks.

[0086] In certain embodiments, the dose of the GC is reduced to a minimum amount to be therapeutically effective following administration of atumelnant, or a pharmaceutically acceptable salt thereof, for at least 16 w eeks. In certain embodiments, the dose of the GC is reduced to a minimum amount to be therapeutically effective following administration of atumelnant, or a pharmaceutically acceptable salt thereof, for at least 28 weeks. In certain embodiments, the dose of the GC is reduced to a physiologic dose following administration of atumelnant, or a pharmaceutically acceptable salt thereof, for at least 32 weeks.

[0087] In certain embodiments, the dose of the GC is > 11 mg / m2 / day prior to administration of atumelnant, or a pharmaceutically acceptable salt thereof. In certain embodiments, the dose of the GC is > 14 mg / m2 / day prior to administration of atumelnant, or a pharmaceutically acceptable salt thereof.Docket No. P00044-WO

[0088] In certain embodiments, the dose of the GC is reduced to a physiologic dose following administration of atumelnant, or a pharmaceutically acceptable salt thereof. In certain embodiments, the physiologic dose of the GC is < 11 mg / m2 / day following administration of atumelnant, or a pharmaceutically acceptable salt thereof. In certain embodiments, the physiologic dose of the GC is > 8 mg / m2 / day following administration of atumelnant, or a pharmaceutically acceptable salt thereof. In certain embodiments, the physiologic dose of the GC is > 8 mg / m2 / day following administration of atumelnant, or a pharmaceutically acceptable salt thereof. In certain embodiments, the physiologic dose of the GC is > 8 mg / m2 / day and < 11 mg / m2 / day following administration of atumelnant, or a pharmaceutically acceptable salt thereof. In certain embodiments, the physiologic dose of the GC is > 8 mg / m2 / day and < 11 mg / m2 / day following administration of atumelnant, or a pharmaceutically acceptable salt thereof.

[0089] In certain embodiments, the dose of the GC is a daily dose of GC.

[0090] In certain embodiments, the GC is selected from the group consisting of hydrocortisone, prednisolone, prednisone, and methylprednisolone. In certain embodiments, the GC is hydrocortisone. In certain embodiments, the GC is prednisolone. In certain embodiments, the GC is prednisone. In certain embodiments, the GC is methylprednisolone.

[0091] In certain embodiments, treating comprises reducing the subject’s serum level of androstenedione (A4) from baseline. In certain embodiments, the subject’s serum level of A4 is reduced from baseline to < upper limit of normal (ULN). In certain embodiments, the subject’s serum level of A4 is reduced by > 25% from baseline. In certain embodiments, the subject’s serum level of A4 is reduced by > 50% from baseline. In certain embodiments, the subject’s serum level of A4 is reduced by > 75% from baseline.

[0092] In certain embodiments, the subject’s serum level of A4 is reduced to < 120% of baseline.

[0093] In certain embodiments, the subject’s serum level of A4 is reduced by at least 50%. at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, or at least 80% from baseline. In certain embodiments, the subject’s serum level of A4 is reduced by at least 50% from baseline. In certain embodiments, the subject’s serum level of A4 is reduced by at least 55% from baseline. In certain embodiments, the subject’s serum level of A4 is reduced by at least 60% from baseline. In certain embodiments, the subject’s serum level of A4 is reduced by at least 65% from baseline. In certain embodiments, the subject’s serum level of A4 is reduced by at least 70% from baseline. In certain embodiments, the subject’s serum level of A4 is reduced by at least 75% from baseline. In certain embodiments, the subject’s serum level of A4 is reduced by at least 80% from baseline.Docket No. P00044-WO

[0094] In certain embodiments, treating comprises reducing the subject’s serum levels of A4 by at least 65% from baseline following administration of 40 mg of atumelnant, or a free base equivalent amount of a pharmaceutically acceptable salt thereof, for at least 12 weeks. In certain embodiments, treating comprises reducing the subject’s serum levels of A4 by at least 80% from baseline following administration of 80 mg of atumelnant, or a free base equivalent amount of a pharmaceutically acceptable salt thereof, for at least 12 weeks. In certain embodiments, treating comprises reducing the subject’s serum levels of A4 by at least 82% from baseline following administration of 120 mg of atumelnant, or a free base equivalent amount of a pharmaceutically acceptable salt thereof, for at least 12 weeks.

[0095] In certain embodiments, treating comprises reducing the subject’s serum levels of A4 to <ULN following administration of 40 mg. 80 mg. or 120 mg of atumelnant, or a free base equivalent amount of a pharmaceutically acceptable salt thereof, for at least 2 weeks. In certain embodiments, treating comprises reducing the subject’s serum levels of A4 to <ULN following administration of 40 mg, 80 mg, or 120 mg of atumelnant, or a free base equivalent amount of a pharmaceutically acceptable salt thereof, for at least 12 weeks.

[0096] In certain embodiments, the subject’s serum level of A4 is a morning serum level of A4.

[0097] In certain embodiments, treating comprises reducing the subject’s serum level of 17-hydroxyprogesterone (17-OHP) from baseline. In certain embodiments, the subject’s serum level of 17-OHP is reduced by > 25% from baseline. In certain embodiments, the subject’s serum level of 17-OHP is reduced by > 50% from baseline. In certain embodiments, the subject’s serum level of 17-OHP is reduced by > 75% from baseline.

[0098] In certain embodiments, the subject’s serum level of 17-OHP is reduced by at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, or at least 85% from baseline. In certain embodiments, the subject’s serum level of 17-OHP is reduced by at least 50% from baseline. In certain embodiments, the subject’s serum level of 17-OHP is reduced by at least 55% from baseline. In certain embodiments, the subject’s serum level of 17-OHP is reduced by at least 60% from baseline. In certain embodiments, the subject’s serum level of 17-OHP is reduced by at least 65% from baseline. In certain embodiments, the subject’s serum level of 17-OHP is reduced by at least 70% from baseline. In certain embodiments, the subject’s serum level of 17-OHP is reduced by at least 75% from baseline. In certain embodiments, the subject’s serum level of 17-OHP is reduced by at least 80% from baseline. In certain embodiments, the subject’s serum level of 17-OHP is reduced by at least 85% from baseline.Docket No. P00044-WO

[0099] In certain embodiments, treating comprises reducing the subject’s serum levels of 17-OHP by at least 80% from baseline following administration of 40 mg of atumelnant, or a free base equivalent amount of a pharmaceutically acceptable salt thereof, for at least 12 weeks. In certain embodiments, treating comprises reducing the subject’s serum levels of 17-OHP by at least 85% from baseline following administration of 80 mg of atumelnant, or a free base equivalent amount of a pharmaceutically acceptable salt thereof, for at least 12 w eeks. In certain embodiments, treating comprises reducing the subject’s serum levels of 17-OHP by at least 70% from baseline following administration of 120 mg of atumelnant, or a free base equivalent amount of a pharmaceutically acceptable salt thereof, for at least 12 weeks.

[0100] In certain embodiments, the subject’s serum level of 17-OHP is a morning serum level of 17-OHP.

[0101] In certain embodiments, treating comprises reducing the subject’s serum levels of one or more of 11 -deoxycorticosterone (11-DOC), ll(3-hydroxy androstenedione (11-OHA4), 11-ketoandrostenedione (ll-ketoA4), 1 l|3-hydroxytestosterone (11-OHT), and 11 -ketotestosterone (11-ketoT) from baseline. In certain embodiments, treating comprises reducing the subject’s serum levels of 11 -deoxycorticosterone (11-DOC) from baseline. In certain embodiments, treating comprises reducing the subject’s serum levels of 1 l(3-hydroxyandrostenedione (11-OHA4) from baseline. In certain embodiments, treating comprises reducing the subject’s serum levels of 11 -ketoandrostenedione (1 l-ketoA4) from baseline. In certain embodiments, treating comprises reducing the subject’s serum levels of 1 ip-hydroxy testosterone (11-OHT) from baseline. In certain embodiments, treating comprises reducing the subject's serum levels of 11-ketotestosterone (11-ketoT) from baseline.

[0102] In certain embodiments, treating comprises reducing the subject’s serum levels of 11-OHA4 by at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, or at least 85% from baseline. In certain embodiments, treating comprises reducing the subject’s serum levels of 11-0HA4 by at least 40% from baseline. In certain embodiments, treating comprises reducing the subject's serum levels of 11-OHA4 by at least 45% from baseline. In certain embodiments, treating comprises reducing the subject’s serum levels of 11-OHA4 by at least 50% from baseline. In certain embodiments, treating comprises reducing the subject’s serum levels of 11-OHA4 by at least 55% from baseline. In certain embodiments, treating comprises reducing the subject’s serum levels of 11-OHA4 by at least 60% from baseline. In certain embodiments, treating comprises reducing the subject’s serum levels of 11-OHA4 by at least 65% from baseline. In certain embodiments, treating comprises reducing the subject’s serum levels of 11-OHA4 by at least 70% fromDocket No. P00044-WO baseline. In certain embodiments, treating comprises reducing the subject’s serum levels of 11-0HA4 by at least 75% from baseline. In certain embodiments, treating comprises reducing the subject’s serum levels of 11-0HA4 by at least 80% from baseline. In certain embodiments, treating comprises reducing the subject’s serum levels of 11-OHA4 by at least 85% from baseline.

[0103] In certain embodiments, treating comprises reducing the subject’s serum levels of 11-OHA4 by at least 45% from baseline following administration of 40 mg of atumelnant. or a free base equivalent amount of a pharmaceutically acceptable salt thereof, for at least 2 weeks. In certain embodiments, treating comprises reducing the subject’s serum levels of 11-OHA4 by at least 60% from baseline following administration of 40 mg of atumelnant, or a free base equivalent amount of a pharmaceutically acceptable salt thereof, for at least 12 weeks.

[0104] In certain embodiments, treating comprises reducing the subject’s serum levels of 11-OHA4 by at least 70% from baseline following administration of 80 mg of atumelnant. or a free base equivalent amount of a pharmaceutically acceptable salt thereof, for at least 2 weeks. In certain embodiments, treating comprises reducing the subject’s serum levels of 11-OHA4 by at least 65% from baseline following administration of 80 mg of atumelnant, or a free base equivalent amount of a pharmaceutically acceptable salt thereof, for at least 12 weeks.

[0105] In certain embodiments, treating comprises reducing the subject’s serum levels of 11-OHA4 by at least 85% from baseline following administration of 120 mg of atumelnant, or a free base equivalent amount of a pharmaceutically acceptable salt thereof, for at least 2 weeks. In certain embodiments, treating comprises reducing the subject’s serum levels of 11-OHA4 by at least 80% from baseline following administration of 120 mg of atumelnant. or a free base equivalent amount of a pharmaceutically acceptable salt thereof, for at least 12 weeks.

[0106] In certain embodiments, treating comprises reducing the subject’s serum levels of 11-ketoT by at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least 75% from baseline. In certain embodiments, treating comprises reducing the subject's serum levels of 11-ketoT by at least 40% from baseline. In certain embodiments, treating comprises reducing the subject’s serum levels of 11-ketoT by at least 45% from baseline. In certain embodiments, treating comprises reducing the subject’s serum levels of 11-ketoT by at least 50% from baseline. In certain embodiments, treating comprises reducing the subject’s serum levels of 11-ketoT by at least 55% from baseline. In certain embodiments, treating comprises reducing the subject’s serum levels of 11-ketoT by at least 60% from baseline. In certain embodiments, treating comprises reducing the subject's serum levels of 11-ketoT by at least 65% from baseline. In certain embodiments, treating comprises reducing theDocket No. P00044-WO subject's serum levels of 11-ketoT by at least 70% from baseline. In certain embodiments, treating comprises reducing the subject’s serum levels of 11-ketoT by at least 75% from baseline.

[0107] In certain embodiments, treating comprises reducing the subject’s serum levels of 11-ketoT by at least 40% from baseline following administration of 40 mg of atumelnant, or a free base equivalent amount of a pharmaceutically acceptable salt thereof, for at least 2 weeks. In certain embodiments, treating comprises reducing the subject’s serum levels of 11-ketoT by at least 55% from baseline following administration of 40 mg of atumelnant, or a free base equivalent amount of a pharmaceutically acceptable salt thereof, for at least 12 weeks.

[0108] In certain embodiments, treating comprises reducing the subject’s serum levels of 11-ketoT by at least 55% from baseline following administration of 80 mg of atumelnant, or a free base equivalent amount of a pharmaceutically acceptable salt thereof, for at least 2 weeks. In certain embodiments, treating comprises reducing the subject’s serum levels of 11-ketoT by at least 55% from baseline following administration of 80 mg of atumelnant, or a free base equivalent amount of a pharmaceutically acceptable salt thereof, for at least 12 weeks.

[0109] In certain embodiments, treating comprises reducing the subject’s serum levels of 11-ketoT by at least 75% from baseline following administration of 120 mg of atumelnant, or a free base equivalent amount of a pharmaceutically acceptable salt thereof, for at least 2 weeks. In certain embodiments, treating comprises reducing the subject’s serum levels of 11-ketoT by at least 75% from baseline following administration of 120 mg of atumelnant, or a free base equivalent amount of a pharmaceutically acceptable salt thereof, for at least 12 weeks.

[0110] In certain embodiments, treating comprises reducing the subject’s serum levels of one or more of testosterone and progesterone from baseline.[OHl] In certain embodiments, treating comprises reducing the subject’s serum level of testosterone from baseline. In certain embodiments, the subject's serum levels of testosterone are reduced by >50% from baseline. In certain embodiments, the subject’s serum levels of testosterone are reduced by >60% from baseline. In certain embodiments, the subject’s serum levels of testosterone are reduced by >70% from baseline. In certain embodiments, the subject’s serum levels of testosterone are reduced by >80% from baseline.

[0112] In certain embodiments, treating comprises reducing the subject’s serum level of progesterone from baseline.

[0113] In certain embodiments, treating comprises reducing the subject’s serum levels of one or more of cortisol and 21-deoxy cortisol from baseline. In certain embodiments, treating comprisesDocket No. P00044-WO reducing the subject’s serum levels of cortisol from baseline. In certain embodiments, treating comprises reducing the subject’s serum levels of 21 -deoxy corti sol from baseline.

[0114] In certain embodiments, treating comprises reducing the subject’s serum level of one or more of renin and aldosterone from baseline.

[0115] In certain embodiments, treating comprises reducing the aldosterone / renin ratio from baseline.

[0116] In certain embodiments, treating comprises reducing the luteinizing hormone (LH) / follicle-stimulating hormone (FSH) ratio from baseline.

[0117] In certain embodiments, the subject has acne. In certain embodiments, subject reports their acne has improved following administration of the ACTH antagonist. In certain embodiments, subject reports their acne has improved following administration of the insurmountable ACTH antagonist. In certain embodiments, subject reports their acne has improved following administration of atumelnant, or a pharmaceutically acceptable salt thereof.

[0118] In certain embodiments, the sum of the left and right adrenal gland volumes is referred to as adrenal gland size.

[0119] In certain embodiments, treating comprises reducing the subject’s adrenal gland size from baseline. In certain embodiments, treating comprises reducing the subject’s adrenal gland size from baseline following administration of the ACTH antagonist for at least 2 weeks. In certain embodiments, treating comprises reducing the subject’s adrenal gland size from baseline following administration of the insurmountable ACTH antagonist for at least 2 w eeks. In certain embodiments, treating comprises reducing the subject’s adrenal gland size from baseline following administration of atumelnant, or a pharmaceutically acceptable salt thereof, for at least 2 weeks. In certain embodiments, treating comprises reducing the subject's adrenal gland size from baseline following administration of atumelnant, or a pharmaceutically acceptable salt thereof, for at least 12 weeks.

[0120] In certain embodiments, treating comprises reducing the subject’s adrenal gland size by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or at least 75% from baseline. In certain embodiments, treating comprises reducing the subject’s adrenal gland size by at least 5% from baseline. In certain embodiments, treating comprises reducing the subject’s adrenal gland size by at least 10% from baseline. In certain embodiments, treating comprises reducing the subject’s adrenal gland size by at least 15% from baseline. In certain embodiments, treating comprises reducing the subject’s adrenal gland size by at leastDocket No. P00044-WO 20% from baseline. In certain embodiments, treating comprises reducing the subject’s adrenal gland size by at least 25% from baseline. In certain embodiments, treating comprises reducing the subject's adrenal gland size by at least 30% from baseline. In certain embodiments, treating comprises reducing the subject’s adrenal gland size by at least 35% from baseline. In certain embodiments, treating comprises reducing the subject's adrenal gland size by at least 40% from baseline. In certain embodiments, treating comprises reducing the subject’s adrenal gland size by at least 45% from baseline. In certain embodiments, treating comprises reducing the subject’s adrenal gland size by at least 50% from baseline. In certain embodiments, treating comprises reducing the subject’s adrenal gland size by at least 55% from baseline. In certain embodiments, treating comprises reducing the subject’s adrenal gland size by at least 60% from baseline. In certain embodiments, treating comprises reducing the subject’s adrenal gland size by at least 65% from baseline. In certain embodiments, treating comprises reducing the subject’s adrenal gland size by at least 70% from baseline. In certain embodiments, treating comprises reducing the subject’s adrenal gland size by at least 75% from baseline.

[0121] In certain embodiments, treating comprises reducing the subject’s waist circumference from baseline. In certain embodiments, treating comprises reducing the subject’s body mass index (BMI) from baseline.

[0122] In certain embodiments, treating comprises reducing the subject’s serum level of hemoglobin A1C (HbAlC) from baseline.

[0123] In certain embodiments, treating comprises reducing the subject’s blood pressure from baseline.

[0124] In certain embodiments, treating comprises reducing the subject’s lipid levels from baseline. In certain embodiments, the lipids are selected from one or more of total cholesterol, triglycerides, high-density lipoprotein, and low-density lipoprotein. In certain embodiments, the lipid is cholesterol. In certain embodiments, the lipid is triglycerides. In certain embodiments, the lipid is high-density lipoprotein. In certain embodiments, the lipid is low-density lipoprotein.

[0125] In certain embodiments, treating comprises increasing the subject’s bone mineral density (BMD) from baseline.

[0126] In certain embodiments, treating comprises increasing one or more of the subject’s markers of bone resorption from baseline. In certain embodiments, the markers of bone resorption are selected from N-telopeptide (NTX), C-telopeptide (CTX), and pyridinoline crosslinks. In certain embodiments, the marker of bone resorption is N-telopeptide (NTX). In certainDocket No. P00044-WO embodiments, the marker of bone resorption is C-telopeptide (CTX). In certain embodiments, the marker of bone resorption is pyridinoline cross-links.

[0127] In certain embodiments, treating comprises increasing one or more of the subject’s markers of bone formation from baseline. In certain embodiments, the markers of bone formation are selected from bone-specific alkaline phosphatase (BSAP), osteocalcin, and serum procollagen type 1 N-terminal propeptide (P1NP). In certain embodiments, the marker of bone formation is bone-specific alkaline phosphatase (BSAP). In certain embodiments, the marker of bone formation is osteocalcin. In certain embodiments, the marker of bone formation is serum procollagen type 1 N-terminal propeptide (P1NP).

[0128] In certain embodiments, treating comprises decreasing bone turnover (osteocalcin) from baseline.

[0129] In certain embodiments, the subject’s reproductive function improves.

[0130] In certain embodiments, the subject is > 18 years of age.

[0131] In certain embodiments, the subject is male. In certain embodiments, treating comprises reducing the subject’s serum ratio of A4 / testosterone from baseline. In certain embodiments, the subject has testicular adrenal rests tumor (TART). In certain embodiments, the volume of the TART is referred to as size. In certain embodiments, the subject’s TART has reduced in size from baseline. In certain embodiments, the subject’s sperm count improves from baseline.

[0132] In certain embodiments, the subject’s serum ratio of A4 / testosterone is reduced by at least 0.5, at least 1, at least 1.5, at least 2, at least 2.5, at least 3, at least 3.5, or at least 4 from baseline. In certain embodiments, the subject’s serum ratio of A4 / testosterone is reduced by at least 0.5 from baseline. In certain embodiments, the subject’s serum ratio of A4 / testosterone is reduced by at least 1 from baseline. In certain embodiments, the subject’s serum ratio of A4 / testosterone is reduced by at least 1.5 from baseline. In certain embodiments, the subject’s serum ratio of A4 / testosterone is reduced by at least 2 from baseline. In certain embodiments, the subject’s serum ratio of A4 / testosterone is reduced by at least 2.5 from baseline. In certain embodiments, the subject’s serum ratio of A4 / testosterone is reduced by at least 3 from baseline. In certain embodiments, the subject’s serum ratio of A4 / testosterone is reduced by at least 3.5 from baseline. In certain embodiments, the subject’s serum ratio of A4 / testosterone is reduced by at least 4 from baseline.

[0133] In certain embodiments, the subject’s serum ratio of A4 / testosterone is reduced by at least 3.5 from baseline following administration of 40 mg of atumelnant or a free base equivalent amount of a pharmaceutically acceptable salt thereof. In certain embodiments, the subject’sDocket No. P00044-WO serum ratio of A4 / testosterone is reduced by at least 1.5 from baseline following administration of 80 mg of atumelnant or a free base equivalent amount of a pharmaceutically acceptable salt thereof. In certain embodiments, the subject’s serum ratio of A4 / testosterone is reduced by at least 4 from baseline following administration of 120 mg of atumelnant or a free base equivalent amount of a pharmaceutically acceptable salt thereof.

[0134] In certain embodiments, the subject is female. In certain embodiments, the subject has hirsutism. In certain embodiments, the subject reports their hirsutism has improved following administration of the ACTH antagonist. In certain embodiments, the subject reports their hirsutism has improved following administration of the insurmountable ACTH antagonist. In certain embodiments, the subject reports their hirsutism has improved following administration of atumelnant, or a pharmaceutically acceptable salt thereof.

[0135] In certain embodiments, treating comprises reducing the female subject’s serum levels of testosterone from baseline. In certain embodiments, the female subject’s serum levels of testosterone are reduced by >50% from baseline. In certain embodiments, the female subject’s serum levels of testosterone are reduced by >60% from baseline. In certain embodiments, the female subject's serum levels of testosterone are reduced by >70% from baseline. In certain embodiments, the female subject's serum levels of testosterone are reduced by >80% from baseline.

[0136] In certain embodiments, the subject has menstrual dysfunction. In certain embodiments, the subject reports their menstrual dysfunction has improved following administration of the ACTH antagonist. In certain embodiments, the subject reports their menstrual dysfunction has improved following administration of the insurmountable ACTH antagonist. In certain embodiments, the subject reports their menstrual dysfunction has improved following administration of atumelnant, or a pharmaceutically acceptable salt thereof.

[0137] In certain embodiments, the subject is female and treating comprises reducing the subject’s level of progesterone from baseline. In certain embodiments, the subject’s level of progesterone is sufficiently reduced to improve the subject’s fertility. In certain embodiments, the subject begins menstruating normally following administration of the ACTH antagonist. In certain embodiments, the subject begins menstruating normally following administration of the insurmountable ACTH antagonist. In certain embodiments, the subject begins menstruating normally following administration of atumelnant, or a pharmaceutically acceptable salt thereof.

[0138] In certain embodiments, the subject is not using contraception. In certain embodiments, the contraception is selected from hormonal and an intrauterine device. In certain embodiments,Docket No. P00044-WO the contraception is hormonal. In certain embodiments, the contraception is an intrautenne device.

[0139] In certain embodiments, the atumelnant, or a pharmaceutically acceptable salt thereof, is administered as a daily dose. In certain embodiments, the daily dose of atumelnant, or a pharmaceutically acceptable salt thereof, is equivalent to 80 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant, or a pharmaceutically acceptable salt thereof, is increased by an amount equivalent to 40 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant, or a pharmaceutically acceptable salt thereof, is equivalent to 120 mg of atumelnant free base. In certain embodiments, atumelnant, or a pharmaceutically acceptable salt thereof, is administered as a single daily dose.

[0140] In certain embodiments, the pharmaceutically acceptable salt of atumelnant is atumelnant maleate.

[0141] In certain embodiments, the subject has hyperandrogenism.

[0142] In certain embodiments, the subject has polycythemia. In certain embodiments, treating comprises resolving the subject's polycythemia. In certain embodiments, treating comprises improving the subject’s polycythemia.

[0143] In certain embodiments, the CAH is caused by 21 -hydroxylase deficiency.

[0144] In certain embodiments, the subject is concurrently on mineralocorticoid replacement therapy. In certain embodiments, the subject is concurrently on fludrocortisone therapy.

[0145] In certain embodiments, the subject is a human. In certain embodiments, the human is an adult.

[0146] Provided is a pharmaceutical composition for use in treating a subject with congenital adrenal hyperplasia (CAH) on a physiologic dose of a glucocorticoid (GC), wherein the composition comprises an adrenocorticotropic hormone (ACTH) antagonist, and at least one pharmaceutically acceptable carrier or excipient.

[0147] Also provided is a pharmaceutical composition for use in treating a subject with congenital adrenal hyperplasia (CAH) on a physiologic dose of a glucocorticoid (GC), wherein the composition comprises atumelnant, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.

[0148] In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration. In someDocket No. P00044-WO embodiments, the pharmaceutical composition is formulated for administration to a mammal by oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, or a capsule.

[0149] In certain embodiments, the patient reports a change from baseline in their Congenital Adrenal Hyperplasia Symptom and Impact Survey (CAHS1S). In certain embodiments, the patient reports a reduction from baseline in their CAHSIS. In certain embodiments, the patient reports a reduction from baseline for one or more of fatigue, concentration, pain (e.g. muscle or joint pain), acne, unwanted hair growth, headaches, dizziness, nausea, low mood / sadness, worry / anxiety, and irritability. In certain embodiments, the patient further reports a reduction from baseline in vomiting. In certain embodiments, the patient further reports a reduction from baseline for one or more of avoiding an activity, being unable to finish an activity, accomplishing less than wanted, or interference in participating in social activities

[0150] In certain embodiments, the patient reports a reduction from baseline for fatigue. In certain embodiments, the reduction from baseline for fatigue is an integer selected from 0-10. In certain embodiments, the reduction from baseline for fatigue is an integer selected from 0, 1.2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0151] In certain embodiments, the patient reports a reduction from baseline for concentration. In certain embodiments, the reduction from baseline for concentration is an integer selected from 0-10. In certain embodiments, the reduction from baseline for concentration is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0152] In certain embodiments, the patient reports a reduction from baseline for pain. In certain embodiments, the reduction from baseline for pain is an integer selected from 0-10. In certain embodiments, the reduction from baseline for pain is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0153] In certain embodiments, the patient reports a reduction from baseline for acne. In certain embodiments, the patient reports a reduction from baseline for acne severity. In certain embodiments, the reduction from baseline for acne severity is an integer selected from 0-10. In certain embodiments, the reduction from baseline for acne severity is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, the patient reports a reduction from baseline for acne bothersomeness. In certain embodiments, the reduction from baseline for acne bothersomeness is an integer selected from 0-10. In certain embodiments, the reduction from baseline for acne bothersomeness is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.Docket No. P00044-WO

[0154] In certain embodiments, the patient reports a reduction from baseline for unwanted hair growth. In certain embodiments, the patient reports a reduction from baseline for the amount of unwanted hair grow th. In certain embodiments, the reduction from baseline for the amount of unw anted hair growth is an integer selected from 0-10. In certain embodiments, the reduction from baseline for the amount of unwanted hair growth is an integer selected from 0, 1, 2. 3, 4, 5, 6, 7, 8, 9, and 10. In certain embodiments, the patient reports a reduction from baseline for unw anted hair growth bothersomeness. In certain embodiments, the reduction from baseline for unw anted hair growth bothersomeness is an integer selected from 0-10. In certain embodiments, the reduction from baseline for unwanted hair growth bothersomeness is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0155] In certain embodiments, the patient reports a reduction from baseline for headaches. In certain embodiments, the reduction from baseline for headaches is an integer selected from 0-10. In certain embodiments, the reduction from baseline for headaches is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0156] In certain embodiments, the patient reports a reduction from baseline for dizziness. In certain embodiments, the reduction from baseline for dizziness is an integer selected from 0-10. In certain embodiments, the reduction from baseline for dizziness is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0157] In certain embodiments, the patient reports a reduction from baseline for nausea. In certain embodiments, the reduction from baseline for nausea is an integer selected from 0-10. In certain embodiments, the reduction from baseline for nausea is an integer selected from 0, 1, 2, 3. 4, 5, 6, 7, 8, 9, and 10.

[0158] In certain embodiments, the patient reports a reduction from baseline for low mood / sadness. In certain embodiments, the reduction from baseline for low mood / sadness is an integer selected from 0-10. In certain embodiments, the reduction from baseline for low mood / sadness is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0159] In certain embodiments, the patient reports a reduction from baseline for worry / anxiety. In certain embodiments, the reduction from baseline for worry / anxiety is an integer selected from 0-10. In certain embodiments, the reduction from baseline for worry / anxiety is an integer selected from 0, 1, 2. 3, 4, 5, 6, 7, 8, 9. and 10.

[0160] In certain embodiments, the patient reports a reduction from baseline for irritability. In certain embodiments, the reduction from baseline for irritability is an integer selected from 0-10.Docket No. P00044-WO In certain embodiments, the reduction from baseline for irritability is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

[0161] In certain embodiments, the patient further reports a reduction from baseline for vomiting. In certain embodiments, the reduction from baseline for vomiting is an integer selected from 0-99. In certain embodiments, the reduction from baseline for nausea is an integer selected from 0, 1, 2, 3, 4. 5, 6, 7, 8, 9, and 10.

[0162] In certain embodiments, the patient further reports a reduction from baseline in avoiding an activity. In certain embodiments, the baseline is all of the time and the reduction from baseline is to most of the time, some of the time, a little of the time, or none of the time. In certain embodiments, the baseline is most of the time and the reduction from baseline is to some of the time, a little of the time, or none of the time. In certain embodiments, the baseline is some of the time and the reduction from baseline is to a little of the time, or none of the time. In certain embodiments, the baseline is a little of the time and the reduction from baseline is to none of the time.

[0163] In certain embodiments, the patient further reports a reduction from baseline in being unable to finish an activity. In certain embodiments, the baseline is all of the time and the reduction from baseline is to most of the time, some of the time, a little of the time, or none of the time. In certain embodiments, the baseline is most of the time and the reduction from baseline is to some of the time, a little of the time, or none of the time. In certain embodiments, the baseline is some of the time and the reduction from baseline is to a little of the time, or none of the time. In certain embodiments, the baseline is a little of the time and the reduction from baseline is to none of the time.

[0164] In certain embodiments, the patient further reports a reduction in accomplishing less than wanted. In certain embodiments, the baseline is all of the time and the reduction from baseline is to most of the time, some of the time, a little of the time, or none of the time. In certain embodiments, the baseline is most of the time and the reduction from baseline is to some of the time, a little of the time, or none of the time. In certain embodiments, the baseline is some of the time and the reduction from baseline is to a little of the time, or none of the time. In certain embodiments, the baseline is a little of the time and the reduction from baseline is to none of the time.

[0165] In certain embodiments, the patient further reports a reduction of interference in participating in social activities. In certain embodiments, the baseline is all of the time and the reduction from baseline is to most of the time, some of the time, a little of the time, or none of the time. In certain embodiments, the baseline is most of the time and the reduction fromDocket No. P00044-WO baseline is to some of the time, a little of the time, or none of the time. In certain embodiments, the baseline is some of the time and the reduction from baseline is to a little of the time, or none of the time. In certain embodiments, the baseline is a little of the time and the reduction from baseline is to none of the time.

[0166] Congenital Adrenal Hyperplasia (CAH)

[0167] Congenital adrenal hyperplasia (CAH) is a series of rare autosomal recessive diseases of the adrenal glands due to mutations in key enzymes involved in adrenal steroidogenesis. The most common cause of CAH is 21 -hydroxylase deficiency (21-OHD), accounting for over 90% of cases of CAH. This '‘classic form” of CAH is due to complete loss of 21 -OH activity and has a worldwide incidence ranging from ~1 : 14,000 to 1 : 18,000.

[0168] The diagnosis of classic 21 -OH deficiency is based on elevated levels of the immediate enzyme substrate 17-hydroxy progesterone (17-OHP). Screening is routinely performed in newborn screening programs by measuring 17-OHP. An elevated level is sensitive for CAH, but falsely high 17-OHP levels can occur in premature, sick, and stressed infants. Second-tier screening can confirm elevated levels seen on the newborn screen. In cases where the data are equivocal, a stimulation test demonstrating an exaggerated rise in 17-OHP in response to an exogenous dose of ACTH may be required.

[0169] Classic CAH due to 2-OHD deficiency results in a lack of cortisol and aldosterone production, which can cause salt-wasting adrenal crises in the neonate and life-long adrenal insufficiency. In the absence of cortisol, the hypothalamus and pituitary gland are not subject to negative feedback, resulting in elevated adrenocorticotropic hormone (ACTH) levels, which in turn drives excess adrenal androgen production. This excess ACTH acts on the adrenal glands resulting in bilateral adrenal hyperplasia and, due to 21 -OH deficiency, elevated steroid precursors, such as androstenedione (A4), which can cause clinical hyperandrogenism.

[0170] In females, hyperandrogenism can result in hirsutism, acne, male-pattern baldness, menstrual irregularities, oligomenorrhea or amenorrhea, infertility, short stature, and frank virilization, manifesting in the newborn as ‘intersex.’

[0171] Poorly controlled childhood CAH results in short stature. Childhood hyperandrogenism in boys results in premature puberty / adrenarche with resultant premature fusion of the epiphyses. In men, hyperandrogenism can suppress gonadotropin secretion, resulting in reduced testes size, reduced testicular testosterone secretion, and spermatogenesis. Furthermore, chronic ACTH stimulation may also contribute to the formation of testicular adrenal rest tumors (TART) in men, which can be confused with malignant testicular tumors, and cause irreversible testicularDocket No. P00044-WO damage and potential infertility. There are no therapies to prevent the development of TART other than intensified glucocorticoid treatment.

[0172] In adult males, hyperandrogenism disrupts the hypothalamic-pituitary-gonadal (HPG) axis, resulting in impaired spermatogenesis, abnormal A4 / testosterone (A4:T) ratios, and TARTs (even in the presence of normal serum testosterone levels).

[0173] Current treatment of CAH centers on replacing deficient adrenal hormones (i.e., cortisol and aldosterone) and suppressing excess androgen production. Given that there are no other approved nonhormonal medications for CAH in the United States (US), glucocorticoid therapy- must not only serve to replace the deficiency, but also provide feedback inhibition at the pituitary to decrease ACTH secretion and thereby reduce adrenal androgen production.

[0174] Atumelnant

[0175] Atumelnant, i.e. the compound of Formula (I), is an oral, first-in-class adrenocorticotropic hormone (ACTH) receptor antagonist that binds to the melanocortin 2 receptor (MC2R) to block ACTH-mediated steroidogenesis from the adrenal gland. The structure of the compound of Formula (I) is shown below:Formula (I).

[0176] ACTH is a 39-amino acid peptide synthesized by anterior pituitary corticotropic cells and is secreted in response to hypothalamic corti cotrophin releasing hormone (CRH) and stressful stimuli. As part of the hypothalamic-pituitary-adrenal (HP A) axis, ACTH activates the melanocortin 2 receptor (MC2R) on the adrenal gland. MC2R is expressed on the adrenal cortex and requires the MC2R accessory protein (MRAP) for both surface expression and binding to ACTH. Binding of ACTH to the MC2R / MRAP complex on adrenal cortical cells activates its G-protein (Gs) to elevate intracellular cyclic adenosine monophosphate (cAMP) levels, which in turn stimulate cortisol synthesis and secretion by regulating multiple steps in the steroidogenic pathway.

[0177] By acting selectively at MC2R, atumelnant is a potential novel treatment for diseases that are characterized by ACTH-mediated pathological elevations of adrenal steroid hormones. ThisDocket No. P00044-WO predicted ability to suppress adrenally derived androgens while maintaining mineralocorticoid production (due to lack of activity on angiotensin type 2 [AT II] receptor) makes atumelnant a novel treatment option for CAH.

[0178] In conjunction, atumelnant may also be an effective treatment for hyperandrogenism observed in CAH subjects, and may result in improvement in the associated problems, such as acne; hirsutism and menstrual dysfunction in women; and TART in men.

[0179] Atumelnant, including the synthesis thereof, is disclosed in U.S. Patent No. 11,566,015, the entire contents of which is incorporated by reference.EXAMPLES

[0180] Example 1: An approximately 42-week phase 3 randomized, double-blind, multicenter, placebo-controlled study to evaluate the safety and efficacy of atumelnant in approximately 150 adult participants with classic congenital adrenal hyperplasia.

[0181] FIG. 1 shows the study schema, wherein A4=androstenedione, EOS=end of study, EOT=end of treatment, GC=glucocorticoid, GCR=glucocorticoid reduction, OLE=open-label extension, and R=randomization. Screening visits should occur 2 weeks (±3 days) apart and the second Screening Visit should occur at least 1 week prior to Day 1.

[0182] Definitions and Abbreviations

[0183] 11 -DOC= 11 -deoxycorticosterone;

[0184] 1 l-ketoA4=ll -ketoandrostenedione;

[0185] 1 l-ketoT= 11 -ketotestosterone;

[0186] 1 l-0HA4=l ip-hydroxyandrostenedione;

[0187] 11 -OHT= 1 ip-hy dr oxy testosterone;

[0188] 17-OHP=17-hydroxyprogesterone;

[0189] 25-OH=25-hydroxy;

[0190] A4=androstenedione;

[0191] ACTH=adrenocorticotropic hormone;

[0192] AE=adverse event;

[0193] BMD=bone mineral density;

[0194] BMI=body mass index;

[0195] BSA=body surface area;Docket No. P00044-WO

[0196] BSAP=bone-specific alkaline phosphatase;

[0197] CAH=congenital adrenal hyperplasia;

[0198] CTX=C-telopeptide;

[0199] DXA=dual energy X-ray absorptiometry;

[0200] ECG=electrocardiogram;

[0201] FSH=follicle-stimulating hormone;

[0202] GC=glucocorticoid;

[0203] HDL=high-density lipoprotein;

[0204] LDL=low-density lipoprotein;

[0205] LH=luteinizing hormone;

[0206] NTX=N-telopeptide;

[0207] PlNP=procollagen type 1 N-terminal propeptide;

[0208] SAE=serious adverse event;

[0209] TART=testicular adrenal rest tumor;

[0210] TEAE=treatment-emergent adverse event;

[0211] ULN=upper limit of normal.

[0212] Objectives and Endpoints

[0213] The primary efficacy objective of the study is to evaluate the efficacy of atumelnant, compared with placebo, in reducing daily GC dosage while maintaining adrenal androgen control at the end of the 32-week treatment period, with the pri mary efficacy endpoint being the proportion of participants with morning post-GC A4 <ULN who are on physiologic GC replacement at week 32.

[0214] A secondary' efficacy objective is to evaluate efficacy of atumelnant, compared with placebo, in reducing adrenal steroid levels and other CAH disease burden at week 2, with a secondary efficacy objective being percent change from baseline of morning 17-OHP at week 32.

[0215] An additional secondary efficacy objective is to evaluate efficacy of atumelnant, compared with placebo, in reducing daily GC dosage while maintaining adrenal androgen control at the end of the 32-week treatment period, with an additional secondary' efficacyDocket No. P00044-WO endpoint being the proportion of participants with morning pre-GC A4 <ULN who are on physiologic GC replacement at week 32.

[0216] Another secondary efficacy objective is the percent change from baseline in GC daily dose when morning post-GC A4 <ULN at week 32.

[0217] An additional secondary objective is to evaluate efficacy of atumelnant, compared with placebo, in reducing daily GC dosage while maintaining adrenal androgen control at the end of the 32-week treatment period and reducing adrenal androgens over time, with an additional secondary endpoint being proportion of participants with physiologic GC replacement at week 32 while morning serum post-GC A4 <120% of baseline or <ULN. Another secondary endpoint is proportion of participants with >25%, >50%, and >75% reduction in morning serum A4 over time. Another secondary endpoint is proportion of participants with physiologic GC replacement while morning serum post-GC A4 <ULN over time. An additional secondary endpoint is time-to-first normalization of morning serum post-GC A4 while on physiologic GC replacement. Another secondary endpoint is proportion of participants with >25%, >50%, and >75% reduction in morning serum 17-OHP over time. An additional secondary endpoint is change and percent change from baseline in morning 17-OHP, ACTH, testosterone, cortisol, A4, 11-DOC. progesterone, 21 -deoxy cortisol, 11-0HA4, H-ketoA4, 11-OHT, and 11-ketoT over time. Another secondary endpoint is change and percent change from baseline in morning A4 / testosterone ratio over time (in male participants only). An additional secondary endpoint is change from baseline in renin, aldosterone, and aldosterone / renin ratio over time. Another secondary endpoint is change from baseline in serum LH / FSH ratio over time.

[0218] An additional secondary objective is to measure the pharmacokinetics of atumelnant, with another secondary endpoint is plasma and / or blood concentrations of atumelnant.

[0219] An additional secondary objective is to evaluate the impact of atumelnant on the clinical signs, symptoms, co-morbidities, and outcomes of CAH. Additional secondary endpoints are changes from baseline in hirsutism (female participants only) and acne (both male and female participants) over time. An additional secondary7endpoint is change from baseline in menstrual regularity at week 32 in premenopausal female participants not using hormonal or intrauterine device contraception. Another secondary endpoint is change from baseline in BMI over time. An additional secondary endpoint is change from baseline in waist circumference overtime. Another secondary7endpoint is change from baseline in blood pressure over time. An additional secondary7endpoint is change from baseline in glucose tolerance over time. Another secondary endpoint is change from baseline in lipids (total cholesterol, triglycerides, LDL, HDL) over time. Additional secondary7endpoints are changes from baseline in BMD (DXA) and markers of boneDocket No. P00044-WO resorption (NTX. CTX, and pyridinoline cross-links), bone formation (BSAP, osteocalcin, and serum P1NP), and bone turnover (osteocalcin) overtime. Another secondary endpoint is overall participant satisfaction (all participants) at week 32. Another secondary endpoint is change from baseline in CAHSIS over time.

[0220] An additional objective is to evaluate efficacy of atumelnant compared with placebo in reducing other CAH disease burden at the end of the 32 week treatment period, with an additional exploratory endpoint being percent change from baseline in TART size at week 32 in male participants only. An additional exploratory endpoint is change from baseline in participant-reported outcomes ( PGI-S / C, CAHQL, SF-36, BDI-II, EQ-5D) over time and at week 32.

[0221] An additional exploratory endpoint is evaluating the effect of atumelnant on semen quality by assessing the change from baseline over time for: semen volume, sperm concentration, motility, morphology; and total motile sperm count (TMSC): semen volume (mL) x total sperm concentration (xlO6 / mL) x percent mobile sperm.

[0222] An additional exploratory endpoint is assessing changes in reproductive hormones from baseline over time for estrone, estradiol, inhibin B, LH, testosterone, and A4:T ratio.

[0223] An additional exploratory endpoint is evaluating TART volume via testicular ultrasound by a central radiologist.

[0224] Interventional Model

[0225] The interventional model is a parallel group. The study intervention assignment method is 2: 1 randomization following screening. The study participants are adults with Classic CAH. The patients are >18 to <75 years of age at the time of signing the ICF.

[0226] The two treatment groups are presented in the following matrix:Arm: Intervention Type Target Enrollment 80 mgaonce daily with option fordose escalation to 120 mgaonce atumelnant maleate 100dailyPlacebo control 50“Free-base equivalent

[0227] Description of Study Periods

[0228] The study will consist of the following 2 or 3 periods over a total of approximately 42 weeks: Screening Period (up to 6 weeks). Treatment Period (32 weeks). Follow-up period (4Docket No. P00044-WO weeks) if not continuing to the OLE study. The screening period is up to 6 weeks. Participants must be compliant and on stable GO regimen for at least 3 months prior to Screening.

[0229] Treatment Period: Weeks 1 to 32

[0230] The treatment period consists of an initial GC stable period (Day 1 to Week 2), followed by a GC Reduction Period I (Week 2 to Week 12), atumelnant / GC fixed-dose period (Week 12 to Week 16), atumelnant / placebo dose escalation / GC Reduction Period II (Week 16 to Week 28), and atumelnant / GC fixed-dose period (Week 28 to Week 32). Participants will be randomly assigned in a 2: 1 ratio (stratified by baseline A4 levels and GC dose) to receive atumelnant 80 mg once daily in the evening or placebo. Blood and urine samples will be collected at specified timepoints to assess PK, PD, and safety. All PD samples should be drawn prior to and after the morning dose of GC replacement except for visits in which only a single PD sample is required, which should be collected 2-3 hours after their morning GC dose but prior to 11:00 am.

[0231] Follow-Up Period: Weeks 32 to 36

[0232] If eligible, participants who have completed Week 32 (EOT) may be offered participation in a separate long-term OLE study. If the long-term extension study is opened at the investigative site and participants sign informed consent for the long-term extension study, the Follow-Up Visit and the EOS Visit will not be conducted, as treatment on atumelnant will not be interrupted. Participants who do not continue to the OLE study or are not deemed eligible for it will continue to be monitored during a 4-week follow-up concluding with the EOS Visit.

[0233] Key Inclusion Criteria

[0234] Participants are male or female, between >18 to <75 years of age at the time of signing the ICF. Participants are willing and able to understand and adhere to the study procedures as specified in the protocol and comply with the study treatment. Participants have classic CAH due to 21-OHD confirmed by the Investigator and approved by the Medical Monitor.

[0235] Participants with screening levels of pre-GC levels of morning serum A4 as follows: A4 >ULN and treated with <11 mg / m2 / day (physiologic) GC doses; or normal A4 >0.5xULN to 1 * ULN) and treated with >14 mg / m2 / day GC doses; or A4 >ULN and treated with >11 mg / m2 / day GC doses.

[0236] Participants who fail screening based on findings the investigator believes are temporary and not reflective of the usual state of the participant can be considered for rescreening. These cases should be discussed with the medical monitor. On a stable (defined as no dose change of >5 mg / day hydrocortisone equivalent within 3 months prior to screening) regimen of GCDocket No. P00044-WO replacement (e.g., hydrocortisone, prednisolone, prednisone, methylprednisolone, dexamethasone, cortisone acetate) at the time of informed consent.

[0237] If treated with mineralocorticoids (fludrocortisone), the dose should be stable for at least 1 month prior to Screening with an upright plasma renin activity (PRA) during screening that is not greater than ULN on the participant’s usual sodium intake. If PRA is >ULN, the participant must have systolic blood pressure > 100 mmHg, without orthostatic hypotension and with serum sodium and potassium in the normal range.. If on estrogen therapy (any route), the dose must be stable for at least 3 months prior to Screening.

[0238] Key Exclusion Criteria

[0239] Subjects with a diagnosis of any form of CAH other than classic 21-OHD are excluded.

[0240] Subjects treated with other GC formulations as defined by the following: unstable doses of inhaled GCs, and / or injectable or oral betamethasone or triamcinolone use within 30 days of first screening visit are excluded.

[0241] Subjects with ahistory of bilateral adrenalectomy, hypopituitarism, or other condition requiring chronic GC therapy are excluded.

[0242] Subjects with clinically significant medical condition or abnormal laboratory tests, as judged by the investigator, other than CAH are excluded.

[0243] Subjects with a history of major surgery / surgical therapy for any cause within 30 days prior to first screening visit are excluded.

[0244] Subjects with ahistory of diabetes mellitus treated with insulin for less than 6 weeks prior to screening, or with change in total daily insulin dose by >30% within 6 weeks prior to screening are excluded.

[0245] Subjects with poorly controlled diabetes mellitus defined as having an HbAlc >8.5% (>69 mmol / mL), or estimated HbAlc based on fructosamine if HbAlc is not evaluable (e.g., due to hemoglobinopathies) are excluded.

[0246] Subjects with hypothyroidism who are not receiving adequate hormone replacement therapy based on thyroid hormone levels measured at the time of screening, as determined by the investigator, are excluded.

[0247] Subjects with ahistory of unstable angina or acute myocardial infarction within 12 weeks prior to screening or other clinically significant cardiac disease at the time of screening as judged by the investigator are excluded.Docket No. P00044-WO

[0248] Subjects with concomitant mental condition rendering him / her unable to understand the nature, scope, and possible consequences of the study, and / or evidence of poor compliance with medical instructions are excluded.

[0249] Subjects with ahistory of cancer excluding cured / treated dermal squamous or basal cell carcinoma or cervical carcinoma in situ are excluded.

[0250] Women who are pregnant or lactating or, if of childbearing potential, who are unwilling to use highly effective contraception as described in this study are excluded.

[0251] Male participants who are unwilling to use highly effective contraception as described in this study are excluded.

[0252] Subjects with a known history of illicit drug or alcohol abuse within the last year are excluded.

[0253] Subjects with use of antiandrogen therapy in the past 3 months (e.g., spironolactone, finasteride, cyproterone acetate, flutamide) are excluded.

[0254] Subjects with use of medications that are strong inducers of CYP3A4 within 30 days prior to day 1 of the study are excluded. These include but are not limited to apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, or St. John’s wort. Subjects with use of medications (all routes of administration; i.e., oral, topical, and inhaled) or ingestion of food (e g., grapefruit juice) that are strong or moderate inhibitors of CYP3A4 within 7 days prior to day 1 of the study are excluded. Examples include but are not limited to protease inhibitors and NNRTIs for HIV or HCV, antifungals (e.g., ketoconazole), some antibiotics(e.g., ciprofloxacin) and calcium channel blockers (e.g., diltiazem), and antidepressants (e.g., fluvoxamine).

[0255] Subjects with use of medications that are strong or moderate inducers of P-gp within 30days prior to day 1 of the study are excluded. These include but are not limited to apalutamide, carbamazepine, fosphenytoin, lorlatinib. phenytoin, rifampicin, or St. John's wort.

[0256] Subjects with use of medications that are strong or moderate inhibitors of P-gp within 14 days prior to day 1 of the study are excluded. These include but are not limited to amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, lapatinib, protease inhibitors and NNRTIs for HIV or HCV (lopinavir and ritonavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir), or verapamil, propafenone, quinidine, or ranolazine.Docket No. P00044-WO

[0257] Subjects with use of P-gp substrates, such as digoxin, edoxaban, fexofenadine, and dabigatran extexilate are excluded, as they may be subject to enhanced absorption and increased exposure when given concomitantly with atumelnant. Subjects with use of any investigational drug within the past 60 days or 5 half-lives (whichever is longer) prior to the first dose; or plan to use an investigational drug in another study are excluded.

[0258] Subjects with average (of 3 ECGs) QTcF interval >450 msec (men) or >470 msec (women), PR interval >220 msec, QRS interval >120 msec, second- or third-degree atrioventricular block, left bundle branch block, or hemiblock at Screening are excluded.Subjects with renal insufficiency as measured by eGFR rate using the CKD-EPI formula <40 mL / min / 1.73m2are excluded.

[0259] Subjects with significant liver disease or ALT and / or AST >3xULN, and / or TBil >1.5xULN during screening are excluded.

[0260] Subjects with previously diagnosed Gilbert’s syndrome not accompanied by other hepatobiliary disorders and associated with TBil <3.5 mg / dL (<51.3 pmol / L) will be permitted.

[0261] Subjects with known history of, or concern for, risk of hypersensitivity reaction to atumelnant or any of its excipients are excluded.

[0262] Subjects who are committed to an institution by virtue of an order issued either by the judicial or administrative authorities are excluded.

[0263] Subjects with an increased risk of developing adrenal insufficiency as judged by the investigator are excluded.

[0264] Subjects with use of oral betamethasone or budesonide within 30 days of screening are excluded.

[0265] Subjects with severe erythrocytosis as judged by the Investigator are excluded.

[0266] Use of atumelnant prior to screening.

[0267] Study Participant Prohibitions

[0268] Meals and Dietary Restrictions: Participants are to refrain from consumption of Seville oranges, grapefruit and grapefruit hybrids, pomelos, sour citrus fruits (such as citron, kaffir limes, and Buddha’s hand), food preparations that contain more than 200 g of these fruits, or more than 8 ounces of juices containing these fruits, starting 7 days before the first dose of atumelnant until after the final dose.

[0269] Schedule of EventsDocket No. P00044-WO

[0270] Disclosed in the table below is the schedule of activities. A dashindicates the activity is not necessary on at the indicated time.Treatment Period FollowScreening Period up Period 32b / 36b / DayStudy Week -6 to -la2b5b8b12b16b20b24b28bEO 34 EO 1bT SStudy Window- (± (± (±3 (±3 (±3)- (±3) (±3) (±3) (±3) (±4) (±4) (days) 3) 3) ) )Onsite Visit* X X X X - X - X X - X X X - Phone VisiC - - - - X - X - - X - - - X Informed consent X - Medical history X - Full physicalexamination,height, bodyweight, BM1, X - X - X - BSA, waistcircumference,and vital signsSymptom- directed physicalexamination,weight, BMI, - - - X - X - X X - X X - - BSA, waistcircumference,and vital signsDrug screens X - ECG (triplicate) X - X X - X - - X - X X X - AE review X X X X X X X X X X X X X X Review of prior orconcomitant X X X X X X X X X X X X X X medicationsReview oflifestyle - X X X X X X X X X X X X - considerationsAdrenalinsufficiency- - X X - X - X X - X - - - awarenesstrainingAdrenalinsufficiency X X X X X X X X X X X X X XassessmentsDocket No. P00044-WO Treatment Period FollowScreeninup g PeriodPeriod 32bZ 36bZ DayStudy Week -6 to -la2b5b8b12b16b20b24b28bEO 34bEO 1T SStudy Window (±3 (±3 (±3)- - (± (± (±3) (±3) (±3) (±3) (±4) (±4) (days) 3) 3) ) )Onsite Visit* X X X X - X - X X - X X X - Phone VisiP - - - - X - X - - X - - - X Study drug- - X - - X - X X - X - - - dispensing*5Study drug dose- - - - - - - - X - - - - - escalationStudy drug- - - X - X - X X - X X - - accountabilityProvideparticipants withinstructions forAtumelnantDosing Diary,X - GlucocorticoidAdministrationDiary, andMenstrual CycleDiaryfGlucocorticoid- - - X - - nsXsX csX dsX isX esX tsX - r u osGlucocorticoidAdministration - X X X X X X X X X X X X X I) i arx reviewAtumelnantDosing Diary - - - X X X X X X X X X - - reviewMenstrual CycleDiary review - X X X X X X X X X X X X - (females only)Urinalysis X - - X - - - - X - - X X - Hematology,clinical chemistry. X - X X - X - - X - X X X - INR, PT / PTTHbAlc X - - - - - - X - - - X - - Free T4, TSH,X - - - - X - X - - X X X -Total T3Docket No. P00044-WO Treatment Period FollowScreeninup g PeriodPeriod 32bZ 36bZ DayStudy Week -6 to -la2b5b8b12b16b20b24b28bEO 34 EO 1bT SStudy Window (±3 (±3 (±3)- - (± (± (±3) (±3) (±3) (±3) (±4) (±4) (days) 3) 3) ) )Onsite Visit* X X X X - X - X X - X X X - Phone VisiP - - - - X - x - - X - - - X PD biomarkers17-OHP, ACTH(plasma), cortisol,testosterone, A4,11 -DOC, xhX* x;xj- X* - x;X* - X* x;X* - progesterone, 21- deoxy cortisol,11-0HA4, 11- ketoA4, 11-OHT,11-ketoTSerum aldosterone- - x;Xs- X* - - X* - x;- X* - and PR A'BSAP,osteocalcin,serum P1NP,- - X - - - X - - - - X X - NTX, CTX, andpyridinolinecross-linksCYP450 and 21- hydroxylase A2 - - X - - - - - - - - - - - genotypingSerologyHIV antibody, X - HBsAg, and HCVantibodyPK onsite - - - xk- xk- xkxk- xkxkxk- Mitra device PK- - - X1- X1- X1X1- X1X1- - samplingPregnancy testX - X X X X X X X X X X X - (WOCBP)mLH / FSH - - x;X* - xj- X* - - - x;- - FSH (femaleswho arepostmenopausalX X - with less than1 year ofamenorrhea only)11Docket No. P00044-WO Treatment Period FollowScreeninup g PeriodPeriod 32bZ 36bZ DayStudy Week -6 to -la2b5b8b12b16b20b24b28bEO 34bEO 1T SStudy Window (±3 (±3 (±3)- - (± (± (±3) (±3) (±3) (±3) (±4) (±4) (days) 3) 3) ) )Onsite Visit* X X X X - X - X X - X X X - Phone Visit0- - - - X - X - - X - - - X Estradiol - - X X - X - X - - - X - - Estrone, inhibin- - X - - - - X - - - X - - BsDXA Scan - (BMD / body X - - - - - - - X - - composition)Testicular - ultrasound (males X - - - - Xs- - X - - only)0Semen analysis8X - - - - X - - - X - - Non-contrast - adrenal CT scan X - - - - - - - X - - (optional)pCAHSISq- X X - - X - X X - X X - - PGI-Sq- X X - - X - X X - X X - - PGI-Cq- - X - - X - X X - X X - - CAHQLq- - X - - X - X - - - X - - SF-36v2q- - X - - X - X - - X X - - Beck Depression - - - X - - X X - - X X - - Inventory11EQ-5D-5Lq- - X - - X - X - - X X - - Treatment - - - - Satisfaction - - - - - - X - - Questionnaire4Participant - - - - - - X - - - - X - -Interview111-DOC=11 -deoxycorticosterone; 1 l-ketoA4=l 1 -ketoandrostenedione;1 l-ketoT=l 1 -ketotestosterone; 1 l-0HA4=l 10-hydroxy androstenedione;11-OHT=110-hydroxy testosterone: 17-OHP=17-hydroxyprogesterone; A4=androstenedione: ACTH=adrenocorticotropic hormone; AE=adverse event; BMD=bone mineral density:BMI=body mass index; BSA=body surface area; BSAP=bone-specific alkaline phosphatase; CAH=congenital adrenal hyperplasia; CAHQL=CAH HRQoL Instrument; CAHSIS=CAH Symptoms and Impacts Survey; CT=computed tomography; CTX=C-telopeptide telopeptide; CYP450=cytochrome P450; DXA=dual energy X-ray absorptiometry; ECG=electrocardiogram; EOS=end of study; EOT=end of treatment; EQ-5D-5L=EuroQol 5 dimension; FSH=follicle-stimulating hormone; GC=glucocorticoid; HbAlc=hemoglobin Ale; HBsAg=hepatitis B virusDocket No. P00044-WO surface antigen; HCV=hepatitis C virus; HRQoL=health-related quality of life;INR=intemational normalized ratio; LFMuteinizing hormone; NTX^N-telopeptide telopeptide; OLE=open-label extension; PlNP=procollagen type 1 N-terminal propeptide;PD=pharmacodynamic(s); PGI-C=Patient Global Impression of Change questionnaire;PGI-S=Patient Global Impression of Severity questionnaire; PK=pharmacokinetic(s);PRA=plasma renin activity; PT=prothrombin time; PTT=partial thromboplastin time; QD=once daily; SF-36v2=36-Item Short Form Survey; T3=triiodothyronine; T4=thyroxine;TSH=thyroid-stimulating hormone; VAMS=Volumetrically Accurate Microsampling;WOCBP=women of childbearing potentialaScreening visits should occur 2 weeks (±3 days) apart. The second Screening Visit should occur at least 1 week prior to Day 1.bThe target Visit Day should be the last day of the Study Week. To calculate the target Visit Day, multiply the Study Week 7.* Screening visit 2 and visits on Week 8, and Week 28 can be converted to home health visits at the discretion of the Investigator.cMay be converted to an onsite visit as required.dInformed consent form may be signed up to a week prior to the start of Screening.eStarting the evening of Day 1 and ending the evening before the Week 32 / EOT Visit, each participant will administer study drug between 21:00 and 23:00 at approximately the same time each evening, QD.fThe Glucocorticoid Administration Diary should be completed by the study participant every' day starting at the first Screening Visit and continuing through Week 36 (EOS) or Week 32 (EOT) for participants continuing to the OLE. Atumelnant Administration Diary should be completed by the study participant every day starting at Day 1 and continuing through Week 32. Menstrual Cycle Diary' should be completed by all female study participants the beginning of each menstrual cycle to the end of each menstrual cycle starting on the first Screening Visit and continuing through the EOS Visit or Week 32 (EOT) for participants continuing to the OLE. Diaries may be completed at home or at onsite visits.gSee text for GC reduction guidance. A follow-up phone call should be conducted 1 week later (±2 days) to assess tolerability.hBiomarkers should be draw n at least 3 weeks before the planned Day 1. At the first Screening Visit, PD biomarker blood draws can be done at any time after the informed consent form is signed but before their morning GC dose.1Prior to receiving the morning GC replacement dose, a blood sample for PD biomarkers will be draw n. A second blood sample for PD biomarkers will be draw n at least 2-3 hours after the morning GC dose but prior to 11 :00 hours. Participants not on morning GC should still have 2 morning blood samples taken 2 to 3 hours apart. Ensure the time of the last dose of GC taken prior to the first blood sample is documented.* A single blood sample for PD biomarkers will be drawn 2-3 hours after morning GC dose but prior to 11 :00 hours. The screening Visit 2 sample must be drawn prior to receiving the morning GC replacement.jFor participants on fludrocortisone (mineralocorticoid) replacement, serum aldosterone and PRA will be obtained prior to administration of this medication.kA single PK sample will be collected during the study visit.1A Mitra VAMS PK sample will be collected by the study participant prior to the evening atumelnant dose on the night before the visit.mSerum pregnancy test to be conducted by central laboratory at Screening and thereafter a urine pregnancy test monthly to be conducted locally unless otherwise specified by local regulations or in the judgment of the Investigator. If a urine pregnancy test does not coincide with an onsite visit, then a home pregnancy test will be performed. The home pregnancy test(s) will be provided to WOCBP participants and the study staff will contact the participants for results. IfDocket No. P00044-WO positive, the study drug will be discontinued, and an onsite blood pregnancy test will be conducted to confirm the results in an unscheduled visit.nTo confirm participant reproductive category, 2 FSH tests must be conducted 2 to 4 weeks apart during Screening for the participant subpopulation of women who are postmenopausal with less than 1 year of amenorrhea. A documented, historical test result measured prior to Screening may be used as 1 of the 2 measurements. The FSH value should be >30 IU / L to confirm menopausal status.0A DXA scan and testicular ultrasound should be done after the first Screening Visit and prior to study drug dosing on Day 1. Another ultrasound will be done at Week 32 (EOT) ±2 weeks.pAn optional non-contrast adrenal CT scan will be conducted at selected sites after the first Screening Visit and prior to study drug dosing on Day 1. Another non-contrast adrenal CT scan will be conducted at Week 32 (EOT) ±2 weeksqCompleted at site visits.rParticipant interviews are optional and will be performed via telephone or video conferencing software. Interview should be conducted as close as possible (preferably within 4 weeks) to the study visit.sOnly at selected sites with men consenting to participate in male reproductive function assessments.

[0271] Risks and Mitigation Strategies

[0272] Adrenal insufficiency (including hypotensive adrenal insufficiency)

[0273] Participants will have stepwise reductions in GC dose to physiological doses (<11 mg / m2 / day) between Weeks 2 to 12 and Weeks 16 to 28 (i.e., to doses taken by those with non-CAH causes of adrenal failure). Participants will have weekly in person or telephone review to ensure tolerability of the dose reduction, specifically focused on symptoms suggestive of adrenal insufficiency or related to dose reduction, such as fatigue, myalgia, and nausea (GC withdrawal syndrome). Investigators and participants will be permitted to increase the GC dose as judged clinically appropriate.

[0274] Atumelnant suppresses ACTH-induced cortisol production, and while unlikely, it is possible that participants on stable doses of GCs with residual cortisol production may¬ experience symptoms of adrenal insufficiency. Other risk factors for adrenal insufficiency for participants on long-term GC therapy, include intercurrent illness and / or poor adherence with GC replacement.

[0275] Participants enrolled in the study will be educated to recognize the signs and symptoms of adrenal insufficiency and about the importance of increasing the dose of GC therapy, according to local practices, if necessary for periods of stress (sick-day rules).

[0276] Participants are required to document GC dose and regimen daily in a diary that will be reviewed at study visits. Participants will also be regularly assessed for clinical evidence of hypoadrenalism and instructed on when to contact the study doctor. Unscheduled visits may be necessary to assess cases of suspected or confirmed adrenal insufficiency.Docket No. P00044-WO

[0277] Detailed Study Description

[0278] This is a Phase 3. global, multi center, randomized, double-blind, placebo-controlled study in adult participants (male or female age >18 to <75 years) with classic CAH due to 21-OHD who have been on a stable regimen of GCs for at least 3 months to evaluate efficacy, safety, PK, and PD of atumelnant administered once per day. Selected sites will also investigate the effects of atumelnant on male reproductive function in consenting participants with classic CAH in an optional substudy as part of this Phase 3 protocol.

[0279] Following a 3- to 6-week Screening Period, eligible participants will enter the Treatment Period where they will be randomly assigned in a 2: 1 ratio to receive either atumelnant 80 mg once daily (with an option for dose escalation to 120 mg once daily at week 20) or placebo. Enrollment will include participants with morning levels of serum A4 as follows: A4 >ULN and treated with <11 mg / m2 / day (physiologic) GC doses; or normal A4 (above mid-range to <ULN) and treated with >14 mg / m2 / day GC doses; or A4 >ULN and treated with >11 mg / m2 / day GC doses.

[0280] Following randomization to a treatment group, participants will remain on a stable GC dose for the first 2 weeks of treatment. After then, GC reduction may occur starting on the week 2 visit and continuing until the week 12 Visit with suggested reductions of 2.5 mg to 10 mg of hydrocortisone (rounding to the nearest number when non-hydrocortisone GC conversion is used) or equivalent per visit.

[0281] All participants will receive adrenal insufficiency training during the study conduct as per the SOA. Morning serum A4 will be measured at week 16 of the treatment period to determine if atumelnant dose escalation is needed. Subsequently on week 20 of the treatment period, participants with persistent hyperandrogenism, as defined by morning serum A4 >ULN, will receive an additional dose of 40 mg daily (up to a total dose of 120 mg daily) of atumelnant (or placebo) for the remainder of the treatment penod based on results from the preceding study visit on week 16. Those participants with serum A4 levels within the reference range will remain on 80 mg once daily atumelnant (or placebo).

[0282] At the end of the 32-week randomized treatment period, eligible participants may enroll in a separate OLE study. Those participants who do not continue to the OLE study, or are not deemed eligible for it, will continue to be monitored during a 4-week follow-up period.

[0283] Participant Group Assignments are disclosed in the table below:Docket No. P00044-WO Group A4 Level GC Dose 1 >lxULN <11 mg / m2 / day 2 >0.5x to IxULN >14 mg / m2 / day 3 >lxULN >11 mg / m2 / day Not eligible <lxULN <11 mg / m2 / dayA4=androstenedione; GC=glucocorticoid; ULN=upper limit of normal

[0284] Using a 2: 1 (atumelnant to placebo) randomization ratio and assuming a true between-treatment difference in response of 50%, if there is a 65% response in atumelnant and a15% response in placebo (i.e., an equivalent odds ratio of 10.5), a sample size of 135 participants will provide at least 99% power at the 2-sided 5% significance level. This holds for a variety of different assumptions with respect to response rates. Assuming a 10% dropout rate, 150 participants will be randomized.

[0285] Screening Period (Up to 6 Weeks)

[0286] The purpose of the screening period is to perform all investigations required to establish a participant's baseline status and eligibility for the study. Participants will sign the ICF prior to initiation of any study procedures. WOCBP will need to recall the first day of their last menstrual cycle at Screening and continue to track their cycle throughout the study.

[0287] Participants must be compliant and on a stable GC regimen for at least 3 months prior to screening. Rescreening is permitted if a participant does not meet all eligibility requirements. Additional rescreening is only permitted with the consent of the medical monitor. Assessments from the previous screening may be used at the discretion of the medical monitor. Participants who rescreen will need to sign a new ICF.

[0288] All assessments to be performed during the screening period are detailed in the SOA. Participants will fast overnight for at least 6 hours before designated clinic visits. Baseline scrotal (testicular) ultrasound will be performed in male participants to assess for the presence of a TART.

[0289] It is expected that the pre-study GC regimen will be held stable during the screening period. Participants, legal guardians, and caretakers will be instructed to complete a diary during all parts of the study in which signs and symptoms of adrenal insufficiency, when to contact the study team, any interventions (e.g., change in GC dose), and other information (e.g., concomitant illness, event triggers) will be captured.

[0290] Treatment Period (Day 1 to Week 32)Docket No. P00044-WO

[0291] The treatment period consists of an initial GC stable period (2 weeks), followed by a GC reduction period I (10 weeks), atumelnant / GC fixed-dose period (4 weeks), atumelnant / placebo dose escalation / GC reduction period II (12 weeks), and atumelnant / GC fixed-dose period (4 weeks). Participants will be randomly assigned in a 2: 1 ratio (stratified by baseline A4 levels and GC dose) to receive atumelnant 80 mg once daily in the evening or placebo. Blood and urine samples will be collected at specified timepoints to assess PK, PD, and safety. If a participant’s GC regimen is augmented due to sick-day rules, the participant must resume their prior steroid dosing regimen for at least 7 days before their next scheduled PD biomarker assessment. Of note, this 7-day window supersedes all other visit windows. If the GC dose is adjusted for any other reason (i.e., GC withdrawal symptoms), the participant should remain on a stable dose for at least 3 days.

[0292] 2-Week Glucocorticoid Stable Period (Day 1 to Week 2)

[0293] During this period, the GC dose will be maintained except for intercurrent illness (i.e., “sick-day” rules). Any change in GC dose should be discussed with the medical monitor. Participants will document the time of dosing of the study drug as well as time and dose in a GC Administration diary.

[0294] 10-Week Glucocorticoid Reduction Period I (Week 2 to Week 12)

[0295] GC reductions will occur during weeks 2, 5, 8, and 12. The suggested GC reductions for each visit are of 2.5 mg to 10 mg of hy drocortisone or equivalent, but alternative reduction regimens may be implemented based on the investigator’s clinical judgment with the intent of achieving physiological doses (<11 mg / m2 / day) by Week 12. Dose reductions should not go below 8 mg / m2 / day. If the participant is on multiple daily doses of GCs, the investigator should prioritize reductions of the night-time dose. Following each visit resulting in a GC reduction, the investigator will contact the participant by telephone a week (±2 days) after the study visit to assess the tolerability of GC reduction, which should be reconsidered if signs or symptoms of GC deficiency occur, adrenal insufficiency or clinically significant hyperandrogenism occur. To support individualized GC dose reductions, androstenedione results (A4) will be available to the Investigator, the GC dose reductions will still need to proceed even in the presence of transient PD biomarker increases, provided that the participant remains asymptomatic. The investigator is encouraged to communicate as necessary with the participants during the GC reduction period. If the GC dose is increased temporarily (i.e., due to GC withdrawal syndrome), the participant should remain on the same treatment regimen for at least 3 days before their next scheduled PD biomarker assessment. Of note, this 3-day window supersedes all other visit windows.Mineralocorticoid doses will be adjusted as needed during this period. If necessary, aDocket No. P00044-WO participant’s GC dose can be temporarily increased, but the investigator should resume the GC reduction schedule as soon as possible thereafter. Unscheduled visits may be arranged if clinical assessments or laboratory tests are needed.

[0296] 4-Week Glucocorticoid Fixed-Dose Period (Week 12 to Week 16)

[0297] During this period, the GC dose established in the Week 12 Visit will be maintained until PD measurements in the week 16 Visit, except for the occurrence of intercurrent illness (i.e., “sick-day” rules). Any change in GC dose should be discussed with the Medical Monitor. Participants will document the time of dosing of the study drug as well as time and dose of GCs in a GC Administration diary. All PD samples should be drawn prior to and after the morning dose of GC replacement.

[0298] 12- Week Atumelnant / Placebo Dose Escalation / Glucocorticoid Reduction II Period (Week 16 to Week 28)

[0299] On week 16, a blood sample will be obtained to determine morning serum A4, and additional PD and safety biomarkers. The goal of the GC reduction period II from week 16 to week 28 is to allow the investigator to reduce a participant’s GC dose level to reach GC physiologic doses <11 mg / m2 / day if not previously achieved. The GC dose should not be reduced to below 8 mg / m2 / day. GC reductions will occur on weeks 16, 20, 24, and 28. Following each visit resulting in GC reduction, the investigator will contact the participant by telephone a week (±2 days) after the study visit to assess the tolerability of the GC reduction, which should be reconsidered if signs or symptoms of GC deficiency, adrenal insufficiency or clinically significant hyperandrogenism occur. To support individualized GC dose reductions, androstenedione results (A4) will be available to the Investigator, the GC dose reductions will still need to proceed even in the presence of transient A4 increases, provided that the participant remains asymptomatic. The Investigator is encouraged to communicate with the participant as necessary during the GC reduction period. If the GC dose is increased temporarily (i.e., due to GC withdrawal syndrome), the participant should remain on the same treatment regimen treatment for at least 3 days before their next scheduled PD biomarker assessment. Of note, this 3-day window supersedes all other visit windows.

[0300] At Week 20, participants with morning serum A4 levels obtained at Week 16 >ULN will receive an additional dose of 40 mg / day (120 mg / day total) atumelnant. or matching placebo.

[0301] 4-Week Atumelnant / Glucocorticoid Fixed-Dose Period (Week 28 to Week 32)Docket No. P00044-WO

[0302] During this period, the GC dose established in the week 28 Visit will be maintained until the EOT Visit (week 32) except for the occurrence of intercurrent illness (i.e., ‘’sick-day” rules). Any change in GC dose should be discussed with the Medical Monitor.

[0303] A follow-up testicular ultrasound will be performed in male participants during the last week of the treatment period (week 32).

[0304] Follow-Up Period (Week 32 to Week 36)

[0305] If eligible, participants who have completed the week 32 (EOT) visit may be offered participation in a separate long-term OLE study. If the long-term extension study is opened at the investigative site and participants sign informed consent for the long-term extension study, the week 34 (Follow-Up) visit and the week 36 (EOS) visit are not applicable, as treatment on atumelnant will not be interrupted. Participants who do not continue to the OLE study or are not deemed eligible for it will continue to be monitored during a 4-week follow-up period until the EOS Visit During the safety follow up period, the participant’s GC dose should be adjusted by the Investigator as clinically indicated.

[0306] End of the Study

[0307] The date of the last visit of the last participant will be considered the end of the study.

[0308] Treatment Period and Study Period Definitions for Individual Participants

[0309] The following terms are study conventions as they relate to individual participants: EOT is defined as the date of the last dose of study drug. Week 36 (EOS) visit) is defined as the date that final data are collected after a participant completes the follow-up period or after early termination. Treatment period is defined as the study period that begins on the day of enrollment (Day 1) and ends at the EOT visit. A participant is considered to have completed the study if he / she has completed the last scheduled procedure specified at the EOS visit or continued to the OLE study.

[0310] Inclusion Criteria

[0311] To be eligible to participate in this study, an individual must meet all the following criteria:

[0312] Male or female, between >18 to <75 years of age at the time of signing the ICF.

[0313] Willing and able to understand and adhere to the study procedures as specified in the protocol and comply with the study treatment.

[0314] Have classic CAH due to 21-OHD confirmed by the Investigator and approved by the medical monitor.Docket No. P00044-WO

[0315] Participants with screening levels of pre-GC morning serum A4 as follows: A4 >ULN and treated with <11 mg / m2 / day (physiologic) GC doses, or normal A4 (above mid-range to <ULN) and treated with >14 mg / m2 / day GC doses, or A4 >ULN and treated with >11 mg / m2 / day GC doses.

[0316] Participants who fail Screening based on findings the Investigator believes are temporary and not reflective of the usual state of the participant can be considered for rescreening. These cases should be discussed with the medical monitor.

[0317] On a stable (defined as no dose change of >5 mg / day hydrocortisone equivalent within 3 months prior to Screening) regimen of GC replacement (e.g., hydrocortisone, prednisolone, prednisone, methylprednisolone, dexamethasone, cortisone acetate) at the time of informed consent.

[0318] If treated w ith mineralocorticoids (fludrocortisone), the dose should be stable for at least 1 month prior to Screening with an upright plasma renin activity (PRA) during screening that is not greater than ULN on the participant’s usual sodium intake. If PRA is > ULN. the participant must have systolic blood pressure > 100 mmHg, without orthostatic hypotension and with serum sodium and potassium in the normal range.

[0319] If on estrogen therapy (any route), the dose must be stable for at least 3 months prior to Screening.

[0320] Female participants who engage in heterosexual intercourse must: be of nonchildbearing potential, defined as either surgically sterile (i.e., hysterectomy, bilateral salpingectomy, or bilateral oophorectomy), or agree to use a highly effective or a clinically acceptable method of contraception from the beginning of Screening until at least 2 weeks after the last dose of study drug.

[0321] Contraceptive use by men and women also should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

[0322] Periodic abstinence (i.e., calendar, ovulation, symptothermal, postovulation methods) and withdraw al are not acceptable methods of contraception.

[0323] Male participants who engage in heterosexual intercourse must: agree to use a condom when sexually active with a female partner of childbearing potential from Screening until at least 2 weeks after the last dose of study drug (or be surgically sterile [i.e., vasectomy with a confirmed absence of sperm in ejaculate]), or agree to remain abstinent on a long-term and persistent basis during the study and until at least 2 weeks after the last dose of study drug, agree to not donate sperm for the duration of the study and until at least 2 w eeks after the last dose ofDocket No. P00044-WO study drug. For selected sites and participants consenting to the male reproductive function assessments: willing and able to provide semen samples at specified timepoints; able to comply with abstinence requirements (2 to 7 days) prior to each collection; signed informed consent for participation in the sub-study.

[0324] For selected sites and participants consenting to the male reproductive health assessment substudy:a. Willing and able to provide semen samples at specified timepoints.b. Able to comply with abstinence requirements (2 to 7 days) prior to each collection.c. Signed informed consent for participation in the substudy.

[0325] Exclusion Criteria

[0326] An individual who meets any of the following criteria will be excluded from participation in this study.

[0327] Diagnosis of any form of CAH other than classic 21-OHD.

[0328] Treated with other GC formulations as defined by the following: unstable doses of inhaled GCs, and / or injectable or oral betamethasone or triamcinolone use within 30 days of first screening visit.

[0329] Stress dose of GC therapy within 1 week of start of screening, defined as any dose above the normal maintenance dose, including but not limited to IV or IM hydrocortisone; history of bilateral adrenalectomy, hypopituitarism, or other condition requiring chronic GC therapy.

[0330] Clinically significant medical condition or abnormal laboratory tests, as judged by the investigator, other than CAH.

[0331] History of major surgery / surgical therapy for any cause within 30 days prior to first screening visit.

[0332] Diabetes mellitus treated with insulin for less than 6 weeks prior to screening, or with change in total daily insulin dose by >30% within 6 weeks prior to screening.

[0333] Poorly controlled diabetes mellitus defined as having an HbAlc >8.5% (>69 mmol / mL), or estimated HbAlc based on fructosamine if HbAlc is not evaluable (e.g., due tohemoglobinopathies).Docket No. P00044-WO

[0334] Participants with hypothyroidism who are not receiving adequate hormone replacement therapy based on thyroid hormone levels measured at the time of screening, as determined by the investigator.

[0335] History of unstable angina or acute myocardial infarction within 12 weeks prior to screening or other clinically significant cardiac disease at the time of screening as judged by the investigator.

[0336] Participants with polycythemia and prior thrombotic events as judged by the investigator.

[0337] Concomitant mental condition rendering him / her unable to understand the nature, scope, and possible consequences of the study, and / or evidence of poor compliance with medical instructions.

[0338] Active malignant disease within the last 5 years prior to Screening excluding dermal squamous or basal cell carcinoma of the skin with complete local excision or resected cervical carcinoma in situ.

[0339] Women who are pregnant or lactating or, if of childbearing potential, who are unwilling to use highly effective contraception as described in this study; male participants who are unwilling to use highly effective contraception as described in this study.

[0340] Known history of illicit drug or alcohol abuse within the last year.

[0341] Use of antiandrogen therapy in the past 3 months (e.g., spironolactone, finasteride, cyproterone acetate, flutamide); use of testosterone, androgen-containing supplements, aromatase inhibitors, or growth hormone.

[0342] Use of medications that are strong inducers of CYP3A4 within 30 days prior to day 1 of the study, these include but are not limited to apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, or St. John’s wort.

[0343] Use of medications (all routes of administration; i.e., oral, topical, and inhaled) or ingestion of food (e.g., grapefruit juice) that are strong or moderate inhibitors of CYP3A4 within 7 days prior to day 1 of the study. Examples include but are not limited to protease inhibitors and NNRTIs for HIV or HCV, antifungals (e.g., ketoconazole), some antibiotics (e.g., ciprofloxacin) and calcium channel blockers (e.g., diltiazem), and antidepressants (e.g., fluvoxamine).

[0344] Use of medications that are strong or moderate inducers of P-gp within 30 days prior to day 1 of the study. These include but are not limited to apalutamide, carbamazepine, fosphenytoin, lorlatinib, phenytoin, rifampicin, or St. John's wort.Docket No. P00044-WO

[0345] Use of medications that are strong or moderate inhibitors of P-gp within 14 days prior to day 1 of the study, these include but are not limited to amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, lapatinib, protease inhibitors and NNRTIs for HIV or HCV (lopinavir and ritonavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir), or verapamil, propafenone, quinidine, or ranolazine.

[0346] Use of P-gp substrates, such as digoxin, edoxaban, fexofenadine, and dabigatran extexilate, as they may be subject to enhanced absorption and increased exposure when given concomitantly with atumelnant.

[0347] Use of any investigational drug within the past 60 days or 5 half-lives (whichever is longer) prior to the first dose; or plan to use an investigational drug in another study.

[0348] Average (of 3 ECGs) QTcF interval >450 msec (men) or >470 msec (women),PR interval >220 msec, QRS interval >120 msec, second- or third-degree atrioventricular block, left bundle branch block, or hemiblock at screening.

[0349] Renal insufficiency as measured by eGFR rate using the CKD-EPI formula<30 mL / min / 1.73m2; significant liver disease or ALT and / or AST >3*ULN, and / or TBil >1.5xULN during Screening. Participants with previously diagnosed Gilbert’s syndrome not accompanied by other hepatobiliary disorders and associated with TBil <3.5 mg / dL (<51.3 pmol / L) will be permitted.

[0350] Know n history of, or concern for, risk of hypersensitivity reaction to atumelnant or any of its excipients; participants w ho are committed to an institution by virtue of an order issued either by the judicial or administrative authorities.

[0351] Participants with an increased risk of developing adrenal insufficiency as judged by the Investigator; use of oral betamethasone or budesonide within 30 days of Screening.

[0352] Severe erythrocytosis as judged by the Investigator.

[0353] Use of a corticotropin-releasing factor receptor antagonist within 14 days of Screening.

[0354] For selected sites and participants consenting to the male reproductive health assessment study: History of obstructive azoospermia or known non-CAH related infertility. Any condition or use of medication that may confound reproductive assessments. Previous testicular surgery affecting fertility potential (unless fully recovered).

[0355] Test Product, Reference Therapy, and Other Medications

[0356] The test product, reference therapy, and other medications administered in the trial are disclosed in the table below:Docket No. P00044-WO Corticosteroid

[0357] Atumelnant Placebo Therapy Intervention Atumelnant Control Glucocorticoid and Name mineralocorticoid therapyDrug Class MC2R competitive Not applicable Corticosteroids antagonistDrug CRN04894 maleate Not applicable Various agents, Substance including cortisone acetate, hydrocortisone, prednisolone, prednisone, methylprednisolone, meprednisone, dexamethasone, fludrocortisone Dose Tablet Tablet Variable per participant FormulationUnit Dose 80 mg, 120 mgaMatching placebo Variable per participant Strength(s) (80 mg or 120 mg)Dosage Level(s) Single dose Single dose Variable per participant Route of Oral Oral Oral AdministrationUse Experimental Experimental Standard of care IMP and IMP IMP AxMPAxMPAxMP=auxiliary medicinal product; HDPE=high-density polyethylene; IMP=investigational medicinal product; MC2R=melanocortin 2 receptoraFree-base equivalent.

[0358] Dosing and Administration

[0359] Atumelnant should be taken between 21 :00 and 23:00 at approximately the same time each evening throughout the study, and if applicable at approximately the same time as the evening GCs. GC doses will be held and administered in the clinic after the predose PD sample at onsite visits. The timing of each study visit should be as consistent as possible.

[0360] Participant Assignment, Randomization, and Blinding

[0361] Eligible participants will be randomly assigned in a 2:1 ratio to receive either atumelnant 80 mg once daily or placebo. At week 20, participants on atumelnant may receive an additional dose of 40 mg / day (total dose of 120 mg / day) or continue on 80 mg daily. Participants on placebo will continue to receive placebo tablets. At week 20, the dose may be increased to 120 mg / day of matching placebo.Docket No. P00044-WO

[0362] Dose Escalation

[0363] The starting dose will be 80 mg of atumelnant (active) or placebo for daily oral administration for 20 weeks. At week 20, after a DMC has reviewed PD levels from week 16, the dose should increase to 120 mg of atumelnant or placebo for daily oral administration until week 32 if the 80 mg dose is well tolerated and the week 16 A4 is >ULN. If the week 16 A4 is <ULN, the dose will remain at 80 mg once daily atumelnant or placebo until the conclusion of the treatment period.

[0364] Concomitant Therapy

[0365] Concomitant therapy is considered any therapy — including vaccines, medications (prescription and over the counter), and nonmedications (procedures, vitamins, herbal / dietary supplements, and / or alternative medicinal products [e.g., essential oils]) — other than study drug that is administered at any time during the study (i.e., from informed consent until EOT [for those continuing to the OLE study] or EOS Visit).

[0366] Permitted Therapy Exogenous Corticosteroids and Adrenal Insufficiency

[0367] Auxiliary Medicinal Products

[0368] During the study, the Investigator is to assess compliance with ongoing GC replacement therapy by reviewing the Glucocorticoid Administration Diary and to monitor for possible signs and symptoms of GC deficiency / adrenal insufficiency.

[0369] Dosing of GC therapies will be administered as standard of care and consistent with sick-day rules and / or periods of stress. GC deficiency / adrenal insufficiency teaching should be according to local practices and the instruction of the local Investigator, which may require an alternative GC regimen.

[0370] In the event of clinical suspicion of GC deficiency / adrenal insufficiency based on signs and symptoms, GC therapy should be adjusted as appropriate for concomitant illness, consistent with sick-day rules. Throughout a study, if a participant’s GC regimen is augmented due to sick-day rules, the participant must resume their prior steroid dosing regimen for at least 7 days before their next scheduled PD biomarker assessment. Of note, this 7-day window supersedes all other visit windows. If the GC dose is adjusted for any other reason (i.e., GC withdrawal symptoms), the participant should remain on a stable dose for at least 3 days.

[0371] Severe (hypotensive) adrenal insufficiency is defined as an acute deterioration in health status including, but not limited to, signs and symptoms associated with absolute hypotension (systolic blood pressure <100 mm Hg) or relative hypotension (systolic blood pressure >20 mmDocket No. P00044-WO Hg lower than usual for participant), with features that resolve within 1 to 2 hours after parenteral GC (usually hydrocortisone 100 mg IV) administration (i.e., a marked resolution of hypotension within 1 hour and improvement in clinical symptoms over a period of 2 hours).

[0372] The prescribed dose adjustment in exogenous GCs and duration of such adjustment is to be determined by the Investigator based on presenting signs and symptoms. Prior to providing supplemental doses of exogenous GC therapy, if possible, blood should be collected for measurement of urea, creatinine, sodium, potassium, glucose, and any scheduled hormone measurements.

[0373] For participants diagnosed with mild to moderate adrenal insufficiency during the study, study drug dosing may continue, under careful supervision, if 1 of the following scenarios occur: participant is adherent with GC replacement and asymptomatic, or any symptoms or signs related to mild to moderate adrenal insufficiency responded promptly to an increased dose of GC treatment as determined by the Investigator.

[0374] Participants receiving supraphysiologic GC therapy due to severe (hypotensive) adrenal insufficiency are to discontinue study drug until clinical resolution and at least 5 half-lives (approximately 5 days) have elapsed, and the participant has resumed their GC regimen.

[0375] Mineralocorticoid therapy (e g., fludrocortisone) is considered an auxiliary medication in this study and may be continued at the participant’s pre-study dose, provided it has been stable for at least 3 months prior to screening. Adjustments to mineralocorticoid dosing during the study are permitted only if clinically indicated (e.g.. based on blood pressure, serum electrolytes, or renin activity), and must be documented accordingly. The use and dose of mineralocorticoids will be recorded as concomitant medication throughout the study. Participants requiring initiation or major adjustment of mineralocorticoid therapy during the study may be evaluated for continued eligibility at the discretion of the Investigator in consultation with the Sponsor.

[0376] Signs and Symptoms of Adrenal Insufficiency

[0377] Signs and symptoms of adrenal insufficiency are discussed in the table below:Docket No. P00044-WO Cortisol Deficiency Aldosterone DeficiencyFatigue, anorexia, nausea, vomiting, Orthostatic hypotension defined as a decrease abdominal pain, muscle or joint pain, in systolic blood pressure >20 mm Hg and / or weakness, lethargy, fever, confusion, coma a decrease in diastolic blood pressure Laboratory findings: hyponatremia, >10 mm Hg upon standing for 2 to 5 minutes hypoglycemia, inappropriately low serum compared with supine blood pressure. If the cortisol levels, anemia, hypercalcemia participant is unable to stand, blood pressure and pulse may be taken in a sitting position with legs dependent.Laboratory findings: hyperkalemia, low aldosterone, hyponatremia, elevated renin Hypotensive Adrenal InsufficiencyAcute deterioration in health status including, but not limited to, the above signs and symptoms associated with absolute hypotension (systolic blood pressure <100 mm Hg) or relative hypotension (systolic blood pressure >20 mm Hg lower than usual), with features that resolve within 1 to 2 hours after parenteral glucocorticoid administration (i.e., a marked resolution of hypotension within 1 hour and improvement in clinical symptoms over a period of 2 hours).

[0378] Discontinuation of Study Drug

[0379] All participants will be informed that they have the right to withdraw from study drug dosing at any time, for any reason, without prejudice, and without having to justify their reasons or decisions. Temporary discontinuation of study drug with rechallenge may be considered as appropriate.

[0380] Criteria for Permanent Discontinuation of Study Intervention

[0381] Reasons for the Investigator to discontinue the participant from further study participation include but are not limited to the following:

[0382] Occurrence of AEs for which study treatment, protocol-specified non-investigational product, and / or study participation discontinuation is desired by the participant or considered necessary’ by the Investigator or the Medical Monitor.

[0383] Positive pregnancy test.

[0384] Indication of clinically significant cardiac symptoms or findings, including but not limited to the following: (a) based on the average of triplicate ECGs, QTcF >500 msec (or QTcF >530 msec in participants with a bundle branch block) repeated on a second set of ECGs at least 2 hours apart and confirmed by the investigator, (b) an increase in QTcF >60 msec from baseline with an absolute QTcF <500 msec (confirmed by the Investigator) based on the average of triplicate ECGs, (c) any ventricular tachyarrhythmia associated with symptoms of hemodynamic response, (d) sustained ventricular tachycardia (lasting >30 seconds) irrespective of symptoms, (e) torsades de pointes. (f) cardiac arrest, (g) cardiac pause >5 seconds observed on an ECG, (h)Docket No. P00044-WO Type II second-degree block or third-degree atrioventricular block, (i) new occurrence of clinically significant, symptomatic bradycardia, (j) initiation of a concomitant medication during the study that prolongs the QT interval and is associated with Torsades de pointes, (k) any supraventricular tachyarrhythmia associated with symptoms of hemodynamic instability.

[0385] Other clinically significant drug-related abnormalities. Liver function stopping criteria. Investigator’s decision (i.e., if in the Investigator's opinion it is not in the best medical interest for the participant to continue participation in the study for reasons other than AEs. such as behavioral, compliance, or administrative reasons). Participant has a need for a prohibited concomitant therapy. Any other protocol deviation that may result in a significant risk to the participant's safety or protocol deviations that will interfere with assessment of the efficacy of this study, including participant’s noncompliance with the study procedures / study protocol. Inability to fulfill study requirements and procedures. Death.

[0386] Temporary Discontinuation or Interruption of Study Intervention

[0387] Temporary discontinuation of study drug of up to 10 days due to tolerability (including adrenal insufficiency) may be allowed (discontinuation lasting more than 10 days will be considered permanent discontinuation from treatment).

[0388] Rechallenge

[0389] If, in the investigator’s judgment, the benefit versus risk balance weighs in favor of resuming study drug after a temporary study drug interruption or dose reduction, the medical monitor should be consulted.

[0390] Participants receiving supraphysiologic GC therapy due to severe (hypotensive) adrenal insufficiency are to discontinue study drug until clinical resolution and at least 5 half-lives (approximately 5 days) have elapsed. If, in Investigator’s judgment, the benefit versus risk balance weighs in favor of resuming study drug at a lower dose, then the medical monitor’s approval is required.

[0391] Blood samples collected in this study may be stored for a maximum of 2 years (unless otherwise specified [e.g., future biomarker analyses]) after the study is completed at a facility selected by the sponsor to enable further analysis.

[0392] Glucocorticoid Dose Reduction

[0393] Each participant will record their daily GC doses in the Glucocorticoid Administration Diary including the type of GC, dose, and the time of dosing.Docket No. P00044-WO

[0394] The Glucocorticoid Administration Diary will be distributed at the first Screening Visit. This diary is to be reviewed by site personnel at the visits specified in the SOA.

[0395] All participants will be on long-term GC replacement therapy which will be modified as part of the 10-week GC Reduction Period I and the 12-week GC Reduction Period II.

[0396] Further GC reduction guidance will be provided in a supplemental document.

[0397] Glucocorticoid Reduction Period I

[0398] The goal of the GC dose Reduction Period I from Week 2 to Week 12 is to reach the target physiologic dose level of <11 mg / m2 / day hydrocortisone equivalent by' Week 12.

[0399] Any change in the GC dose and regimen must be documented in the Glucocorticoid Administration Diary' along with the precipitating event (e.g., scheduled GC reduction). The Glucocorticoid Administration Diary' will be reviewed during all study visits.

[0400] Participants entering the study will be educated to recognize the signs and symptoms of adrenal insufficiency. It is expected that participants may experience symptoms such as fatigue, nausea, abdominal discomfort, or arthralgias, especially as doses get closer to physiological levels. Participants should be advised of these possible symptoms and to contact the investigator if symptoms persist or worsen. Participants will still be regularly assessed for clinical evidence of hypoadrenalism and instructed on when to contact the study doctor for further assessments. Unscheduled visits may be conducted as needed.

[0401] Glucocorticoid Reduction Period II

[0402] The goal of the GC Reduction Period II from Week 16 to Week 28 is to allow the investigator to reduce a participant’s GC dose level to reach GC physiologic doses<11 mg / m2 / day if not previously achieved. The GC dose should not be reduced to below 8 mg / m2 / day.

[0403] PD Biomarker Draws

[0404] Prior to receiving the morning GC replacement dose, blood for PD biomarkers will be drawn on Day 1 for baseline. A second blood sample will be taken 2 to 3 hours after morning GC dosing but prior to 11 :00 hours. On all visits, participants will hold their morning GC dose until arriving at the study site. Visits should start as early in the morning as possible (preferably 07:00-08:00) to minimize any delay in administration of the morning GC dose and the timing of each study visit should be as consistent as possible. A second blood sample will be taken 2-3 hours after morning GC dosing but prior to 11:00 hours at the visits reflected in the schedule of activities. Participants not on morning GC should still have 2 morning blood samples taken 2 toDocket No. P00044-WO 3 hours apart, if applicable. Screening visit 1 PD biomarker blood draws can be done at any time after the ICF is signed. Screening Visit PD biomarker blood draws should be taken prior to morning GC replacement dose.

[0405] Bone Marker Assessments

[0406] The following bone marker assessments will be obtained as described in the SOA: BMD (DXA); Bone resorption (NTX, CTX, and pyridinoline cross-links). Bone formation (BSAP, osteocalcin, and serum P1NP). Bone turnover (osteocalcin).

[0407] Testicular Ultrasound

[0408] Testicular ultrasound wi 11 be performed according to the study site procedures for the evaluation TARTs at visits specified in the SOA. An ultrasound is required for all male participants.

[0409] Male Reproductive Health Assessment Study (Optional)

[0410] At selected sites, participants who consent for the Male Reproductive Health Assessment substudy will have semen collection and testing performed locally at visits specified in the SOA (Section 1.3).

[0411] Based on the WHO Laboratory Manual for the Examination and Processing of Human Semen, 6thedition, a summarized guidance for semen (sperm) collection is as follows:1. Method of collection:a. Masturbation is the preferred method for semen collection.b. Coitus interruptus is not recommended due to risk of contamination or incomplete collection.c. If masturbation is not possible, special nontoxic condoms (nonspermicidal, specifically designed for fertility testing) may be used. Standard condoms must not be used due to the presence of spermicides and latex toxicity.2. Abstinence period:a. Samples should be collected after 2 to 7 days of sexual abstinence.b. The range balances variability and gives optimal sperm concentration.

[0412] Sites performing semen collection will provide appropriate private facilities to ensure participant comfort and confidentiality'. All samples and data collected will be securely handled in accordance with GCP and local regulations, with access limited to authorized personnel.

[0413] Further information including handling, processing, and analysis of semen samples is detailed in the WHO manual.

[0414] Non-Contrast CT ScanDocket No. P00044-WO

[0415] An optional adrenal non-contrast CT scan should be performed locally in selected study sites at visits specified in the SOA. Image acquisition standards will be provided and must be followed to allow proper evaluation of adrenal volume.

[0416] DXA Scan

[0417] DXA scans will be performed locally at the visits specified in the SOA to assess bone mineral density and body composition.

[0418] Medical History

[0419] Medical history will be taken at the first Screening Visit and updated throughout the study as needed. All participants’ medical history should include congenital adrenal hyperplasia.

[0420] Adrenal Insufficiency Awareness Training and Assessments

[0421] Adrenal insufficiency awareness training should be performed on the timepoints specified in the SOA. Participants entering the study will be educated to recognize the signs and symptoms of adrenal insufficiency and about the importance of increasing the dose of GC therapy, according to local practices, if necessary for periods of stress (sick-day rules).

[0422] Adrenal insufficiency assessments should be performed on the timepoints specified in the SOA to monitor for possible signs or symptoms of adrenal insufficiency.

[0423] Physical Examinations

[0424] Perform a full physical examination and measure body weight and waist circumference at the timepoints specified in the SOA. Height is to be measured once, at Screening. The examination is to include an assessment of the head (external), eyes, ears, nose, throat, lungs, cardiovascular system, abdomen, musculoskeletal system, skin, lymph nodes, CNS, and, where appropriate, other body systems. BMI will be calculated as weight in kilograms divided by¬ height squared in meters.

[0425] Symptom-directed physical examinations should be conducted at timepoints specified in the SOA and may also be conducted due to a TEAE or other available safety data as an unscheduled assessment.

[0426] Vital Signs

[0427] Measure vital signs (resting and standing blood pressure and heart rate, resting respiratory rate, and body temperature) as per standard practice at the timepoints specified in the SOA.Docket No. P00044-WO

[0428] Standard blood pressure should be measured in the supine position after resting for 5 minutes. Measure standing blood pressure and standing heart rate after the participant has been supine for 5 minutes followed by standing for 2 to 5 minutes.

[0429] Electrocardiograms

[0430] Collect ECGs at the timepoints specified in the SOA. The ECG assessment is to be a standard 12-lead ECG performed in triplicate (1 to 3 minutes apart) after the participant has rested quietly in the supine position for at least 10 minutes without significant stimulation (e.g., noise, television). Additional ECGs outside of the planned assessments are to be collected, if clinically indicated (e.g., participants with palpitations, lightheadedness).

[0431] The ECG parameters that are to be assessed include a summary of findings as well as measurement of the pulse rate, QT, QTcF, and PR interval, and QRS duration based on the ECG machine readings.

[0432] All ECG assessments will be assessed by the Investigator for any findings that require medical attention and will also be read by an ECG central reader. The clinical significance of any ECG findings will be determined by the Investigator, including after the central reading result is available. Only the investigator’s assessment will be recorded in the eCRF. Any potentially significant outlier values should be confirmed by the ECG central reader. Any ECG measurement determined to be clinically significant (occurring after signing the ICF) will be noted as an AE on the appropriate eCRF page(s). Such abnormalities will be monitored until the end of the study or until resolution if considered related to the study drug.

[0433] Participant-Reported Assessments

[0434] Planned timepoints for all participant-reported assessments are provided in the SOA.

[0435] When these assessments are scheduled on the same day or visit, the order will be as follows:1. Glucocorticoid Administration Diary: completed at home or site visits.2. Atumelnant Dosing Diary7: completed at home.3. Menstrual Cycle Diary (females only): completed at home.4. CAHSIS: completed at site visits.5. PGI-C and PGI-S: completed at site visits.6. CAHQL: completed at site visits.7. SF-36v2: completed at site visits.Docket No. P00044-WO 8. Beck Depression Inventory: completed at site visits.9. EQ-5D-5L: completed at site visits.10. Treatment Satisfaction Questionnaire: completed at a site visit.

[0436] These assessments will be completed using an eCOA platform.

[0437] Participant Diaries

[0438] Glucocorticoid Administration Diary

[0439] Each participant will record their daily GC doses in the Glucocorticoid Administration Diary, which will be reviewed by the Investigator as specified in the SOA. Information captured in the diary should include the type of GC, the time of dosing, and dose taken.

[0440] Atumelnant Dosing Diary

[0441] The Atumelnant Dosing Diary is to be reviewed by site personnel at the visits specified in the SOA. It is expected that the Atumelnant Dosing Diary' will include the actual dose administered and the actual date and time of dose administration. Any missed doses should be documented appropriately in the dosing diary.

[0442] Menstrual Cycle Diary (Demale Only)

[0443] The Menstrual Cycle Diary should be completed by all female study participants from the beginning of each menstrual cycle to the end of each menstrual cycle starting on the first Screening Visit and continuing through the EOS Visit as specified in the SOA.

[0444] Participant-Reported Questionnaires

[0445] CAHSIS1.1. The CAHSIS measures key aspects of adrenal insufficiency, androgen excess, and glucocorticoid overexposure that are experienced by patients with Classic CAH. Respondents are asked to evaluate their symptoms and how those symptoms have impacted their daily lives over the past 7 days. CAHSIS is a novel patient-reported outcome instrument. Evidence to support its content validity has been documented, and efforts to evaluate the instrument’s measurement properties are underway. The CAHSIS is completed by the participant as specified in the SOA. The CAHSIS questions are as follows:

[0446] For each question, please choose the answer that best describes how you have been feeling during the past 7 days because of your CAH.1. During the past 7 days, how severe was your fatigue at its worst?Docket No. P00044-WO 0 1 2 3 4 5 6 7 8 9 10No fatigue Worst possible fatigue2. During the past 7 days, how hard was it to concentrate on activities or tasks (including those at work or school or around the house)?

[0447] 2 3 4 5 6 7 8 9 10

[0449] Not hard to [04

[0451]

[0452]

[0453]

[0454]

[0455] [045

[0457] Extremely concentrate hard to concentrate 3. During the past 7 days, how severe was your pain (e g., muscle or joint pain) at its worst? 0 1 2 3 4 5 6 7 8 9 10No pain Worst possible pain4. During the past 7 days, how severe was the acne on your face or body at its worst? 0 1 2 3 4 5 6 7 8 9 10No acne Very severe (clear skin) acne5. During the past 7 days, how bothered were you by acne on your face or body? 0 1 2 3 4 5 6 7 8 9 10 Not at all Extremely bothered by bothered by acne acne6. During the past 7 days, how much unwanted hair growth did you have on your face or body?0 1 2 3 4 5 6 7 8 9 10No unwanted An extreme hair growth amount of unwanted hair growthDocket No. P00044-WO During the past 7 days, how bothered were you by unwanted hair growth on your face or body?0 1 2 3 4 5 6 7 8 9 10 Not at all Extremely bothered by bothered by unwanted hair unwanted hair growth growthDuring the past 7 days, how severe were your headaches at their worst? 0 1 2 3 4 5 6 7 8 9 10No headaches Worst possible headachesDuring the past 7 days, how often did you feel dizzy?0 1 2 3 4 5 6 7 8 9 10 None of All of the time the time . During the past 7 days, how often did you feel nauseous?0 1 2 3 4 5 6 7 8 9 10 None of All of the time the time . During the past 7 days, how many times did you vomit in total? times. During the past 7 days, how often did you have feelings of low mood or sadness?0 1 2 3 4 5 6 7 8 9 10 None of All of the time the time . During the past 7 days, how often did you have feelings of worry or anxiety?0 1 2 3 4 5 6 7 8 9 10 None of All of the time the timeDocket No. P00044-WO 14. During the past 7 days, how often did you feel irritable?0 1 2 3 4 5 6 7 8 9 10 None of All of the time the time15. During the past 7 days, how often did you avoid an activity because you did not have enough energy'.'None of the A little of the Some of the Most of the All of the time time time time time16. During the past 7 days, how often were you unable to finish an activity after starting it because you did not have enough energy?None of the A little of the Some of the Most of the All of the time time time time time17. During the past 7 days, how often did you accomplish less than you wanted because of your symptoms of CAH?None of the A little of the Some of the Most of the All of the time time time time time18. During the past 7 days, how often did your symptoms of CAH interfere with participating in social activities (e.g., attend an event, meet with friends or family)?None of the A little of the Some of the Most of the All of the time time time time time

[0458] Global Impressions of Change and Severity

[0459] The PGI-S assesses the participant’s perception of the severity of CAH symptoms at times specified in the SOA.

[0460] The PGI-C assesses the participant’s perception of the change in severity of CAH symptoms at times specified in the SOA.

[0461] CAHQL

[0462] The CAHQL captures CAH-specific HRQoL outcomes within 7 domains: General Health, Adrenal Insufficiency, Glucocorticoid Excess, Physical Functioning, Mental Health andDocket No. P00044-WO Cognition, Social Functioning, and Sexual Functioning (Flokas 2024). Participants will complete the CAHQL as specified in the SOA.

[0463] SF-36v2

[0464] The SF-36v2 is a 36-item, general health-based survey of quality of life (Patel 2007) to be completed by participants as specified in the SOA.

[0465] Beck Depress! on Inven tory

[0466] The Beck Depression Inventory measures the intensity of depressive symptoms in psychiatric and nonpsychiatric populations (Dozois 2004). The 21 -item measure should be completed by participants at times specified in the SOA.

[0467] EQ-5D-5L

[0468] The EQ-5D-5L (5 severity levels EQ-5D), developed by the EuroQoL Group, is a standardized instrument to be completed by the participant at times specified in the SOA for use as a measure of health outcomes applicable to a wide range of health conditions.

[0469] Treatment Satisfaction Questionnaire

[0470] This questionnaire asks participants to rate the satisfaction of their treatment at Week 32 / EOT.

[0471] Participant Interview

[0472] Participants may have the opportunity to participate in qualitative interviews conducted at 2 timepoints during their participation in the treatment period. The interviews will only be available to participants in certain countries, and participants in those applicable countries will have the option explicitly stated in the consent form to confirm their agreement to participate in the interviews. The interviews will collect information in the participant’s words regarding their own perceptions of their experiences with CAH both before and during the clinical study.Specifically, interview participants will be asked to describe their CAH symptoms and impacts before the clinical study and their expectations of treatment prior to entering the study.Participants will then be asked to describe how, if at all, their CAH symptoms and impacts changed during the clinical study, and to describe the meaningfulness of any changes experienced. Participants may also be asked to discuss their experiences with the clinical study. The participant interviews will be performed via telephone or video conferencing software and will be audio recorded and transcribed.

[0473] Adverse Events of Special InterestDocket No. P00044-WO

[0474] An AES1 is an AE of special medical or scientific interest to the Sponsor. For this study, adrenal insufficiency is considered to be an AESI.

[0475] Pharmacokinetics

[0476] During the Treatment Period, blood samples will be collected for the measurement of atumelnant and / or its metabolite(s) concentration in plasma and whole blood as specified in the SOA. Instructions for the collection and handling of biological samples will be provided by the Sponsor in the Laboratory Manual. The time of the last meal prior to atumelnant dosing will be collected on PK sampling days. The actual date and time (24-hour clock time) of collection of each sample will be recorded. The actual date and time of last dose of study drug prior to each sample collection will also be recorded.

[0477] Pharmacodynamics

[0478] A pharmacodynamic biomarker panel (17-OHP, ACTH [plasma], cortisol, testosterone, A4, 11-DOC, progesterone, 21 -deoxy cortisol, 11-0HA4, ll-ketoA4, 11-OHT, 11-ketoT) will be measured as specified in the SOA.

[0479] Genetics

[0480] During Day 1, blood samples will be collected for the measurement of CYP450 and 21 -hydroxylase A2 genoty ping in plasma as specified in the SOA. Instructions for the collection and handling of biological samples will be provided by the Sponsor in the Laboratory Manual.

[0481] The blood sample should be stored for future assessment of genetic variants if needed (e.g., predict efficacy, ADME, or safety signal).

[0482] Sample Size Determination

[0483] The sample size of 150 participants (100 in atumelnant arm and 50 in the placebo arm) is based on a power calculation of the primary endpoint and considerations for the size of the safety database.

[0484] Eligible participants will be stratified at randomization according to baseline A4 (> vs <ULN) and baseline GC dose (supraphysiologic dose: yes vs no). With 2: 1 randomization ratio, assuming a true between-treatment difference in response of 50%, if 65% response in atumelnant and 15% response in placebo (i.e., an equivalent odds ratio of 10.5), a sample size of 135 participants will provide at least 99% power based on Fisher’s exact test at the 2-sided 5% significance level. This holds for a variety of different assumptions with respect to response rates. For example, there is a greater than 93% power to detect a between-treatment difference asDocket No. P00044-WO small as 30% (i.e., 45% response in atumelnant and 15% response in placebo). Assuming a 10% dropout rate prior to Week 32, 150 participants should be randomized.

[0485] Participants who withdraw from the study will not be replaced. These sample size assumptions were evaluated using SAS™ 9.4.

[0486] Childbearing Potential and Contraception Guidance

[0487] The definitions of childbearing potential are in accordance with the Clinical Trials Coordination Group Recommendations related to contraception and pregnancy testing in clinical trials version 1.2 (2024).

[0488] Women of Childbearing Potential

[0489] WOCBP are defined as women who are physiologically capable of becoming pregnant. Women in the following categories are considered WOCBP (fertile): Following menarche. From the time of menarche until becoming postmenopausal unless permanently sterile (see below).

[0490] Women of Nonchildbearing Potential

[0491] Women in the following categories are considered WONCBP:

[0492] Premenopausal female with permanent infertility due to 1 of the following:

[0493] Documented hysterectomy.

[0494] Documented bilateral salpingectomy.

[0495] Documented bilateral oophorectomy.

[0496] For individuals with permanent infertility due to an alternate medical cause other than the above.

[0497] Note: Documentation can come from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview.

[0498] Postmenopausal female:

[0499] A high FSH level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or HRT However, in the absence of 12 months of amenorrhea, confirmation with 2 FSH measurements are required to determine if the participant is postmenopausal. A documented, historical test result measured prior to Screening may be used as 1 of the 2 measurements. The FSH value should be >30 IU / L to confirm status.

[0500] Females on HRT and whose menopausal status is in doubt must discontinue HRT to allow confirmation of postmenopausal status before study enrollment.Docket No. P00044-WO

[0501] Fertile Man

[0502] A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy.

[0503] Contraception Guidance

[0504] A participating WOCBP must use 1 of the highly effective forms of birth control listed below (preferable those with low user dependency) for the duration of the study and until at least 2 weeks after the last dose of study drug.

[0505] A participating WOCBP should be placed on effective birth control as soon as medically reasonable and before initiation of study drug.

[0506] The Clinical Trials Coordination Group Recommendations related to contraception and pregnancy testing in clinical trials version 1.2 (2024) include the use of highly effective forms of birth control. These methods include the following:a. Combined (estrogen- and progestogen-containing) hormonal contraception associated with the inhibition of ovulation:b. Oral, intravaginal, or transdermal.c. Progestogen-only hormonal contraception associated with the inhibition of ovulation:d. Oral, injectable, or implantable.e. Note: Oral birth control pills are not considered a highly effective form of birth control, and, if they are selected, they must be used with a second, barrier method of contraception such as condoms with or without spermicide.f. Intrauterine device.g. Intrauterine hormone-releasing system.h. Bilateral tubal occlusion.i. Vasectomized male partner.j. Note: This is only considered a highly effective form of birth control when the vasectomized partner is the sole partner of the study participant and there has been a medical assessment confirming surgical success:k. A sterile man is defined as having definitive evidence of infertility previously demonstrated with azoospermia in a semen sample examination.Docket No. P00044-WO l. Sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of exposure associated with the study drug).m. Note: Total sexual abstinence should only be used as a contraceptive method if it is in line with the participant’s usual and preferred lifestyle. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods), declaration of abstinence for the duration of exposure to study drug, and withdrawal are not acceptable methods of contraception.

[0507] A male participant with partners of childbearing potential who take part in this study must use condoms during sexual intercourse in addition to 1 of the highly effective methods of contraception listed below, from the time of Screening until at least 2 weeks after taking the last dose of study drug. If a female partner of a male participant is already pregnant, the male participant must use condoms during sexual intercourse for the duration of the study and until at least 2 weeks after taking the last dose of study drug. Nonsterile men must refrain from sperm donation for the duration of the study and until at least 2 weeks after the last dose of study drug.

[0508] Of note, barrier contraception (including male and female condoms with or without spermicide) is not considered a highly effective method of contraception and, if used, this method must be combined with another acceptable method listed above.

[0509] Required laboratory tests

[0510] Protocol-Required Laboratory Tests are disclosed in the table below:Laboratory Tests ParametersHematology Platelet countRBC count / hemoglobin / hematocritRBC indices: MCVMCH%ReticulocytesWBC count with Neutrophilsdifferential: LymphocytesMonocytesEosinophilsBasophilsHematology7PT / INR PTT(coagulation)Docket No. P00044-WO Laboratory Tests ParametersClinical chemistry3BUN AST Phosphorus Potassium ALT Magnesium Creatinine (and eGFR) GGT Albumin Sodium Alkaline phosphatasebBicarbonate Calcium Total and direct bilirubinGlucose (fasting) Total proteinFasting lipid panel Uric acidHbAlc ChlorideHormones LH / FSH TSH Renin Progesterone Free T4 Aldosterone Estradiol Total T3Inhibin BRoutine urinalysis pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esteraseMicroscopic examination (if blood or protein is abnormal) Toxicology urine drug screen (to include at minimum: amphetamines,barbiturates, cocaine, opiates, benzodiazepines, and PCP)dPregnancy testing Highly sensitive serum or urine hCG pregnancy test (as needed for WOCBP)CFSH (in women of nonchildbearing potential only)Serology HIV antibody, HBsAg, and HCV antibodyPD biomarkers 17-OHP, ACTH (plasma), testosterone, cortisol, A4, 11-DOC,progesterone, 21-deoxycortisol, 11-0HA4, ll-ketoA4, 11-OHT, 11-ketoTPK Atumelnant in plasma and whole bloodBone markers Markers of bone resorption (NTX, CTX, and pyridinoline crosslinks), bone formation (BSAP, osteocalcin, and serum P1NP), and bone turnover (osteocalcin)Genetics Required: CYP450 and 21-hydroxylase gene mutation (plasma) 11 -DOC= 11 -deoxycorticosterone; 11 -keto A4= 11 -ketoandrostenedione; 11 -ketoT=l 1 -ketotestosterone; 11 -0HA4= 11 P-hydroxy androstenedione; 11 -OHT= 11 -hy droxytestosterone; 17-OHP=17-hydroxyprogesterone; 25-OH=25-hydroxy; A4=androstenedione;ACTH=adrenocorticotropic hormone; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BMD=bone mineral density7; BSAP=bone-specific alkaline phosphatase; BUN=blood urea nitrogen; CTX=C -terminal telopeptide; CYP450=cytochrome P450;DXA=dual energy X-ray absorptiometry; eGFR=estimated glomerular fdtration rate;FSH=follicle-stimulating hormone; GGT=gammaglutamyl transferase; HbAlc=hemoglobin Ale; HBsAg=hepatitis B surface antigen; hCG=human chorionic gonadotropin; HCV=hepatitis C virus; INR=intemational normalized ratio; LH=luteinizing hormone; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; NTX=N-terminal telopeptide; PlNP=procollagen type 1 N-terminal propeptide; PD=pharmacodynamic(s); PK=pharmacokinetic(s);PT=prothrombin time; PTT=partial thromboplastin time; RBC=red blood cell;T3=triiodothyronine; T4=thyroxine; TSH=thyroid-stimulating hormone; WBC=white blood cell; WOCBP=woman of childbearing potentialaDetails of liver chemistry stopping criteria and required actions and follow-up must be reported to the Sponsor in an expedited manner.Docket No. P00044-WObIf alkaline phosphatase is elevated, consider fractionating.cSerum pregnancy test to be conducted by central laboratory at Screening and urine pregnancy test at all other timepoints. These tests should be conducted locally unless otherwise specified by local regulations or in the judgment of the Investigator.dAlcohol screening will only be done at the discretion of the Investigator and will be conducted per the site’s standard procedures and using their local laboratory.

[0511] Reductions in Adrenal Volume in Patients With Congenital Adrenal Hyperplasia Receiving Once-Daily Oral Atumelnant (CRN04894): Interim Results From a 12-Week, Phase 2, Open-Label Study

[0512] In a Phase 2, open-label, dose-finding study of atumelnant (40 mg, 80 mg, or 120 mg) in adults with classic CAH (21 -hydroxylase deficiency) (NCT05907291), treatment with atumelnant for 12 weeks demonstrated potent blockade of the adrenal MC2R and was associated with consistent reduction in adrenal size.

[0513] Change in adrenal gland size from baseline to Week 12 was an exploratory endpoint.

[0514] Adrenal gland size and morphology were assessed via magnetic resonance imaging (MRI) following a standardized image acquisition protocol at baseline (during screening and prior to atumelnant dosing on Day 1) and Week 12.

[0515] All MRI assessments were read by a single central radiologist; total volume was derived as the sum of the left and right adrenal gland volumes. If only one side has evaluable volume, then that is set to the total volume.

[0516] At baseline, total bilateral adrenal volume (reference range, 8-10 mL) was >10 mL in 18 / 19 participants (median [range] 22 [9.8-943.6] mL). Following 12 weeks of atumelnant treatment, 15 / 19 participants had a decline in total adrenal volume (see FIG. 3).

[0517] Consistent decrease in adrenal volume was seen across dose cohorts. For all cohorts combined, median (range) total adrenal volume was reduced by 5.2 (-77.5 to 9.1) mL, a median (range) reduction from baseline of 19.1% (-78.3% to 49.2%).

[0518] Total Adrenal Volume Percent Reduction From Baseline to Week 12 for the 40 mg, 80 mg, and 120 mg cohort were 21.7%, 17.6%, and 26.7%, respectively.

[0519] These results demonstrate the plasticity of adrenal tissue in adults with longstanding CAH and that ongoing adrenal hyperplasia is dependent on continued exposure to excess ACTH.

[0520] Rapid and Sustained Reduction of 11-Oxygenated Androgens in Adults With Classic Congenital Adrenal Hyperplasia Following Once-Daily Oral AtumelnantDocket No. P00044-WO

[0521] A hallmark of classic congenital adrenal hyperplasia (CAH) is 21 -hydroxylase deficiency (21-OHD), which disrupts normal steroidogenesis pathways, resulting in decreased cortisol and aldosterone levels and excess adrenal androgens. Traditional biomarkers of disease activity include 17-hydroxy progesterone (17-OHP) and androstenedione (A4). The adrenals produce 1 l[3-hydroxy androstenedione (11-0HA4). which is metabolized to the potent androgen 11-ketotestosterone (11-ketoT); these 11 -oxygenated androgens contribute to the total androgen burden in patients with CAH.

[0522] In a Phase 2, open-label, dose-finding study in adults with classic CAH (NCT05907291), treatment with atumelnant (40 mg, 80 mg, or 120 mg) demonstrated rapid and profound reductions in morning A4 and 17-OHP within 2 weeks that were maintained for the duration of treatment.

[0523] Participants were enrolled into cohorts to receive 1 of 3 fixed doses (40 mg, 80 mg. or 120 mg) of once-daily oral atumelnant administered nightly for 12 weeks. Serum measurements for biomarker assessments were made at Day 1 (baseline) and at Weeks 2, 6, and 12, prior to receiving morning glucocorticoid (GC) dose.

[0524] A total of 28 participants (40 mg, n=l 1 ; 80 mg, n=l 1 ; 120 mg, n=6) completed treatment. For all participants, the baseline 11-0HA4 was mean (range) 997 (142-3128) ng / dL; baseline 11-ketoT was mean (range) 303 (54-1292) ng / dL.

[0525] Participant Demographics and Baseline Characteristics are presented in the table below:Atumelnant Atumelnant Atumelnant All 40 mg 80 mg 120 mg participants Parameters(n=ll) (n=ll) (n=6) (N=28) Age, years, mean 28 (20-45) 33 (22-42) 34 (22-47) 31 (20-47) (range)4 (36) 8 (73) 3 (50) 15 (54) Female, n (%)Baseline biomarker evels, ng / dL, mean (range)828 1092 1131 997 11-0HA4(142-2185) (171-3128) (350-1858) (142-3128) 298 273 367 303 11-ketoT(66-1292) (54-680) (141-547) (54-1292) GC dose, mg / day, 30 31 23 29 mean (range)3(20-40) (20-40) (20-30) (20-40)11-ketoT, 11-ketotestosterone; 11-OHA4. 11 f-hydroxyandrostenedione; GC, glucocorticoid.aGC dose in hydrocortisone equivalents.Docket No. P00044-WO

[0526] There was a rapid, substantial, and sustained decrease in morning serum 11-OHA4 levels following treatment with atumelnant. At Week 2, the mean (SE) percent change from baseline for the 40-, 80-, and 120-mg cohorts was -49% (9.8), -74% (6.9), and -85% (4.6), respectively. At Week 12, the mean (SE) percent change from baseline was -60% (10.8), -68% (11.4), and -82% (3.5), respectively.

[0527] There was a rapid, substantial, and sustained decrease in morning serum 11-ketoT levels following treatment with atumelnant. At Week 2, the mean (SE) percent change from baseline for the 40-, 80-, and 120-mg cohorts was -40% (11.1), -56% (13.0), and -79% (7.3), respectively. At Week 12, the mean (SE) percent change from baseline was -58% (10.0), -58% (13.2), and -77% (7.2), respectively.

[0528] Once daily, oral atumelnant results in rapid and substantial reductions of 11-oxygenated androgens. Baseline 11-OEIA4 and 11-ketoT levels in participants with CAH were considerably higher than previously published ranges of circulating levels in healthy individuals, atumelnant treatment for 12 weeks normalized 11 -oxygenated androgen levels. These results are in addition to the reductions in traditional biomarkers A4 and 17-OHP in participants with classic CAH, with clinical activity observed across all doses

[0529] The reduction in total androgen burden may be linked to improvements in clinical outcomes previously reported within the 12-week time frame of this study.

[0530] Traditional androgen markers may not fully reflect the total androgen burden in CAH, thus monitoring potent 11 -oxygenated androgens may improve disease management and optimize therapy.

[0531] Reductions of Androstenedione and 17 Hydroxyprogesterone in Adults With Classical Congenital Adrenal Hyperplasia: Interim Results From a 12-Week, Phase 2, Open-Label Study

[0532] Below are results from cohorts of a 12-week, Phase 2, open-label, dose-finding study of atumelnant in patients with CAH (NCT05907291).

[0533] Adults with classic CAH (21 -hydroxylase deficiency) on a stable dose of glucocorticoid (GC) replacement (>15 mg hydrocortisone equivalent) for >6 months and androstenedione (A4) level >1.5 times the upper limit of normal (ULN) were enrolled in 3 dose cohorts (40 mg, 80 mg, or 120 mg) and received oral atumelnant once daily for 12 weeks.

[0534] The primary efficacy endpoint was change from baseline (CFB) to week 12 in early morning pre-GC serum A4. CFB in pre-GC serum 17-hydroxy progesterone (17-OHP) levels and, in men, serum A4: testosterone were secondary and exploratory' endpoints, respectively.Docket No. P00044-WO

[0535] Menstrual cycle diaries were completed by female patients throughout the study period.28 patients (54% women; mean [range] age 31.3 [20-47] years; mean [range] GC dose 28.4 [20-40] rng / day [hydrocortisone equivalent]) had completed treatment (40 mg, n=ll; 80 mg, n=ll; 120 mg, n=6).

[0536] Overall, baseline median (range) A4 was 1049 (116-2755) ng / dL (reference range [RR]; women 30-200 ng / dL; men 40-150 ng / dL) and baseline median (range) 17-OHP was 12,750 (453-44,000) ng / dL (RR: women <80 ng / dL [follicular], <285 ng / dL [luteal]; men, <220 ng / dL). There were no meaningful differences between groups in baseline values.

[0537] At week 12, median (range) morning A4 was reduced from baseline by 65% (5.5%-94%), 80% (22%-99%), and 82% (54%-91%) and 17-OHP was reduced by 84% (1.8%-97%), 86% (21%-99%), and 70% (12%-95%) in the 40-, 80-, and 120-mg cohorts, respectively. At week 12, mean morning A4 was reduced from baseline by 60%, 68%, and 82%, and 17-OHP was reduced by 66%, 67%, and 65% in the 40-, 80-, and 120-mg cohorts, respectively.

[0538] At week 12, A4 was <ULN in 3 / 11, 6 / 11, and 3 / 6 patients, respectively, and started as early as week 2 of treatment (earliest measure).

[0539] Median (range) A4:testosterone (n=12) was reduced from 4.88 (0.51-10.35), 2.51 (0.30-6.39), and 4.76 (0.57-5.33) at baseline to 1.17 (0.47-7.09), 1.46 (0.07-1.69), and 0.52 (0.09-0.64) at week 12 in the 40-, 80-, and 120-mg cohorts, respectively (normal <1).

[0540] Of 10 women with evaluable data, 6 of 10 with irregular menses (40 mg, n=2; 80 mg, n=3; 120 mg, n=l) had improvement in regularity of menstruation at the end of study. Of 13 women with evaluable data, 8 of 13 with baseline testosterone > ULN achieved normal levels at week 12 (40 mg, n = 2; 80 mg, n = 4; 120 mg, n = 2).

[0541] Overall, rapid, substantial, and sustained reductions in A4 and 17-OHP were demonstrated with administration of atumelnant in adult patients with classical CAH.

[0542] Conclusions

[0543] Once-daily. oral atumelnant showed profound, rapid, and sustained suppression of A4 and 17-OHP in participants with CAH, with clinical activity observed across all doses.

[0544] Reductions of 80% and 65% in A4 and 17-OHP, respectively, were achieved in the 120-mg cohort.

[0545] Atumelnant resulted in dose-dependent A4 lowering, with >50% of participants achieving normalization in the 80-mg and 120-mg cohorts.

[0546] Atumelnant treatment reduced A4: testosterone in male participants.Docket No. P00044-WO

[0547] The majority of oligomenorrheic females of childbearing potential resumed regular menses; testosterone levels were substantially reduced in hyperandrogenemic female participants.

[0548] Once-Daily Oral Atumelnant (CRN04894) Induces Rapid, Substantial, and Sustained Reductions of Androstenedione and 17- Hydroxyprogesterone and Allows Glucocorticoid Reduction in Adults With Classic Congenital Adrenal Hyperplasia:Final Results From a 12-Week, Phase 2, Open-Label Study

[0549] Atumelnant (CRN04894) is a first-in-class, once-daily, oral, selective melanocortin type 2 receptor competitive antagonist for treatment of congenital adrenal hyperplasia (CAH). A 12-week, Phase 2, open-label study was conducted to determine the effectivedose of atumelnant to normalize androstenedione (A4) levels with and without glucocorticoid (GC) reduction. Adults with classic CAH (21 -hydroxylase deficiency) with a A4 level >1.5 times the upper limit of normal (ULN) & on a stable (>6 months) GC dose (>15mg hydrocortisone (HC) equivalent) were enrolled in 4 cohorts of oral atumelnant (Cohorts 1-3: stable GC dose, PM atumelnant dosing 40, 80, or 120 mg; Cohort 4: forced GC dose tapering to a target of HC equiv. <11 mg / m2 / day, 80 mg [AM]).

[0550] The primary efficacy endpoint was change from baseline (CFB) to Week 12 in early morning pre-GC dose serum A4. CFB in pre-GC serum 17-hydroxyprogesterone (17-OHP) was a secondary efficacy endpoint. Proportion of participants with morningserum A4 <ULN on physiologic GC dose (<11 mg / m2 / day) and percent CFB in GC daily dose over time were exploratory' endpoints for Cohort 4.

[0551] As of October 17, 2025, 38 participants (55.3% women; mean [range] age 33.2 [20-64] years; mean [range] GC dose 27.1 [20-40] mg / day [hydrocortisone equivalent]) were enrolled (40 mg, n=l 1; 80 mg, n=l 1; 120 mg, n=6; 80 mg with GC reduction, n=10). Overall, baseline median (range) for A4 was 980.8 (116-2755) ng / dL (reference range [RRJ; women 30-200 ng / dL, men 40-150 ng / dL) and for 17-OHP was 12,175 (453-44,000) ng / dL(RR: women <80 ng / dL [follicular], <285 ng / dL [luteal]; men, <220 ng / dL). At Week 12, the median (range) percent CFB for in morning serum A4 was -65% (-94%, -5.5%), -80% (-99%, -22%). -82% (-91%, -54%), and -75% (-90%, -27%) and for 17-OHP was -82% (-97%. -1.8%), -86% (-99%, 21%), -69% (-95%, -12%), and -73% (-92%, 107%) in the 40-, 80-, 120-, and 80-mg with GC reduction cohorts, respectively. Of participants in Cohort 4, 3 / 8 (38%) had morning serum A4 <ULN at Week 12; of those, 2 / 3 (67%) were on a physiologic GC dose. At Week 12, mean (SD) GC daily dose was decreased from baseline by 17.6% (25.7%), 7 / 8 participants (87.5%) were on a physiologic GC daily dose. In all, 31 patients -had >1Docket No. P00044-WO treatment-emergent adverse events, the most common were headache (n=13) and fatigue (n=6), none were severe or serious, and none led to discontinuation. There were16 participants with treatment-related adverse events, the 2 most common were headache (n=5) and adrenal insufficiency (n=3).

[0552] In the Cohort 4 group, 7 / 8 pts (87.5%) achieved physiologic GC levels and clinically meaningful reductions in GCs at Week 12 (17.6% mean GC reduction). The treatment resulted in a mean 67% reduction in serum A4 (pre-GC dose) from Baseline to Week 12 in an evaluable cohort of N=8 subjects, which is similar to what was observed in cohort 1 (80 mg PM dosing, 70%) where GC levels were maintained throughout study.

[0553] Overall, rapid, substantial, and sustained reductions in A4 and 17- OHP were observed with GCs reduced to the physiological range. Similar responses to atumelnant were demonstrated with PM and AM administration of atumelnant in adult patients with classic CAH.Additional EmbodimentsEmbodiment 1. A method of treating congenital adrenal hyperplasia (CAH) in a subject on glucocorticoid (GC) therapy comprising administering to the subject an adrenocorticotropic hormone (ACTH) antagonist; wherein GC therapy comprises administering to the subject a dose of a GC; and wherein the dose of the GC is reduced following administration of the ACTH antagonist.Embodiment 2. A method of treating hyperandrogenism in a subject with CAH on glucocorticoid (GC) therapy comprising administering to the subject an adrenocorticotropic hormone (ACTH) antagonist; wherein GC therapy comprises administering to the subject a dose of a GC; and wherein the dose of the GC is reduced following administration of the ACTH antagonist.Embodiment 3. The method of any one of Embodiments 1-2, wherein the ACTH antagonist is an insurmountable ACTH antagonist.Embodiment 4. The method of any one of Embodiments 1-3, wherein the ACTH antagonist is atumelnant, or a pharmaceutically acceptable salt thereof.Embodiment 5. A method of treating congenital adrenal hyperplasia (CAH) in a subject on glucocorticoid (GC) therapy comprising administering to the subject atumelnant, or a pharmaceutically acceptable salt thereof; wherein GC therapy comprises administering to the subject a dose of a GC; and wherein the dose of the GC is reduced following administration of atumelnant, or a pharmaceutically acceptable salt thereof.Docket No. P00044-WO Embodiment 6. A method of treating hyperandrogenism in a subject with CAH on glucocorticoid (GC) therapy comprising administering to the subject atumelnant, or a pharmaceutically acceptable salt thereof; wherein GC therapy comprises administering to the subject a dose of a GC; and wherein the dose of the GC is reduced following administration of atumelnant, or a pharmaceutically acceptable salt thereof.Embodiment 7. The method of any one of Embodiments 1-6. wherein the dose of the GC is > 11 mg / m2 / day.Embodiment 8. The method of any one of Embodiments 1-7. wherein the dose of the GC is14 mg / m2 / day.Embodiment 9. The method of any one of Embodiments 1-8, wherein the dose of the GC is reduced via one or more GC dose reductions.Embodiment 10. The method of any one of Embodiments 4-9, wherein a GC dose reduction is done following administration of atumelnant, or a pharmaceutically acceptable salt thereof, for at least 2 weeks.Embodiment 11. The method of any one of Embodiments 4-10, wherein one or more GC dose reductions are done following administration of atumelnant, or a pharmaceutically acceptable salt thereof, for at least 5 weeks.Embodiment 12. The method of any one of Embodiments 4-11, wherein one or more GC dose reductions are done following administration of atumelnant, or a pharmaceutically acceptable salt thereof, for at least 8 weeks.Embodiment 13. The method of any one of Embodiments 4-12, wherein one or more GC dose reductions are done following administration of atumelnant, or a pharmaceutically acceptable salt thereof, for at least 12 weeks.Embodiment 14. The method of any one of Embodiments 4-13, wherein the dose of the GC is reduced to a minimum amount to be therapeutically effective following administration of atumelnant, or a pharmaceutically acceptable salt thereof, for at least 16 weeks.Embodiment 15. The method of any one of Embodiments 4-13, wherein the dose of the GC is reduced to a minimum amount to be therapeutically effective following administration of atumelnant, or a pharmaceutically acceptable salt thereof, for at least 28 weeks.Embodiment 16. The method of any one of Embodiments 4-16, wherein the dose of the GC is reduced to a physiologic dose following administration of atumelnant, or a pharmaceutically acceptable salt thereof, for at least 32 weeks.Docket No. P00044-WO Embodiment 17. The method of any one of Embodiments 14-16, wherein the dose of the GC is reduced to a physiologic dose a GC.Embodiment 18. The method of any one of Embodiments 1-13, wherein the physiologic dose of the GC is < 11 mg / m2 / day.Embodiment 19. The method of any one of Embodiments 1-18, wherein the GC is selected from the group consisting of hydrocortisone, prednisolone, prednisone, and methylprednisolone. Embodiment 20. The method of any one of Embodiments 1-19, wherein treating comprises reducing the subject’s serum level of androstenedione (A4) from baseline.Embodiment 21. The method of any one of Embodiments 1-20, wherein the subject’s serum level of A4 is reduced from baseline to < upper limit the normal (ULN).Embodiment 22. The method of any one of Embodiments 1-21, wherein the subject’s serum level of A4 is reduced by > 25% from baseline.Embodiment 23. The method of any one of Embodiments 1-22, wherein the subject’s serum level of A4 is reduced by > 50% from baseline.Embodiment 24. The method of any one of Embodiments 1-23, wherein the subject’s serum level of A4 is reduced by > 75% from baseline.Embodiment 25. The method of any one of Embodiments 1-24, wherein the subject’s serum level of A4 is reduced to < 120% of baseline.Embodiment 26. The method of any one of Embodiments 1-25, wherein the subject's serum level of A4 is measured after GC therapy.Embodiment 27. The method of any one of Embodiments 1-25, wherein the subject’s serum level of A4 is measured before GC therapy.Embodiment 28. The method of any one of Embodiments 1-27, wherein the subject’s serum level of A4 is a morning serum level of A4.Embodiment 29. The method of any one of Embodiments 1-28, wherein treating comprises reducing the subject’s serum level of 17-hy dr oxy progesterone (17-OHP) from baseline.Embodiment 30. The method of any one of Embodiments 1-29, wherein the subject’s serum level of 17-OHP is reduced by > 25% from baseline.Embodiment 31. The method of any one of Embodiments 1-30, wherein the subject’s serum level of 17-OHP is reduced by > 50% from baseline.Docket No. P00044-WO Embodiment 32. The method of any one of Embodiments 1-31, wherein the subject’s serum level of 17-OHP is reduced by > 75% from baseline.Embodiment 33. The method of any one of Embodiments 29-32, wherein the subject’s serum level of 17-OHP is a morning serum level of 17-OHP.Embodiment 34. The method of any one of Embodiments 1-33, wherein treating comprises reducing the subject’s serum levels of one or more of 11 -deoxycorticosterone (11-DOC), 110-hydroxyandrostenedione (11-0HA4), 11 -ketoandrostenedione (l l-ketoA4), 110-hydroxytestosterone (11-OHT), and 11 -ketotestosterone (11-ketoT) from baseline.Embodiment 35. The method of any one of Embodiments 1-34, wherein treating comprises reducing the subject’s serum levels of one or more of testosterone and progesterone from baseline.Embodiment 36. The method of any one of Embodiments 1-35, wherein treating comprises reducing the subject’s serum level of testosterone from baseline.Embodiment 37. The method of any one of Embodiments 1 -36, wherein treating comprises reducing the subject’s serum level of progesterone from baseline.Embodiment 38. The method of any one of Embodiments 1-37, wherein treating comprises reducing the subject’s serum levels of one or more of cortisol and 21-deoxy cortisol from baseline.Embodiment 39. The method of any one of Embodiments 1-38, wherein treating comprises reducing the subject’s serum level of one or more of renin and aldosterone from baseline.Embodiment 40. The method of any one of Embodiments 1-39, wherein treating comprises reducing the aldosterone / renin ratio from baseline.Embodiment 41. The method of any one of Embodiments 1 -40, wherein treating comprises reducing the luteinizing hormone (LH) / follicle-stimulating hormone (FSH) ratio from baseline. Embodiment 42. The method of any one of Embodiments 1-41, wherein the subject has acne. Embodiment 43. The method of any one of Embodiments 4-42, wherein the subject reports their acne has improved following administration of atumelnant, or a pharmaceutically acceptable salt thereof.Embodiment 44. The method of any one of Embodiments 1-43, wherein treating comprises reducing the subject’s adrenal gland size from baseline.Docket No. P00044-WO Embodiment 45. The method of any one of Embodiments 1-44, wherein treating comprises reducing the subject’s waist circumference from baseline.Embodiment 46. The method of any one of Embodiments 1-45, wherein treating comprises reducing the subject’s body mass index (BMI) from baseline.Embodiment 47. The method of any one of Embodiments 1-46, wherein treating comprises reducing the subject’s serum level of hemoglobin A1C (HbAlC) from baseline.Embodiment 48. The method of any one of Embodiments 1-47, wherein treating comprises reducing the subject’s blood pressure from baseline.Embodiment 49. The method of any one of Embodiments 1-48, wherein treating comprises reducing the subject’s lipid levels from baseline.Embodiment 50. The method of Embodiment 49, wherein the lipids are selected from one or more of total cholesterol, triglycerides, high-density lipoprotein, and low-density lipoprotein. Embodiment 51. The method of any one of Embodiments 1-50, wherein treating comprises increasing the subject’s bone mineral density (BMD) from baseline.Embodiment 52. The method of any one of Embodiments 1-51, wherein treating comprises increasing the subject’s markers of bone resorption from baseline.Embodiment 53. The method of Embodiment 52, wherein the markers of bone resorption are selected from N-telopeptide (NTX), C-telopeptide (CTX), and pyndinoline cross-links.Embodiment 54. The method of any one of Embodiments 1-53, wherein treating comprises increasing the subject’s markers of bone formation from baseline.Embodiment 55. The method of Embodiment 54, wherein the markers of bone formation are selected from bone-specific alkaline phosphatase (BSAP), osteocalcin, and serum procollagen type 1 N-terminal propeptide (P1NP).Embodiment 56. The method of any one of Embodiments 1-55, wherein treating comprises decreasing bone turnover (osteocalcin) from baseline.Embodiment 57. The method of any one of Embodiments 1-38, wherein the subject’s reproductive function improves.Embodiment 58. The method of any one of Embodiments 1-57, wherein the subject is male. Embodiment 59. The method of Embodiment 58, wherein treating comprises reducing the subject’s serum ratio of A4 / testosterone from baseline.Docket No. P00044-WO Embodiment 60. The method of any one of Embodiments 58-59, wherein the subject has testicular adrenal rests tumor (TART).Embodiment 61. The method of Embodiment 60, wherein the subject’s TART has reduced in size from baseline.Embodiment 62. The method of any one of Embodiments 57-61, wherein the subject’s sperm count improves from baseline.Embodiment 63. The method of any one of Embodiments 1-57, wherein the subject is female. Embodiment 64. The method of Embodiment 63, wherein the subject has hirsutism.Embodiment 65. The method of any one of Embodiments 4-64, wherein the subject reports their hirsutism has improved following administration of atumelnant, or a pharmaceutically acceptable salt thereof.Embodiment 66. The method of any one of Embodiments 63-65, wherein the subject has menstrual dysfunction.Embodiment 67. The method of Embodiment 66, wherein the subject reports their menstrual dysfunction has improved following administration of atumelnant, or a pharmaceutically acceptable salt thereof.Embodiment 68. The method of any one of Embodiments 63-67, wherein the subject is female and treating comprises reducing the subject’s level of progesterone from baseline.Embodiment 69. The method of Embodiment 68, wherein the subject’s level of progesterone is sufficiently reduced to improve the subject’s fertility.Embodiment 70. The method of any one of Embodiments 63-69, wherein the subject begins menstruating normally following administration of atumelnant, or a pharmaceutically acceptable salt thereof.Embodiment 71. The method of any one of Embodiments 63-70, wherein the subject is not using contraception.Embodiment 72. The method of Embodiment 71, wherein the contraception is selected from hormonal and an intrauterine device.Embodiment 73. The method of any one of Embodiments 4-72, wherein atumelnant, or a pharmaceutically acceptable salt thereof, is administered as a daily dose.Embodiment 74. The method of Embodiment 73, wherein the daily dose of atumelanant is equivalent to 80 mg of atumelnant free base.Docket No. P00044-WO Embodiment 75. The method of Embodiment 74, wherein the daily dose of atumelnant is increased by an amount equivalent to 40 mg of atumelnant free base.Embodiment 76. The method of any one of Embodiments 4-73, wherein the daily dose of atumelanant is equivalent to 120 mg of atumelnant free base.Embodiment 77. The method of any one of Embodiments 74-76, wherein atumelnant, or a pharmaceutically acceptable salt thereof, is administered as a single daily dose.Embodiment 78. The method of any one of Embodiments 4-77, wherein the atumelnant is a pharmaceutically acceptable salt of atumelnant.Embodiment 79. The method of Embodiment 78, wherein the pharmaceutically acceptable salt of atumelnant is atumelnant maleate.Embodiment 80. The method of any one of Embodiments 1, 3-5, and 6-79, wherein the subject has hyperandrogenism.Embodiment 81. The method of any one of Embodiments 1-80, wherein the subject has polycythemia.Embodiment 82. The method of Embodiment 80, wherein treating comprises resolving the subject’s polycythemia.Embodiment 83. The method of Embodiment 80, wherein treating comprises improving the subject’s polycythemia.Embodiment 84. The method of any one of Embodiments 1-83, wherein the dose of the GC is a daily dose of GC.Embodiment 85. A pharmaceutical composition for use in treating a subject with congenital adrenal hyperplasia (CAH) on a physiologic dose of a glucocorticoid (GC), wherein the composition comprises an adrenocorticotropic hormone (ACTH) antagonist.Embodiment 86. Use of an adrenocorticotropic hormone (ACTH) antagonist in the manufacture of a medicament for treating a subject with congenital adrenal hyperplasia (CAH) on a physiologic dose of a glucocorticoid (GC).Embodiment 87. A pharmaceutical composition for use in treating a subject with congenital adrenal hyperplasia (CAH) on a physiologic dose of a glucocorticoid (GC). wherein the composition comprises atumelnant, or a pharmaceutically acceptable salt thereof.Docket No. P00044-WO Embodiment 88. Use of atumelnant, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a subject with congenital adrenal hyperplasia (CAH) on a physiologic dose of a glucocorticoid (GC).

Claims

Docket No. P00044-WO CLAIMS WHAT IS CLAIMED IS:

1. A method of treating congenital adrenal hyperplasia (CAH) in a subject on glucocorticoid (GC) therapy comprising administering to the subject an adrenocorticotropic hormone (ACTH) antagonist; wherein the subject is > 18 years of age; wherein GC therapy comprises administering to the subject a dose of a GC; and wherein the dose of the GC is reduced following administration of the ACTH antagonist.

2. A method of treating hyperandrogenism in a subject with CAH on glucocorticoid (GC) therapy comprising administering to the subject an adrenocorticotropic hormone (ACTH) antagonist; wherein the subject is > 18 years of age; wherein GC therapy comprises administering to the subject a dose of a GC; and wherein the dose of the GC is reduced following administration of the ACTH antagonist.

3. The method of claim 1 or 2, wherein the ACTH antagonist is an insurmountable ACTH antagonist.

4. The method of any one of claims 1-3, wherein the dose of the GC is > 11 mg / m2 / day prior to administration of the ACTH antagonist.

5. The method of any one of claims 1-4, wherein the dose of the GC is > 14 mg / m2 / day prior to administration of the ACTH antagonist.

6. The method of any one of claims 1-5, wherein the dose of the GC is reduced following administration of the ACTH antagonist via one or more reductions of the dose of the GC.

7. The method of any one of claims 1-6, wherein a reduction of the dose of the GC is done following administration of the ACTH antagonist for at least 2 weeks.

8. The method of any one of claims 1-7, wherein a reduction of the dose of the GC is done following administration of the ACTH antagonist for at least 5 weeks.

9. The method of any one of claims 1-8, wherein a reduction of the dose of the GC is done following administration of the ACTH antagonist for at least 8 weeks.

10. The method of any one of claims 1-8, wherein a reduction of the dose of the GC is done following administration of the ACTH antagonist for at least 12 weeks.

11. The method of any one of claims 1-10, wherein the dose of the GC is reduced to a minimum amount to be therapeutically effective following administration of the ACTH antagonist for at least 16 weeks.Docket No. P00044-WO 12. The method of any one of claims 1-10, wherein the dose of the GC is reduced to a minimum amount to be therapeutically effective following administration of the ACTH antagonist for at least 28 weeks.

13. The method of any one of claims 1-12, wherein the dose of the GC is reduced to a physiologic dose following administration of the ACTH antagonist for at least 32 w eeks.

14. The method of claim 11 or 12, wherein the dose of the GC is reduced to a physiologic dose.

15. The method of claim 13 or- 14, wherein the physiologic dose of the GC is < 11 mg / m2 / day.

16. The method of any one of claims 1-15, wherein the GC is selected from the group consisting of hydrocortisone, prednisolone, prednisone, and methylprednisolone.

17. The method of any one of claims 1-16. wherein treating comprises reducing the subject’s serum level of androstenedione (A4) from baseline.

18. The method of claim 17, wherein the subject's serum level of A4 is reduced from baseline to < upper limit of normal (ULN).

19. The method of claim 18, wherein the subject's serum level of A4 is reduced by > 25% from baseline.

20. The method of claim 18, wherein the subject’s serum level of A4 is reduced by > 50% from baseline.

21. The method of claim 18, wherein the subject’s serum level of A4 is reduced by > 75% from baseline.

22. The method of any one of claims 17-21, wherein the subject’s serum level of A4 is reduced to < 120% of baseline.

23. The method of any one of claims 17-22, wherein the subject’s serum level of A4 is a morning serum level of A4.

24. The method of any one of claims 1-23, wherein treating comprises reducing the subject’s serum level of 17 -hydroxy progesterone (17-OHP) from baseline.

25. The method of claim 24, wherein the subject’s serum level of 17-OHP is reduced by > 25% from baseline.

26. The method of claim 24, wherein the subject’s serum level of 17-OHP is reduced by > 50% from baseline.Docket No. P00044-WO 27. The method of claim 24, wherein the subject’s serum level of 17-OHP is reduced by > 75% from baseline.

28. The method of any one of claims 24-27 wherein the subject’s serum level of 17-OHP is a morning serum level of 17-OHP.

29. The method of any one of claims 1-28, wherein treating comprises reducing the subject’s serum levels of one or more of 11 -deoxycorticosterone (11-DOC), 1 ip-hydroxy androstenedione (11-0HA4), 11 -ketoandrostenedione (ll-ketoA4), lip-hydroxytestosterone (11-OHT), and 11-ketotestosterone (11-ketoT) from baseline.

30. The method of any one of claims 1-29. wherein treating comprises reducing the subject’s serum levels of one or more of testosterone and progesterone from baseline.

31. The method of any one of claims 1-29. wherein treating comprises reducing the subject's serum level of testosterone from baseline.

32. The method of any one of claims 1-29. wherein treating comprises reducing the subject’s serum level of progesterone from baseline.

33. The method of any one of claims 1-32, wherein treating comprises reducing the subject’s serum levels of one or more of cortisol and 21 -deoxy cortisol from baseline.

34. The method of any one of claims 1-33, wherein treating comprises reducing the subject’s serum level of one or more of renin and aldosterone from baseline.

35. The method of any one of claims 1-34, wherein treating comprises reducing the aldosterone / renin ratio from baseline.

36. The method of any one of claims 1-35, wherein treating comprises reducing the luteinizing hormone (LH) / follicle-stimulating hormone (FSH) ratio from baseline.

37. The method of any one of claims 1-36, wherein the subject has acne.

38. The method of claim 37, wherein the subject reports their acne has improved following administration of the ACTH antagonist.

39. The method of any one of claims 1-38, wherein treating comprises reducing the subject’s adrenal gland size from baseline.

40. The method of any one of claims 1-39, wherein treating comprises reducing the subject’s waist circumference from baseline.

41. The method of any one of claims 1-40, wherein treating comprises reducing the subject’s body mass index (BMI) from baseline.Docket No. P00044-WO 42. The method of any one of claims 1-41. wherein treating comprises reducing the subject’s serum level of hemoglobin A1C (HbAlC) from baseline.

43. The method of any one of claims 1-42, wherein treating comprises reducing the subject’s blood pressure from baseline.

44. The method of any one of claims 1-43, wherein treating comprises reducing the subject’s lipid levels from baseline.

45. The method of claim 44, wherein the lipids are selected from one or more of total cholesterol, triglycerides, high-density lipoprotein, and low-density lipoprotein.

46. The method of any one of claims 1-45, wherein treating comprises increasing the subject’s bone mineral density (BMD) from baseline.

47. The method of any one of claims 1-46, wherein treating comprises increasing the subject’s markers of bone resorption from baseline.

48. The method of 47, wherein the markers of bone resorption are selected from N-telopeptide (NTX). C-telopeptide (CTX), and pyridinoline cross-links.

49. The method of any one of claims 1-48. wherein treating comprises increasing the subject's markers of bone formation from baseline.

50. The method of 49, wherein the markers of bone formation are selected from bonespecific alkaline phosphatase (BSAP), osteocalcin, and serum procollagen type 1 N-terminal propeptide (P1NP).

51. The method of any one of claims 1-50, wherein treating comprises decreasing bone turnover (osteocalcin) from baseline.

52. The method of any one of claims 1-51, wherein the subject’s reproductive function improves.

53. The method of any one of claims 1-52, wherein the subject is male.

54. The method of claim 53, wherein treating comprises reducing the subject’s serum ratio of A4 / testosterone from baseline.

55. The method of claim 53 or 54, wherein the subject has testicular adrenal rests tumor (TART).

56. The method of claim 55, wherein the subject’s TART has reduced in size from baseline.

57. The method of any one of claims 53-56, wherein the subject’s sperm count improves from baseline.Docket No. P00044-WO 58. The method of any one of claims 1-52, wherein the subject is female.

59. The method of claim 58, wherein the subject has hirsutism.

60. The method of claim 59, wherein the subject reports their hirsutism has improved following administration of the ACTH antagonist.

61. The method of any one of claims 58-60, wherein the subject has menstrual dysfunction.

62. The method of claim 61, wherein the subject reports their menstrual dysfunction has improved following administration of the ACTH antagonist.

63. The method of any one of claims 58-62, wherein treating comprises reducing the subject’s level of progesterone from baseline.

64. The method of claim 63, wherein the subject’s level of progesterone is sufficiently reduced to improve the subject’s fertility.

65. The method of any one of claims 58-64, wherein the subject begins menstruating normally following administration of the ACTH antagonist.

66. The method of any one of claims 58-65, wherein the subject is not using contraception.

67. The method of claim 66, wherein the contraception is selected from hormonal and an intrauterine device.

68. The method any one of claims 1-67, wherein the ACTH antagonist is administered as a daily dose.

69. The method of claim 1 , wherein the subject has hyperandrogenism.

70. The method of any one of claims 1-69, wherein the subject has polycythemia.

71. The method of claim 70, wherein treating comprises resolving the subject’s polycythemia.

72. The method of claim 70, wherein treating comprises improving the subject’s polycythemia.

73. The method of any one of claims 1-72, wherein the dose of the GC is a daily dose of GC.

74. The method of any one of claims 1-73, wherein the ACTH antagonist is atumelnant or a pharmaceutically acceptable salt thereof.

75. The method of claim 74, wherein the daily dose of atumelnant, or the pharmaceutically acceptable salt thereof, is equivalent to 80 mg of atumelnant free base.Docket No. P00044-WO 76. The method of claim 75. wherein the daily dose of atumelnant, or the pharmaceutically acceptable salt thereof, is increased by an amount equivalent to 40 mg of atumelnant free base.

77. The method of claim 74, wherein the daily dose of atumelnant, or the pharmaceutically acceptable salt thereof, is equivalent to 120 mg of atumelnant free base.

78. The method of any one of claims 74-77, wherein atumelnant, or a pharmaceutically acceptable salt thereof, is administered as a single daily dose.

79. The method of any one of claims 74-78, wherein the pharmaceutically acceptable salt of atumelnant is atumelnant maleate.

80. A pharmaceutical composition for use in treating a subject with congenital adrenal hyperplasia (CAH) on a physiologic dose of a glucocorticoid (GC), wherein the subject is > 18 years of age and wherein the composition comprises an adrenocorticotropic hormone (ACTH) antagonist.

81. Use of an adrenocorticotropic hormone (ACTH) antagonist in the manufacture of a medicament for treating a subject with congenital adrenal hyperplasia (CAH) on a physiologic dose of a glucocorticoid (GC), wherein the subject is > 18 years of age.

82. A pharmaceutical composition for use in treating a subject with congenital adrenal hyperplasia (CAH) on a physiologic dose of a glucocorticoid (GC), wherein the subject is > 18 years of age and wherein the composition comprises atumelnant or a pharmaceutically acceptable salt thereof.

83. Use of atumelnant, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a subject with congenital adrenal hyperplasia (CAH) on a physiologic dose of a glucocorticoid (GC), wherein the subject is > 18 years of age.

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