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. P00045-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 / 777,857, filed on March 26, 2025; U.S. Provisional Patent Application No. 63 / 837,255, filed on July 2, 2025; U.S. Provisional Patent Application No. 63 / 947,669, filed on December 23, 2025; and U.S. Provisional Patent Application No. 63 / 961.733, filed on January 16. 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 overtreatment 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. P00045-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. P00045-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 > 15 mg / m2 / day prior to administration of atumelnant or a pharmaceutically acceptable salt tereof.

[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, reduction of the dose of the GC is done following 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 a GC. 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), 11 (3-hydroxy androstenedione (11-0HA4), 11-Docket No. P00045-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. P00045-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.

[0045] In some embodiments, the daily dose of atumelnant, or a pharmaceutically acceptable salt thereof, is equivalent to 6-80 mg of atumelnant free base. In some embodiments, the daily dose of atumelnant, or a pharmaceutically acceptable salt thereof, is equivalent to 6-48 mg ofDocket No. P00045-WO atumelnant free base. In some embodiments, the daily dose of atumelnant, or a pharmaceutically acceptable salt thereof, is equivalent to 40-80 mg of atumelnant free base.

[0046] 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.

[0047] In some embodiments, the subject has hyperandrogenism.

[0048] 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.

[0049] In some embodiments, the subject is an infant, a toddler, a child, or a teenager.

[0050] In some embodiments, treating includes preventing premature growth plate closure.

[0051] In some embodiments, treating includes preventing premature puberty.

[0052] In some embodiments, the dose of the GC is a daily dose of GC.

[0053] 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.

[0054] 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).

[0055] 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.

[0056] 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

[0057] FIG. 1 shows the design schema of the pediatric study.

[0058] FIG. 2 show s the inability to produce cortisol leads to loss of negative feedback and excess adrenocorticotropic hormone in those with congenital adrenal hyperplasia.Docket No. P00045-WO

[0059] FIG. 3 shows the part A study schema.

[0060] FIG. 4 shows the part B study schema.

[0061] FIG. 5 shows the part C study schema.

[0062] FIG. 6 shows the change From Baseline in Total Adrenal Volume Per Patient from an adult phase 2 study.DETAILED DESCRIPTION

[0063] 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 understand that the invention may be practiced without these details. In other instances, w ell-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 word '“comprise’7and 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.

[0064] 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.

[0065] 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.

[0066] As used herein, “about” means ±10% of the stated value, and includes more specifically values of ±5%, ±2%, and ±1% of the stated value.

[0067] 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.

[0068] 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 itsDocket No. P00045-WO parts that impairs normal functioning, and is typically manifested by distinguishing signs and symptoms.

[0069] 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.

[0070] 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.

[0071] As used herein, atumelnant refers to a compound having the structure of Formula (I) shown below:Formula (I).

[0072] Atumelnant is also known as CRN04894, CRN04894 free base. A-[(3S)-1-Azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2J?)-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-[(2 / ?)-2-ethyl-4-[l-(trifluoromethyl)cyclobutanecarbonyl]-piperazin-l-yl]pyridine-2-carboxamide free base. 6-(2-Ethoxyphenyl)-3-((7?)-2-ethyl-4-(l-(trifluoromethyl)cyclobutane-l-carbonyl)piperazin-l-yl)-N-((S)-quinuclidin-3-yl)picolinamide, and 6-(2-Ethoxyphenyl)-3-((J?)-2-ethyl-4-(l -(trifluoromethyl)cyclobutane-l-carbonyl)piperazin-l-yl)-N-((S)-quinuclidin-3-yl)picolinamide free base.

[0073] 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 freeDocket No. P00045-WO 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).

[0074] 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).

[0075] 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 a pediatric subject (i. e. , < 18 years of age).

[0076] As used herein, “pharmaceutically acceptable” refers 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.

[0077] 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 anDocket No. P00045-WO 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.

[0078] 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, ethnicity7, race, target illness, abnormalities of renal or hepatic function, 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).

[0079] As used herein, “treating” or “treatment” refers to therapeutic applications to slow or stop progression of a disorder, and / or alleviate symptoms thereof.

[0080] As used herein, “infant” refers to a human subject from birth to the first year of life.

[0081] As used herein, “toddler” refers to a human subject typically between 1 and 3 years old.

[0082] As used herein, “child” refers to a human subject typically between 4 and 12 years old.

[0083] As used herein, “teenager” refers to a human subject between 13 and 18 years old.

[0084] Methods of Treatment

[0085] Disclosed herein is a method of treating congenital adrenal hyperplasia (C AH) 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.

[0086] 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.

[0087] In certain embodiments, the GC is reduced via one or more reductions of the dose of the GCDocket No. P00045-WO

[0088] In certain embodiments, a dose 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.

[0089] 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.

[0090] In certain embodiments, the ACTH antagonist is an insurmountable ACTH antagonist.

[0091] In certain embodiments, the ACTH antagonist is atumelnant, or a pharmaceutically acceptable salt thereof.

[0092] In certain embodiments, the ACTH antagonist is administered in the morning. In certain embodiments atumelnant, or a pharmaceutically acceptable salt thereof, is administered in the morning.

[0093] 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.

[0094] 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.

[0095] In certain embodiments, the GC is reduced via one or more GC dose reductions.

[0096] 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 certainDocket No. P00045-WO 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 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 12 weeks.

[0097] 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 weeks. 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.

[0098] 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 > 15 mg / m2 / day prior to administration of atumelnant, or a pharmaceutically acceptable salt thereof.

[0099] 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.

[0100] In certain embodiments, the dose of the GC is a daily dose of GC.

[0101] 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.Docket No. P00045-WO

[0102] 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.

[0103] In certain embodiments, the subject’s serum level of A4 is reduced to < 120% of baseline.

[0104] 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.

[0105] In certain embodiments, the dose of the GC is > 11 mg / m2 / day. In certain embodiments, the subject’s serum level of A4 is reduced by < 20% from baseline. In certain embodiments, the subject’s serum level of A4 is reduced by < 20%, and the subject’s GC dose is reduced by 1 to 2 mg / m2 / day. In certain embodiments, the subject’s serum level of A4 is reduced by < 20%, and the subject’s GC dose is reduced by 1 mg / m2 / day. In certain embodiments, the subject’s serum level of A4 is reduced by < 20%, and the subject’s GC dose is reduced by 2 mg / m2 / day. In certain embodiments, the subject’s serum level of A4 is reduced by >20% to <40% from baseline. In certain embodiments, the subject’s serum level of A4 is reduced by >20% to <40% from baseline, and the subject’s GC dose is reduced by 2 to 3 mg / m2 / day. In certain embodiments, the subject’s serum level of A4 is reduced by >20% to <40% from baseline, and the subject’s GC dose is reduced by 2 mg / m2 / day. In certain embodiments, the subject’s serum level of A4 is reduced by >20% to <40% from baseline, and the subject’s GC dose is reduced by 3 mg / m2 / day. In certain embodiments, the subject’s serum level of A4 is reduced by >40% from baseline. In certain embodiments, the subject’s serum level of A4 is reduced by >40% from baseline, and the subject’s GC dose is reduced by 3 to 4 mg / m2 / day. In certain embodiments, the subject’s serum level of A4 is reduced by >40% from baseline, and the subject’s GC dose isDocket No. P00045-WO reduced by 3 mg / m2 / day. In certain embodiments, the subject’s serum level of A4 is reduced by >40% from baseline, and the subject’s GC dose is reduced by 4 mg / m2 / day.

[0106] In certain embodiments, the subject’s serum level of A4 is a morning serum level of A4.

[0107] 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.

[0108] 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.

[0109] In certain embodiments, the subject’s serum level of 17-OHP is a morning serum level of 17-OHP.

[0110] In certain embodiments, treating comprises reducing the subject’s serum levels of one or more of 11 -deoxycorticosterone (11-DOC), 1 l(3-hydroxy androstenedione (11-OHA4), 11-ketoandrostenedione (ll-ketoA4), 110-hydroxy testosterone (11-OHT), and 11 -keto testosterone (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 lip-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 11 |3-hydroxy testosterone (11-OHT) from baseline. In certain embodiments, treating comprises reducing the subject’s serum levels of 11-ketotestosterone (11-ketoT) from baseline.Docket No. P00045-WO

[0111] 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-OHA4 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% from baseline. In certain embodiments, treating comprises reducing the subject’s serum levels of 11-OHA4 by at least 75% from baseline. In certain embodiments, treating comprises reducing the subject’s serum levels of 11-OHA4 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.

[0112] 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 the 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.

[0113] In certain embodiments, treating comprises reducing the subject’s serum levels of one or more of testosterone and progesterone from baseline.Docket No. P00045-WO

[0114] 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.

[0115] In certain embodiments, treating comprises reducing the subject’s serum level of progesterone from baseline.

[0116] In certain embodiments, comprises reducing the subject’s serum levels of one or more of cortisol and 21 -deoxy cortisol from baseline. In certain embodiments, comprises reducing the subject’s serum levels of cortisol from baseline. In certain embodiments, comprises reducing the subject’s serum levels of 21 -deoxy cortisol from baseline.

[0117] In certain embodiments, treating comprises reducing the subject’s serum level of one or more of renin and aldosterone from baseline.

[0118] In certain embodiments, treating comprises reducing the aldosterone / renin ratio from baseline.

[0119] In certain embodiments, treating comprises reducing the luteinizing hormone (LH) / follicle-stimulating hormone (FSH) ratio from baseline.

[0120] 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.

[0121] In certain embodiments, the sum of the left and right adrenal gland volumes is referred to as adrenal gland size.

[0122] 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 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 leastDocket No. P00045-WO 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.

[0123] 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 least 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.

[0124] 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.

[0125] In certain embodiments, treating comprises reducing the subject’s serum level of hemoglobin A1C (HbAlC) from baseline.

[0126] In certain embodiments, treating comprises reducing the subject’s blood pressure from baseline.Docket No. P00045-WO

[0127] 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.

[0128] In certain embodiments, treating comprises increasing the subject’s bone mineral density (BMD) from baseline.

[0129] 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 certain embodiments, the marker of bone resorption is C-telopeptide (CTX). In certain embodiments, the marker of bone resorption is pyridinoline cross-links.

[0130] 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 ty pe 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).

[0131] In certain embodiments, treating comprises decreasing bone turnover (osteocalcin) from baseline.

[0132] In certain embodiments, the subject’s reproductive function improves.

[0133] 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.

[0134] 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 ofDocket No. P00045-WO 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.

[0135] 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.

[0136] In certain embodiments, the subject’s Modified Ferriman-Gallwey visual analog scale is reduced following administration of the ACTH antagonist. In certain embodiments, the subject’s Modified Ferriman-Gallwey visual analog scale is reduced following administration of the insurmountable ACTH antagonist. In certain embodiments, the subject’s Modified Ferriman-Gallwey visual analog scale is reduced following administration of atumelnant, or a pharmaceutically acceptable salt thereof.

[0137] In certain embodiment’s the subject’s Modified Ferriman-Gallwey visual analog scale at baseline is > 8.

[0138] In certain embodiments, the subject’s Modified Ferriman-Gallwey visual analog scale is reduced by an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31. 32. 33, 34, 35, or 36 from baseline.

[0139] In certain embodiments, the subject’s Modified Ferriman-Gallwey visual analog scale for the upper lip is reduced by an integer selected from 1. 2, 3, or 4 from baseline.

[0140] In certain embodiments, the subject's Modified Ferriman-Gallwey visual analog scale for the chin is reduced by an integer selected from 1, 2, 3, or 4 from baseline.

[0141] In certain embodiments, the subject’s Modified Ferriman-Gallwey visual analog scale for the chest is reduced by an integer selected from 1, 2, 3, or 4 from baseline.

[0142] In certain embodiments, the subject’s Modified Ferriman-Gallwey visual analog scale for the arm is reduced by an integer selected from 1, 2, 3, or 4 from baseline.Docket No. P00045-WO

[0143] In certain embodiments, the subject’s Modified Ferriman-Gallwey visual analog scale for the upper abdomen is reduced by an integer selected from 1, 2, 3, or 4 from baseline.

[0144] In certain embodiments, the subject’s Modified Ferriman-Gallwey visual analog scale for the lower abdomen is reduced by an integer selected from 1, 2, 3, or 4 from baseline.

[0145] In certain embodiments, the subject’s Modified Ferriman-Gallwey visual analog scale for the upper back is reduced by an integer selected from 1, 2, 3, or 4 from baseline.

[0146] In certain embodiments, the subject’s Modified Ferriman-Gallwey visual analog scale for the lower back is reduced by an integer selected from 1, 2, 3, or 4 from baseline.

[0147] In certain embodiments, the subject’s Modified Ferriman-Gallwey visual analog scale for the thighs is reduced by an integer selected from 1, 2, 3, or 4 from baseline.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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. P00045-WO the contraception is hormonal. In certain embodiments, the contraception is an intrauterine device.

[0152] In certain embodiments, the atumelnant, or a pharmaceutically acceptable salt thereof, is administered as a daily dose.

[0153] In certain embodiments, the daily dose of atumelnant is equivalent to 6 mg to 80 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is equivalent to 12 mg to 80 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is equivalent to 24 mg to 80 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is equivalent to 40 mg to 80 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is equivalent to 48 mg to 80 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is equivalent to 6-48 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is equivalent to 12-48 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is equivalent to 24-48 mg of atumelnant free base.

[0154] In certain embodiments, the daily dose of atumelnant is equivalent to 6 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is equivalent to 12 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is equivalent to 24 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is equivalent to 40 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is equivalent to 48 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is equivalent to 80 mg of atumelnant free base.

[0155] In certain embodiments, the daily dose of atumelnant is increased by an amount equivalent to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 12, 18, 20, 24, 30, 36, 40, 42, 46, or 48 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is increased by an amount equivalent to 1 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is increased by an amount equivalent to 2 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is increased by an amount equivalent to 3 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is increased by an amount equivalent to 4 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is increased by an amount equivalent to 5 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is increased by an amount equivalent to 6 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is increased by an amount equivalent to 7 mg of atumelnant free base. In certain embodiments, the daily dose ofDocket No. P00045-WO atumelnant is increased by an amount equivalent to 8 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is increased by an amount equivalent to 9 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is increased by an amount equivalent to 10 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is increased by an amount equivalent to 11 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is increased by an amount equivalent to 12 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is increased by an amount equivalent to 18 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is increased by an amount equivalent to 20 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is increased by an amount equivalent to 24 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is increased by an amount equivalent to 30 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is increased by an amount equivalent to 36 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is increased by an amount equivalent to 40 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is increased by an amount equivalent to 42 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is increased by an amount equivalent to 46 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is increased by an amount equivalent to 48 mg of atumelnant free base.

[0156] In certain embodiments, the daily dose of atumelnant is increased following 1-28 weeks of administration of atumelnant. In certain embodiments, the daily dose of atumelnant is increased following 1 week of administration of atumelnant. In certain embodiments, the daily dose of atumelnant is increased following 2 weeks of administration of atumelnant. In certain embodiments, the daily dose of atumelnant is increased following 3 weeks of administration of atumelnant. In certain embodiments, the daily dose of atumelnant is increased following 4 weeks of administration of atumelnant. In certain embodiments, the daily dose of atumelnant is increased follow ing 5 weeks of administration of atumelnant. In certain embodiments, the daily dose of atumelnant is increased following 6 weeks of administration of atumelnant. In certain embodiments, the daily dose of atumelnant is increased following 7 weeks of administration of atumelnant. In certain embodiments, the daily dose of atumelnant is increased following 8 w eeks of administration of atumelnant. In certain embodiments, the daily dose of atumelnant is increased following 9 weeks of administration of atumelnant. In certain embodiments, the daily¬ dose of atumelnant is increased following 10 weeks of administration of atumelnant. In certain embodiments, the daily dose of atumelnant is increased following 11 weeks of administration ofDocket No. P00045-WO atumelnant. In certain embodiments, the daily dose of atumelnant is increased following 12 weeks of administration of atumelnant. In certain embodiments, the daily dose of atumelnant is increased following 13 weeks of administration of atumelnant. In certain embodiments, the daily dose of atumelnant is increased following 14 weeks of administration of atumelnant. In certain embodiments, the daily dose of atumelnant is increased following 15 weeks of administration of atumelnant. In certain embodiments, the daily dose of atumelnant is increased following 16 w eeks of administration of atumelnant. In certain embodiments, the daily dose of atumelnant is increased following 17 w eeks of administration of atumelnant. In certain embodiments, the daily¬ dose of atumelnant is increased following 18 weeks of administration of atumelnant. In certain embodiments, the daily dose of atumelnant is increased following 19 weeks of administration of atumelnant. In certain embodiments, the daily dose of atumelnant is increased following 20 weeks of administration of atumelnant. In certain embodiments, the daily dose of atumelnant is increased following 21 w eeks of administration of atumelnant. In certain embodiments, the daily dose of atumelnant is increased following 22 weeks of administration of atumelnant. In certain embodiments, the daily dose of atumelnant is increased following 23 w eeks of administration of atumelnant. In certain embodiments, the daily dose of atumelnant is increased following 24 weeks of administration of atumelnant. In certain embodiments, the daily dose of atumelnant is increased following 25 weeks of administration of atumelnant. In certain embodiments, the daily dose of atumelnant is increased following 26 weeks of administration of atumelnant. In certain embodiments, the daily dose of atumelnant is increased following 27 w eeks of administration of atumelnant. In certain embodiments, the daily dose of atumelnant is increased following 28 weeks of administration of atumelnant.

[0157] In certain embodiments, the daily dose of atumelnant is equivalent to 80 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant is increased by an amount equivalent to 40 mg of atumelnant free base. In certain embodiments, the daily dose of atumelnant 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.

[0158] In certain embodiments, the atumelnant is a pharmaceutically acceptable salt of atumelnant. In certain embodiments, the pharmaceutically acceptable salt of atumelnant is atumelnant maleate.

[0159] In certain embodiments, the subject has hyperandrogenism.Docket No. P00045-WO

[0160] 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.

[0161] In certain embodiments, the CAH is caused by 21 -hydroxylase deficiency.

[0162] In certain embodiments, the subject is concurrently on mineralocorticoid replacement therapy. In certain embodiments, the subject is concurrently on fludrocortisone therapy.

[0163] In certain embodiments, the subject is a pediatric patient. In certain embodiments, the subject is a pediatric patient that weights > 45 kg. In certain embodiments, the subject is a pediatric patient that weights < 45 kg,

[0164] In certain embodiments, the subject is an infant, a toddler, a child, or a teenager. In certain embodiments, the subject is an infant. In certain embodiments, the subject is a toddler. In certain embodiments, the subject is a child. In certain embodiments, the subject is a teenager.

[0165] In certain embodiments, treating comprises preventing premature growth plate closure.

[0166] In certain embodiments, treating comprises preventing premature puberty.

[0167] In certain embodiments, the subject is a human. In certain embodiments, the human is an adult.

[0168] 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.

[0169] 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.

[0170] 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 some 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.Docket No. P00045-WO

[0171] Congenital Adrenal Hyperplasia (CAH)

[0172] Congenital adrenal hyperplasia consists of a group of inborn errors of adrenal steroidogenesis. Deficiency of 21-OHD accounts for 95% of CAH cases. It results in defective conversion of 17-OHP to 11-DOC and leads to hypocortisolism and hyperandrogenism due to the accumulation of the androgen and hormone precursors. The estimated prevalence is 1:15,000 in the adult population and 1:10,000 in the pediatric population.

[0173] Classic CAH presents in the neonatal period. In the absence of newborn screening, males with salt-wasting classic CAH are typically diagnosed within the first 6 months of life and females within the first month of life, due to the virilizing effect of adrenal androgens that can result in ambiguous female genitalia.

[0174] Clinical symptoms are similar in children and adolescents. Simple virilizing CAH, which maintains some mineralocorticoid and GC production, and therefore is not life-threatening in infancy, can present in childhood. Males with simple virilizing classic CAH are typically diagnosed at 2 to 4 years of age, while females are usually diagnosed before 2 years of age.

[0175] Classic CAH due to 21-OHD 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 ACTH levels, which in turn drives excess adrenal androgen production (see FIG. 2). This excess ACTH acting on the adrenal glands results in bilateral adrenal hyperplasia and, due to 21-OHD, steroid precursors such as A4 which can cause clinical hyperandrogenism.

[0176] 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’.

[0177] 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 TARTs in men, and which can be confused with malignant testicular tumors, cause irreversible testicular damage and potential infertility'. There are no therapies to prevent the development of TARTs, other than intensified GC treatment.

[0178] AtumelnantDocket No. P00045-WO

[0179] 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).

[0180] ACTH is a 39-amino acid peptide synthesized by anterior pituitary corticotropic cells and is secreted in response to hypothalamic corti co trophin 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 accessory7protein (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.

[0181] 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. This 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.

[0182] 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.

[0183] 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

[0184] Definitions and Abbreviations

[0185] 11 -DOC'- 11 -deoxycorticosterone;Docket No. P00045-WO

[0186] 11 -keto A4= 11 -ketoandrostenedione;

[0187] 1 l-ketoT=l 1 -ketotestosterone;

[0188] 1 l-0HA4=l 1 (3-hydroxy androstenedione;

[0189] 11-OHT=11 (3-hydroxy testosterone;

[0190] 17-OHP=17-hydroxyprogesterone;

[0191] 25-OH=25-hydroxy;

[0192] A4=androstenedione;

[0193] ACTH=adrenocorticotropic hormone;

[0194] AE=adverse event;

[0195] BMD=bone mineral density;

[0196] BMI=body mass index;

[0197] BSA=body surface area;

[0198] BSAP=bone-specific alkaline phosphatase;

[0199] CAH=congenital adrenal hyperplasia;

[0200] CTX=C-telopeptide;

[0201] DXA=dual energy X-ray absorptiometry;

[0202] ECG=electrocardiogram;

[0203] FSH=follicle-stimulating hormone;

[0204] GC=glucocorticoid;

[0205] HDL=high-density lipoprotein;

[0206] LDL=low-density lipoprotein;

[0207] LH=luteinizing hormone;

[0208] NTX=N-telopeptide;

[0209] PlNP=procollagen type 1 N-terminal propeptide;

[0210] SAE=serious adverse event;

[0211] TART=testicular adrenal rest tumor;

[0212] TEAE=treatment-emergent adverse event;Docket No. P00045-WO

[0213] ULN=upper limit of normal.

[0214] Example 1: A Phase 2 / 3 Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Atumelnant Treatment in Pediatric Participants with Congenital Adrenal Hyperplasia Including a Long-Term Extension

[0215] Number of participants: A total of approximately 153 participants may be enrolled in the study (planned and optional cohorts) ages 1 to < 18 years old. Part A (Phase 2) will enroll a maximum of 48 participants. Part B (Phase 3) will enroll approximately 105 participants.Participants in Part A and B are eligible to enroll in Part C (OLE).

[0216] Study duration: The total duration of each part of the study:

[0217] Part A is up to 18 weeks (6-week Screening Period, 8-week Treatment Period, and 4-week Follow-up Period).

[0218] Part B is up to 38 weeks (6-week Screening Period, 28-week Treatment Period, and 4-week Follow-up Period).

[0219] Part C is up to 5 years; however, duration is dependent on timing of participant enrollment.

[0220] Part A and Part B Key Inclusion Criteria.

[0221] Male or female at birth, 1 to <18 years of age. Diagnosis of classic CAH due to 21-OHD who have been on stable GCs. A4 >ULN. Stable GC replacement (>11 mg / m2 / day hydrocortisone or equivalent) for at least one month prior to Screening. Body weight >10 kg.

[0222] Part C Key Inclusion Criteria:

[0223] Participants that completed Part A or Part B will be able to participate in Part C if, in investigator’s opinion, it would benefit the participant, and regardless of age.

[0224] Part A and Part B Key Exclusion Criteria:

[0225] Other forms of CAH. Poorly controlled diabetes as judged by the Investigator.

[0226] Part A (Phase 2): Open-label, semi-sequential cohorts, dose ranging, pk / pd, 8-week safety and efficacy, dose determination for Part B

[0227] The objectives and safety endpoints of Part A (Phase 2) are disclosed in the table below:Safety Objectives Safety EndpointsDocket No. P00045-WO • To evaluate the safety and tolerability • Incidence of TEAEs, includingof atumelnant in pediatric participants treatment-emergent SAEs and any with CAH AEs leading to discontinuation Primary Efficacy Objective Primary Efficacy Endpoint• To evaluate efficacy of atumelnant, • Change from baseline in morning measured by change from baseline in (before 11 : 00) serum A4 at Week 8 serum A4Secondary Objectives Secondary Endpoints• To evaluate efficacy of atumelnant, • Change from baseline in morning measured by change from baseline in (before 11:00) serum 17-OHP at serum 17-OHP Week 8• To measure the pharmacokinetic • Plasma and / or blood concentrations of profile of atumelnant atumelnant17-OHP=17-hydroxyprogesterone; A4=androstenedione; AE=adverse event; CAH=congenital adrenal hyperplasia; SAE=serious adverse events; TEAE=treatment-emergent adverse events.

[0228] Part A: Overall Study Design'.

[0229] Part A is an open-label, semi-sequential cohort study to evaluate the safety, efficacy, and PK of atumelnant treatment in pediatric participants with classic CAH.

[0230] Up to 4 cohorts may be included. The first 3 cohorts are for ages 12 to <18 years and will be sequential, and SRC review of data and approval to proceed is required prior to enrolling each subsequent cohort. The fourth cohort is for ages 1 to 11 years old and will begin when a suitable pediatric formulation and supporting juvenile toxicology data are available, and following SRC review of Cohorts 1 and 2 data. For each cohort, the study will be comprised of a Screening Period (up to 6 weeks), a Dosing Period (8 weeks), and a Follow-Up Period(4 weeks). An optional open-label, long-term extension period up to 5 years (Part C) will be offered to participants after the Dosing Period. For participants entering the long-term extension study, the Follow-up Period will not need to be completed. All participants will receive atumelnant administered QD as add on to ongoing pre-study GCs and, if applicable, fludrocortisone.

[0231] Eligible participants are those with CAH due to 21-OHD who are 1 to <18 years of age.

[0232] Key aspects of study interventions are disclosed in the table below:Part A: Key Aspects of Study InterventionsIntervention Model: Semi-Sequential cohortsDocket No. P00045-WO Control Method: No controlStudy Intervention Eligible participants will be enrolled in the cohort that is open afterAssignment Method: completion of the Screening period.

[0233] Key aspects of the study populations are disclosed in the table below:Part A: Key Aspects of Study PopulationPopulation Type: Pediatric patients, male and femaleIndication: Classic CAHPopulation Age: 1 to <18 yearsSite Distribution Multi-site and multi-regional

[0234] Part A: Total Number of Participants

[0235] A maximum of 48 participants will be enrolled in Cohorts 1 to 4.

[0236] Dosing and Cohort Advancement

[0237] The 4 cohorts are presented in the following table below:Cohort Age Target SRC Atumelnant Dose (years) Enrollment ApprovalParticipants forInitiation1 12 to Up to 12 No >45 kg: 40 mg QD given in the <18 morninga2 12 to Up to 12 Yes >45 kg: 80 mg QD given in the <18 morninga3 (Optional) 12 to Up to 12 Yes >45 kg: 20 to 80 mg per day <18 frequency TBD4a 6 to 11 Up to 6 Yes >10 kg: 20 to 80 mg QD adult equivalent given in the morning 4b 1 to 5 Up to 6 Yes aDosing based on body weight bracketbQD=once daily; SRC=Safety Review Committee; TBD=to be determinedThe morning dose should be taken at approximately the same time of day, each day throughout the study. Atumelnant and GCs should be taken at approximately the same time (recommend between 7:00 to 9:00 am).bThe doses for Cohorts 4a and 4b are predicted based on individual baseline body weight to result in exposures similar to 20, 40, or 80 mg QD in adults. Target exposure (e.g., 20, 40, or 80 mg QD adult equivalent dose) will be determined based on emerging data from preceding cohorts. These dose predictions may be adjusted based on emerging adult and adolescent data, with an expected dose range between 6 to 80 mg per day.Docket No. P00045-WO

[0238] Part B (Phase 3): Double-blind, randomized, placebo controlled, confirmatory, 28-week safety, efficacy, and pk / pd

[0239] The objectives and safety endpoints of Part B (Phase 3) are disclosed in the table below:Primary Efficacy Objective Primary Efficacy EndpointTo evaluate efficacy of atumelnant in Percent change from baseline in GC daily reducing daily GC dose while dose (in hydrocortisone equivalents, maintaining adrenal androgen control mg / m2 / day) at Week 28 while serum early morning (before 11 :00) A4 < ULN Key Secondary Efficacy Objective Key Secondary Efficacy EndpointsTo evaluate efficacy of atumelnant to Change from baseline in serum early reduce A4 levels and reduce GC dosing morning A4 at Week 4Change from baseline in serum early morning 17-OHP at Week 4 Proportion of participants with physiologic GC dose (<11 mg / m2 / day) while serum early morning A4 <ULN at Week 28 Other Secondary Objectives Other Secondary End pointsTo evaluate efficacy of atumelnant to Percent change from baseline in GC daily reduce GC dosing dose (in hydrocortisone equivalents,mg / m2 / day) at Week 28Proportion of participants with physiologic GC dose at Week 28Percent change from baseline in glucocorticoid daily dose when serum early morning A4 <1.2xBaseline or <ULN at Week 28To measure the pharmacokinetic profile Plasma and blood concentrations of of atumelnant atumelnantTo evaluate atumelnant compared to Change from baseline in QoL at Week 28 placebo in overall QoLSafety Objectives Safety EndpointsTo evaluate the safety' and tolerability of Incidence of TEAEs, including treatment- atumelnant in pediatric participants with emergent-SAEs and any AEs leading to CAH discontinuation17-OHP=17-hydroxyprogesterone; A4=androstenedione; AE=adverse event; CAH=congenital adrenal hyperplasia; GC=glucocorticoid; QoL=quality of life; SAE=serious adverse events; TEAE=treatment-emergent adverse events; ULN=upper limit of normal.

[0240] Part B: Overall Study Design:

[0241] Part B is the double-blind, placebo controlled confirmatory portion of the study to evaluate the safety and efficacy of atumelnant in pediatric participants with classic CAH due toDocket No. P00045-WO 21-OHD. The dose for the study will be determined by Part A. There will be a Screening Period, up to 6-weeks, followed by a placebo controlled, randomized, double-blind approximately 28- week period (participants will be randomized to either atumelnant or placebo in a 2: 1 ratio), followed by an open-label, long-term, safety and efficacy extension period up to 5 years (Part C). If a participant does not want to participate in Part C or the investigator does not think it is in the participant’s best interest, a Follow-Up Period (4 weeks) would be conducted instead.

[0242] Key aspects of study interventions are disclosed in the table below:Intervention Model: Randomized. Parallel Arms, Double-BlindControl Method: Placebo control armStudy Intervention Eligible participants will be randomized by an Interactive Assignment Method: Response Technology solution.Part B: Kev Aspects of Study PopulationPopulation Type: Pediatric patients, male and femaleIndication: Classic CAHPopulation Age: 1 to <18 yearsSite Distribution: Multi-site, multi-regional

[0243] Part B: Methods to Minimize Bias

[0244] Part B is randomized, double-blind, and placebo controlled. The participant, investigator, all study center personnel, and the sponsor will be blinded to the participant’s treatment. Efficacy endpoints are based on laboratory values.

[0245] Part B: Total Number of Participants

[0246] Approximately 105 participants will be randomized.

[0247] Part B: Dosing

[0248] Participants will be dosed based on bracket of body weight: 10 to <25 kg; 25 to <45 kg; >45 kg.

[0249] Part C (OLE): Open-label long-term safety and efficacy for Part A and B participants to move into after completion of Part A or Part B

[0250] The objectives and safety endpoints of Part C (OLE) are disclosed in the table below:Docket No. P00045-WO Primary Efficacy Endpoint

[0251] Primary Efficacy ObjectiveTo evaluate efficacy of atumelnant, Change from baseline in morning measured by change from baseline in (before 11:00) serum A4 over time A4Secondary Efficacy Objectives Secondary Efficacy EndpointsTo evaluate efficacy of atumelnant. Change from baseline in morning measured by change from baseline in (before 11:00) serum 17-OHP over serum 17-OHP timeTo evaluate efficacy of atumelnant, Percent change from baseline in daily as assessed by GC need GC dose (in hydrocortisone equivalents, mg / m2 / day) over time Proportion of participants with physiologic GC dose (<11 mg / m2 / day) while serum early morning A4 <ULN over time.Safety Objectives Safety EndpointsTo evaluate the safety and tolerability Incidence of TEAEs, including of atumelnant treatment-emergent SAEs and any AEs leading to discontinuation Incidence of adrenal insufficiency and adrenal crisisIncidence of hospitalizations related to CAH17-OHP=17-hydroxy progesterone; A4=androstenedione; AE=adverse event; CAH=congenital adrenal hyperplasia; GC=glucocorticoid; SAE=serious adverse events; TEAE=treatment-emergent adverse events.

[0252] Part C: Overall Study Design'.

[0253] Part C is a single-arm, open-label, long-term safety and efficacy study of atumelnant in pediatric participants with classic CAH due to 21-OHD that completed participation in either Part A or Part B of this study.

[0254] Participants will enter directly into this OLE period; there will not be a screening period. The treatment period will be up to 5 years, with a follow-up visit (Final Visit / EOS Visit) at the end of the study.Docket No. P00045-WO

[0255] Participants from Part A will enter Part C and have a day 1 Visit (this is the same day as EOT in Part A) and start a GC taper at week 4 ending at week 16, have a week 18 visit, and then start quarterly visits.

[0256] Participants from Part B will enter Part C and have a day 1 visit (this is the same day as EOT in Part B), then a week 2 and 6 visit and then start quarterly visits.

[0257] Key aspects of study interventions are disclosed in the table below:Intervention Model: Open-label, Single- ArmControl Method: No controlStudy Intervention Eligible participants will continue from either Part A or Part B Assignment Method: and be assigned to atumelnant treatment.Part C: Kev Aspects of Study PopulationPopulation Type: Pediatric patients, male and femaleIndication: Classic CAHPopulation Age: Age 1 year and aboveSite Distribution: Multi-site, multi-regionalPart C: Methods to Minimize BiasPart C is open label. Efficacy endpoints are based on laboratory' values.Part C: Total Number of ParticipantsA maximum of 153 participants will be enrolled.

[0258] Part C: Dosing

[0259] For the Part A participants, the initial dose will be the same as their final dose in the Part A segment. Once a dose is selected for their body weight bracket for Part B, Part C participants will be switched to the dose approved for Part B.

[0260] For the Part B participants, the dose will be the same dose as assigned in Part B based on bracket of body weight: 10 to <25 kg; 25 to <45 kg; >45 kg.

[0261] Atumelnant should be taken in the morning at approximately the same time of day, each day throughout the study, and at approximately the same time as the GCs.

[0262] Once participants are in quarterly visits, additional adjustments to the atumelnant dose may be allowed (within limits) to target A4 to allow for better GC dose reduction to the physiological dose.

[0263] Test Product, Reference Therapy, and Other MedicationsDocket No. P00045-WO

[0264] Test product reference therapy, and other medications are disclosed in the table below:

[0265] Drug Atumelnant Placebo Glucocorticoid Therapy Label Part A, B, and C Part B Part A, B, and C Intervention Atumelnant Control Glucocorticoid Therapy NameDrug Class MC2R competitive Not applicable Corticosteroid antagonistDrug CRN04894 maleate Not applicable Various agents, including Substance hydrocortisone,prednisolone, prednisone, methylprednisolone, dexamethasone Dosage Form Tablet for weight Tablet for weight Variable per participant bracket >45 kg bracket >45 kgAppropriate oral Appropriate oraldosage form for dosage form forweight bracket <45 kg weight bracket <45 kgUnit Dose Variable per Matching Placebo Variable per participant Strength(s) participant based onweightDosage Variable per Matching Placebo Variable per participant Level(s) participant based onweightAdministratio Oral Oral OralnUse Experimental Control Standard of CareIMP and IMP IMP AxMPNIMP / AxMPAxMP=auxiliary medicinal product; IMP=investigational medicina product;MC2R=melanocortin 2 receptor; NIMP=non investigational medici nal product.

[0266] Study Schema

[0267] This Phase 2 / 3 / OLE study is designed in 3 parts under a single protocol. FIG. 1 provides the overall study design defining each part. Each part is individual described in FIG. 3-5: Part A: Open-label, semi-sequential cohorts, dose ranging, PK / PD, 8-week safety and efficacy (see FIG.3). Dose determination for Part B. Part B: Randomized, double-blind, placebo controlled, 28-Docket No. P00045-WO week safety, efficacy, and PK / PD (see FIG. 4). Part C: Open-label long-term safety and efficacy after completion of either Part A or Part B (see FIG. 5).

[0268] Risks Associated With Under- or Over-Replacement of Glucocorticoids (Exogenous Glucocorticoids, Mineralocorticoids) in Congenital Adrenal Hyperplasia

[0269] Risks associated with under- or over-replacement of glucocorticoids in CAH patients are disclosed in the table below:Under-replacement Over-replacement

[0270] BodySystemCardiovascular Low blood pressure, hyponatremia, High blood pressure, volume hyperkalemia due to absent retention, edema, hypernatremia, mineralocorticoid hypokalemiaLiver Hypoglycemia due to decreased Hyperglycemia,gluconeogenesis hypertriglyceridemia due to increased gluconeogenesis and lipolysisBone Reduced final adult height due to Osteopenia, osteoporosis due to early epiphyseal closure as a result glucocorticoid-induced inhibition of increased adrenal androgens of osteoclast function, vitamin D antagonismIncreased bone massAdipose tissue Weight loss Increased fat mass (adrenocortical obesity), predominantly of centripetal distribution Muscle Muscle weakness, myalgia Muscle atrophy, myopathySource: Adapted from (Reisch 2011).

[0271] Risks and Mitigation Strategies: Part A, PartB, and Part C

[0272] Risks and mitigation strategies for parts A, B, and C are disclosed in the table below:Summary of Data / Rationale Mitigation StrategyPotential Risk offor RiskClinicalSignificanceStudy Intervention - AtumelnantAdrenal Atumelnant is an MC2R Participants enrolled in the study and insufficiency competitive antagonist caregivers will be educated to (including recognize the signs and symptoms ofadrenal insufficiency and about theDocket No. P00045-WO Summary of Data / Rationale Mitigation StrategyPotential Risk offor RiskClinicalSignificancehypotensive adrenal Adrenal insufficiency and importance of increasing the dose of insufficiency). hypotensive adrenal GC therapy, according to local insufficiency practices, if necessary for periods of stress (sick day rules).Participants / caregivers 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.In Part B and Part C, participants will have a stepwise reduction in GC doses and participants / caregivers will continue the education process of recognizing adrenal insufficiency. Investigators and participant / caregivers will be allowed to increase their GC dose as judged clinically appropriate.Study ProceduresVenipuncture Additional blood draws may be Study staff are to follow safe necessary if the initial draw is practices for venipuncture.not successful. As with anyStudy staff experienced in venipuncture procedure, there isperforming phlebotomy on pediatric the potential for a venous bloodpopulation.clot and / or infection.Use of microtubes to minimize amount of blood collected.ECG The patches applied to the skin Shaving items may be used in case a for the procedure could cause participant needs to have his chest skin irritation and / or hair hair shaved.removal. Extensive chest hairmay need to be shaved beforethe procedure.Docket No. P00045-WO Potential Risk of Summary of Data / Rationale Mitigation Strategyfor RiskClinicalSignificanceUltrasound Ultrasound waves may heat the Symptomatic measurestissues slightly and, in somecases, it can also produce smallpockets of gas in body fluids ortissues.Risk to pregnancy Recommendation for Participants are to adhere to the contraceptive requirements and contraception requirements pregnancy testing during described in the study.clinical studies with atumelnantare presented in line with EUCTCG Guidelines (version 1.2)or an investigational medicinalproduct where human data onpregnancies is limited or notavailable.CTCG=Clinical Trials Coordination Group; ECG=electrocardiogram; EU=European Union; GC=glucocorticoid; MC2R=melanocortin 2 receptor.

[0273] Estimand

[0274] Not applicable for Part A and Part C.

[0275] For Part B, the primary objective is to demonstrate the superiority of atumelnant compared to placebo in the mean percent change from baseline in GC daily dose (in hydrocortisone equivalents, mg / m2 / day) while serum early morning A4 < ULN at week 28. The estimand for the primary objective is defined by the following components.

[0276] Population: The target population is pediatric participants with classic CAH due to 21-OHD, as defined by the protocol inclusion and exclusion criteria. The analysis population is FAS.

[0277] Variable: Percent change from baseline in GC daily dose (in hydrocortisone equivalents, mg / m2 / day) while serum early morning A4 < ULN at week 28.

[0278] Intercurrent Events and Handling Rules: If a participant experiences a decrease in GC daily dose but serum early morning A4 >ULN at week 28, the GC daily dose endpoint will be set to zero percent change from baseline. Any increases from baseline in GC daily dose will be reported as such, regardless of A4 value. If a participant discontinues study drug but stays on study through week 28, the participant’s observed GC daily dose or serum early morning A4Docket No. P00045-WO value at week 28 will be used in the analysis. Missing data of GC daily dose or serum early morning A4 value will be imputed using multiple imputation. Details will be specified in the SAP.

[0279] Population-Level Summary: The treatment difference in the least squares means between the atumelnant group and placebo group will be provided with the associated 95% CI.

[0280] Description of Study Design

[0281] This is a 3-part study. Eligible participants are those with classic CAH due to 21-OHD who are 1 to <18 years of age; in Part C, ages 1 year and above are allowed to account for aging of the participants. All participants will receive study drug (atumelnant or placebo, if applicable) administered QD as add on to ongoing pre-study GCs and, if applicable, fludrocortisone.

[0282] Part A is an open-label, semi-sequential cohort study to evaluate the safety, efficacy, and PK of atumelnant treatment in pediatric participants with classic CAH due to 21-OHD. Up to 4 cohorts may be included. For each cohort, the study will be comprised of a Screening Period (up to 6 weeks), a Dosing Period (8 weeks), and a Follow-Up Period (4 weeks), the Follow-Up Period is not required if the participant continues in Part C.

[0283] Part B is the double-blind, placebo controlled confirmatory portion of the study to evaluate the safety and efficacy of atumelnant in pediatric participants with classic CAH due to 21-OHD. The weight-based doses for the study will be determined by Part A. There will be a 6-w eek Screening Period followed by a placebo controlled, randomized, double-blind approximately 28-week period (participants will be randomized to either atumelnant or placebo in a 2: 1 ratio) and a Follow-Up Period (4 weeks), the Follow-Up Period is not required if the participant continues in Part C.

[0284] Part C is a single-arm, open-label long-term portion of the study to evaluate the safety and efficacy of atumelnant in pediatric participants with classic CAH due to 21-OHD that completed participation in either Part A or B of this study. Participants will enter directly into this OLE period; there will not be a Screening Period. The treatment period will be up to 5 years, with a final Follow-up Visit (Final Visit / EOS Visit) at the end of the study.

[0285] Additional Background Information

[0286] Pediatric patients with CAH suffer many comorbidities as a result of excess androgens and / or excess exogenous GCs used to control their disease; demonstrating the unmet need in this age group. Excess androgens can cause clinical hyperandrogenism and significant and serious morbidity including growth and development issues (atypical genitalia, early puberty, abnormalDocket No. P00045-WO growth for age, lack of fertility ). as well as increased cardiovascular, obesity, and osteoporosis risks. Life-long, excessive (supraphysiological) therapeutic doses of GC replacement therapy result in multiple comorbidities such as hypertension, depression, diabetes, weight gain, abnormal growth for age, and osteoporosis.

[0287] Treatment Period and Study Period Definitions for Individual Participants

[0288] The following terms are the study conventions as they relate to individual participants in Part A, Part B, or Part C:

[0289] EOT is defined as the date of the last dose of study drug, including early termination.

[0290] EOS Visit is defined as the date that final data are collected after a participant completes the Follow-up Visit (Final Visit / EOS Visit) for each study part or after Early Termination.

[0291] Treatment Period is defined as the study period that begins on the day of enrollment and ends at EOT.

[0292] A participant is considered to have completed either Part A or Part B of the study if he / she has completed the last scheduled procedure specified at the EOS Visit in the part enrolled or entered Part C the OLE.

[0293] End of Study Conduct Definition

[0294] Part A EOS conduct is defined as the date of the last visit for the last enrolled participant in Part A at all study sites participating in Part A.

[0295] Part B EOS conduct is defined as the date of the last visit for the last enrolled participant in Part B at all study sites participating in Part B.

[0296] Part C EOS conduct is defined as the date of the last visit for the last enrolled participant in Part C at all study sites participating in Part C.

[0297] For regulatory purposes, the EOS conduct is defined as the date of the last visit for the last enrolled participant at all study sites, which will be the last visit last participant in Part C. This will trigger end of study activities such as country7notifications and registry updates.

[0298] Selection of Study Population

[0299] This study will be conducted in a pediatric population (ages 1 to <18 years) of both female and male participants diagnosed with classic CAH due to 21-OHD. In Part C (OLE), ages 1 year and above are allowed to account for aging of the participants. Participants must meet all inclusion criteria and no exclusion criteria to participate.

[0300] Inclusion CriteriaDocket No. P00045-WO

[0301] Part A and B participants are eligible to be included in the study only if all the following criteria apply:1. Male or female at birth, between 1 to <18 years of chronological age at the time of signing the ICF.2. Total body weight at Screening is at least 10 kg: Part A Cohorts 1, 2, and 3: >45 kg for ages 12 to <18 years.3. Have a medically confirmed diagnosis of classic CAH due to 21-OHD based on standard medically accepted criteria such as elevated 17-OHP level, confirmed CYP21A2 genotype, positive newborn screening with confirmatory second-tier testing, or cosyntropin stimulation.4. Participants must have an elevated morning (before 11:00) serum A4 level >ULN during screening obtained prior to morning GC administration. Participants who failed screening based on findings the investigator believes are temporary and not reflective of the usual state of the participant (e.g., normal A4 levels when the participant usually is well above this value) can be considered for rescreening. These cases should be discussed with the medical monitor.5. Participants must be on a stable supraphysiologic GC replacement therapy (hydrocortisone, prednisolone, prednisone, methylprednisolone, dexamethasone) for at least one month prior to screening defined as a dose of >11 mg / m2 / day hydrocortisone or equivalent.6. Compliance, as judged per Investigator discretion, with GC replacement and mineralocorticoid replacement (if applicable) regimen documented during the screening Period.7. Normal TSH and T4 within 3 months of screening per age-appropriate range.8. Female participants who have had their first menstrual cycle and 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 method of contraception from the beginning of Screening until at least 2 weeks after the last dose of study drug. Contraceptive use by men and women also should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Periodic abstinence (i.e., calendar, ovulation, symptothermal. postovulation methods) and withdrawal are not acceptable methods of contraception.9. 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 longterm 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 weeks after the last dose of study drug. Must be willing and able to comply with the study procedures as specified in the protocol and comply with the study treatment.Docket No. P00045-WO

[0302] Part C inclusion critena require participants to complete treatment in either Part A or Part B and in the investigator’s opinion it would benefit the participant to continue in Part C, regardless of age.

[0303] Exclusion Criteria

[0304] Part A and Part B: Individuals in Part A and Part B who meet any of the following criteria will be excluded from participation in this study.

[0305] Diagnosis of any form of CAH other than classic 21-OHD.

[0306] Participants treated with other GC formulations as defined by: unstable doses of inhaled GCs, and / or injectable or oral betamethasone, budesonide, or triamcinolone use within 30 days of Screening.

[0307] Stress dose of GC therapy within 2 w eeks of start of screening, defined as any dose above the normal maintenance dose, including but not limited to IV or IM hydrocortisone.

[0308] Use of antiandrogen therapy 3 months prior to screening (e.g., spironolactone, finasteride, cyproterone acetate, flutamide).

[0309] Use of growth hormones within 1 week of start of screening for short acting, or w ithin 6 weeks of start of Screening for long acting.

[0310] Use of a corticotropin-releasing factor receptor antagonist within 14 days of screening.

[0311] 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.

[0312] Participants with any clinically significant abnormal laboratory test during screening or clinically significant concomitant disease other than CAH including but not limited to cardiovascular disease; moderate or severe renal insufficiency (estimated glomerular filtration rate <60 mL / min / 1.73 m2using CKD-EPI formula) at screening; or significant liver disease or ALT and / or AST >3*ULN, and / or TBil >1.5xULN during Screening. TBil >1.5><ULN (Participants with Gilbert’s syndrome can be included with TBil >1.5xULN as long as direct bilirubin is <1.5xULN AND <35% of TBil).

[0313] History of bilateral adrenalectomy, hypopituitarism, or other condition requiring chronic GC therapy.

[0314] History of major surgery / surgical therapy for any cause within 4 weeks prior to screening.Docket No. P00045-WO

[0315] Poorly controlled diabetes mellitus as judged by the investigator.

[0316] 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.

[0317] History of cancer excluding cured / treated dermal squamous or basal cell carcinoma or cervical carcinoma in situ.

[0318] Ages 12 to <18: QTcF interval >450 msec (males) or >470 msec (females), PR interval >220 msec, QRS interval >120 msec, second- or third-degree atrioventricular block, left bundle branch block, or hemiblock at Screening.

[0319] Ages 1 to 11 : Anything abnormal, even if not clinically significant, is an exclusion. A cardiologist can override a machine reading.

[0320] Abnormal sleep / wake cycles (as determined by the Investigator).

[0321] Participants with know n history of (that is within the past 12 months) or current alcohol or drug abuse.

[0322] Participants with any 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.

[0323] Participants with a known allergy or hypersensitivity to any of the test materials or related compounds, including being at high risk of adrenal insufficiency as judged by the Investigator.

[0324] Female participants who are pregnant or lactating.

[0325] Participants who have been dosed with an investigational drug (other than atumelnant) in any prior clinical study within 60 days or 5 half-lives (whichever is longer) prior to the first dose.

[0326] Part C:

[0327] Individuals in Part C who do not meet the Part C Inclusion Criteria.

[0328] Meals and Dietary Restrictions

[0329] Participants are to refrain from consumption of Seville oranges, grapefruit, pomelos, sour citrus fruits (such as citron, kaffir limes, Buddha’s hand), grapefruit hybrids, food preparations that contain more than 200 grams 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. OtherDocket No. P00045-WO types of fruit juice (e.g., apple juice, orange juice, cranberry juice, grape juice) are acceptable. The time of the last meal prior to atumelnant dosing will be collected on PK sampling days.

[0330] Other Activity

[0331] Any activity resulting in abnormal sleep / wake cycles is to be avoided. The expectation is for participants to keep regular sleep habits. Deviations from typical sleep schedules should be reported to the investigator.

[0332] Description of Study Drug: Test Product, Reference Therapy, and Other Medications

[0333] Test product, reference therapy, and other medications are disclosed in the table below:Atumelnant Placebo Glucocorticoid Drug LabelTherapyPart A, B, and C Part BPart A, B, and C Intervention Atumelnant Control Glucocorticoid Name TherapyDrug Class MC2R competitive Not applicable Corticosteroid antagonistDrug Substance CRN04894 maleate Not applicable Various agents, including hydrocortisone, prednisolone, prednisone, methylprednisolone, dexamethasone Dosage Form Tablet for weight Tablet for weight bracket Variable per bracket >45 kg >45 kg participant Appropriate oral Appropriate oral dosagedosage form for weight form for weight bracketbracket <45 kg <45 kgUnit Dose Part A: see Table A Matching Placebo Variable per Strength(s) participant Part B: see Table BPart C: see Table CDosage Level(s) Part A: see Table A Matching Placebo Variable per participant Part B: see Table BPart C: see Table CAdministration Oral Oral OralDocket No. P00045-WO Atumelnant Placebo Glucocorticoid Drug LabelTherapyPart A, B, and C Part BPart A, B, and C Use Experimental Control Standard of Care IMP and IMP IMP AxMPNIMP / AxMPAxMP=auxiliary medicinal product; IMP=investigational medicinal product;MC2R=melanocortin 2 receptor; NIMP=non investigational medicinal product.Table A: Part A Study Drug InformationWeight Group >45 kg <45 kgRoute of Administration Oral OralDosage Form Tablet Appropriate oral dosage form for the age groupUnit Dose strengths 20 mg, 40 mg, 80 mgaTargeting approximately 6 mg to 24 mgaDoses Administered in the 40 mg, 80 mg 6 mg, 12 mg, 24 mg, 48 mg Study Additional / intermediate Additional / intermediate doses as doses as recommended bv recommended by the SRC the SRCActive Comparator Not applicable Not applicableControl Not applicable Not applicableRescue Medication Not applicable Not applicableSRC=Safety Review Committee.aFree base equivalent.Docket No. P00045-WO Table B: Part B Study Drug InformationWeight Group >45 kg <45 kgRoute of Administration Oral OralDosage Form Tablet Appropriate oral dosage form for this age groupUnit Dose strengths 20 mg, 40 mg, and / or Targeting approximately 6 mg to 80 mga12 mgaDoses Administered in The dose will be The dose per weight bracket will be the Study determined based on doses determined based on doses studied in studied in Part A and the Part A and the resulting data. resulting data.Active Comparator Not applicable Not applicableControl Placebo PlaceboRescue Medication Not applicable Not applicableaFree base equivalentTable C: Part C Study Drug InformationWeight Group >45 kg <45 kgRoute of Oral OralAdministrationDosage Form Tablet Appropriate oral dosage form for this age group.Unit Dose 20 mg, 40 mg, 80 mgaTargeting approximately 1 mg to strengths 12 mgbDoses For the Part A participants, the For the Part A participants, the initial Administered in initial dose for Part C will be the dose for Part C will be the same as the Studybsame as their final dose in Part their final dose in Part A. Once a A. Once a dose is selected for dose is selected for their body weight their body weight bracket for bracket for Part B, the Part A Part B, the Part A participants participants will be switched to that will be switched to that dose. dose.For the Part B participants, the For the Part B participants, the dose dose will be the same dose as will be the same dose as assigned in assigned in Part B based on the Part B based on bracket of body >45 kg bracket of body weight. weight.As a new weight bracket is met, the dose will be adjusted.Active Not applicable Not applicableComparatorControl Not applicable Not applicableRescue Not applicable Not applicableMedication“Free base equivalent.Docket No. P00045-WObAdditional adjustments to atumelnant (within limits) may be allowed, refer to the Pharmacy Manual.

[0334] Dosing and Administration

[0335] Study drug should be taken in the morning at approximately the same time of day (recommend between 7:00 and 9:00 am), each day throughout the study, and at approximately the same time as the morning dose of GCs. Atumelnant and GC doses will be held and administered in the clinic after the predose PK and / or PD sample at onsite visits. Visits should start as early in the morning as possible (preferably 07:00 to 08:00 am), to minimize any delay in administration of the morning GC dose and the timing of each study visit should be as consistent as possible.

[0336] Participant Assignment, Randomiz,ation and Blinding

[0337] Part A

[0338] All eligible participants will receive open-label atumelnant in Part A. There is no randomization or blinding in Part A.

[0339] Part B

[0340] Part B is a randomized, double-blind, placebo-controlled study. The participant, investigator, all study center personnel, and the sponsor will be blinded to the participant's treatment.

[0341] Eligible participants in Part B will be randomized in a double-blind manner by an Interactive Response Technology solution to either atumelnant or placebo in a 2: 1 ratio.

[0342] Part C

[0343] All participants will receive open-label atumelnant in the OLE. There is no randomization or blinding in Part C.

[0344] Concomitant Therapy

[0345] Concomitant therapy is considered any therapy — including vaccines, medications (prescription and over the counter), and non-medi cations (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).

[0346] All prior therapies (medication and nonmedication) received within 60 days prior to informed consent are to be recorded in the same manner as concomitant therapy.Docket No. P00045-WO

[0347] If a new therapy should become necessary for any reason during the study, the participant is required to inform the Investigator immediately.

[0348] Prohibited Therapy

[0349] Use of antiandrogen therapy 3 months prior to Screening (e.g., spironolactone, finasteride, cyproterone acetate, flutamide).

[0350] Use of testosterone, androgen-containing supplements, aromatase inhibitors, or growth hormone.

[0351] 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.

[0352] 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), calcium channel blockers (e.g., diltiazem), and antidepressants(e.g., fluvoxamine).

[0353] Use of medications that are strong or moderate inducers of P-gp w ithin 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.

[0354] 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 (such as lopinavir and ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir) or verapamil, propafenone, quinidine, or ranolazine.

[0355] Use of any investigational drug (other than atumelnant) 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.

[0356] Betamethasone, budesonide, and triamcinolone by any route within 30 days of Screening.

[0357] Permited Therapy - Exogenous Glucocorticoids and Adrenal Insufficiency

[0358] Auxiliary Medicinal ProductsDocket No. P00045-WO

[0359] Glucocorticoids are permitted in the study as background intervention. Dosing of GC therapies will be administered as standard of care and consistent with sick day rules in situations of stress, GC deficiency / adrenal insufficiency teaching according to local practices and the instruction of the local investigator, which may require an alternative GC regimen. Participants and caregivers should be educated on situations (such as illness or other events associated with significant physical stress) that require increased GC dosing.

[0360] Glucocorticoid Dose Reduction During Part B or Part C

[0361] In Part B and Part C, participants will gradually decrease their GC dosage in up to 4 steps over 4 months to reach a target of <11 mg / m2 / day but not lower than 8 mg / m2 / day (in hydrocortisone dose equivalents adjusted for body surface area.). The ability to decrease the GC dose is based on the individual participant’s A4 levels.

[0362] When the Investigator obtains the A4 results, they will determine if it is appropriate to adjust the GC dose, and if so by what degree. They will contact the participant / caregiver and provide instructions on how to adjust the dose, as well as provide instructions on recognizing adrenal insufficiency and when to call the Investigator. The site should conduct a follow-up phone call within a week to assess tolerability. The participant will have a follow-up visit approximately 2 weeks later.

[0363] Mineralocorticoid doses should be adjusted as needed during the study as GCs are reduced, to maintain renin levels within the normal range. Glucocorticoid reduction should be halted and reevaluated if the participant exhibits symptoms or signs of GC insufficiency. GC dose increases can be made at Investigators’ or participants’ discretion. Stress dosing (sick day rules) is allowed during this period of GC dose reduction and throughout the study.

[0364] Throughout the 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 increased temporarily 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.

[0365] Guide for Glucocorticoid Dose Adjustments During Part B (Randomized, Placebo Controlled Treatment Period) or Part C (Open-Label Extension)

[0366] Guidance for glucocorticoid dose adjustments during part B or part Care disclosed in the table below:Docket No. P00045-WO Current Glucocorticoid Dose Adjustment Percent Change from BaselineA4 Level(First Dose Respective of StudyPart) in Serum Androstenedione(A4)Any increase >ULN Consider whether glucocorticoid dose needs to be increasedAny increase <ULN Maintain current glucocorticoid dose No changea<ULN Maintain current glucocorticoid dose >ULN Consider increasing glucocorticoid dose Any decrease >ULN Maintain current glucocorticoid dose Decrease of <20% <ULN If >11 mg / m2 / day, 1 to 2 mg / m2 / day glucocorticoid dose decreaseIf <11 mg / m2 / day, additional decrease can be made in the judgment of the InvestigatorDecrease of >20% to <40% <ULN If >11 mg / m2 / day, 2 to 3 mg / m2 / day glucocorticoid dose decreaseIf <11 mg / m2 / day, additional decrease can be made in the judgment of the InvestigatorDecrease of >40% <ULN If >11 mg / m2 / day, 3 to 4 mg / m2 / day glucocorticoid dose decreaseIf <11 mg / m2 / day, additional decrease can be made in the judgment of theInvestigatorA4=androstenedione; ULN=upper limit of normal.aWithin reasonable variability in the opinion of the Investigator.

[0367] Conditions for Halting GC Dose Reduction’.

[0368] The dose should be reverted to the previous tolerable level if any of the signs / symptoms below are present:

[0369] Unacceptable hyperandrogenism symptoms in the Investigator’s opinion (e g., hirsutism, acne).

[0370] Signs or symptoms of GC withdrawal or GC insufficiency.Docket No. P00045-WO

[0371] Glucocorticoid Dose Adjustments During Part C Quarterly Visit Phase

[0372] For participants who are on >11 mg / m2 / day GC dose or are <11 mg / m2 / day with A4 less than the ULN, the Investigator can further decrease the GC dose.

[0373] Adrenal Insufficiency / GC Deficiency

[0374] In the event of clinical suspicion of GC deficiency / adrenal insufficiency, GC therapy should be immediately resumed at prescribed doses if the participant has been nonadherent or, the GC dose increased as appropriate for concomitant illness, consistent with sick day rules GC deficiency / adrenal insufficiency teaching according to local practices and the instruction of the local Investigator and which may require an alternative GC regimen. 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 mm Hg lower than usual), 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).

[0375] The prescribed dose increase in exogenous GCs and duration of such increase is to be determined by the local Investigator based on presenting signs and symptoms. Prior to providing supplemental doses or increasing the regular dose of exogenous GC therapy, if possible, blood should be collected for measurement of urea, creatinine, sodium, potassium, glucose, and any scheduled hormone measurements.

[0376] 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.

[0377] 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 (~5 days) have elapsed, and the participant has resumed their GC regimen.

[0378] Signs and symptoms of cortisol deficiency and aldosterone deficiency are disclosed in the table below:Docket No. P00045-WO Cortisol Deficiency Aldosterone DeficiencyFatigue, anorexia, nausea, vomiting, Orthostatic hypotension defined as: a abdominal pain, muscle or joint pain, decrease in systolic blood pressure >20 mm weakness, lethargy, fever, confusion, coma. Hg and / or a decrease in diastolic blood pressure >10 mm Hg upon standing for 2 to 5 Laboratory findings: hyponatremia,minutes compared with supine blood hypoglycemia, inappropriately low serumpressure. If the participant is unable to stand, cortisol levels, anemia, hypercalcemiablood pressure and pulse may be taken in sitting position with legs dependent.Laboratory findings: hyperkalemia, low aldosterone, hyponatremia, elevated renin

[0379] Signs and symptoms for hypotensive adrenal insufficient are disclosed in the table below: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).

[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:

[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:

[0385] 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.

[0386] 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.Docket No. P00045-WO

[0387] Any ventricular tachyarrhythmia associated with symptoms of hemodynamic instability.

[0388] Sustained ventricular tachycardia (lasting >30 seconds) irrespective of symptoms.

[0389] Torsades de pointes.

[0390] Cardiac arrest.

[0391] Cardiac pause >5 seconds observed on ECG.

[0392] Type II second degree block or third-degree atrioventricular block.

[0393] New occurrence of clinically significant, symptomatic bradycardia.

[0394] Initiation of a concomitant medication during the study which prolongs the time interval between Q and T waves (QT interval) and is associated with Torsades de pointes.

[0395] Any supraventricular tachyarrhythmia associated with symptoms of hemodynamic instability.

[0396] Other clinically significant drug-related abnormalities.

[0397] 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).

[0398] Participant has a need for a prohibited concomitant therapy. Any exposure to a prohibited concomitant medication should be discussed promptly with the Medical Monitor.

[0399] 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, or death.

[0400] Rechallenge

[0401] 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 (~5 days) have elapsed.

[0402] Bone Age

[0403] Bone age will be assessed for participants ages 6 and above via X-ray (single posterior-anterior radiograph) of the left hand and wrist using the Greulich and Pyle method as long as the most recent prior bone age was less than 14 years for females and less than 16 years for males (until mature bone age). If there is a known history of trauma or surgery involving the left handDocket No. P00045-WO or wrist, the right hand and wrist can be used for bone age assessment. If bone age was assessed within 30 days of day 1 and the fdm can be provided, this can be used for the day 1 bone age. Otherwise, all X-rays will be acquired by the site and sent to a central imaging facility for evaluation. A study procedure manual will be provided by the central imaging facility that will include all X-ray related acquisition and submission details.

[0404] Participants will be asked to provide films of a historical bone age, i.e., the most recent bone age (only if a prior bone age was performed) that was obtained at least 6 months prior to the day 1 bone age assessment, which may be sent for central reading. The day 1 X-ray to assess bone age may be performed up to 7 days prior to the study visit. The time window for a bone age X-ray that needs to be repeated due to an inadequate initial scan is within 2 w eeks of the actual study visit (including day 1 visit). Bone age assessment is not required at the early termination visit if the participant had a bone age assessment within 3 months prior.

[0405] Testicular Ultrasound

[0406] Testicular ultrasound will be performed in males >6 years of age according to the study site procedures for the evaluation of TARTs at visits specified in the SOA.

[0407] PD Biomarker Draws

[0408] Prior to receiving the morning study drug dose and GC replacement dose, blood for PD biomarkers will be drawn. The blood draw should be one of the first activities performed at the start of the visit. 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 study drug dose, and the timing of each study visit should be as consistent as possible. Screening PD biomarker blood draws can be done at any time after the 1CF is signed.

[0409] Tanner Stage

[0410] Tanner staging (1 to 5) will include assessment of pubic hair (males and females), breast development (females), and genital development (males). Due to the subjectivity of Tanner genital staging for males, testicular volume will be assessed using a Prader orchidometer to assign a Tanner stage equivalent as follows: Tanner stage 1: <4 mL; Tanner stage 2: >4 mL and <8 mL; Tanner stage 3: >8 and <12 mL; Tanner stage 4: >12 and <15 mL; and Tanner stage 5: >15 mL (Nokoff 2019). If genital staging by testicular volume (assessed with Prader orchidometer) differs from genital staging based on clinical appearance of the scrotum, testes, and penis, the Tanner genital stage for males should be based on testicular volume.Docket No. P00045-WO

[0411] Tanner stage should be assessed in all participants at Screening and day 1 (baseline). Historical assessment of Tanner staging is acceptable if Tanner stage 5 has been previously documented. Tanner stage will not be required to be assessed at day 1 if the Investigator determines that the Tanner stage is unlikely to have changed since Screening; in this case, the screening Tanner stage will be considered the baseline. Participants who are Tanner stage 5 do not need further assessment of Tanner stage at subsequent visits.

[0412] Hirsutism Questionnaire

[0413] The Modified Ferri man-Gallwey visual analog scale will be utilized to assess hirsutism in female participants 8 years of age and above.

[0414] The Investigator will evaluate the level of terminal hair growth based on visually scoring the amount of terminal hair growth. A score of 0-4 is assigned to each area examined, such that a score of 0 represents the absence of terminal hairs, a score of 1 minimally evident terminal hair growth, and a score of 4 extensive terminal hair grow th. Each of the 9 body areas (upper lip, chin, chest, arm, upper abdomen, lower abdomen, upper back, lower back, and thighs) is rated from 0 (absence of terminal hairs) to 4 (extensive terminal hair growth), and the numbers in each area are added for a total score. A score of 8 or more is considered to represent hirsutism.

[0415] If the participant / caregiver refuses the assessment it will not be considered a protocol deviation.

[0416] Medical History

[0417] A medical history will be taken at the Screening Visit and updated as needed throughout the study. All participants’ medical history should include congenital adrenal hyperplasia.

[0418] Physical Examinations, Height, Weight, Waist Circumference, BMI

[0419] Physical Exam

[0420] Perform a full physical examination at Screening and day 1, examination is to include assessment of head (external), eyes, ears, nose, and throat, lungs, cardiovascular system, abdomen, musculoskeletal system, skin, lymph nodes, CNS, and, where appropriate, other body systems. A symptom directed physical exam at subsequent visits.

[0421] Height

[0422] Height will be measured using a wall-mounted stadiometer in a participant without shoes, while instructed to stand tall with feet flat on the floor, heels against the wall, and looking straight forward. Participants less than 3 years of age may be measured with a length board, butDocket No. P00045-WO all measurements during the study should be made with the same technique (stadiometer or length board). Measurements should be recorded to the nearest 0.1 cm. Height will be measured (using a stadiometer or length board) in all participants as specified in the respective SOA. Participants who have grow n less than 2.5 cm within the past year, have complete fusion of epiphyses on the hand / wrist radiograph, or are more than 2 years past menarche (females) are not required to continue to have height measurements. Height will be expressed in cm and in SDS according to the CDC growth charts.

[0423] Weight

[0424] Weight will be measured using a digital scale and recorded to the nearest 0.1 kg with participants not wearing shoes or outerwear (e.g., jackets or coats). Weight will be expressed in kg and in SDS according to CDC growth charts.

[0425] Waist Circumference

[0426] Waist circumference is defined as abdominal circumference located midway between the lower rib margin and the iliac crest. Measures must be obtained in standing position with a non-stretchable measuring tape and to the nearest 0.5 cm or 0.2 inch. The tape should touch the skin but not compress soft tissue, and twists in the tape should be avoided. The participant should be asked to breathe normally. The same measuring tape should be used throughout the study.

[0427] BMI

[0428] BMI will be calculated as weight in kilograms divided by height squared in meters.

[0429] Vital Signs

[0430] Vital signs should be taken before any scheduled blood draws.

[0431] Measure vital signs: blood pressure should be measured in the supine position after resting for 5 minutes, resting respiratory rate, and body temperature as per standard practice at the timepoints specified in the respective SOA.

[0432] Electrocardiograms

[0433] ECGs should be taken before any scheduled blood draws.

[0434] Collect ECGs at the timepoints specified in the respective SOA. The ECG assessment for age >6 years, triplicate 12-lead at Screening, single other visits; Age 1 to 5 years, single 6-lead or 12-lead at timepoints indicated in the respective SOA. Triplicate ECGs (1 to 3 minutes apart) should be performed after the participant has rested quietly in the supine position for at least 10 minutes without significant stimulation (noise, television, etc.). Additional ECGs outside ofDocket No. P00045-WO the planned assessments are to be collected, per protocol, if clinically indicated (e.g., participants with palpitations, lightheadedness).

[0435] The ECG parameters that are to be assessed include a summary of findings as well as measurement of the pulse rate, QT, QTcF, and time interval between P and R waves (PR), and time interval of the QRS complex (QRS duration) based on the ECG machine readings.

[0436] All ECG assessments will be assessed by the Investigator for any findings that require medical attention. The clinical significance of any ECG findings will be determined by the Investigator. 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.

[0437] Pregnancy Testing

[0438] Pregnancy testing (urine or serum as required by local regulations) should be conducted at the end of relevant systemic exposure plus an additional 14 days and correspond with the time frame for female participant contraception in the Inclusion Criteria.

[0439] Additional serum or urine pregnancy tests may be performed, as determined necessary by the Investigator or required by local regulation, to establish the absence of pregnancy at any time during the participant’s participation in the study.

[0440] Participant-Reported Assessments

[0441] Participant Diaries

[0442] Completing the diaries can be done with the assistance of a parent or caregiver, as needed. When these assessments are scheduled on the same day or visit, the order will be as follows:

[0443] Glucocorticoid Administration Dian- : completed at home.

[0444] Atumelnant Dosing Diary: completed at home.

[0445] Menstrual Cycle Diary (female only): completed at home.

[0446] Glucocorticoid Administration Diary

[0447] Each participant will record their GC dose in the Glucocorticoid Administration Diary¬ beginning at screening through the end of the study including the specific type of GC, any changes to the dose, timing or frequency including missed doses or stress dosing and the reason for any changes. During Part A and Part B daily GC dosing will be recorded, during Part C,Docket No. P00045-WO changes to GC dosing will be recorded. The diary will be reviewed by the investigator as specified in respective SOA.

[0448] The usual daily regimen will be converted to hydrocortisone dose equivalents (mg / m2 / day).

[0449] During the study, the Investigator is to assess compliance with ongoing GC replacement, review Glucocorticoid Administration Diary', and monitor for possible signs and symptoms of GC deficiency / adrenal insufficiency.

[0450] Atumelnant Dosing Diary

[0451] The Atumelnant Administration Diary should be completed by the study participant / caregiver every day starting at Day 1 and continuing through the morning of EOT. The 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 or noncompliance should be documented appropriately in the dosing diary .

[0452] Menstrual Cycle Diary (Female Only)

[0453] The Menstrual Cycle Diary should be completed by all female study participants (who have started menstruation) 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.

[0454] Pediatric QoL Questionnaires

[0455] As a participant reaches a new age bracket, the new age bracket questionnaire will be utilized.

[0456] Patient reported and caregiver reported outcomes questionnaires are disclosed in the table below:Specific Questionnaire Age Range in Completed By

[0457] GroupYearsfor CompletionEuroQol ™ EQ-5D-Y-5L 8 and above Participant PedsQL™ PARENT REPORT for 2 to 4 Parent / Caregiver TODDLERS ™PedsQL™ PARENT REPORT for 5 to 7 Parent / Caregiver YOUNG CHILDREN ™Docket No. P00045-WO

[0457] Group Specific Questionnaire Age Range in Completed By Yearsfor CompletionPedsQL™ PARENT REPORT for 8 to 12 Parent / Caregiver CHILDREN™ParticipantCHILD REPORT™PedsQL™ TEEN REPORT™ 13 and above ParticipantMerck Acne-QoL 13 and above ParticipantInternal CaGI-C CAH All Parent / Caregiver Internal CaGI-S CAH All Parent / Caregiver Medworks Media PQ-LES-Q 6 and above Participant PROMIS ® Neuro-QoL Anxiety 8 and above Participant PROMIS ® Neuro-QoL Depression 8 and above ParticipantCaGI-C=Caregiver Global Impression of Change; CaGI-S=Caregiver Global Impression of Severity; CAH=congenital adrenal hyperplasia; PedsQL=Pediatric quality' of life inventory; PQ-LES-Q=Pediatric Quality' of Life Enjoyment and Satisfaction Questionnaire; QoL=Quality of Life.

[0458] EQ-5D-Y-5L

[0459] EQ-5D-Y-5L for Participants 8 years of age and above

[0460] This instrument has children self-report on 5 dimensions of health: Mobility, Looking After Myself, Usual Activities, Pain / Discomfort, and being Worried, Sad, or Unhappy. Each dimension has 3 levels of severity: “no problems’", “some problems”, or “a lot of problems” (Scott 2017). The participant indicates his / her health state by checking the box next to the most appropriate statement.

[0461] Participants also rate their overall health on a 0 to 100 hash-marked, vertical visual analogue scale, where 100 is labeled “The best health you can imagine” and 0 is labeled “The worst health you can imagine.” This instrument has been validated in international population samples of children and adolescents (Ravens-Sieberer 2010).

[0462] Pediatric Quality of Life Instrument

[0463] The Pediatric Quality' of Life Instrument (PedsQL™) Generic Core Scales encompass: 1) Physical Functioning, 2) Emotional Functioning, 3) Social Functioning, and 4) School Functioning (Vami 2001). The PedsQL has been shown to be a valid instrument in pediatricDocket No. P00045-WO participants (Vami 2006). The instructions ask how much of a problem each item has been during the past one month. A 5-point Likert response scale is used (0=never a problem; l=almost never a problem; 2=sometimes a problem; 3=often a problem; 4=almost always a problem). Items are reverse-scored and linearly transformed to a 0 to 100 scale, so that higher scores indicate better health-related quality of life.

[0464] Acne-QoL

[0465] The Acne-QoL measures the quality of life among persons with mild, moderate, and severe facial acne and will be administered to participants 13 years of age and above. The questionnaire is organized into 4 domains: Self Perception, Role-social, Role-emotional, and Acne Symptoms.

[0466] Caregiver Global Impressions of Change and Severity

[0467] The CaGI-S assesses the participant’s perception of the severity of CAH symptoms using a 5-point rating scale (none, mild, moderate, severe, and very severe) at times specified in the SOA.

[0468] The CaGLC assesses the participant's perception of the change in severity of CAH symptoms using a 7-point rating scale (much better, moderately better, a little better, no change, a little worse, moderately worse, and much worse) at times specified in the SOA.

[0469] Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire

[0470] The PQ-LES-Q measures life satisfaction over the past week (Endicott 2006). The PQ-LES-Q is a 15-item questionnaire that uses a 5-point rating scale (from 1 - Very Poor to 5 -Very Good). Participants 6 years of age and older will complete the PQ-LES-Q at times specified in the SOA.

[0471] Neuro-QoL Anxiety and Neuro-QoL Depression

[0472] The pediatric Neuro-QoL includes generic and targeted item banks. The generic domains include physical function, emotional health (including depression and anxiety), and social health. Participants 8 years of age and older will complete the Pediatric Depression - Short Form and Pediatric Anxiety - Short Form at times specified in the SOA. Each domain consists of 8 questions with a recall period of 7 days.

[0473] Participant and / or Parent / Caregiver Interviews

[0474] Participants and / or their parents / caregivers may have the opportunity to participate in qualitative interviews conducted at the timepoints during their participation in the study. TheDocket No. P00045-WO interviews will only be available to participants and / or parents / caregivers in certain countries and those applicable countries 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 and / or parent’ s / caregi ver’s words regarding their own perceptions of their experiences (or their child’s experiences) with CAH both before and during the clinical study. Specifically, interview participants will be asked to describe their or their child’s CAH symptoms and impacts before the clinical study and their expectations of treatment prior to entering the study. Participants and / or parents / caregivers will then be asked to describe how, if at all, their or their child’s CAH symptoms and impacts changed during the clinical study, and to describe the meaningfulness of any changes experienced. Participants and / or parents / caregivers may also be asked to discuss experiences with the clinical study. The participant and / or parent / caregiver interviews will be performed via telephone or video conferencing software and will be audio recorded and transcribed.

[0475] Adverse Events of Special Interest

[0476] An AESI is an AE of special medical or scientific interest to the Sponsor. For this study, the adrenal insufficiency is considered to be an AESI.

[0477] Pharmacokinetics

[0478] During the treatment period, blood samples will be collected for the measurement of CRN04894 concentration in plasma and whole blood as specified in the respective SOA.Instructions for the collection and handling of biological samples will be provided by the Sponsor in the Laboratory Manual. 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.

[0479] Pharmacodynamics

[0480] A pharmacodynamic biomarker panel (17-OHP, ACTH (plasma), testosterone, A4, 11-DOC, 21 -deoxy cortisol, 11-0HA4, ll-ketoA4, 11-OHT, 11-ketoT, cortisol) will be measured as timepoints specified in the respective SOA. Additional PD biomarkers may be tested if deemed necessary.

[0481] Genetics

[0482] During the Day 1, blood samples will be collected for the measurement of CYP450 and 21 -hydroxylase A2 genotyping in plasma as specified in the respective SOA. Instructions for theDocket No. P00045-WO collection and handling of biological samples will be provided by the Sponsor in the Laboratory Manual.

[0483] The blood sample should be stored for future assessment of genetic variants (e.g., predict efficacy, absorption, distribution, metabolism, and excretion, or safety signal).

[0484] Definitions and supporting operational details

[0485] Childbearing Potential and Contraception Guidance

[0486] The definitions of childbearing potential are in accordance with the CTCG Recommendations related to contraception and pregnancy testing in clinical trials (version 1.2).

[0487] Women of Childbearing Potential

[0488] Women of Childbearing Potential are defined as women who are physiologically capable of becoming pregnant. Women in the following categories are considered WOCBP (fertile):

[0489] Following menarche.

[0490] From the time of menarche until becoming postmenopausal unless permanently sterile (see below).

[0491] Women of Nonchildbearing Potential (WONCBP)

[0492] Women in the following categories are considered WONCBP:

[0493] Premenopausal female with permanent infertility due to 1 of the following:

[0494] Documented hysterectomy.

[0495] Documented bilateral salpingectomy.

[0496] Documented bilateral oophorectomy.

[0497] For individuals with permanent infertility due to an alternate medical cause other than the above.

[0498] Postmenopausal female.

[0499] A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.

[0500] 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 theDocket No. P00045-WO 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.

[0501] Females on HRT and whose menopausal status is in doubt must discontinue HRT to allow confirmation of postmenopausal status before study enrollment.

[0502] Fertile Man

[0503] A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy.

[0504] Protocol-Required Laboratory Tests

[0505] Protocol-required laboratory tests are disclosed in the table below:Laboratory Parameters Central Tests Lab Hematology Platelet count Preferred RBC count / Hemoglobin / Hematocrit Preferred RBC indices: MCV Preferred MCH% ReticulocytesWBC count with Neutrophils Preferred differential:LymphocytesMonocytesEosinophilsBasophilsHematology PT / INR PTT Preferred (coagulation)Clinical BUN AST Phosphorus Preferred chemistryaPotassium ALT MagnesiumCreatinine (and eGFR) GGTAlbuminSodium AlkalinephosphatasebBicarbonatCalciumeTotal and directGlucose (fasting)cbilirubinFasting lipid panelcTotal proteinHbAlcDocket No. P00045-WO Laboratory Parameters Central Tests Lab Uric acidChlorideHormones LH / FSH (male and SHBG Renin Required female participants thatTSH Aldosteronhave reached puberty)eFree T4EstradiolTotal T3Routine urinalysis pH, glucose, protein, blood, ketones, bilirubin, Preferred urobilinogen, nitrite, leukocyte esteraseMicroscopic examination (if blood or protein is abnormal) Pregnancy testing Highly -sensitive serum or urine hCG pregnancy test (as Preferred needed for WOCBP)dFSH (in women of nonchildbearing potential only)Serology HIV antibody, HBsAg and hepatitis C virus antibody Preferred PD biomarkers 17-OHP, ACTH (plasma), testosterone, A4, 11-DOC. Required 21 -deoxy cortisol, 11-0HA4, ll-ketoA4, 11-OHT, 11- ketoT, cortisolPK Atumelnant (plasma and whole blood) RequiredGenetics CYP450 and 21 -hydroxylase gene mutation (plasma) Required11-DOC= 11 -deoxy corticosterone; 1 l-ketoT=l 1 -ketotestosterone;1 l-ketoA4=l 1 -ketoandrostenedione; 1 l-0HA4=l 10-hydroxyandrostenedione;1 l-OHT=110-hydroxy testosterone; 17-OHP=17-hydroxyprogesterone; A4=androstenedione; ACTH =adrenocorticotropic hormone; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; eGFR=estimated glomerular filtration rate;FSH=follicle-stimulating hormone; GGT=gamma-glutamyl transferase; HbAlc=hemoglobin A1C; HBsAg=hepatitis B surface antigen; hCG=human chorionic gonadotropin; HIV=human immunodeficiency virus; INR=intemational normalized ratio; LH=luteinizing hormone;MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; PD=pharmacodynamic; PK=pharmacokinetic; PT=prothrombin time; PTT=partial thromboplastin time; RBC=red blood cell; SHBG=sex hormone binding globulin; T3=triiodothyronine; T4=thyroxine; TSH=thyroid stimulating hormone; WBC=white blood cell; WOCBP=women of childbearing potential.aDetails of liver chemistry stopping criteria and required actions and follow-up are given in this protocol. Must be reported to the sponsor in an expedited manner.bIf alkaline phosphatase is elevated, consider fractionating.cFasting not required for participants ages 1 to 5. Fasting status will be collected.Docket No. P00045-WOdSerum pregnancy test to be conducted by central lab 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.

[0506] 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

[0507] 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.

[0508] Change in adrenal gland size from baseline to Week 12 was an exploratory endpoint.

[0509] 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.

[0510] 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.

[0511] 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. 6).

[0512] 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%).

[0513] 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.

[0514] 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.

[0515] Rapid and Sustained Reduction of Il-Oxygenated Androgens in Adults With Classic Congenital Adrenal Hyperplasia Following Once-Daily Oral Atumelnant

[0516] A hallmark of classic congenital adrenal hyperplasia (CAH) is 21 -hydroxylase deficiency (21-OHD), which disrupts normal steroidogenesis pathways, resulting in decreased cortisol andDocket No. P00045-WO aldosterone levels and excess adrenal androgens. Traditional biomarkers of disease activity include 17-hydroxy progesterone (17-OHP) and androstenedione (A4). The adrenals produce 11 p-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.

[0517] 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.

[0518] 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.

[0519] A total of28 participants (40 mg, n=l l; 80 mg, n=ll; 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.

[0520] Participant Demographics and Baseline Characteristics are presented in the table below:Atumelnant Atumelnant Atumelnant All 40 mg 80 mg 120 mg participants Parameters(n=H) (n=H) (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, lip-hydroxyandrostenedione; GC, glucocorticoid.aGC dose in hydrocortisone equivalents.Docket No. P00045-WO

[0521] 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.

[0522] 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.

[0523] 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

[0524] 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.

[0525] 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.

[0526] Reductions of Androstenedione and 17 Hydroxyprogesterone in Adults With Classical Congenital Adrenal Hyperplasia: Interim Results From a 12-Week, Phase 2, Open-Label Study

[0527] Below are results from cohorts of a 12-week, Phase 2, open-label, dose-finding study of atumelnant in patients with CAH (NCT05907291).

[0528] 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.Docket No. P00045-WO

[0529] 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.

[0530] 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] mg / day [hydrocortisone equivalent]) had completed treatment (40 mg, n=ll; 80 mg, n=ll: 120 mg, n=6).

[0531] 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.

[0532] 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.

[0533] 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).

[0534] 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).

[0535] 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).

[0536] Overall, rapid, substantial, and sustained reductions in A4 and 17-OHP were demonstrated with administration of atumelnant in adult patients with classical CAH.

[0537] Conclusions

[0538] 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.

[0539] Reductions of 80% and 65% in A4 and 17-OHP, respectively, were achieved in the 120-mg cohort.Docket No. P00045-WO

[0540] Atumelnant resulted in dose-dependent A4 lowering, with >50% of participants achieving normalization in the 80-mg and 120-mg cohorts.

[0541] Atumelnant treatment reduced A4:testosterone in male participants.

[0542] The majority of oligomenorrheic females of childbearing potential resumed regular menses; testosterone levels were substantially reduced in hyperandrogenemic female participants.

[0543] 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

[0544] 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]).

[0545] 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.

[0546] As of October 17, 2025, 38 participants (55.3% yvomen; 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 yvas 980.8 (116-2755) ng / dL (reference range [RR]; women 30-200 ng / dL, men 40-150 ng / dL) and for 17-OHP was 12,175 (453-44,000) ng / dL(RR: yvomen <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-,Docket No. P00045-WO 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 >1 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).

[0547] 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.

[0548] 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.Docket No. P00045-WO 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.Embodiment 6. A method of treating hyperandrogenism in a subject with CAH on glucocorticoid (GC) therapy compnsing 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 is > 15 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.Docket No. P00045-WO 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.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.Docket No. P00045-WO Embodiment 29. The method of any one of Embodiments 1-28, wherein treating comprises reducing the subject’s serum level of 17 -hydroxy 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.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). lip-hydroxyandrostenedione (11-OHA4), 11 -ketoandrostenedione (l l-ketoA4), 11 [3-hydroxytestosterone (1 1-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.Docket No. P00045-WO 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.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 pyridinoline 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.Docket No. P00045-WO 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.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 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.Docket No. P00045-WO Embodiment 72. The method of Embodiment 71, wherein the contraception is selected from hormonal and an intrauterine device.Embodiment 73. The method any one of Embodiment 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 6-80 mg of atumelnant free base.Embodiment 75. The method of Embodiment 74, wherein the daily dose of atumelnant is equivalent to 6-48 mg of atumelnant free base.Embodiment 76. The method any one of Embodiments 4-73, wherein the daily dose of atumelanant is equivalent to 40-80 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. The method of any one of Embodiments 1-84, wherein the subject is an infant, a toddler, a child, or a teenager.Embodiment 86. The method of Embodiment 85, wherein treating comprises preventing premature growth plate closure.Docket No. P00045-WO Embodiment 87. The method of Embodiment 85, wherein treating comprises preventing premature puberty.Embodiment 88. 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 89. 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 90. 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.Embodiment 91. 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).Embodiment 92. The method of Embodiment 7, wherein the subject’s serum level of A4 is reduced by < 20% from baseline.Embodiment 93. The method of Embodiment 92, wherein the subject's GC dose is reduced by 1 to 2 mg / m2 / day.Embodiment 94. The method of Embodiment 7, wherein the subject’s serum level of A4 is reduced by >20% to <40% from baseline.Embodiment 95. The method of Embodiment 94, wherein the subject's GC dose is reduced by 2 to 3 mg / m2 / day.Embodiment 96. The method of Embodiment 7, wherein the subject’s serum level of A4 is reduced by >40% from baseline.Embodiment 97. The method of Embodiment 94, wherein the subject’s GC dose is reduced by 3 to 4 mg / m2 / day.Embodiment 98. The method of any one of Embodiments 5-87 and 92-97, wherein the atumelnant, or a pharmaceutically acceptable salt thereof, is administered in the morning.

Claims

Docket No. P00045-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 > 15 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 1-9, 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. P00045-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 claim 4 or 5, wherein the subject’s serum level of A4 is reduced to < 20% of baseline.

24. The method of claim 23, wherein the subject’s GC dose is reduced by 1 to 2 mg / m2 / day.

25. The method of claim 4 or 5, wherein the subject’s serum level of A4 is reduced by > 20% to < 40% from baseline.

26. The method of claim 25, wherein the subject’s GC dose is reduced by 2 to 3 mg / m2 / day.

27. The method of claim 4 or 5, wherein the subject’s serum level of A4 is reduced by > 40% from baseline.Docket No. P00045-WO 28. The method of claim 27 , wherein the subject’s GC dose is reduced by 3 to 4 mg / m2 / day.

29. The method of any one of claims 17-28, wherein the subject's serum level of A4 is a morning serum level of A4.

30. The method of any one of claims 1-29, wherein treating comprises reducing the subject’s serum level of 17-hydroxyprogesterone (17-OHP) from baseline.

31. The method of claim 30, wherein the subject’s serum level of 17-OHP is reduced by > 25% from baseline.

32. The method of claim 30, wherein the subject’s serum level of 17-OHP is reduced by > 50% from baseline.

33. The method of claim 30, wherein the subject’s serum level of 17-OHP is reduced by > 75% from baseline.

34. The method of any one of claims 30-33, wherein the subject’s serum level of 17-OHP is a morning serum level of 17-OHP.

35. The method of any one of claims 1-34, wherein treating comprises reducing the subject’s serum levels of one or more of 11 -deoxycorticosterone (11-DOC), 1 ip-hydroxy androstenedione (11-OHA4), 11 -ketoandrostenedione (11 -ketoA4), 1 1 ^-hydroxy testosterone (I l-OHT). and 11-ketotestosterone (11-ketoT) from baseline.

36. The method of any one of claims 1-35, wherein treating comprises reducing the subject’s serum levels of one or more of testosterone and progesterone from baseline.

37. The method of any one of claims 1-36, wherein treating comprises reducing the subject’s serum level of testosterone from baseline.

38. The method of any one of claims 1-37, wherein treating comprises reducing the subject’s serum level of progesterone from baseline.

39. The method of any one of claims 1-38, wherein treating comprises reducing the subject’s serum levels of one or more of cortisol and 21-deoxy cortisol from baseline.

40. The method of any one of claims 1-39, wherein treating comprises reducing the subject’s serum level of one or more of renin and aldosterone from baseline.

41. The method of any one of claims 1-40, wherein treating comprises reducing the aldosterone / renin ratio from baseline.

42. The method of any one of claims 1-41, wherein treating comprises reducing the luteinizing hormone (LH) / follicle-stimulating hormone (FSH) ratio from baseline.Docket No. P00045-WO 43. The method of any one of claims 1-42. wherein the subject has acne.

44. The method of claim 43, wherein the subject reports their acne has improved following administration of the ACTH antagonist.

45. The method of any one of claims 1-44, wherein treating comprises reducing the subject’s adrenal gland size from baseline.

46. The method of any one of claims 1-45, wherein treating comprises reducing the subject’s waist circumference from baseline.

47. The method of any one of claims 1 -46, wherein treating comprises reducing the subject’s body mass index (BMI) from baseline.

48. The method of any one of claims 1-47, wherein treating comprises reducing the subject’s serum level of hemoglobin A1C (HbAlC) from baseline.

49. The method of any one of claims 1-48, wherein treating comprises reducing the subject’s blood pressure from baseline.

50. The method of any one of claims 1-49, wherein treating comprises reducing the subject’s lipid levels from baseline.

51. The method of claim 50, wherein the lipids are selected from one or more of total cholesterol, triglycerides, high-density lipoprotein, and low-density lipoprotein.

52. The method of any one of claims 1-51, wherein treating comprises increasing the subject’s bone mineral density (BMD) from baseline.

53. The method of any one of claims 1-52. wherein treating comprises increasing the subject’s markers of bone resorption from baseline.

54. The method of 53, wherein the markers of bone resorption are selected from N-telopeptide (NTX), C-telopeptide (CTX), and pyridinoline cross-links.

55. The method of any one of claims 1-54, wherein treating comprises increasing the subject’s markers of bone formation from baseline.

56. The method of 55, wherein the markers of bone formation are selected from bonespecific alkaline phosphatase (BSAP), osteocalcin, and serum procollagen type 1 N-terminal propeptide (P1NP).

57. The method of any one of claims 1-56, wherein treating comprises decreasing bone turnover (osteocalcin) from baseline.Docket No. P00045-WO 58. The method of any one of claims 1-57, wherein the subject’s reproductive function improves.

59. The method of any one of claims 1-58, wherein the subject is male.

60. The method of claim 59, wherein treating comprises reducing the subject’s serum ratio of A4 / testosterone from baseline.

61. The method of claims 59 or 60, wherein the subject has testicular adrenal rests tumor (TART).

62. The method of claim 61 , wherein the subject’s TART has reduced in size from baseline.

63. The method any one of claims 59-62, wherein the subject’s sperm count improves from baseline.

64. The method of any one of claims 1-58, wherein the subject is female.

65. The method of claim 64, wherein the subject has hirsutism.

66. The method of claim 55, wherein the subject reports their hirsutism has improved following administration of the ACTH antagonist.

67. The method of any one of claims 64-66, wherein the subject has menstrual dysfunction.

68. The method of claim 67, wherein the subject reports their menstrual dysfunction has improved following administration of the ACTH antagonist.

69. The method of any one of claims 64-68, wherein treating comprises reducing the subject’s level of progesterone from baseline.

70. The method of claim 69, wherein the subject’s level of progesterone is sufficiently reduced to improve the subject’s ferti 1 i ty.

71. The method of any one of claims 64-70, wherein the subject begins menstruating normally following administration of the ACTH antagonist.

72. The method of any one of claims 64-71, wherein the subject is not using contraception.

73. The method of claim 72, wherein the contraception is selected from hormonal and an intrauterine device.

74. The method any one of claims 1-73, wherein the ACTH antagonist is administered as a daily dose.

75. The method of any one of claims 1 and 3-74, wherein the subject has hyperandrogenism.

76. The method of any one of claims 1-75, wherein the subject has polycythemia.Docket No. P00045-WO 77. The method of claim 76, wherein treating comprises resolving the subject’s polycythemia.

78. The method of claim 76, wherein treating comprises improving the subject’s polycythemia.

79. The method of any one of claims 1-78, wherein the dose of the GC is a daily dose of GC.

80. The method of any one of claims 1-79, wherein the subject is an infant, a toddler, a child, or a teenager.

81. The method of claim 80, wherein treating comprises preventing premature growth plate closure.

82. The method of claim 80, wherein treating comprises preventing premature puberty.

83. The method of any one of claims 1-82, wherein the ACTH antagonist is administered in the morning.

84. The method of any one of claims 1-83, wherein the ACTH antagonist is atumelnant, or a pharmaceutically acceptable salt thereof.

85. The method of claim 84, wherein the daily dose of atumelnant, or the pharmaceutically acceptable salt thereof, is equivalent to 6-80 mg of atumelnant free base.

86. The method of claim 84, wherein the daily dose of atumelnant, or the pharmaceutically acceptable salt thereof, is equivalent to 6-48 mg of atumelnant free base.

87. The method of claim 84, wherein the daily dose of atumelnant, or the pharmaceutically acceptable salt thereof, is equivalent to 40-80 mg of atumelnant free base.

88. The method of any one of claims 84-87, wherein atumelnant, or a pharmaceutically acceptable salt thereof, is administered as a single daily dose.

89. The method of any one of claims 84-88, wherein the pharmaceutically acceptable salt of atumelnant is atumelnant maleate.

90. 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.

91. 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.Docket No. P00045-WO 92. 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.

93. 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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