Compositions and methods for the treatment of congenital adrenal hyperplasia

Abstract

Compositions and methods for the treatment of congenital adrenal hyperplasia (CAH) are provided.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 503,248, filed May 19, 2023, and U.S. Provisional Patent Application No. 63 / 631,658, filed April 9, 2024, each of which is hereby incorporated by reference in its entirety.

[0002] Compositions and methods for the treatment of congenital adrenal hyperplasia (CAH) are provided herein.

Background Art

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

[0004] The current available treatments for CAH in the United States are only glucocorticoid therapies. However, the doses of glucocorticoids required to adequately suppress androgen production to effectively treat classical CAH are often higher than those required for physiological replacement. These high doses result in well - documented side effects of chronic supraphysiological glucocorticoid exposure, which is essentially an iatrogenic condition of Cushing's syndrome (CS). Thus, CAH patients often chronically suffer from varying degrees of androgen excess caused by the disease, along with the various complications of chronic supraphysiological glucocorticoid therapy used to treat the disease, so the balance between undertreatment and overtreatment is delicate.

[0005] In patients with CAH, insufficient glucocorticoid supplementation can lead to hypotension, hyponatremia, and hyperkalemia due to the absence of mineralocorticoids; hypoglycemia due to decreased gluconeogenesis; decreased final adult height due to premature epiphyseal closure caused by increased adrenal androgens and bone mass; weight loss; and muscle weakness and myalgia. In patients with CAH, excessive glucocorticoid supplementation can lead to hypertension, volume retention, edema, hypernatremia, and hypokalemia; hypertriglyceridemia due to increased hyperglycemia, gluconeogenesis, and lipolysis; osteopenia and osteoporosis due to inhibition of glucocorticoid-induced osteoclast function and vitamin D antagonism; increased fat mass (i.e., adrenal cortical obesity), mainly with afferent distribution; and muscle atrophy and myopathy.

[0006] As described above, the consequences of glucocorticoid under- or over-supplementation have significant effects on numerous bodily systems, including the cardiovascular, hepatic, bone, adipose tissue, and muscular systems. Therefore, there remains an unmet need for novel compositions and methods useful for the treatment of CAH that avoid the drawbacks associated with glucocorticoid therapy. This disclosure satisfies these and other needs, which become apparent with reference to the following disclosures. [Overview of the Initiative]

[0007] A method is provided for treating congenital adrenal hyperplasia (CAH) in a subject, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject.

[0008] [ka]

[0009] Also provided is a method for treating androgen hypertension in a subject having CAH, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject.

[0010] [ka]

[0011] In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective dose.

[0012] In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in amounts equivalent to about 40 mg to about 160 mg of formula (I), about 80 mg to about 160 mg of formula (I), about 80 mg to about 120 mg of formula (I), about 80 mg of formula (I), about 120 mg of formula (I), or about 160 mg of formula (I).

[0013] In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in one or more unit dosage forms. In these embodiments, a unit dosage form may contain the compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to about 40 mg of formula (I).

[0014] In certain embodiments, the unit dosage form is an oral unit dosage form.

[0015] In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered daily. In this embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered once daily.

[0016] In certain embodiments, CAH is caused by 21-hydroxylase deficiency.

[0017] In certain embodiments, the subject is simultaneously receiving glucocorticoid replacement therapy. In this embodiment, the subject may be simultaneously receiving hydrocortisone, prednisolone, prednisone, or methylprednisolone therapy.

[0018] In certain embodiments, the subject is simultaneously receiving mineralocorticoid replacement therapy. In this embodiment, the subject may also be simultaneously receiving fludrocortisone therapy.

[0019] In certain embodiments, treating comprises reducing the serum level of the subject's androstenedione (A4) from baseline. In this embodiment, the serum level of A4 in the subject can be reduced by more than 75%, more than 80%, more than 85%, or more than 90% from baseline.

[0020] In certain embodiments, treating comprises reducing the serum level of the subject's 17-hydroxyprogesterone (17-OHP) from baseline. In this embodiment, the serum level of 17-OHP in the subject can be reduced by more than 75%, more than 80%, more than 85%, more than 90%, or more than 95% from baseline.

[0021] In certain embodiments, treating comprises reducing the serum level of one or more of 11-deoxycorticosterone (11-DOC), 11β-hydroxyandrostenedione (11-OHA4), 11-ketoandrostenedione (11-ketoA4), 11β-hydroxytestosterone (11-OHT), and 11-ketotestosterone (11-ketoT) in the subject from baseline. In this embodiment, the baseline can be measured in the morning.

[0022] In certain embodiments, treating comprises reducing adrenal size, reducing abdominal circumference, or reducing the level of hemoglobin A1C (HbA1C).

[0023] In certain embodiments, the subject has androgen excess disorder.

[0024] In certain embodiments, the subject has acne. In this embodiment, the subject can report that the acne has improved after administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0025] In certain embodiments, the subject has hirsutism. In this embodiment, the subject can report that hirsutism has improved after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0026] In certain embodiments, the subject has menstrual dysfunction. In this embodiment, the subject can report that menstrual dysfunction has improved after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0027] In certain embodiments, the subject has testicular adrenal rest tumors (TART). In this embodiment, the subject's TART can improve after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0028] In certain embodiments, the subject is female. In this embodiment, treating includes reducing the serum level of the subject's testosterone from baseline. In this embodiment, the serum level of the subject's testosterone can be reduced by more than 50%, more than 60%, more than 70%, or more than 80% from baseline.

[0029] Also provided is a pharmaceutical composition for use in the treatment of a patient having CAH, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0030]

Chemical formula

[0031] Also provided is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a patient having CAH.

[0032]

Chemical formula

[0033] Also provided are pharmaceutical compositions for use in the treatment of androgen excess in subjects having CAH, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0034] [ka]

[0035] The use of the compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a drug for treating androgen excess in patients with CAH is also provided.

[0036] [ka] [Brief explanation of the drawing]

[0037] [Figure 1] This shows an initial cohort 1 analysis of the mean change ± standard error (SE) from baseline in morning serum androstenedione (A4) (ng / dL), where ULN represents the upper limit of normal. [Figure 2] This shows the mean change from baseline ± SE of morning serum 17-hydroxyprogesterone (17-OHP) (ng / dL) in the initial cohort 1 analysis. [Figure 3] This shows an initial cohort 1 analysis of the mean change from baseline ± SE of morning plasma adrenocorticotropic hormone (ACTH) (pg / mL), where ULN represents the upper limit of normal. [Figure 4] This shows the initial cohort 1 analysis of the mean change from baseline ± SE of morning serum testosterone (ng / dL) in female participants. [Figure 5] This shows the initial cohort 1 analysis of the mean change from baseline ± SE of morning serum testosterone (ng / dL) in male participants. [Figure 6]This shows the mean change from baseline ± SE in morning serum dehydroepiandrosterone (DHEA) (ng / mL) in the initial cohort 1 analysis. [Figure 7] This shows the initial cohort 1 analysis of the mean change from baseline ± SE in morning serum dehydroepiandrosterone sulfate (DHEA-S) (mcg / dL). [Figure 8] This shows an analysis of the initial cohort 1 of morning serum 11-deoxycorticosterone (ng / dL), where ULN represents the upper limit of normal, and the mean change from baseline ± SE. [Figure 9] This shows the mean change from baseline ± SE in morning serum 21-deoxycortisol (ng / dL) in the initial cohort 1 analysis. [Figure 10] This shows the initial cohort 1 analysis of the mean change from baseline ± SE in morning serum androstenedione (A4) / testosterone in male participants. [Modes for carrying out the invention]

[0038] The following description includes specific details to provide a complete understanding of various embodiments. However, those skilled in the art will understand that the invention can be practiced without these details. In other examples, well-known structures are not shown or described in detail to avoid unnecessarily obscuring the description of embodiments. Unless the context requires otherwise, the word “comprise” and its variations, e.g., “comprises” and “comprising,” throughout this specification and the following claims should be interpreted in an open, comprehensive sense, i.e., “includes but not limited to.” Furthermore, the headings provided herein are for convenience only and do not constitute an interpretation of the scope or meaning of the claimed invention.

[0039] Throughout this specification, any reference to “one embodiment,” “an embodiment,” “several embodiments,” or “a particular embodiment” means that a particular feature, structure, or characteristic described in relation to an embodiment is included in at least one embodiment. Therefore, the occurrence of the phrases “in one embodiment,” “in an embodiment,” “in several embodiments,” or “in a particular embodiment” in various places throughout this specification does not necessarily refer to the same embodiment. Furthermore, a particular feature, structure, or characteristic may be combined in any preferred manner in one or more embodiments.

[0040] Furthermore, as used herein and in the appended claims, the singular forms "a," "an," and "the" refer to multiple subjects unless the context clearly indicates otherwise.

[0041] As used herein, "approximately" means ±10% of the stated value, and more specifically, includes values ​​of ±5%, ±2%, and ±1% of the stated value.

[0042] As used herein, “administering to a patient” means the process of introducing a composition or dosage form to a patient via means of introduction recognized in the art.

[0043] As used herein, the term “disorder” is intended to be used interchangeably with the terms “disease,” “syndrome,” and “condition” (as in medical conditions), all in that they reflect an abnormal medical condition of the body or part thereof of a human or animal that impairs normal function, and are typically expressed by distinguishing between signs and symptoms.

[0044] As used herein, formula (I) refers to a compound having the structure shown below.

[0045] [ka]

[0046] The compound of formula (I) is CRN04894, CRN04894 free base, N-[(3S)-1-azabicyclo[2.2.2]octane-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]-piperazine-1-yl]pyridine-2-carboxamide (IUPAC name), N-[(3S)-1-azabicyclo[2.2.2]octane-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl] It is also known as the free base of [nyl]-piperazine-1-yl]pyridine-2-carboxamide, 6-(2-ethoxyphenyl)-3-((R)-2-ethyl-4-(1-(trifluoromethyl)cyclobutan-1-carbonyl)piperazine-1-yl)-N-((S)-quinuclidin-3-yl)picolinamide, and 6-(2-ethoxyphenyl)-3-((R)-2-ethyl-4-(1-(trifluoromethyl)cyclobutan-1-carbonyl)piperazine-1-yl)-N-((S)-quinuclidin-3-yl)picolinamide.

[0047] As used herein, “dose” means the measured amount of the activator taken by a patient at one time. In certain embodiments where the activator is not the free base of the compound of formula (I), the amount is the molar equivalent of the corresponding amount of the free base of the compound of formula (I). For example, drugs are often packaged in a pharmaceutically acceptable salt form, such as the maleate of the compound of formula (I), and the dosage strength refers to the mass of the corresponding molar equivalent of the free base. As an example, 47.56 mg of the maleate of the compound of formula (I) is the molar equivalent of 40.00 mg of the free base of the compound of formula (I).

[0048] As used herein, “effective amount” and “therapeutic effective amount” of a drug, compound, medicine, or composition are amounts that are nontoxic and effective in producing several desired therapeutic effects when administered to a subject or patient (e.g., a human subject or patient).

[0049] As used herein, “patient,” “individual,” or “subject” means a mammal, including humans, in which therapy is desired, and generally refers to the recipient of therapy.

[0050] As used herein, “pharmaceutically acceptable” means a material that is biologically or otherwise undesirable, i.e., a material that can be incorporated into a pharmaceutical composition for a patient without causing an undesirable biological effect or without interacting in a harmful manner with any of the other components of the composition containing it. When the term “pharmaceutically acceptable” is used to refer to a pharmaceutically acceptable carrier or excipient, it is implied that the carrier or excipient meets the necessary standards of toxicity and manufacturing testing, or that it is included in the Inactive Ingredients Guide prepared by the U.S. Food and Drug Administration. “Pharmacologically active” (or “active”) derivative or analogue means a derivative or analogue that has the same type and degree of pharmacological activity as the parent compound. The term “pharmaceutically acceptable salt” includes acid addition salts formed with a suitable inorganic acid, inorganic base, or organic base.

[0051] As used herein, “risk” means the probability or opportunity of an adverse reaction, injury, or other undesirable outcome arising from a medical procedure. “Acceptable risk” means the measure of the risk of harm, injury, or disease arising from a medical procedure that is acceptable to an individual or group. Whether a risk is “acceptable” depends on the benefits that the individual or group perceives to be obtainable in exchange for taking the risk, whether they accept the scientific and other advice provided about the magnitude of the risk, and many other factors, both political and social. “Acceptable risk” of an adverse reaction means that the probability of the adverse reaction occurring is small, or the consequences are very minor, or the benefits (perceived or actual) of the activator are very large, so that an individual or group in society is willing to take on or accept the risk of an adverse reaction. “Unacceptable risk” of an adverse reaction means that an individual or group in society, after weighing the likelihood of an adverse reaction occurring, the consequences of the adverse reaction, and the benefits (perceived or actual) of the activator, is unwilling to take on or accept the risk of an adverse reaction. "Being at risk" means being in a condition or illness characterized by a high level of risk or susceptibility. Risk assessment involves identifying and characterizing the nature, frequency, and severity of risks associated with the use of a product.

[0052] As used herein, “safety” means the incidence or severity of adverse events associated with the administration of the activator, including adverse effects related to patient-related factors (e.g., age, sex, ethnicity, race, target disease, abnormal renal or hepatic function, comorbidities, metabolic status, or environmental genetic characteristics) and activator-related factors (e.g., dose, plasma levels, duration of exposure, or concomitant drugs).

[0053] As used herein, “to treat” or “treatment” refers to a therapeutic use for the purpose of slowing or stopping the progression of a disorder and / or alleviating its symptoms.

[0054] Treatment method A method is provided for treating congenital adrenal hyperplasia (CAH) in a subject, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject.

[0055] [ka]

[0056] Also provided is a method for treating androgen hypertension in a subject having CAH, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject.

[0057] [ka]

[0058] In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective dose.

[0059] In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 40 mg to about 160 mg of formula (I). In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 80 mg to about 160 mg of formula (I). In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 80 mg to about 120 mg of formula (I).

[0060] In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 40 mg of formula (I). In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 80 mg of formula (I). In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 120 mg of formula (I). In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 160 mg of formula (I).

[0061] In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in one or more unit dosage forms. In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in two or more unit dosage forms. In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in three or more unit dosage forms. In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in four or more unit dosage forms.

[0062] In certain embodiments, the unit dosage form contains an amount equivalent to about 40 mg of formula (I) of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0063] In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in two unit dosage forms, each unit dosage form containing an amount equivalent to approximately 40 mg of formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in three unit dosage forms, each unit dosage form containing an amount equivalent to approximately 40 mg of formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in four unit dosage forms, each unit dosage form containing an amount equivalent to approximately 40 mg of formula (I) or a pharmaceutically acceptable salt thereof.

[0064] In certain embodiments, the unit dosage form is an oral unit dosage form.

[0065] In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered daily. In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily. In embodiments in which the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in two or more unit dosage forms (i.e., two, three, or four unit dosage forms), once daily administration includes administering all unit dosage forms simultaneously, or administering a first unit dosage form and then immediately administering each additional unit dosage form until all unit dosage forms have been administered to the subject.

[0066] In certain embodiments, CAH is caused by 21-hydroxylase deficiency.

[0067] In certain embodiments, the subject is simultaneously receiving glucocorticoid replacement therapy. In certain embodiments, the subject is simultaneously receiving hydrocortisone, prednisolone, prednisone, or methylprednisolone therapy. In certain embodiments, the subject is simultaneously receiving hydrocortisone therapy. In certain embodiments, the subject is simultaneously receiving prednisolone therapy. In certain embodiments, the subject is simultaneously receiving prednisone therapy. In certain embodiments, the subject is simultaneously receiving methylprednisolone therapy.

[0068] In certain embodiments, the subjects are simultaneously receiving mineralocorticoid replacement therapy. In certain embodiments, the subjects are simultaneously receiving fludrocortisone therapy.

[0069] In certain embodiments, treatment involves reducing the serum level of the target androstenedione (A4) from baseline. In certain embodiments, the serum level of the target A4 is reduced by more than 25% from baseline. In certain embodiments, the serum level of the target A4 is reduced by more than 50% from baseline. In certain embodiments, the serum level of the target A4 is reduced by more than 75% from baseline. In certain embodiments, the serum level of the target A4 is reduced by more than 80% from baseline. In certain embodiments, the serum level of the target A4 is reduced by more than 85% from baseline. In certain embodiments, the serum level of the target A4 is reduced by more than 90% from baseline.

[0070] In certain embodiments, the reduction in the serum level of the subject A4 from baseline is maintained for at least one week after discontinuation of treatment with CRN04894. In certain embodiments, the reduction in the serum level of the subject A4 from baseline is maintained for at least two weeks after discontinuation of treatment with CRN04894. In certain embodiments, the reduction in the serum level of the subject A4 from baseline is maintained for at least three weeks after discontinuation of treatment with CRN04894. In certain embodiments, the reduction in the serum level of the subject A4 from baseline is maintained for at least four weeks after discontinuation of treatment with CRN04894. In certain embodiments, the reduction in the serum level of the subject A4 from baseline is maintained throughout the course of treatment with CRN04894.

[0071] In certain embodiments, subjects have a baseline serum A4 level of 1.2 times or more above the upper limit of normal. In certain embodiments, subjects have a baseline serum A4 level of 1.5 times or more above the upper limit of normal. In certain embodiments, the upper limit of normal is approximately 150 ng / dL for adult males and approximately 200 ng / dL for adult females. In certain embodiments, the upper limit of normal is approximately 140 ng / dL for adolescent males at least 16 years old and approximately 210 ng / dL for adolescent males at least 17 years old. In certain embodiments, the upper limit of normal is approximately 240 ng / dL for adolescent females at least 16 years old.

[0072] In certain embodiments, treatment involves reducing the serum level of the target 17-hydroxyprogesterone (17-OHP) from baseline. In certain embodiments, the serum level of the target 17-OHP is reduced by more than 25% from baseline. In certain embodiments, the serum level of the target 17-OHP is reduced by more than 50% from baseline. In certain embodiments, the serum level of the target 17-OHP is reduced by more than 75% from baseline. In certain embodiments, the serum level of the target 17-OHP is reduced by more than 80% from baseline. In certain embodiments, the serum level of the target 17-OHP is reduced by more than 85% from baseline. In certain embodiments, the serum level of the target 17-OHP is reduced by more than 90% from baseline. In certain embodiments, the serum level of the target 17-OHP is reduced by more than 95% from baseline.

[0073] In certain embodiments, the reduction in the target serum 17-OHP level from baseline is maintained for at least one week after discontinuation of treatment with CRN04894. In certain embodiments, the reduction in the target serum 17-OHP level from baseline is maintained for at least two weeks after discontinuation of treatment with CRN04894. In certain embodiments, the reduction in the target serum 17-OHP level from baseline is maintained for at least three weeks after discontinuation of treatment with CRN04894. In certain embodiments, the reduction in the target serum 17-OHP level from baseline is maintained for at least four weeks after discontinuation of treatment with CRN04894. In certain embodiments, the reduction in the target serum 17-OHP level from baseline is maintained throughout the course of treatment with CRN04894.

[0074] In certain embodiments, the subject has a baseline 17-OHP serum level of 1,000 ng / dL or higher. In certain embodiments, the subject has a baseline 17-OHP serum level of 30.3 nmol / L or higher.

[0075] In certain embodiments, treatment involves reducing the serum levels of one or more of the following targets from baseline: 11-deoxycorticosterone (11-DOC), 11β-hydroxyandrostenedione (11-OHA4), 11-ketoandrostenedione (11-ketoA4), 11β-hydroxytestosterone (11-OHT), and 11-ketotestosterone (11-ketoT).

[0076] In certain embodiments, the baseline is measured in the morning.

[0077] In certain embodiments, the treatment includes reducing the size of the adrenal gland.

[0078] In certain embodiments, the treatment includes reducing waist circumference.

[0079] In certain embodiments, the treatment includes reducing the level of hemoglobin A1C (HbA1C).

[0080] In certain embodiments, the subject has androgen hypersensitivity.

[0081] In certain embodiments, the subject has acne. In certain embodiments, the subject reports that their acne has improved after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof. For example, the subject may report the improvement in their acne on a patient questionnaire.

[0082] In certain embodiments, the subject has hirsutism. In certain embodiments, the subject reports improvement in hirsutism after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof. For example, the subject may report improvement in hirsutism on a patient questionnaire.

[0083] In certain embodiments, the subject has menstrual dysfunction. In certain embodiments, the subject reports improvement in menstrual dysfunction after administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof. For example, the subject may report improvement in menstrual dysfunction using a patient questionnaire or menstrual cycle diary.

[0084] In certain embodiments, the subject has a residual adrenal tumor of the testis (TART). In certain embodiments, the subject's TART is improved after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, improvement of the subject's TART includes, but is not limited to, reducing testicular pain, reducing the number of tumors, reducing the size of one or more tumors, or preventing the development of additional tumors.

[0085] In certain embodiments, the subject is a human being. In certain embodiments, the human being is an adult. In certain embodiments, the human being is an adolescent human being.

[0086] In certain embodiments, treatment involves reducing the serum level of the target testosterone from baseline. In certain embodiments, the serum level of the target testosterone is reduced by more than 50% from baseline. In certain embodiments, the serum level of the target testosterone is reduced by more than 60% from baseline. In certain embodiments, the serum level of the target testosterone is reduced by more than 70% from baseline. In certain embodiments, the serum level of the target testosterone is reduced by more than 80% from baseline.

[0087] In certain embodiments, the subjects are women. In certain embodiments, treatment involves reducing the serum testosterone levels of the female subjects from baseline. In certain embodiments, the serum testosterone levels of the female subjects are reduced by more than 50% from baseline. In certain embodiments, the serum testosterone levels of the female subjects are reduced by more than 60% from baseline. In certain embodiments, the serum testosterone levels of the female subjects are reduced by more than 70% from baseline. In certain embodiments, the serum testosterone levels of the female subjects are reduced by more than 80% from baseline.

[0088] In certain embodiments, the reduction in the serum level of the target testosterone from baseline is maintained for at least one week after discontinuation of treatment with CRN04894. In certain embodiments, the reduction in the serum level of the target testosterone from baseline is maintained for at least two weeks after discontinuation of treatment with CRN04894. In certain embodiments, the reduction in the serum level of the target testosterone from baseline is maintained for at least three weeks after discontinuation of treatment with CRN04894. In certain embodiments, the reduction in the serum level of the target testosterone from baseline is maintained for at least four weeks after discontinuation of treatment with CRN04894. In certain embodiments, the reduction in the serum level of the target testosterone from baseline is maintained throughout the course of treatment with CRN04894.

[0089] Pharmaceutical composition A pharmaceutical composition is provided for use in the treatment of subjects with congenital adrenal hyperplasia (CAH), wherein the composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0090] [ka]

[0091] Also provided are pharmaceutical compositions for use in the treatment of androgen overdose in subjects having CAH, wherein the composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0092] [ka]

[0093] In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0094] In certain embodiments, the pharmaceutical composition contains an amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof equivalent to about 40 mg to about 160 mg of formula (I). In certain embodiments, the pharmaceutical composition contains an amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof equivalent to about 80 mg to about 160 mg of formula (I). In certain embodiments, the pharmaceutical composition contains an amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof equivalent to about 80 mg to about 120 mg of formula (I).

[0095] In certain embodiments, the pharmaceutical composition contains an amount equivalent to about 40 mg of formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains an amount equivalent to about 80 mg of formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains an amount equivalent to about 120 mg of formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains an amount equivalent to about 160 mg of formula (I) or a pharmaceutically acceptable salt thereof.

[0096] In certain embodiments, the pharmaceutical compositions provided herein may be provided in unit dosage forms or multi-dose dosage forms. As used herein, a unit dosage form refers to a physically distinct unit that is suitable for administration to a subject and is individually packaged as known in the art. Each unit dose contains a predetermined amount of the active ingredient in association with the necessary pharmaceutically acceptable carrier or excipients to produce the desired therapeutic effect. Examples of unit dosage forms include individually packaged tablets. A unit dosage form may be administered in fractions or in multiple doses. A multi-dose dosage form is a fraction of an isolated unit. This refers to multiple identical unit dosage forms packaged in a single container, administered in a single dose form. An example of a multi-dose dosage form is a bottle of tablets.

[0097] In certain embodiments, the pharmaceutical composition is a unit dosage form containing an amount equivalent to about 40 mg of formula (I) of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0098] In certain embodiments, the pharmaceutical composition is a unit dosage form that is an oral unit dosage form.

[0099] In certain embodiments, the pharmaceutical composition is administered daily. In certain embodiments, the pharmaceutical composition is administered once daily.

[0100] In certain embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers or excipients. Examples of pharmaceutically acceptable carriers or excipients include, but are not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, flow promoters, colorants, dye migration inhibitors, sweeteners, and flavoring agents.

[0101] In certain embodiments, CAH is caused by 21-hydroxylase deficiency.

[0102] In certain embodiments, the subject is simultaneously receiving glucocorticoid replacement therapy. In certain embodiments, the subject is simultaneously receiving hydrocortisone, prednisolone, prednisone, or methylprednisolone therapy. In certain embodiments, the subject is simultaneously receiving hydrocortisone therapy. In certain embodiments, the subject is simultaneously receiving prednisolone therapy. In certain embodiments, the subject is simultaneously receiving prednisone therapy. In certain embodiments, the subject is simultaneously receiving methylprednisolone therapy.

[0103] In certain embodiments, the subjects are simultaneously receiving mineralocorticoid replacement therapy. In certain embodiments, the subjects are simultaneously receiving fludrocortisone therapy.

[0104] In certain embodiments, treatment involves reducing the serum level of the target androstenedione (A4) from baseline. In certain embodiments, the serum level of the target A4 is reduced by more than 25% from baseline. In certain embodiments, the serum level of the target A4 is reduced by more than 50% from baseline. In certain embodiments, the serum level of the target A4 is reduced by more than 75% from baseline. In certain embodiments, the serum level of the target A4 is reduced by more than 80% from baseline. In certain embodiments, the serum level of the target A4 is reduced by more than 85% from baseline. In certain embodiments, the serum level of the target A4 is reduced by more than 90% from baseline.

[0105] In certain embodiments, the reduction in the serum level of the subject A4 from baseline is maintained for at least one week after discontinuation of treatment with CRN04894. In certain embodiments, the reduction in the serum level of the subject A4 from baseline is maintained for at least two weeks after discontinuation of treatment with CRN04894. In certain embodiments, the reduction in the serum level of the subject A4 from baseline is maintained for at least three weeks after discontinuation of treatment with CRN04894. In certain embodiments, the reduction in the serum level of the subject A4 from baseline is maintained for at least four weeks after discontinuation of treatment with CRN04894. In certain embodiments, the reduction in the serum level of the subject A4 from baseline is maintained throughout the course of treatment with CRN04894.

[0106] In certain embodiments, subjects have a baseline serum A4 level of 1.2 times or more above the upper limit of normal. In certain embodiments, subjects have a baseline serum A4 level of 1.5 times or more above the upper limit of normal. In certain embodiments, the upper limit of normal is approximately 150 ng / dL for adult males and approximately 200 ng / dL for adult females. In certain embodiments, the upper limit of normal is approximately 140 ng / dL for adolescent males at least 16 years old and approximately 210 ng / dL for adolescent males at least 17 years old. In certain embodiments, the upper limit of normal is approximately 240 ng / dL for adolescent females at least 16 years old.

[0107] In certain embodiments, treatment involves reducing the serum level of the target 17-hydroxyprogesterone (17-OHP) from baseline. In certain embodiments, the serum level of the target 17-OHP is reduced by more than 25% from baseline. In certain embodiments, the serum level of the target 17-OHP is reduced by more than 50% from baseline. In certain embodiments, the serum level of the target 17-OHP is reduced by more than 75% from baseline. In certain embodiments, the serum level of the target 17-OHP is reduced by more than 80% from baseline. In certain embodiments, the serum level of the target 17-OHP is reduced by more than 85% from baseline. In certain embodiments, the serum level of the target 17-OHP is reduced by more than 90% from baseline. In certain embodiments, the serum level of the target 17-OHP is reduced by more than 95% from baseline.

[0108] In certain embodiments, the reduction in serum levels of the target 17-OHP from baseline is maintained for at least one week after discontinuation of treatment with CRN04894. In certain embodiments, the reduction in serum levels of the target 17-OHP from baseline is maintained for at least two weeks after discontinuation of treatment with CRN04894. In certain embodiments, the reduction in serum levels of the target 17-OHP from baseline is maintained for at least three weeks after discontinuation of treatment with CRN04894. In certain embodiments, the reduction in serum levels of the target 17-OHP from baseline is maintained for at least four weeks after discontinuation of treatment with CRN04894. In certain embodiments, the reduction in serum levels of the target 17-OHP from baseline is maintained throughout the course of treatment with CRN04894.

[0109] In certain embodiments, the subject has a baseline 17-OHP serum level of 1,000 ng / dL or higher. In certain embodiments, the subject has a baseline 17-OHP serum level of 30.3 nmol / L or higher.

[0110] In certain embodiments, treatment involves reducing the serum levels of one or more of the following targets from baseline: 11-deoxycorticosterone (11-DOC), 11β-hydroxyandrostenedione (11-OHA4), 11-ketoandrostenedione (11-ketoA4), 11β-hydroxytestosterone (11-OHT), and 11-ketotestosterone (11-ketoT).

[0111] In certain embodiments, the baseline is measured in the morning.

[0112] In certain embodiments, the treatment includes reducing the size of the adrenal gland.

[0113] In certain embodiments, the treatment includes reducing waist circumference.

[0114] In certain embodiments, the treatment includes reducing the level of hemoglobin A1C (HbA1C).

[0115] In certain embodiments, the subject has androgen hypersensitivity.

[0116] In certain embodiments, the subject has acne. In certain embodiments, the subject reports that their acne has improved after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof. For example, the subject may report the improvement in their acne on a patient questionnaire.

[0117] In certain embodiments, the subject has hirsutism. In certain embodiments, the subject reports improvement in hirsutism after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof. For example, the subject may report improvement in hirsutism on a patient questionnaire.

[0118] In certain embodiments, the subject has menstrual dysfunction. In certain embodiments, the subject reports improvement in menstrual dysfunction after administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof. For example, the subject may report improvement in menstrual dysfunction using a patient questionnaire or menstrual cycle diary.

[0119] In certain embodiments, the subject has a residual adrenal tumor of the testis (TART). In certain embodiments, the subject's TART improved after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, improvement of the subject's TART includes, but is not limited to, reducing testicular pain, reducing the number of tumors, reducing the size of one or more tumors, or preventing the development of additional tumors.

[0120] In certain embodiments, the subject is a human being. In certain embodiments, the human being is an adult. In certain embodiments, the human being is an adolescent human being.

[0121] In certain embodiments, treatment involves reducing the serum level of the target testosterone from baseline. In certain embodiments, the serum level of the target testosterone is reduced by more than 50% from baseline. In certain embodiments, the serum level of the target testosterone is reduced by more than 60% from baseline. In certain embodiments, the serum level of the target testosterone is reduced by more than 70% from baseline. In certain embodiments, the serum level of the target testosterone is reduced by more than 80% from baseline.

[0122] In certain embodiments, the subjects are women. In certain embodiments, treatment involves reducing the serum testosterone levels of the female subjects from baseline. In certain embodiments, the serum testosterone levels of the female subjects are reduced by more than 50% from baseline. In certain embodiments, the serum testosterone levels of the female subjects are reduced by more than 60% from baseline. In certain embodiments, the serum testosterone levels of the female subjects are reduced by more than 70% from baseline. In certain embodiments, the serum testosterone levels of the female subjects are reduced by more than 80% from baseline.

[0123] In certain embodiments, the reduction in the serum level of the target testosterone from baseline is maintained for at least one week after discontinuation of treatment with CRN04894. In certain embodiments, the reduction in the serum level of the target testosterone from baseline is maintained for at least two weeks after discontinuation of treatment with CRN04894. In certain embodiments, the reduction in the serum level of the target testosterone from baseline is maintained for at least three weeks after discontinuation of treatment with CRN04894. In certain embodiments, the reduction in the serum level of the target testosterone from baseline is maintained for at least four weeks after discontinuation of treatment with CRN04894. In certain embodiments, the reduction in the serum level of the target testosterone from baseline is maintained throughout the course of treatment with CRN04894.

[0124] Congenital adrenal hyperplasia (CAH) Congenital adrenal hyperplasia (CAH) is a series of rare autosomal recessive disorders of the adrenal gland caused by mutations in the key enzyme involved in adrenal steroid formation. The most common cause of CAH is 21-hydroxylase deficiency (21-OHD), which accounts for over 90% of CAH cases. This "classic form" of CAH is due to a complete loss of 21-OH activity and has an incidence worldwide ranging from approximately 1:14,000 to 1:18,000.

[0125] The classic diagnosis of 21-OH deficiency is based on elevated levels of the immediate enzyme substrate 17-hydroxyprogesterone (17-OHP). Screening is routinely performed in newborn screening programs by measuring 17-OHP. While elevated levels indicate susceptibility to CAH, falsely elevated 17-OHP levels can occur in premature, morbid, and stressed infants. Second-tier screening can confirm elevated levels seen in newborn screening. If the data is ambiguous, stimulation tests may be needed to demonstrate that 17-OHP is excessively elevated in response to exogenous ACTH doses.

[0126] Typical CAH due to 2-OHD deficiency results in a lack of cortisol and aldosterone production, which can cause salt-wasting adrenal crisis in neonates and lifelong adrenal insufficiency. In the absence of cortisol, the hypothalamus and pituitary gland do not receive negative feedback, leading to elevated adrenocorticotropic hormone (ACTH) levels and excessive adrenal androgen production. This excess ACTH acts on the adrenal glands, resulting in bilateral adrenal hyperplasia and elevated levels of steroid precursors such as androstenedione (A4), which, due to 21-OH deficiency, can cause clinical hyperandrogenism.

[0127] In women, androgen excess can result in hirsutism, acne, male pattern baldness, menstrual irregularities, oligomenorrhea or amenorrhea, infertility, short stature, and apparent masculinization, and may manifest as "intersex" in newborns.

[0128] Poor control of childhood CAH can lead to stunted growth. In boys, childhood androgen hyperactivity results in adrenaline (adrenarche), leading to premature fusion of the epiphyses. In males, androgen hyperactivity can suppress gonadotropin secretion, resulting in reduced testicular size, reduced testicular testosterone secretion, and spermatogenesis. Furthermore, chronic ACTH stimulation also contributes to the formation of residual adrenal tumors (TART) in males, which can be confused with malignant testicular tumors and lead to irreversible testicular damage and potential infertility. There is no therapy to prevent the development of TART other than enhanced glucocorticoid treatment.

[0129] Current treatment for CAH centers on supplementing deficient adrenal hormones (i.e., cortisol and aldosterone) and suppressing excessive androgen production. Given the lack of other approved non-hormonal drugs for CAH in the United States, glucocorticoid therapy must not only help supplement the deficiency but also provide feedback inhibition in the pituitary gland to reduce ACTH secretion, thereby reducing adrenal androgen production.

[0130] CRN04894 CRN04894, i.e., the compound of formula (I), is an orally administered, first-in-class adrenocorticotropic hormone (ACTH) receptor antagonist that binds to the melanocortin 2 receptor (MC2R) and blocks ACTH-mediated steroid production from the adrenal gland. The structure of the compound of formula (I) is shown below.

[0131] [ka]

[0132] ACTH is a 39-amino acid peptide synthesized by pituitary anterior cortical stimuli cells and secreted in response to hypothalamic corticotropin-releasing hormone (CRH) and stress stimuli. As part of the hypothalamic-pituitary-adrenal (HPA) axis, ACTH activates melanocortin 2 receptors (MC2Rs) on the adrenal glands. MC2Rs are expressed on the adrenal cortex and require MC2R accessory proteins (MRAPs) for both surface expression and binding to ACTH. The binding of ACTH to the MC2R / MRAP complex on adrenal cortical cells is linked to the binding of G proteins (G s It activates ) to increase intracellular cyclic adenosine monophosphate (cAMP) levels, and then stimulates cortisol synthesis and secretion by modulating several steps in the steroid production pathway.

[0133] CRN04894 is a potential novel treatment for the disease characterized by pathological elevation of ACTH-mediated adrenal steroid hormones by selectively acting on MC2R. This predicted ability to suppress adrenal-derived androgens while maintaining mineralocorticoid production (due to a lack of activity on the angiotensin type 2 [AT II] receptor) makes CRN04894 a novel therapeutic option for CAH.

[0134] Furthermore, CRN04894 may also be an effective treatment for androgen excess observed in patients with CAH, potentially leading to improvements in related issues such as acne, hirsutism and menstrual dysfunction in women, and TART in men.

[0135] CRN04894, including its synthesis, is disclosed in U.S. Patent No. 11,566,015, which is incorporated by reference in its entirety. [Examples]

[0136] Example 1: A 12-week, open-label, sequential-dosing cohort study to evaluate the safety, efficacy, and pharmacokinetics of CRN04894 treatment in participants with CAH. Research objectives and evaluation items The primary efficacy objective is to evaluate the efficacy of CRN04894 as measured by the change in serum androstenedione (A4) from baseline, and the primary efficacy endpoint is the change in serum A4 from baseline on the morning of week 12 (before 11:00 AM).

[0137] The secondary efficacy objective is to evaluate the efficacy of CRN04894 as measured by the change in serum 17-hydroxyprogesterone (17-OHP) from baseline, and the secondary efficacy endpoint is the change in serum 17-OHP from baseline in the morning (before 11:00 AM) at week 12.

[0138] The safety objective is to evaluate the safety and tolerability of CRN04894 based on the incidence of treatment-related adverse events (TEAEs), including serious adverse events (SAEs) and any adverse events leading to discontinuation (AEs) that occur during treatment.

[0139] Inclusion Criteria We are recruiting participants for this study who have congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency.

[0140] Participants must understand the research procedures and possess the willingness and ability to abide by them.

[0141] Participants will include both males and females aged 18–75 years. Participants aged 16 years may be included at sites located in the United States. Classical 21-hydroxylase deficiency will be confirmed by the principal investigator and approved by the medical monitor.

[0142] Participants are receiving a stable glucocorticoid replacement regimen (e.g., hydrocortisone, prednisolone, prednisone, methylprednisolone) that does not decrease during the study (defined as no dose changes in hydrocortisone equivalent >5 mg / day within 6 months prior to screening). Participants receive hydrocortisone (or its equivalent) as a minimum total daily dose of ≥15 mg.

[0143] Compliance with glucocorticoid and mineralocorticoid supplementation regimens (if applicable), as determined at the discretion of the principal investigator (PI), will be documented during the screening period.

[0144] A4 and 17-OHP levels taken before morning glucocorticoid (GC) administration during screening visit 2 must meet the following criteria: A4 ≥ 1.5 × upper limit of normal (ULN); 17-OHP ≥ 1000 ng / dL (30.3 nmol / L); past results within the last two years are acceptable if the participant has been receiving the current dose of GC since that time. Participants who fail screening based on findings that the investigator considers temporary and not reflect the participant's usual condition (e.g., a normal A4 level when the participant's A4 level is normally far above normal) may be eligible for rescreening. These cases should be discussed with the medical monitor.

[0145] The reference range for serum A4 levels is as follows: approximately 40–150 ng / dL for adult males, approximately 30–200 ng / dL for adult females, approximately 48–140 ng / dL for adolescent males at least 16 years of age, approximately 65–210 ng / dL for adolescent males at least 17 years of age, and approximately 80–240 ng / dL for adolescent females at least 16 years of age.

[0146] If participants are receiving estrogen therapy (via any route), the dose must be stable for at least three months prior to screening.

[0147] Female participants who engage in heterosexual intercourse must be of potential pregnancy, which is defined as either surgically infertile (i.e., hysterectomy, bilateral salpingectomy, tubal ligation for at least 3 months, or bilateral oophorectomy) or having amenorrhea for at least one year postmenopausal. Participants with less than one year of amenorrhea must have a follicle-stimulating hormone (FSH) level of 30 IU / L or higher to confirm menopause. Participants not using hormone replacement therapy must agree to use a highly effective method of contraception from the start of screening until at least two weeks after the last dose of the study drug. The use of contraceptives by men and women must be consistent with local regulations regarding contraception for individuals participating in the clinical study. Periodic abstinence (i.e., calendar method, ovulation method, symptomatic thermometer method, post-ovulation method) and withdrawal are not acceptable methods of contraception.

[0148] Male participants should agree to use condoms if they are sexually active with a fertile female partner from screening until at least two weeks after the last dose of the study drug (or they should agree to be surgically infertile [i.e., vasectomy confirmed to be the absence of sperm in the semen], or to remain abstaining from sex for an extended and sustained period). Male participants must also agree not to provide sperm during the study period and until at least two weeks after the last dose of the study drug.

[0149] Exclusion criteria Participants will be excluded from the study if any of the following criteria apply:

[0150] Diagnosis of other forms of CAH besides the classic 21-hydroxylase deficiency.

[0151] Use of dexamethasone within 30 days of screening.

[0152] A history of bilateral adrenalectomy, hypopituitarism, or other conditions requiring chronic glucocorticoid therapy.

[0153] Night shift workers or those with other reasons related to an irregular sleep / wake cycle.

[0154] A clinically significant unstable medical condition or a chronic disease other than CAH.

[0155] A history of major surgery / surgical treatment for any cause within 4 weeks prior to screening.

[0156] Diabetes mellitus with insulin treatment in less than 6 weeks prior to screening, or with a change in total daily insulin dose of >15% in 6 weeks prior to screening.

[0157] Uncontrolled diabetes mellitus is defined as having a hemoglobin A1c (HbA1c) of 8.5% or higher (≥69 mmol / mL), or, if HbA1c is not evaluable (e.g., due to abnormal hemoglobinopathy), having an estimated HbA1c based on fructosamine.

[0158] Participants with hypothyroidism who have not received adequate hormone replacement therapy based on thyroid hormone levels measured at the time of screening, as determined by the principal investigator.

[0159] A history of unstable angina or acute myocardial infarction within 12 weeks prior to screening, or any other clinically significant cardiac condition at the time of screening, as determined by the principal investigator.

[0160] Concurrent mental conditions that prevent understanding of the nature, scope, and potential outcomes of the study, and / or evidence of inadequate adherence to medical instructions.

[0161] A history of cancer other than cured / treated squamous cell carcinoma of the skin, basal cell carcinoma, or cervical intraepithelial neoplasia.

[0162] Pregnant or breastfeeding.

[0163] A known history of illegal drug or alcohol abuse within the past year.

[0164] Use of antiandrogen therapy in the past 3 months (e.g., spironolactone, finasteride, cyproterone acetate, flutamide)

[0165] Use of testosterone, androgen-containing supplements, aromatase inhibitors, or growth hormone.

[0166] Use of drugs that are potent inducers of cytochrome P450 (CYP) 3A4 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.

[0167] Use of drugs (all routes of administration, i.e., oral, topical, and inhaled) or intake of food that are potent or moderate inhibitors of CYP3A4 within 14 days prior to Day 1 of the study. These include boceprevir, cobicistat, danoprevir and ritonavir, elvitegravir and ritonavir, grapefruit juice (more than 8 ounces per day), indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, nilmatrelvir and ritonavir, paritaprevir and ritonavir, and (ombitasvir and / or dasabuvir), posaconazole, ritonavir, saquinavir and ritonavir. This includes, but is not limited to, telaprevir, tipranavir and ritonavir, telithrosromycin, troleandomycin, voriconazole, clarithromycin, idelalisib, nefazodone, nelfinavir, aprepitant, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, imatinib, tofisopam, and verapamil.

[0168] Use of drugs that are strong or moderate inducers of P-gp within 14 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.

[0169] Use of drugs that are potent or moderate inhibitors of P-glycoprotein (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, lopinavir and ritonavir, propafenone, quinidine, lanolazine, ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir, or verapamil.

[0170] Any use of the investigational drug within the past 60 days or 5 half-lives (whichever is longer) prior to the first dose of the investigational drug, or any planned use of the investigational drug in another study.

[0171] Fridericia's corrected QT(QTcF) interval >450 milliseconds (male) or >470 milliseconds (female), PR interval >220 milliseconds, QRS interval >120 milliseconds, and mean of second or third-degree atrioventricular block, left bundle branch block, or hemiblock (of three ECGs) at the time of screening.

[0172] Renal failure was measured with an estimated glomerular volume (eGFR) < 60 mL / min / 1.73 m2.

[0173] Participants with significant liver disease, or alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST) > 3 × ULN and / or total bilirubin > 1.5 × ULN during screening. Participants with previously diagnosed Gilbert's syndrome, associated with total bilirubin < 3.5 mg / dL (< 51.3 μmol / L) and without other hepatobiliary disorders are acceptable.

[0174] Test design Up to approximately 30 participants will be enrolled in this study. Each cohort will have at least 6 participants, with the possibility of adding up to 6 participants from cohorts 1 and 2 to expand the number of evaluable participants in those cohorts to up to 12. The treatment duration will be up to 84 days (12 weeks) per participant. The total study duration will be up to 140 days per participant (up to 4 weeks of screening, up to 12 weeks of treatment, and up to 4 weeks of follow-up). Visits will be scheduled for screening (2 visits), day 1 (baseline), and at weeks 2 (day 14), 6 (day 42), and 12 (day 84). Safety follow-up visits will be scheduled 2 weeks after the last dose of CRN04894 (week 14, day 98), and telephone calls to collect adverse events (AEs) will be scheduled 4 weeks after the last dose of CRN04894 (week 16, day 112). The research design is described in detail below.

[0175] During screening, changes in glucocorticoid dosage are not permitted except for stress (emergency) administration. Furthermore, participants will maintain their existing fludrocortisone dosage throughout the study. Following the screening period, participants will be assigned to dose cohorts in an open-label manner. The dose cohorts will be run sequentially.

[0176] All cohort participants will continue their existing glucocorticoid replacement regimen / dosage throughout the study. In addition, each cohort will receive CRN04894 once daily (QD) before sleep, between 22:00 and 24:00 (approximately the same time each night), starting on the evening of day 1 and ending the night before the end-of-treatment (EOT) visit at week 12.

[0177] Participants in Cohort 1 will receive 80 mg of CRN04894 once daily. After at least three participants have completed a two-week course of 80 mg of CRN04894 with a QD in Cohort 1, an interim analysis evaluating PD, PK, efficacy, and safety will be reviewed by the Safety Review Committee (SRC). If it is safe to continue, the SRC will recommend administering 120 mg of CRN04894 in Cohort 2. However, based on a review of safety data, the SRC may recommend a lower dose in Cohort 2 (i.e., 40 mg of CRN04894 with a QD). The SRC also has the option to recommend increasing the number of participants in each of Cohort 1 and / or 2 to a total of 12. In this situation, expanded enrollment to the cohort will be completed, and data from the expanded cohort will be reviewed by the SRC before enrollment in subsequent cohorts.

[0178] Cohort 1 will initially complete enrollment with at least six participants before initiating screening for Cohort 2. The same initial dosing and SRC review process used for initiating Cohort 2 will be followed for the optional Cohort 3, where participants will receive up to 160 mg of CRN04894 via QD. The follow-up period will be extended from 12 to 16 weeks. For all cohorts, safety and PD biomarkers will be obtained at the end of week 14 of the follow-up period. Participants will receive a safety phone call for safety assessment at the end of week 16 / end of study (EOS).

[0179] At any time during the study, the SRC may decide to adjust or discontinue the administration of the study drug based on the study drug / study discontinuation criteria.

[0180] Participants will be considered to have completed the study if they complete the final scheduled procedure specified during their EOS visit.

[0181] Table 1 shows a detailed schedule of the activities.

[0182] In Table 1, "X" indicates that the activity is scheduled to be carried out, and "-" indicates that the activity is not scheduled to be carried out.

[0183] [Table 1-1]

[0184] [Table 1-2]

[0185] [Table 1-3]

[0186] Genetics Mutations in the CYP21A2 gene cause varying degrees of loss of 21-hydroxylase activity, resulting in different phenotypes. Participants will be screened for 21-hydroxylase gene mutations at the start of the treatment period.

[0187] Pharmacokinetics (PK) For participants who do not participate in the 24-hour inpatient circadian rhythm assessment during the treatment period, blood samples will be collected (using Mitra volume absorption microsampling [VAMS]) to measure CRN04894 concentrations in plasma and whole blood. The actual date and time (24-hour clock time) of each sample collection will be recorded. The actual date and time of the last administration of the study drug prior to each sample collection will also be recorded.

[0188] Plasma and whole blood CRN04894 concentrations are listed and summarized by cohort and study day for each scheduled collection time point for the PK analysis population, using descriptive statistics.

[0189] Pharmacodynamics (PD) Collect a pharmacodynamic biomarker panel. The biomarker panel includes: 17-Hydroxyprogesterone (17-OHP), Adrenocorticotropic hormone (ACTH) (plasma), testosterone, Androstenedione (A4), Dehydroepiandrosterone (DHEA), Dehydroepiandrosterone sulfate (DHEA-S), 11-deoxycorticosterone (11-DOC), 21-deoxycortisol, 11β-hydroxyandrostenedione (11-OHA4), 11-Ketoandrostenedione (11-ketoA4), 11β-hydroxytestosterone (11-OHT), 11-Ketotestosterone (11-ketoT), Aldosterone, and Lenin.

[0190] To establish PD biomarkers, collect PD biomarkers at the start of the treatment period prior to the first dose of CRN4894.

[0191] Effectiveness evaluation Magnetic Resonance Imaging: Adrenal magnetic resonance imaging (MRI) must be performed locally. To enable proper assessment of adrenal volume, imaging criteria are provided and must be followed. All MRI evaluations are assessed by the principal investigator for findings requiring immediate medical intervention and are also interpreted by the central MRI radiologist. The clinical significance of the MRI findings, including after the central readout is available, is determined by the principal investigator.

[0192] Ultrasonography: Testicular ultrasonography will be performed according to the study institution's procedures for evaluating testicular adrenal remnants (TART). Two ultrasound examinations are required for all male participants: 1) after screening and before treatment, and 2) at the end of treatment. Results will be recorded. All ultrasound evaluations will be assessed by the principal investigator for findings requiring immediate medical attention and will also be read by the central ultrasound radiologist. The clinical significance of the ultrasound findings will be determined by the principal investigator, including after the central readings become available.

[0193] Pharmacodynamic (PD) biomarkers:

[0194] Screening visit 1: PD biomarker blood sampling can be performed at any time after the informed consent form has been signed and will not be used for inclusion criteria assessment.

[0195] Screening visit 2: Blood should be drawn before receiving the morning GC dose.

[0196] Visits 2-7: Two blood draws (approximately 1 hour apart) are performed for PD biomarkers before receiving the morning GC replacement dose. PD biomarker collection should be one of the initial visit activities, performed at the start of the visit. Visits should begin as early as possible (preferably 7:00-8:00) to minimize delays in administering the morning GC dose, and the timing of each study visit should be as consistent as possible. The second set of PD biomarkers should be collected by 11:00 am.

[0197] Circadian rhythm assessment: Upon designated hospital visit, participants will be admitted to the metabolic unit for 24-hour circadian rhythm assessment. The circadian assessment will be conducted at a selected facility with a 24-hour blood collection system. Assessments will be performed on days 7–1, 12–17, and 70–86. The study drug will be administered at approximately 22:00 during the study treatment (days 12–17 and 70–86). Blood will be collected every 4 hours for the measurement of PK, ACTH, A4, 17-OHP, DHEA, 11-DOC, 11-OHA4, 11-ketoA4, 11-OHT, and 11-ketoT over a 24-hour period starting at approximately 10:00, followed by samples at 14:00, 18:00, 22:00, 02:00, 06:00, and 10:00 prior to administration. Saliva is collected simultaneously with blood, except at 2:00 am, for the measurement of A4, 17-OHP, 11-OHA4, 11-ketoA4, 11-OHT, 11-ketoT, and testosterone. In addition, blood is collected once at 6:00 am for testosterone, DHEA-S, and 21-deoxycortisol.

[0198] Safety evaluation: Physical Examination: A comprehensive physical examination will be conducted, and weight and waist circumference will be measured at designated times in the activity schedule. Height and body mass index (BMI) will be measured once at the time of screening. The examination will include assessment of the head (lateral), eyes, ears, nose and throat, lungs, cardiovascular system, abdomen, musculoskeletal system, skin, lymph nodes, central nervous system (CNS), and other physical systems where appropriate.

[0199] Symptom-oriented physical examinations resulting from adverse events (AEs) or other available safety data may be performed as out-of-schedule assessments.

[0200] Vital signs: Vital signs (resting and standing blood pressure, resting respiratory rate, and resting body temperature) are measured according to standard practice.

[0201] Standard blood pressure should be measured in a supine position after a 5-minute rest. Participants should lie on their backs for 5 minutes, then stand for 2-5 minutes, after which standing blood pressure and standing pulse rate should be measured.

[0202] Electrocardiogram (ECG): ECGs are collected at designated points in the activity schedule. The ECG assessment is a standard 12-lead ECG performed three times (at 1-3 minute intervals) after the participant has rested quietly in a supine position for at least 10 minutes without significant stimuli (noise, television, etc.). Additional ECGs outside of the planned assessment are collected according to the protocol if clinically indicated (e.g., participants with palpitations or dizziness).

[0203] The ECG parameters evaluated include a summary of findings, as well as pulse rate measurement, the time interval between the Q wave and the T wave (QT), corrected QT according to Fridericia's formula (QTcF), the time interval between the P wave and the R wave (PR), and the time interval of the QRS complex (QRS duration) based on the ECG machine reading.

[0204] All ECG assessments are initially evaluated by the principal investigator for findings requiring immediate medical attention and are also read by a central ECG reader. The clinical significance of ECG findings is determined by the principal investigator, including after the central readings become available. Potentially significant outliers should be confirmed by the central ECG reader. Any ECG measurements deemed clinically significant (occurring after signing the ICF) are recorded as AEs. Such abnormalities are monitored until the end of the study or, if thought to be related to the study drug, until resolved.

[0205] Clinical Safety Laboratory Tests: Clinical laboratory tests, as well as their timing and frequency, will be disclosed in the activity schedule. Safety laboratory tests will be performed by the central laboratory. Reference ranges will be per central laboratory. The principal investigator must review the test reports, document this review, and record any clinically significant changes that occurred during the study as adverse events (AEs). Test reports must be submitted along with the source documentation. All clinical laboratory tests deemed to have clinically significant abnormalities during study participation must be repeated until the values ​​return to normal or baseline, or until the principal investigator or medical monitor deems them clinically insignificant. If such values ​​do not return to normal / baseline within a period deemed reasonable by the principal investigator, the etiology must be identified and the sponsor notified.

[0206] Clinical safety tests include: blood urea nitrogen (BUN); potassium; creatinine; sodium; calcium; random glucose; glucose (fasting); fasting lipid panel; aspartate aminotransferase / serum glutamate oxaloacetate transaminase (AST / SGOT); alanine aminotransferase / serum glutamate pyruvate transaminase (ALT / SGPT); alkaline phosphates; total bilirubin and direct bilirubin; total protein; uric acid; chloride; phosphate chloride; magnesium; albumin; indirect bilirubin; amylase; lipase.

[0207] Table 2 summarizes the clinical tests required by the protocol.

[0208] [Table 2-1]

[0209] [Table 2-2]

[0210] Pregnancy testing: Pregnancy testing (urine or serum as required by local regulations) must be performed according to the activity schedule. Pregnancy testing (urine or serum as required by local regulations) must be performed for an additional 14 days after the completion of the relevant systemic exposure, and must correspond to the contraception time frame of the female participant. Additional serum or urine pregnancy tests may be performed to confirm the absence of pregnancy at any point during the participant's participation in this study, as determined by the principal investigator or as required by local regulations.

[0211] Adverse events (AEs), serious adverse events (SAEs), and other safety reports An AE is the onset of an undesirable medical condition or exacerbation of an existing medical condition that occurs after or during exposure to a drug, regardless of whether it is considered to be causally related to the drug, and after the moment the informed consent form is signed up until the final follow-up contact.

[0212] Therefore, an AE can be any undesirable or unintended sign (including abnormal laboratory findings), symptom, or disease (new or worsening) during a clinical examination, even if the study drug has not been administered.

[0213] Treatment-related adverse events (TEAEs) are adverse events that occur or worsen after administration of the investigational drug.

[0214] The principal investigator and qualified designated persons are responsible for detecting, documenting, and recording any event that meets the definition of an AE or SAE, and for continuing to follow up on all AEs or SAEs, regardless of whether they are related to the investigational drug or research procedure, or whether they resulted in the participant discontinuing CRN04894. This includes events reported by the participant (or, where applicable, by a caregiver, agent, or legally authorized representative of the participant).

[0215] Period and frequency of AE and SAE information collection: All AEs and SAEs will be collected from the time of signing the informed consent form until 4 weeks after the last dose of the study drug. If an AE / SAE occurs, the principal investigator is responsible for collecting and reviewing all documents related to the event (e.g., hospital progress notes, laboratory reports, and diagnostic reports). The principal investigator will record all relevant AE / SAE information in the eCRF and report all SAEs in paper SAE reports. All SAEs will be recorded immediately and reported to the sponsor or nominee, and under no circumstances will this exceed 24 hours from the initial recognition. The principal investigator will submit updated SAE data to the sponsor within 24 hours of obtaining it. The principal investigator is not obligated to proactively solicit information regarding AEs or SAEs after the completion of study participation. However, if the principal investigator becomes aware of a SAE, including death, at any time after a participant has withdrawn from the study, and determines that the event is reasonably related to the study drug or participation in the study, the principal investigator must promptly notify the sponsor.

[0216] Period and frequency of collecting AE and SAE information: All AEs and SAEs will be collected from the time of ICF signing until 4 weeks after the last dose of the study drug. If an AE / SAE occurs, the principal investigator is responsible for collecting and reviewing all documents related to the event (e.g., hospital progress notes, laboratory reports, and diagnostic reports).

[0217] The principal investigator will record all relevant AE / SAE information in the eCRF and report all SAEs in a paper SAE report.

[0218] All SAEs must be recorded immediately and reported to the sponsor or nominee, and under no circumstances should this be done more than 24 hours after initial recognition. The principal investigator must submit updated SAE data to the sponsor within 24 hours of obtaining it.

[0219] The principal investigator is not obligated to proactively seek information regarding adverse events (AEs) or serious adverse events (SAEs) after the completion of study participation. However, if the principal investigator becomes aware of an SAE, including death, at any time after a participant has withdrawn from the study and determines that the event is reasonably related to the study drug or participation in the study, the principal investigator must promptly notify the sponsor.

[0220] Methods for detecting AEs and SAEs: Care should be taken to avoid introducing bias when detecting AEs and / or SAEs. Open-ended, non-leading oral questions are preferred for inquiring about the occurrence of AEs.

[0221] Follow-up of AEs and SAEs: After the initial AE / SAE report, the principal investigator must proactively follow up with each participant through subsequent visits / contacts. All SAEs and AEs of special interest will be followed up until resolved, stabilized, the event is otherwise explained, or the participant becomes unfollowable.

[0222] The principal investigator has an obligation to perform or arrange for the performance of supplemental measurements and / or evaluations, as medically indicated or at the request of the sponsor or nominee, in order to fully determine the nature and / or causal relationship of the AE or SAE. This may include additional clinical tests or studies, histopathological examinations, or consultations with other healthcare professionals.

[0223] If a participant dies during their participation in the study or during an approved follow-up period, the principal investigator shall, to the extent possible, provide the sponsor or nominee with a copy of the post-mortem findings, including histopathology.

[0224] Regulatory reporting requirements for SAEs: Prompt notification of SAEs by the principal investigator to the sponsor is essential to ensure that legal and ethical obligations regarding participant safety and the safety of the investigational drug during clinical trials are met.

[0225] The sponsor has a legal responsibility to notify both local and other regulatory authorities about the safety of the investigational drug during clinical trials. The sponsor must comply with country-specific regulatory requirements related to safety reporting to regulatory authorities, institutional review boards (IRBs) / independent ethics committees (IECs), and the principal investigator.

[0226] Upon receiving a safety report from the sponsor containing SAEs or other specific safety information (such as a summary or list of SAEs), the principal investigator shall review it together with the Principal Investigator's Brochure (IB) / package insert or other documents and notify the IRB / IEC as necessary, in accordance with local requirements.

[0227] The principal investigator's safety report must be prepared in accordance with local regulatory requirements and sponsor policy if an unexpected serious adverse event (SUSAR) is suspected, and forwarded to the principal investigator as necessary.

[0228] Pregnancy: Details of all pregnancies of female participants and, if instructed, female partners of male participants will be collected after the start of the study drug, and the period for reporting pregnancies must coincide with the period of contraception after intervention.

[0229] Pregnancy itself is not considered an AE or SAE, but pregnancy complications or selective abortion for medical reasons are reported as AEs or SAEs.

[0230] Abnormal pregnancy outcomes (e.g., spontaneous miscarriage, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs and reported as such.

[0231] Participants and their pregnant female partners will be followed up to determine pregnancy outcomes. The principal investigator will collect follow-up information on participants, their pregnant female partners, and newborns, and forward this information to the sponsor.

[0232] Post-study pregnancy-related emergencies (SAEs) that researchers deem reasonably related to the investigational drug are reported to the clinical trial sponsor. While the principal investigator is not obligated to proactively solicit this information from former trial participants / pregnant women's partners, SAEs can be discovered through voluntary reporting.

[0233] Female participants who become pregnant while participating in the study will either discontinue the investigational drug or withdraw from the study.

[0234] Particularly noteworthy adverse events (AESIs): Particularly noteworthy adverse events (AESIs) are AEs of special medical or scientific interest to the sponsor of the clinical trial. In this study, the following events are considered AESIs: Adrenal insufficiency.

[0235] Statistical considerations General Considerations: Summarize continuous outcome items using descriptive statistics including the number of non-missing observations, arithmetic mean, standard deviation, median, first and third quartiles, minimum, and maximum. The number and percentage of participants at each level are used to summarize categorical or ordinal outcome items. Unless otherwise specified, missing or unreported classification results are included in the summary, and the number of participants in the entire analysis set is used as the denominator.

[0236] Safety Analysis: Safety endpoints include investigational drug exposure, adverse events, clinical laboratories, vital signs, and 12-lead ECG. Unless otherwise specified, safety endpoints are summarized for each cohort and overall planned dose level.

[0237] Drug exposure: CRN04894 treatment exposures are summarized by planned dose level for each cohort. Exposure summaries include the number of doses, duration of treatment, and actual dose received.

[0238] Adverse events: Adverse events are summarized by each cohort and by the overall planned dose level. AEs are coded according to the International Medical Terminology (MedDRA) version 25.0 or later.

[0239] A TEAE is defined as an adverse event (AE) that occurs or worsens during or after the administration of the first dose of the study drug. If time for AE observation is unavailable, a TEAE is defined as occurring on or after the first day of administration of the study drug. Non-treatment adverse events are not included in the summary but are included in the list.

[0240] An AE summary table detailing the number and percentage of participants, as well as the number of events, for the following categories is presented: At least one TEAE, At least one TEAE related to the investigational drug, At least one severe TEAE, At least one severe TEAE, At least one serious TEAE related to the investigational drug, At least one TEAE leading to discontinuation of treatment.

[0241] Treatment-related adverse events (AEs) are defined as AEs that are related to the investigational drug. AEs that lack a correlation are considered to be related.

[0242] The incidence of TEAEs is presented using the number of cases, percentages, and number of events for each organ-specific category (SOC) and primary term (PT). SOCs are sorted in descending order of frequency, and PTs within each SOC are sorted in descending order of frequency based on the percentage of AEs among all participants. Participants who experience multiple events related to a particular SOC or PT within a SOC are counted only once for that SOC and / or PT. Individual summaries for each category in the overall AE summary table are created based on the SOC and PT.

[0243] In addition to the AE summaries by SOC and PT, the following are presented in descending order of frequency by PT, based on the percentage of AEs among all participants: TEAE, Treatment-related TEAEs, and Severe TEAE. The following additional list is provided: List of SAEs, List of TEAEs that may lead to discontinuation of treatment List of severe TEAEs, and List of deaths.

[0244] Clinical Laboratory Tests: All sequential laboratory parameters in hematology and clinical chemistry are descriptively summarized at each clinical visit, along with their corresponding changes from baseline. Other sequential clinical laboratory tests are summarized in a similar manner. The number and percentage of participants outside the normal range (normal, low, and high) are also summarized by visit.

[0245] The time profiles of the mean and standard error of the change from baseline for the target clinical test are plotted.

[0246] All test results, including both scheduled and unscheduled results, are compiled into a list, and any results outside the normal range are noted in the list.

[0247] Vital signs, weight, and waist circumference: Vital signs include resting blood pressure (resting and standing), resting respiratory rate, and resting body temperature. Vital signs, weight, and waist circumference are descriptively summarized at each clinical visit. The mean and standard error time profiles of the change in waist circumference from baseline are plotted.

[0248] All vital signs, weight, and waist circumference measurements are included in a table containing both scheduled and unscheduled results.

[0249] Electrocardiogram: Standard 12-lead ECG data are collected based on the activity schedule. Results and changes from baseline are presented for all parameters (heart rate, QT, QTcF, PR interval, and QRS) at each visit. Assessment results are also summarized at each visit. The mean of triple measurements is used for summarization purposes.

[0250] All ECG measurements, including the original triple measurement results and evaluation results, which include both the scheduled and unscheduled results, are listed.

[0251] Primary efficacy analysis: The primary efficacy evaluation item is defined as the change from the baseline of serum A4 in the early morning (before 11:00) at week 12. Analysis of covariance (ANCOVA) is used to analyze the change from the baseline of A4. The model includes the baseline value as a covariate, as well as gender and dose cohort as fixed effects. Modeling of the rate of change from the baseline, including additional baseline characteristics in the ANCOVA model, and sensitivity analysis such as non-parametric tests can be performed, and the details are specified in the SAP. The change from the baseline at each baseline follow-up visit is presented graphically together with box plots. Descriptive statistics are presented for each planned dose level and overall in each cohort for A4 and the corresponding changes from the baseline at each visit.

[0252] Sample size determination: The sample size is based on practical considerations. For the efficacy evaluation items in this study, no formal sample size and power calculations are performed. Up to approximately 30 participants will be enrolled in this study. At least 6 participants will be enrolled in each cohort, and it is possible to add up to 6 participants in any single cohort to expand the evaluable participants in that cohort up to a maximum of 12. Interim analysis: For either cohort 1 or cohort 2, after 3 or more participants in a given cohort have completed 2 weeks of dosing, prepare an analysis for the purposes of the SRC, including PD, PK, efficacy, and safety evaluation items. After all participants in cohort 2 have passed through the treatment period or after early termination of the study treatment, analysis of the efficacy and safety evaluation items for the two cohorts is planned to support regulatory interactions and decision-making.

[0253] Initial analysis of cohort 1 The initial analysis summarizes the data of four participants (n = 4) in Cohort 1 who received 80 mg of CRN04894 QD. There were three female participants (n = 3) and one male participant (n = 1).

[0254] The demographic and baseline characteristics of the participants in Cohort 1 are shown in Table 3 below.

[0255]

Table 3

[0256] The initial analysis of Cohort 1 for percent change from baseline in morning serum A4, morning serum 17-OHP, morning serum testosterone in women, morning serum testosterone in men, and morning serum A4 / testosterone in men is shown in Table 4 below. These changes from baseline are also shown in Figures 1, 2, 4, 5, and 10, respectively.

[0257]

Table 4

[0258] Examination of the Initial Analysis of Cohort 1 Patients with classical CAH who received stable-dose glucocorticoid replacement for at least 6 months (≥18 - 75 years old in the United States, ≥16 years old) were enrolled, and the patients received 80 mg once daily of oral CRN04894 for 12 weeks, followed by a 4-week washout. Four participants (three women, median age 34 years (range 25 - 42 years)) completed 6 weeks, and two participants completed 12 weeks of treatment.

[0259] The baseline morning A4 levels of these participants ranged from 116 to 604 ng / dL (normal reference range is 30 to 200 ng / dL for women and 40 to 150 ng / dL for men). In all participants, administration of CRN04894 resulted in a rapid and significant A4 reduction within two weeks, which was maintained throughout the treatment period: reductions of 86% ± 10% (n=4), 90% ± 9% (n=4), and 88% ± 15% (n=2) (mean ± SD) were observed at weeks 2, 6, and 12, respectively, and all A4 levels were below the upper limit of normal at all post-treatment visits. <ULN)。

[0260] Baseline 17-OHP levels in these participants ranged from 4740 to 6905 ng / dL (normal reference ranges are <220 ng / dL in men, <80 ng / dL [follicular], and <285 ng / dL [corpus luteum] in women). In all participants, administration of CRN04894 resulted in a rapid and significant decrease in 17-OHP within two weeks, which was maintained throughout the treatment period: reductions of 96% ± 2% (mean ± SD) (n=4), 97% ± 0.3% (n=4), and 83% ± 22% (n=2) were observed at weeks 2, 6, and 12, respectively.

[0261] In the three female participants, baseline morning testosterone levels were 114±104 ng / dL (mean ± SD, RR 8–60 ng / dL), and decreases of 61%±53% (mean ± SD) (n=3), 65%±56% (n=3), and 97%±1% (n=2) were observed at weeks 2, 6, and 12, respectively. At baseline, the A4 / T ratio in male patients was 0.3 (normal <0.2), and was normal at subsequent visits at 0.08 (week 2) and 0.06 (week 6). Two female participants in this cohort experienced menstruation for the first time in over two years while receiving CRN04894.

[0262] The mean baseline morning ACTH was in the range of 155 - 1009 pg / mL (the normal reference range is 7.2 - 63 pg / mL). Minor fluctuations in ACTH levels without a consistent directional trend were observed during treatment: at weeks 2, 6, and 12, -25% ± 57% (n = 4), 51% ± 87% (n = 4), and -13% ± 67% (n = 2), respectively.

[0263] Diary and questionnaire

[0264]

Table 5-1

[0265]

Table 5-2

[0266]

Table 6

[0267]

Table 7

[0268]

Table 8

[0269]

Table 9-1

[0270]

Table 9-2

Claims

1. A method for treating congenital adrenal hyperplasia (CAH) in a subject, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject. 【Chemistry 1】

2. A method for treating androgen hypertension in a subject having CAH, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject. 【Chemistry 2】

3. The method according to claim 1 or 2, wherein the compound of formula (I) or the pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount.

4. The method according to any one of claims 1 to 3, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 40 mg to about 160 mg of formula (I).

5. The method according to any one of claims 1 to 3, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 80 mg to about 160 mg of formula (I).

6. The method according to any one of claims 1 to 3, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 80 mg to about 120 mg of formula (I).

7. The method according to any one of claims 1 to 3, wherein the compound of formula (I) or the pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 40 mg of formula (I).

8. The method according to any one of claims 1 to 3, wherein the compound of formula (I) or the pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 80 mg of formula (I).

9. The method according to any one of claims 1 to 3, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 120 mg of formula (I).

10. The method according to any one of claims 1 to 3, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an amount equivalent to about 160 mg of formula (I).

11. The method according to any one of claims 1 to 10, wherein the compound of formula (I) or the pharmaceutically acceptable salt thereof is administered in one or more unit dosage forms.

12. The method according to claim 11, wherein the unit dosage form contains a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to about 40 mg of formula (I).

13. The method according to claim 11 or 12, wherein the unit dosage form is an oral unit dosage form.

14. The method according to any one of claims 1 to 13, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered daily.

15. The method according to any one of claims 1 to 13, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily.

16. The method according to any one of claims 1 to 15, wherein the CAH is caused by 21-hydroxylase deficiency.

17. The method according to any one of claims 1 to 16, wherein the subject is simultaneously receiving glucocorticoid replacement therapy.

18. The method according to any one of claims 1 to 16, wherein the subject is simultaneously receiving hydrocortisone, prednisolone, prednisone, or methylprednisolone therapy.

19. The method according to any one of claims 1 to 16, wherein the subject is simultaneously receiving mineralocorticoid replacement therapy.

20. The method according to any one of claims 1 to 16, wherein the subject is simultaneously receiving fludrocortisone therapy.

21. The method according to any one of claims 1 to 20, wherein treatment comprises reducing the serum level of the subject androstenedione (A4) from baseline.

22. The method according to claim 21, wherein the serum level of the subject A4 is reduced by more than 75% from baseline.

23. The method according to claim 21, wherein the serum level of the subject A4 is reduced by more than 80% from baseline.

24. The method according to claim 21, wherein the serum level of the subject A4 is reduced by more than 85% from baseline.

25. The method according to claim 21, wherein the serum level of the subject A4 is reduced by more than 90% from baseline.

26. The method according to any one of claims 1 to 20, wherein the treatment comprises reducing the serum level of 17-hydroxyprogesterone (17-OHP) of the subject from baseline.

27. The method according to claim 26, wherein the serum level of the target 17-OHP is reduced by more than 75% from baseline.

28. The method according to claim 26, wherein the serum level of the target 17-OHP is reduced by more than 80% from baseline.

29. The method according to claim 26, wherein the serum level of the target 17-OHP is reduced by more than 85% from baseline.

30. The method according to claim 26, wherein the serum level of the target 17-OHP is reduced by more than 90% from baseline.

31. The method according to claim 26, wherein the serum level of the target 17-OHP is reduced by more than 95% from baseline.

32. The method according to any one of claims 1 to 20, wherein treatment comprises reducing the serum level of the subject testosterone from baseline.

33. The method according to claim 32, wherein the serum level of the target testosterone is reduced by more than 50% from baseline.

34. The method according to claim 32, wherein the serum level of the target testosterone is reduced by more than 60% from baseline.

35. The method according to claim 32, wherein the serum level of the target testosterone is reduced by more than 70% from baseline.

36. The method according to claim 32, wherein the serum level of the target testosterone is reduced by more than 80% from baseline.

37. The method according to any one of claims 32 to 36, wherein the subject is female.

38. The method according to any one of claims 1 to 37, wherein treatment comprises reducing the serum level of one or more of the target substances from baseline, including 11-deoxycorticosterone (11-DOC), 11β-hydroxyandrostenedione (11-OHA4), 11-ketoandrostenedione (11-ketoA4), 11β-hydroxytestosterone (11-OHT), and 11-ketotestosterone (11-ketoT).

39. The method according to any one of claims 21 to 36, wherein the baseline is measured in the morning.

40. The method according to any one of claims 1 to 39, wherein treatment includes reducing the size of the adrenal gland.

41. The method according to any one of claims 1 to 39, wherein the treatment includes reducing the waist circumference.

42. The method according to any one of claims 1 to 39, wherein treatment comprises reducing the level of hemoglobin A1C (HbA1C).

43. The method according to any one of claims 1 and 3 to 39, wherein the subject has androgen hypertension.

44. The method according to any one of claims 1 to 39, wherein the subject has acne.

45. The method according to claim 44, wherein the subject reports that their acne improved after administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

46. The method according to any one of claims 1 to 39, wherein the subject has hirsutism.

47. The method according to claim 46, wherein the subject reports that hirsutism improved after administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

48. The method according to any one of claims 1 to 39, wherein the subject has menstrual dysfunction.

49. The method according to claim 48, wherein the subject reports that his menstrual dysfunction improved after administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

50. The method according to any one of claims 1 to 39, wherein the subject has a residual adrenal tumor of the testis (TART).

51. The method according to claim 50, wherein the target TART is improved after administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

52. A pharmaceutical composition for use in the treatment of a subject having CAH, wherein the composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof. 【Transformation 3】

53. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a drug for treating a subject having CAH. 【Chemistry 4】

54. A pharmaceutical composition for use in the treatment of androgen excess in subjects having CAH, wherein the composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof. 【Transformation 5】

55. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a drug for treating androgen excess in subjects with CAH. 【Transformation 6】

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