Compositions and methods for treating congenital adrenocortical hyperplasia

Abstract

Compositions and methods for treating congenital adrenal hyperplasia (CAH) are provided.

Description

[0001] Cross-references to related applications

[0002] 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. US63 / 631,658, filed April 9, 2024, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This article provides compositions and methods for treating congenital adrenal hyperplasia (CAH). Background Technology

[0004] Congenital adrenocortical hyperplasia (CAH) is a series of rare autosomal recessive genetic disorders of the adrenal glands caused by mutations in key enzymes involved in adrenal steroid production.

[0005] Currently, in the United States, the only available treatment for CAH is glucocorticoid therapy. However, to effectively suppress androgen production to treat typical CAH, the required dose of glucocorticoids is often higher than that needed for physiological replacement. These high doses lead to the well-known side effect of prolonged supraphysiological glucocorticoid exposure, which is essentially an iatrogenic condition of Cushing's syndrome (CS). Therefore, there is a delicate balance between undertreatment and overtreatment, as CAH patients often suffer from varying degrees of hyperandrogenism caused by the disease and a variety of complications resulting from long-term supraphysiological glucocorticoid therapy used to treat the disease.

[0006] Inadequate glucocorticoid replacement therapy in patients with CAH can lead to hypotension, hyponatremia, and hyperkalemia (due to mineralocorticoid deficiency); hypoglycemia (due to reduced gluconeogenesis); premature epiphyseal closure due to increased adrenal androgen and bone mass, resulting in decreased adult height; weight loss; and muscle weakness and myalgia. Excessive glucocorticoid replacement therapy in patients with CAH can lead to hypertension, sodium and water retention, edema, hypernatremia, and hypokalemia; hyperglycemia and hypertriglyceridemia due to increased gluconeogenesis and lipolysis; osteopenia and osteoporosis due to glucocorticoid-induced osteoclast inhibition and vitamin D antagonism; increased fat mass (i.e., adrenocortical obesity) with a predominantly centripetal distribution; and muscle atrophy and myopathy.

[0007] As stated above, insufficient or excessive glucocorticoid supplementation can have serious effects on many bodily systems, including the cardiovascular, hepatic, skeletal, adipose tissue, and muscular systems. Therefore, there remains a need for novel compositions and methods for treating CAH that circumvent the drawbacks associated with glucocorticoid therapy. This disclosure addresses these and other needs, as detailed in the following disclosure. Summary of the Invention

[0008] A method for treating congenital adrenal hyperplasia (CAH) in a subject is provided, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0009]

[0010] The present invention also provides a method for treating hyperandrogenemia in subjects with CAH, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0011]

[0012] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount.

[0013] In some 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).

[0014] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in one or more unit dosage forms. In this embodiment, the unit dosage form may contain an amount equivalent to about 40 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0015] In some implementations, the unit dosage form is an oral unit dosage form.

[0016] In some 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.

[0017] In some implementations, CAH is caused by 21-hydroxylase deficiency.

[0018] In some implementations, the subject also receives glucocorticoid replacement therapy. In this implementation, the subject may receive treatment with hydrocortisone, prednisolone, prednisone, or methylprednisolone concurrently.

[0019] In some implementations, the subject also receives mineralocorticoid replacement therapy. In this implementation, the subject may also receive fludrocortisone treatment.

[0020] In some embodiments, the treatment includes reducing the level of androstenedione (A4) in the subject's serum relative to baseline. In this embodiment, the level of A4 in the subject's serum may be reduced by >75%, >80%, >85%, or >90% relative to baseline.

[0021] In some embodiments, the treatment includes reducing the serum level of 17-hydroxyprogesterone (17-OHP) in the subject relative to baseline. In this embodiment, the serum level of 17-OHP in the subject may be reduced by >75%, >80%, >85%, >90%, or >95% relative to baseline.

[0022] In some embodiments, the treatment includes reducing the serum levels 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) relative to baseline in the subject. In this embodiment, the baseline may be measured in the morning.

[0023] In some implementations, treatment includes reducing the size of the adrenal glands, reducing waist circumference, or lowering hemoglobin A1C (HbA1C) levels.

[0024] In some implementations, the subject suffers from hyperandrogenemia.

[0025] In some embodiments, the subject has acne. In this embodiment, the subject may report that their acne improves after administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, the subject has hirsutism. In this embodiment, the subject may report that their hirsutism improves after administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments, the subject suffers from menstrual disorders. In this embodiment, the subject may report that their menstrual disorders improve upon administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments, the subject has a testicular adrenal remnant tumor (TART). In this embodiment, the subject's TART is improved upon administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, the subject is female. In this embodiment, the treatment includes reducing the subject's serum testosterone level relative to baseline. In this embodiment, the subject's serum testosterone level may be reduced by >50%, >60%, >70%, or >80% relative to baseline.

[0030] A pharmaceutical composition for treating patients with CAH is also provided, said composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0031]

[0032] The use of compounds of formula (I) or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating patients with CAH is also provided:

[0033]

[0034] Also provided is a pharmaceutical composition for treating hyperandrogenemia in patients with CAH, said composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0035]

[0036] The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating hyperandrogenism in patients with CAH is also provided:

[0037] Attached Figure Description

[0038] Figure 1 An initial analysis was performed to depict the mean change ± standard error (SE) of morning serum androstenedione (A4) (ng / dL) relative to baseline in cohort 1, where ULN represents the upper limit of normal.

[0039] Figure 2 An initial analysis depicted the mean change ± SE of morning serum 17-hydroxyprogesterone (17-OHP) (ng / dL) relative to baseline in cohort 1.

[0040] Figure 3An initial analysis depicted the mean change ± SE of morning plasma adrenocorticotropic hormone (ACTH) (pg / mL) relative to baseline in cohort 1, where ULN represents the upper limit of normal.

[0041] Figure 4 An initial analysis depicted the mean change ± SE of morning serum testosterone (ng / dL) relative to baseline in female participants in cohort 1.

[0042] Figure 5 An initial analysis depicted the mean change ± SE of morning serum testosterone (ng / dL) relative to baseline in male participants in cohort 1.

[0043] Figure 6 An initial analysis depicted the mean change ± SE of morning serum dehydroepiandrosterone (DHEA) (ng / mL) relative to baseline in cohort 1.

[0044] Figure 7 An initial analysis depicted the mean change ± SE of morning serum dehydroepiandrosterone sulfate (DHEA-S) (mcg / dL) relative to baseline in cohort 1.

[0045] Figure 8 An initial analysis depicted the mean change ± SE of morning serum 11-deoxycorticosterone (ng / dL) relative to baseline in cohort 1, where ULN represents the upper limit of normal.

[0046] Figure 9 An initial analysis depicted the mean change ± SE of morning serum 21-deoxycortisol (ng / dL) relative to baseline in cohort 1.

[0047] Figure 10 An initial analysis depicted the mean change ± SE of morning serum androstenedione (A4) / testosterone relative to baseline in male participants in cohort 1. Detailed Implementation

[0048] In the following description, certain specific details are set forth in order to provide a comprehensive understanding of the various embodiments. However, those skilled in the art will understand that the invention can be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context requires otherwise, the word “comprise” and its variations, such as “comprises” and “comprising”, should be understood in an open and inclusive sense, meaning “including but not limited to”, throughout the specification and the following claims. Furthermore, the headings provided herein are for convenience only and do not constitute an explanation of the scope or meaning of the claimed invention.

[0049] Throughout this specification, references to "one embodiment," "an embodiment," "some embodiments," or "a certain embodiment" refer to a specific feature, structure, or characteristic described with respect to that embodiment being included in at least one embodiment. Therefore, the phrases "in one embodiment," "in one embodiment," "in some embodiments," or "in a certain embodiment" appearing throughout the specification do not necessarily refer to the same embodiment. Furthermore, specific features, structures, or characteristics can be combined in any suitable manner in one or more embodiments.

[0050] Furthermore, unless otherwise expressly stated in the content, the singular forms “a”, “an”, and “the” used in this specification and the appended claims also include plural references.

[0051] As used herein, “about” means ±10% of the value, and more specifically includes ±5%, ±2%, and ±1% of the value.

[0052] As used herein, “administered to a patient” means the process of introducing a composition or dosage form into a patient by a method of administration recognized in the art.

[0053] As used in this article, the term “disorder” is generally used synonymously and interchangeably with the terms “disease,” “syndrome,” and “symptom” (such as medical condition) because they all reflect an abnormal condition of the human or animal body or a part thereof that impairs normal function and is usually manifested as different signs and symptoms.

[0054] As used herein, formula (I) refers to compounds having the following structure:

[0055]

[0056] Compound (I) is also known as CRN04894, CRN04894 free base, N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]-piperazin-1-yl]pyridine-2-carboxamide (IUPAC name), N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1 The free bases of 6-(2-ethoxyphenyl)-3-((R)-2-ethyl-4-(1-(trifluoromethyl)cyclobutane-1-carbonyl)piperazin-1-yl)-N-((S)-quinine-3-yl)pyridinecarboxamide, and 6-(2-ethoxyphenyl)-3-((R)-2-ethyl-4-(1-(trifluoromethyl)cyclobutane-1-carbonyl)piperazin-1-yl)-N-((S)-quinine-3-yl)pyridinecarboxamide.

[0057] As used herein, “dosage” refers to the measured amount of active agent taken by a patient in a single administration. In some embodiments, when the active agent is not a free base of compound (I), its amount is molar equivalent to the corresponding amount of the free base of compound (I). For example, drugs are often packaged in the form of pharmaceutically acceptable salts, such as maleate of compound (I), and the dosage form strength refers to the molar equivalent mass of the corresponding free base. For example, 47.56 mg of maleate of compound (I) is molar equivalent to 40.00 mg of the free base of compound (I).

[0058] As used herein, “effective amount” and “therapeutic effective amount” of a drug, compound, medicine, or composition refer to an amount that is non-toxic and effectively produces certain desired therapeutic effects when administered to a subject or patient (e.g., a human subject or patient).

[0059] As used in this article, "patient," "individual," or "subject" refers to a mammal, including humans, that requires treatment, and generally refers to the recipient of the treatment.

[0060] As used herein, "pharmaceuticalally acceptable" means a substance that does not exhibit any biological or other adverse effects; that is, the substance can be added to a pharmaceutical composition for patient use without causing any undesirable biological effects or harmful interactions with any other components contained in the composition. When the term "pharmaceuticalally acceptable" is used to refer to a drug carrier or excipient, it implies that the carrier or excipient has met the necessary standards for toxicological and manufacturing testing, or is listed in the Inactive Ingredient Guide established by the U.S. Food and Drug Administration (FDA). "Pharmacologically active" (or simply "active"), as in "pharmacologically active" (or "active") derivatives or analogs, refers to a derivative or analog having a pharmacological activity of the same type and substantially equivalent in degree to that of the parent compound. The term "pharmaceuticalally acceptable salt" includes acid addition salts formed with suitable inorganic acids, inorganic bases, or organic bases.

[0061] As used in this article, “risk” refers to the probability or chance of an adverse reaction, injury, or other undesirable consequence resulting from medical treatment. “Acceptable risk” refers to a measure of the risk of harm, injury, or illness resulting from medical treatment that an individual or group can tolerate. Whether a risk is “acceptable” depends on the benefits that an individual or group perceives in taking the risk, whether they accept any scientific and other advice regarding the degree of risk, and many other political and social factors. “Acceptable risk” for an adverse reaction is the risk that an individual or group is willing to take or bear due to the low probability of the adverse reaction, the low consequence, or the high benefit (perceived or actual) of the active agent. “Unacceptable risk” for an adverse reaction is the risk that an individual or group is unwilling to take or bear after weighing the probability of the adverse reaction, the consequences of the adverse reaction, and the benefit (perceived or actual) of the active agent. “Being at risk” means being in a state or condition of high risk or vulnerability. Risk assessment includes identifying and characterizing the nature, frequency, and severity of risks associated with product use.

[0062] As used in this article, “safety” refers to the incidence or severity of adverse events associated with the administration of the active agent, including adverse reactions related to patient-related factors (e.g., age, sex, nationality, race, target disease, abnormal renal or hepatic function, comorbidities, genetic characteristics (e.g., metabolic state or environment)) and active agent-related factors (e.g., dose, plasma level, duration of exposure, or concomitant medications).

[0063] As used in this article, “treating” or “treatment” refers to therapeutic applications that slow or stop the progression of a disease and / or alleviate its symptoms.

[0064] Treatment

[0065] A method for treating a subject with congenital adrenal hyperplasia (CAH) is provided, comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0066]

[0067] The present invention also provides a method for treating hyperandrogenemia in a subject with CAH, comprising administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0068]

[0069] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a therapeutically effective amount.

[0070] In some 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 some 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 some 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).

[0071] In some 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 some 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 some 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 some 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).

[0072] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in one or more unit dosage forms. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in two or more unit dosage forms. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in three or more unit dosage forms. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in four or more unit dosage forms.

[0073] In some embodiments, the unit dosage form contains an amount of formula (I) compound or a pharmaceutically acceptable salt thereof equivalent to about 40 mg.

[0074] In some 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 of the compound of formula (I) or a pharmaceutically acceptable salt thereof equivalent to about 40 mg. In some 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 of the compound of formula (I) or a pharmaceutically acceptable salt thereof equivalent to about 40 mg. In some 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 of the compound of formula (I) or a pharmaceutically acceptable salt thereof equivalent to about 40 mg.

[0075] In some implementations, the unit dosage form is an oral unit dosage form.

[0076] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered daily. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily. In embodiments where 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 the first unit dosage form and then immediately administering each subsequent additional unit dosage form until all unit dosage forms have been administered to the subject.

[0077] In some implementations, CAH is caused by 21-hydroxylase deficiency.

[0078] In some embodiments, the subject concurrently receives glucocorticoid replacement therapy. In some embodiments, the subject concurrently receives hydrocortisone, prednisolone, prednisone, or methylprednisolone. In some embodiments, the subject concurrently receives hydrocortisone. In some embodiments, the subject concurrently receives prednisolone. In some embodiments, the subject concurrently receives prednisone. In some embodiments, the subject concurrently receives methylprednisolone.

[0079] In some implementations, the subject also receives mineralocorticoid replacement therapy. In some implementations, the subject also receives fludrocortisone treatment.

[0080] In some embodiments, the treatment includes reducing the level of androstenedione (A4) in the subject's serum relative to baseline. In some embodiments, the level of A4 in the subject's serum is reduced by >25% relative to baseline. In some embodiments, the level of A4 in the subject's serum is reduced by >50% relative to baseline. In some embodiments, the level of A4 in the subject's serum is reduced by >75% relative to baseline. In some embodiments, the level of A4 in the subject's serum is reduced by >80% relative to baseline. In some embodiments, the level of A4 in the subject's serum is reduced by >85% relative to baseline. In some embodiments, the level of A4 in the subject's serum is reduced by >90% relative to baseline.

[0081] In some embodiments, the decrease in serum A4 levels relative to baseline in the subject is maintained for at least one week after discontinuation of CRN04894 treatment. In some embodiments, the decrease in serum A4 levels relative to baseline in the subject is maintained for at least two weeks after discontinuation of CRN04894 treatment. In some embodiments, the decrease in serum A4 levels relative to baseline in the subject is maintained for at least three weeks after discontinuation of CRN04894 treatment. In some embodiments, the decrease in serum A4 levels relative to baseline in the subject is maintained throughout the entire course of CRN04894 treatment.

[0082] In some implementations, the subject's baseline serum A4 level is greater than or equal to 1.2 times the upper limit of normal. In some implementations, the subject's baseline serum A4 level is greater than or equal to 1.5 times the upper limit of normal. In some implementations, the upper limit of normal is approximately 150 ng / dL for adult males and approximately 200 ng / dL for adult females. In some implementations, the upper limit of normal is approximately 140 ng / dL for adolescent males at least 16 years of age and approximately 210 ng / dL for adolescent females at least 17 years of age. In some implementations, the upper limit of normal is approximately 240 ng / dL for adolescent females at least 16 years of age.

[0083] In some embodiments, the treatment includes reducing the level of 17-hydroxyprogesterone (17-OHP) in the subject's serum relative to baseline. In some embodiments, the level of 17-OHP in the subject's serum is reduced by >25% relative to baseline. In some embodiments, the level of 17-OHP in the subject's serum is reduced by >50% relative to baseline. In some embodiments, the level of 17-OHP in the subject's serum is reduced by >75% relative to baseline. In some embodiments, the level of 17-OHP in the subject's serum is reduced by >80% relative to baseline. In some embodiments, the level of 17-OHP in the subject's serum is reduced by >85% relative to baseline. In some embodiments, the level of 17-OHP in the subject's serum is reduced by >90% relative to baseline. In some embodiments, the level of 17-OHP in the subject's serum is reduced by >95% relative to baseline.

[0084] In some embodiments, the decrease in serum 17-OHP levels relative to baseline in the subject is maintained for at least one week after discontinuation of CRN04894 treatment. In some embodiments, the decrease in serum 17-OHP levels relative to baseline in the subject is maintained for at least two weeks after discontinuation of CRN04894 treatment. In some embodiments, the decrease in serum 17-OHP levels relative to baseline in the subject is maintained for at least three weeks after discontinuation of CRN04894 treatment. In some embodiments, the decrease in serum 17-OHP levels relative to baseline in the subject is maintained for at least four weeks after discontinuation of CRN04894 treatment. In some embodiments, the decrease in serum 17-OHP levels relative to baseline in the subject is maintained throughout the entire course of CRN04894 treatment.

[0085] In some embodiments, the subject's baseline serum 17-OHP level is greater than or equal to 1,000 ng / dL. In some embodiments, the subject's baseline serum 17-OHP level is greater than or equal to 30.3 nmol / L.

[0086] In some implementations, the treatment includes 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) relative to baseline.

[0087] In some implementations, the baseline is measured in the early morning.

[0088] In some implementations, the treatment includes reducing the size of the adrenal glands.

[0089] In some implementations, the treatment includes reducing waist circumference.

[0090] In some implementations, the treatment includes lowering hemoglobin A1C (HbA1C) levels.

[0091] In some implementations, the subject suffers from hyperandrogenemia.

[0092] In some implementations, the subject has acne. In some implementations, 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 improvement in their acne on a patient questionnaire.

[0093] In some implementations, the subject suffers from hirsutism. In some implementations, the subject reports that their hirsutism improves after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof. For example, the subject may report improvement in their hirsutism in a patient questionnaire.

[0094] In some implementations, the subject suffers from menstrual disorders. In some implementations, the subject reports that their menstrual disorders improve upon administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof. For example, the subject may report improvement in their menstrual disorders in a patient questionnaire or menstrual cycle diary.

[0095] In some embodiments, the subject has a testicular adrenal remnant tumor (TART). In some embodiments, the subject's TART is improved upon administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the improvement in the subject's TART includes, but is not limited to, reduction of testicular pain, reduction of the number of tumors, reduction of the size of one or more tumors, or prevention of the occurrence of other tumors.

[0096] In some implementations, the subject is a human. In some implementations, the human is an adult. In some implementations, the human is a teenager.

[0097] In some embodiments, the treatment includes reducing the subject's serum testosterone level relative to baseline. In some embodiments, the subject's serum testosterone level is reduced by >50% relative to baseline. In some embodiments, the subject's serum testosterone level is reduced by >60% relative to baseline. In some embodiments, the subject's serum testosterone level is reduced by >70% relative to baseline. In some embodiments, the subject's serum testosterone level is reduced by >80% relative to baseline.

[0098] In some embodiments, the subject is female. In some embodiments, the treatment includes reducing the serum testosterone level in the female subject relative to baseline. In some embodiments, the serum testosterone level in the female subject is reduced by >50% relative to baseline. In some embodiments, the serum testosterone level in the female subject is reduced by >60% relative to baseline. In some embodiments, the serum testosterone level in the female subject is reduced by >70% relative to baseline. In some embodiments, the serum testosterone level in the female subject is reduced by >80% relative to baseline.

[0099] In some embodiments, the decrease in serum testosterone levels relative to baseline in the subject is maintained for at least one week after discontinuation of CRN04894 treatment. In some embodiments, the decrease in serum testosterone levels relative to baseline in the subject is maintained for at least two weeks after discontinuation of CRN04894 treatment. In some embodiments, the decrease in serum testosterone levels relative to baseline in the subject is maintained for at least three weeks after discontinuation of CRN04894 treatment. In some embodiments, the decrease in serum testosterone levels relative to baseline in the subject is maintained throughout the entire course of CRN04894 treatment.

[0100] Pharmaceutical Composition

[0101] This invention provides a pharmaceutical composition for treating congenital adrenal hyperplasia (CAH) in a subject, wherein the composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0102]

[0103] The present invention also provides a pharmaceutical composition for treating hyperandrogenemia in subjects suffering from CAH, wherein the composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0104]

[0105] In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to about 40 mg to about 160 mg. In some embodiments, the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to about 80 mg to about 160 mg. In some embodiments, the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount equivalent to about 80 mg to about 120 mg.

[0107] In some embodiments, the pharmaceutical composition comprises an amount of formula (I) equivalent to about 40 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises an amount of formula (I) equivalent to about 80 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises an amount of formula (I) equivalent to about 120 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition comprises an amount of formula (I) equivalent to about 160 mg of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, the pharmaceutical compositions provided herein may be provided in single-dose or multi-dose form. As used herein, a single-dose formulation refers to a physically discrete unit suitable for administration to a subject and individually packaged according to methods known in the art. Each single-dose contains a predetermined amount of active ingredient sufficient to produce the desired therapeutic effect, along with the desired pharmaceutical carrier or excipient. Examples of single-dose formulations include individually packaged tablets. Single-dose formulations may be administered in multiple doses or multiple times. Multi-dose formulations refer to multiple identical single-dose formulations packaged in a single container for administration in individual single-dose formulations. Examples of multi-dose formulations include tablet vials.

[0109] In some embodiments, the pharmaceutical composition is a unit dosage form comprising an amount of formula (I) of compound (I) or a pharmaceutically acceptable salt thereof equivalent to about 40 mg.

[0110] In some embodiments, the pharmaceutical composition is in unit dosage form, i.e., oral unit dosage form.

[0111] In some embodiments, the pharmaceutical composition is administered daily. In some embodiments, the pharmaceutical composition is administered once daily.

[0112] In some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers or excipients. Pharmaceutically acceptable carriers or excipients include, but are not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, flow aids, colorants, dye migration inhibitors, sweeteners, and flavoring agents.

[0113] In some implementations, CAH is caused by a deficiency of 21-hydroxylase.

[0114] In some embodiments, the subject concurrently receives glucocorticoid replacement therapy. In some embodiments, the subject concurrently receives hydrocortisone, prednisolone, prednisone, or methylprednisolone. In some embodiments, the subject concurrently receives hydrocortisone. In some embodiments, the subject concurrently receives prednisolone. In some embodiments, the subject concurrently receives prednisone. In some embodiments, the subject concurrently receives methylprednisolone.

[0115] In some implementations, the subject also receives mineralocorticoid replacement therapy. In some implementations, the subject also receives fludrocortisone treatment.

[0116] In some embodiments, the treatment includes reducing the level of androstenedione (A4) in the subject's serum relative to baseline. In some embodiments, the level of A4 in the subject's serum is reduced by >25% relative to baseline. In some embodiments, the level of A4 in the subject's serum is reduced by >50% relative to baseline. In some embodiments, the level of A4 in the subject's serum is reduced by >75% relative to baseline. In some embodiments, the level of A4 in the subject's serum is reduced by >80% relative to baseline. In some embodiments, the level of A4 in the subject's serum is reduced by >85% relative to baseline. In some embodiments, the level of A4 in the subject's serum is reduced by >90% relative to baseline.

[0117] In some embodiments, the decrease in serum A4 levels relative to baseline in the subject is maintained for at least one week after discontinuation of CRN04894 treatment. In some embodiments, the decrease in serum A4 levels relative to baseline in the subject is maintained for at least two weeks after discontinuation of CRN04894 treatment. In some embodiments, the decrease in serum A4 levels relative to baseline in the subject is maintained for at least three weeks after discontinuation of CRN04894 treatment. In some embodiments, the decrease in serum A4 levels relative to baseline in the subject is maintained throughout the entire course of CRN04894 treatment.

[0118] In some embodiments, the subject's baseline serum A4 level is greater than or equal to 1.2 times the upper limit of normal. In some embodiments, the subject's baseline serum A4 level is greater than or equal to 1.5 times the upper limit of normal. In some embodiments, the upper limit of normal for adult males is approximately 150 ng / dL, and for adult females it is approximately 200 ng / dL. In some embodiments, the upper limit of normal for adolescent males at least 16 years of age is approximately 140 ng / dL, and for adolescent males at least 17 years of age it is approximately 210 ng / dL. In some embodiments, the upper limit of normal for adolescent females at least 16 years of age is approximately 240 ng / dL.

[0119] In some embodiments, the treatment includes reducing the level of 17-hydroxyprogesterone (17-OHP) in the subject's serum relative to baseline. In some embodiments, the level of 17-OHP in the subject's serum is reduced by >25% relative to baseline. In some embodiments, the level of 17-OHP in the subject's serum is reduced by >50% relative to baseline. In some embodiments, the level of 17-OHP in the subject's serum is reduced by >75% relative to baseline. In some embodiments, the level of 17-OHP in the subject's serum is reduced by >80% relative to baseline. In some embodiments, the level of 17-OHP in the subject's serum is reduced by >85% relative to baseline. In some embodiments, the level of 17-OHP in the subject's serum is reduced by >90% relative to baseline. In some embodiments, the level of 17-OHP in the subject's serum is reduced by >95% relative to baseline.

[0120] In some embodiments, after discontinuation of CRN04894 treatment, the decrease in the subject's serum 17-OHP level relative to baseline is maintained for at least one week. In some embodiments, after discontinuation of CRN04894 treatment, the decrease in the subject's serum 17-OHP level relative to baseline is maintained for at least two weeks. In some embodiments, after discontinuation of CRN04894 treatment, the decrease in the subject's serum 17-OHP level relative to baseline is maintained for at least three weeks. In some embodiments, after discontinuation of CRN04894 treatment, the decrease in the subject's serum 17-OHP level relative to baseline is maintained for at least four weeks. In some embodiments, during the entire course of CRN04894 treatment, the decrease in the subject's serum 17-OHP level relative to baseline is maintained.

[0121] In some embodiments, the subject's baseline serum 17-OHP level is greater than or equal to 1,000 ng / dL. In some embodiments, the subject's baseline serum 17-OHP level is greater than or equal to 30.3 nmol / L.

[0122] In some implementations, the treatment includes 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) relative to baseline.

[0123] In some implementations, the baseline is measured in the early morning.

[0124] In some implementations, the treatment includes reducing the size of the adrenal glands.

[0125] In some implementations, the treatment includes reducing waist circumference.

[0126] In some implementations, the treatment includes lowering hemoglobin A1C (HbA1C) levels.

[0127] In some implementations, the subject suffers from hyperandrogenemia.

[0128] In some implementations, the subject has acne. In some implementations, 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 improvement in their acne on a patient questionnaire.

[0129] In some implementations, the subject suffers from hirsutism. In some implementations, the subject reports that their hirsutism improves after administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof. For example, the subject may report improvement in their hirsutism in a patient questionnaire.

[0130] In some implementations, the subject suffers from menstrual disorders. In some implementations, the subject reports that their menstrual disorders improve upon administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof. For example, the subject may report improvement in their menstrual disorders in a patient questionnaire or menstrual cycle diary.

[0131] In some embodiments, the subject has a testicular adrenal remnant tumor (TART). In some embodiments, the subject's TART is improved upon administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the improvement in the subject's TART includes, but is not limited to, reduction of testicular pain, reduction of the number of tumors, reduction of the size of one or more tumors, or prevention of the occurrence of other tumors.

[0132] In some implementations, the subject is a human. In some implementations, the human is an adult. In some implementations, the human is a teenager.

[0133] In some embodiments, the treatment includes reducing the subject's serum testosterone level relative to baseline. In some embodiments, the subject's serum testosterone level is reduced by >50% relative to baseline. In some embodiments, the subject's serum testosterone level is reduced by >60% relative to baseline. In some embodiments, the subject's serum testosterone level is reduced by >70% relative to baseline. In some embodiments, the subject's serum testosterone level is reduced by >80% relative to baseline.

[0134] In some embodiments, the subject is female. In some embodiments, the treatment includes reducing the level of serum testosterone in the female subject relative to baseline. In some embodiments, the level of serum testosterone in the female subject is reduced by >50% relative to baseline. In some embodiments, the level of serum testosterone in the female subject is reduced by >60% relative to baseline. In some embodiments, the level of serum testosterone in the female subject is reduced by >70% relative to baseline. In some embodiments, the level of serum testosterone in the female subject is reduced by >80% relative to baseline.

[0135] In some embodiments, the decrease in serum testosterone levels relative to baseline in the subject is maintained for at least one week after discontinuation of CRN04894 treatment. In some embodiments, the decrease in serum testosterone levels relative to baseline in the subject is maintained for at least two weeks after discontinuation of CRN04894 treatment. In some embodiments, the decrease in serum testosterone levels relative to baseline in the subject is maintained for at least three weeks after discontinuation of CRN04894 treatment. In some embodiments, the decrease in serum testosterone levels relative to baseline in the subject is maintained throughout the entire course of CRN04894 treatment.

[0136] Congenital adrenal hyperplasia (CAH)

[0137] Congenital adrenocortical hyperplasia (CAH) is a family of rare autosomal recessive genetic disorders of the adrenal glands caused by mutations in key enzymes involved in adrenal steroid production. The most common cause of CAH is 21-hydroxylase deficiency (21-OHD), accounting for more than 90% of CAH cases. This "classic" CAH is caused by the complete loss of 21-OH activity, and its global incidence ranges from 1 in 14,000 to 1 in 18,000.

[0138] The diagnosis of typical 21-OH deficiency is based on elevated levels of the direct enzyme substrate 17-hydroxyprogesterone (17-OHP). Screening for 17-OHP is routinely performed in newborn screening programs. Elevated levels are sensitive to CAH, but falsely elevated 17-OHP levels may be observed in preterm, ill, and stressed infants. Secondary screening can confirm the elevated levels found in newborn screening. If data are inconclusive, a stimulation test may be necessary to demonstrate an excessive increase in 17-OHP in response to exogenous ACTH doses.

[0139] Typical CAH caused by 21-OH deficiency leads to insufficient cortisol and aldosterone production, resulting in salt-wasting neonatal adrenal crisis and lifelong adrenal insufficiency. Due to the lack of cortisol, the hypothalamus and pituitary gland are no longer subject to negative feedback inhibition, leading to elevated levels of adrenocorticotropic hormone (ACTH), which in turn causes the adrenal glands to produce excessive androgens. Excessive ACTH acts on the adrenal glands, causing bilateral adrenal hyperplasia, and due to 21-OH deficiency, levels of steroid precursors (such as androstenedione (A4)) are elevated, which may lead to clinical hyperandrogenism.

[0140] In women, hyperandrogenism can lead to hirsutism, acne, male pattern baldness, menstrual irregularities, oligomenorrhea or amenorrhea, infertility, short stature, and pronounced masculinization. Newborns may present with "interstitial" characteristics.

[0141] Poorly controlled CAH in childhood can lead to short stature. In boys, childhood hyperandrogenism can cause precocious puberty / early adrenal insufficiency and premature epiphyseal fusion. In males, hyperandrogenism suppresses gonadotropin secretion, leading to reduced testicular volume, decreased testosterone production, and impaired spermatogenesis. Furthermore, long-term ACTH stimulation can also lead to the formation of testicular adrenal remnant tumors (TART) in men, which can be confused with malignant testicular tumors and cause irreversible testicular damage and potential infertility. There are currently no other treatments besides intensive glucocorticoid therapy to prevent the development of TART.

[0142] Currently, the focus of CAH treatment is on replacing the deficient adrenal hormones (i.e., cortisol and aldosterone) and suppressing excessive androgen production. Given that there are no other approved non-hormonal drugs for CAH in the United States, glucocorticoid therapy not only needs to supplement the deficient hormones but also provide feedback inhibition at the pituitary gland to reduce ACTH secretion and thus reduce adrenal androgen production.

[0143] CRN04894

[0144] CRN04894, compound (I), is a first-in-class, orally administered adrenocorticotropic hormone (ACTH) receptor antagonist that binds to the melanocortin 2 receptor (MC2R) to block ACTH-mediated adrenal steroid production. The structure of compound (I) is shown below:

[0145]

[0146] ACTH is a 39-amino acid peptide synthesized by anterior pituitary corticotropin-releasing cells and secreted under hypothalamic corticotropin-releasing hormone (CRH) and stress stimulation. As part of the hypothalamus-pituitary-adrenal (HPA) axis, ACTH activates the melanocortin 2 receptor (MC2R) on the adrenal gland. MC2R is expressed on the adrenal cortex and requires MC2R accessory proteins (MRAPs) for surface expression and binding to ACTH. ACTH binds to the MC2R / MRAP complex, activating its G proteins (Gs), thereby increasing intracellular cyclic adenosine monophosphate (cAMP) levels, which in turn stimulates cortisol synthesis and secretion by regulating multiple steps in the steroid production pathway.

[0147] CRN04894 selectively acts on MC2R and could be a potential novel therapy for ACTH-mediated pathological elevation of adrenal steroid hormones. Due to its lack of activity against angiotensin II type 2 receptors, CRN04894 is expected to inhibit adrenal-derived androgens while maintaining mineralocorticoid production, making it a novel treatment option for CAH.

[0148] Meanwhile, CRN04894 can also effectively treat hyperandrogenism observed in CAH patients and may improve related problems such as acne; hirsutism and menstrual disorders in women; and TART in men.

[0149] CRN04894 (including its synthesis) is disclosed in U.S. Patent No. 11,566,015, the entire contents of which are incorporated herein by reference.

[0150] Example

[0151] Example 1: A 12-week Phase II open-label sequential dosing cohort study designed to evaluate the safety, efficacy, and pharmacokinetics of CRN04894 in participants with CAH.

[0152] Research objectives and endpoints

[0153] The primary efficacy objective was to evaluate the efficacy of CRN04894 as measured by changes in serum androstenedione (A4) relative to baseline. The primary efficacy endpoint was the change in serum A4 relative to baseline in the morning of week 12 (before 11:00 a.m.).

[0154] The secondary efficacy objective was to assess the efficacy of CRN04894 as measured by changes in serum 17-hydroxyprogesterone (17-OHP) relative to baseline. The secondary efficacy endpoint was the change in serum 17-OHP relative to baseline in the morning of week 12 (before 11:00 a.m.).

[0155] The safety objective is to assess 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 (AEs) that lead to discontinuation of treatment.

[0156] Inclusion criteria

[0157] This study will recruit participants with congenital adrenocortical hyperplasia (CAH) caused by 21-hydroxylase deficiency.

[0158] Participants must be willing and able to understand and comply with the research procedures.

[0159] Participants will include men and women aged 18 to 75. Participants as young as 16 may be enrolled at a research center located in the United States. Typical 21-hydroxylase deficiency will be confirmed by the investigators and approved by a medical monitor.

[0160] Participants will receive stable (defined as a dose variation of no more than 5 mg / day of hydrocortisone equivalent) glucocorticoid replacement therapy (e.g., hydrocortisone, prednisolone, methylprednisolone, etc.) within the 6 months prior to screening, and the dose will not be reduced during the study. The minimum total daily dose for participants will be ≥15 mg of hydrocortisone (or an equivalent dose).

[0161] Participants' adherence to glucocorticoid and mineralocorticoid alternative (if applicable) regimens will be recorded during the screening period, based on the judgment of the principal investigator (PI).

[0162] During the second screening visit, A4 and 17-OHP values ​​collected in the morning before taking glucocorticoids (GC) should meet the following criteria: A4 ≥ 1.5 times the upper limit of normal (ULN); 17-OHP ≥ 1000 ng / dL (30.3 nmol / L); if the participant has been taking the current dose of GC since then, historical results from the past 2 years are accepted. Rescreening may be considered if the investigator believes the screening results are only temporary and do not reflect the participant's normal state (e.g., the value is normal when the participant's A4 level is typically much higher). These situations should be discussed with the medical monitor.

[0163] The reference ranges for serum A4 levels are 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 aged 16 and above; approximately 65-210 ng / dL for adolescent males aged 17 and above; and approximately 80-240 ng / dL for adolescent females aged 16 and above.

[0164] If participants are receiving estrogen therapy (any route), the dosage must remain stable for at least 3 months prior to screening.

[0165] Female participants engaging in heterosexual intercourse must be infertile, defined as having undergone surgical sterilization (e.g., hysterectomy, bilateral salpingectomy, tubal ligation for at least 3 months, or bilateral oophorectomy), or having been postmenopausal and have not menstruated for at least 1 year. For participants with less than 1 year of amenorrhea, a follicle-stimulating hormone (FSH) level ≥30 IU / L is required for a definitive diagnosis of menopause. Participants not using hormone replacement therapy must agree to use highly effective contraception from the start of screening until at least 2 weeks after the last administration of the study drug. Contraception for both men and women should comply with local regulations regarding contraception methods for participants in clinical studies. Periodic abstinence (i.e., calendar method, ovulation method, symptom-basal body method, post-ovulation method) and withdrawal are not acceptable.

[0166] Male participants should agree to use condoms during sexual intercourse with female partners of reproductive age from the screening period until at least 2 weeks after taking the last study drug (or have undergone sterilization [i.e., vasectomy and confirmation of no sperm in the semen]); or agree to prolonged abstinence. Male participants should also agree not to donate sperm during the study period and for at least 2 weeks after taking the last study drug.

[0167] Exclusion criteria

[0168] Participants will be excluded from the study if they meet any of the following criteria:

[0169] The diagnosis was any form of CAH other than the typical 21-hydroxylase deficiency.

[0170] Dexamethasone was used within 30 days prior to the screening.

[0171] A history of bilateral adrenalectomy, hypopituitarism, or other conditions requiring long-term glucocorticoid therapy.

[0172] Night shift workers or any other cause of abnormal sleep / wake cycles.

[0173] Clinically significant and unstable medical symptoms or chronic diseases other than CAH.

[0174] History of major surgery / operation for any reason within 4 weeks prior to screening.

[0175] Diabetes treated with insulin for less than 6 weeks prior to screening, or a change of more than 15% in the total daily insulin dose within 6 weeks prior to screening.

[0176] Poorly controlled diabetes is defined as hemoglobin A1c (HbA1c) ≥8.5% (≥69 mmol / mL), or if HbA1c cannot be assessed (e.g. due to hemoglobinopathies), HbA1c is estimated based on fructosamine.

[0177] Participants with hypothyroidism were identified by researchers based on their thyroid hormone levels measured at screening and who were not receiving adequate hormone replacement therapy.

[0178] Students with a history of unstable angina or acute myocardial infarction within 12 weeks prior to screening, or those with other clinically significant heart conditions as determined by the investigator at the time of screening.

[0179] The patient's accompanying mental state prevented him from understanding the nature, scope, and potential consequences of the study, and / or there was evidence that the patient had poor adherence to medical instructions.

[0180] A history of cancer, excluding cured / treated squamous cell carcinoma of the skin, basal cell carcinoma, or cervical carcinoma in situ.

[0181] Pregnancy or breastfeeding period.

[0182] A known history of illicit drug or alcohol abuse within the past year.

[0183] Patients who have received anti-androgen therapy (e.g., spironolactone, finasteride, cyproterone acetate, flutamide) within the past 3 months.

[0184] Has used testosterone, androgen-containing supplements, aromatase inhibitors, or growth hormone.

[0185] Drugs that potently induce cytochrome P450 (CYP) 3A4 were used within 30 days prior to Day 1 of the study. These drugs include, but are not limited to, apalutamide, carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, or St. John's wort.

[0186] Use of any medication (all routes of administration, i.e., oral, topical, and inhalation) or ingestion of any food that is a strong or moderate inhibitor of CYP3A4 within 14 days prior to Day 1 of the study is not permitted. These include, but are not limited to, boprevir, cobistat, danoprevir and ritonavir, averrevir and ritonavir, grapefruit juice (more than 8 ounces daily), indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, nimatrelvir and ritonavir, paliprevir and ritonavir and (obitavir and / or dasabuvir), posaconazole, ritonavir, saquinavir and ritonavir, telaraprevir, telaravir and ritonavir, telithromycin, acetylenol, voriconazole, clarithromycin, ederaris, nefazodone, nelfinavir, aprepitant, ciprofloxacin, conivatan, crizotinib, cyclosporine, and diltiazem. Dronedarone, erythromycin, fluconazole, fluvoxamine, imatinib, tofifoxapane, verapamil.

[0187] Drugs that have been used with strong or moderate P-gp inducers within 14 days prior to Day 1 of the study. These drugs include, but are not limited to, apalutamide, carbamazepine, fosaphenytoin, lorlatinib, phenytoin, rifampin, or St. John's wort.

[0188] Drugs used within 14 days prior to Day 1 of the study that are potent or intermediate-potency P-glycoprotein (P-gp) inhibitors. These include, but are not limited to, amiodarone, carvedilol, clarithromycin, dronedarone, itraconazole, lapatinib, lopinavir and ritonavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir and ritonavir, telaraprevir, telaravir and ritonavir, or verapamil.

[0189] Has used any investigational drug within 60 days or 5 half-lives (whichever is longer) prior to the first administration; or plans to use the investigational drug in another study.

[0190] During screening, Fridricilia-corrected QT interval (QTcF) average (average of 3 ECGs) >450 ms (male) or >470 ms (female), PR interval >220 ms, QRS interval >120 ms, second- or third-degree atrioventricular block, left bundle branch block or hemiconductor block.

[0191] Renal insufficiency, defined as an estimated glomerular filtration rate (eGFR) <60 mL / min / 1.73 m³ / min. 2 As an indicator.

[0192] During the screening period, participants with severe liver disease or alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST) >3×ULN, and / or total bilirubin >1.5×ULN will be eligible to participate. Participants previously diagnosed with Gilbert's syndrome without other hepatobiliary diseases and with total bilirubin <3.5 mg / dL (<51.3 μmol / L) will be allowed to participate.

[0193] Research Design

[0194] This study will recruit up to approximately 30 participants. Each cohort will recruit at least 6 participants, with a possible additional 6 participants in cohorts 1 and 2, for a final maximum of 12 evaluable participants per cohort. The treatment duration for each participant will be a maximum of 84 days (12 weeks). The total study duration for each participant will be a maximum of 140 days (up to 4 weeks of screening, 12 weeks of treatment, and 4 weeks of follow-up). Visit rates will be at screening (2 visits), day 1 (baseline), week 2 (day 14), week 6 (day 42), and week 12 (day 84). Safety follow-up will be conducted two weeks after the last dose of CRN04894 (week 14; day 98), and any adverse events (AEs) will be collected by telephone in week 4 after the last dose of CRN04894 (week 16; day 112). The study design will be discussed in detail below.

[0195] During the screening period, no adjustments to the glucocorticoid dosage are permitted except for stress (emergency) administration. The previously administered fludrocortisone dosage will be maintained throughout the study. After the screening period, participants will be assigned to a dosing cohort using an open-label approach. Dosing cohorts will be administered sequentially.

[0196] Participants in all cohorts will continue their previously used glucocorticoid alternative regimen / dosage throughout the study. In addition, starting on the evening of Day 1 and ending the night before the End of Treatment (EOT) visit at Week 12, each cohort will receive CRN04894 once daily at bedtime (QD) between 22:00 and 24:00 (approximately the same time each night).

[0197] Participants in Cohort 1 will receive 80 mg CRN04894 QD. After at least three participants in Cohort 1 have completed the 2-week 80 mg CRN04894 QD administration, the Safety Review Committee (SRC) will review an interim analysis assessing drug-pharmaceutical (PD), pharmacokinetic (PK), efficacy, and safety. If continued treatment is safe, the SRC will recommend 120 mg CRN04894 for Cohort 2. However, the SRC may, based on safety data review, recommend a lower dose for Cohort 2 (e.g., 40 mg CRN04894 daily). The SRC may also choose to recommend increasing the number of participants in Cohort 1 and / or Cohort 2 to a maximum of 12 each. In this case, expanded recruitment for that cohort will be completed, and the SRC will review the data from the expanded cohort before recruitment for subsequent cohorts.

[0198] Before cohort 2 screening begins, cohort 1 will first complete the recruitment of at least 6 participants. The optional cohort 3 will follow the same initial administration and SRC review process as cohort 2, where participants will receive up to 160 mg of CRN04894 daily. The follow-up period will be extended from week 12 to week 16. Safety and PD biomarkers for all cohorts will be available at the end of week 14 of the follow-up period. Participants will receive a safety call for a safety assessment at the end of week 16 / end of study (EOS).

[0199] At any time during the study, the SRC may decide to adjust or discontinue the study drug dosage based on the study drug / study discontinuation criteria.

[0200] If a participant completes the last scheduled procedure specified in the EOS visit, they are considered to have completed the study.

[0201] Table 1 provides a detailed schedule of events.

[0202] In Table 1, "X" indicates that the activity has been scheduled for execution, and "-" indicates that the activity has not been scheduled for execution.

[0203]

[0204]

[0205]

[0206]

[0207] 11-OHA4 = 11β-hydroxyandrostenedione, 11-DOC = 11-deoxycorticosterone, 11-ketoT = 11-ketotestosterone, 11-OHT = 11-hydroxytestosterone, 17-OHP = 17-hydroxyprogesterone, A4 = androstenedione, ACTH = adrenocorticotropic hormone, AE = adverse events, CAH = congenital adrenocortical hyperplasia, DHEA = dehydroepiandrosterone, DHEA-S = dehydroepiandrosterone sulfate, ECG = electrocardiogram, EOS = end of study, EOT = end of treatment, FSH = ovum Follicle-stimulating hormone; GC = glucocorticoid, HbA1C = glycated hemoglobin, INR = international normalized ratio, PT = prothrombin time, PTT = partial thromboplastin time, TSH = thyroid-stimulating hormone, LH = luteinizing hormone, MRI = magnetic resonance imaging, P1NP = type 1 procollagen N propeptide, PD = pharmacodynamics, PK = pharmacokinetics, QOL = quality of life, SHBG = sex hormone-binding globulin, T4 = thyroxine, VAMS = volumetric absorbance microsampling, WOCBP = women of reproductive age.

[0208] Informed consent can be signed one week prior to the visit.

[0209] b MRI and ultrasound examinations should be performed after the second screening visit and before the administration of the study drug on day 1.

[0210] Starting from the evening of day 1 and ending the evening before the 12th week / EOT visit, each cohort will receive CRN04894 once daily before bedtime (QD) between 22:00 and 24:00 (approximately the same time each night).

[0211] For visits 2–7: Two blood samples will be drawn (approximately 1 hour apart) to detect PD biomarkers before the morning GC replacement dose. PD biomarker collection should be one of the first activities performed at the start of the visit. Visits should begin as early as possible in the morning (ideally 7:00–8:00 AM) to minimize delays in taking the morning GC, and the timing of each study visit should be as consistent as possible. The second set of PD biomarker collection should be no later than 11:00 AM. PD biomarker blood collection for visit 1 (week 4) can be performed at any time after informed consent is signed and will not be used for inclusion criteria assessment. For screening visit 2 (week 2): Blood should be drawn before taking the morning GC.

[0212] Blood samples will be collected for PK at each visit. Mitra VAMS samples will also be collected during the PK collection at the 4th and 6th visits.

[0213] For participants receiving fludrocortisone (mineralocorticoid) replacement therapy, serum aldosterone and plasma renin activity will be measured prior to administration of this medication.

[0214] If the circadian rhythm assessment and visit are on the same day, participants who participated in the circadian rhythm assessment will not have their PD biomarkers or PK samples recollected at the 3rd, 4th, or 6th visit.

[0215] Participants in the study will have their Mitra VAMSPK samples collected the night before their fourth and sixth visits, prior to taking the medication.

[0216] i is completed by the participants at home every day.

[0217] The circadian rhythm assessment will be conducted at a selected location with 24-hour blood collection capability. Assessments will be performed between days -7 and 1, days 12 and 17, and days 70 and 86. The study drug will be administered at approximately 22:00 during the assessment periods of treatment (days 12 and 17 and days 70 and 86). Blood samples will be drawn every 4 hours to measure PK, ACTH, A4, 17-OHP, DHEA, 11-DOC, 11-OHA4, 11-ketoA4, 11-OHT, and 11-ketoT for 24 hours, starting at approximately 10:00, followed by sampling at 14:00, 18:00, 22:00 before administration, 02:00, 06:00, and 10:00. Except at 2:00 AM (when participants are allowed to sleep), saliva will be collected simultaneously with blood to measure A4, 17-OHP, 11-OHA4, 11-ketoA4, 11-OHT, 11-ketoT, and testosterone. Additionally, blood will be drawn once more at 6:00 AM to measure testosterone, DHEA-S, and 21-deoxycortisol.

[0218] Genetics

[0219] Mutations in the CYP21A2 gene can lead to varying degrees of loss of 21-hydroxylase activity, resulting in different phenotypes. Participants will undergo 21-hydroxylase gene mutation screening at the start of treatment.

[0220] Pharmacokinetics (PK)

[0221] During treatment, blood samples will be collected from participants who did not participate in the 24-hour inpatient circadian rhythm assessment to measure the concentration of CRN04894 in plasma and whole blood (using Mitra Volume Absorption Microsampling [VAMS]). The actual date and time (24-hour 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.

[0222] The concentrations of CRN04894 in plasma and whole blood of the PK analysis population at each predetermined collection time point will be listed and summarized by cohort and study day, and descriptive statistical analysis will be performed.

[0223] Pharmacodynamics (PD)

[0224] A biomarker set will be mapped. This biomarker set will include the following:

[0225] 17-Hydroxyprogesterone (17-OHP);

[0226] Adrenocorticotropic hormone (ACTH) (plasma);

[0227] Testosterone;

[0228] Androstenedione (A4);

[0229] Dehydroepiandrosterone (DHEA);

[0230] Dehydroepiandrosterone sulfate (DHEA-S);

[0231] 11-Deoxycorticosterone (11-DOC);

[0232] 21-Deoxycortisol;

[0233] 11β-hydroxyandrostenedione (11-OHA4);

[0234] 11-Ketoandrostenedione (11-KetoA4);

[0235] 11β-hydroxytestosterone (11-OHT);

[0236] 11-Ketotestosterone (11-ketoT);

[0237] Aldosterone; and

[0238] Renin.

[0239] At the start of treatment and before the first administration of CRN4894, PD biomarker samples will be collected to determine the baseline of PD biomarkers.

[0240] efficacy assessment

[0241] Magnetic Resonance Imaging: Adrenal Magnetic Resonance Imaging (MRI) should be performed locally. We will provide image acquisition standards, which must be followed to properly assess adrenal volume. All MRI evaluations will be assessed by the investigator to determine if there are any findings requiring immediate medical attention and will be read by a radiologist at the MRI center. The clinical significance of any MRI findings will be determined by the investigator, including after the center readings are available.

[0242] Ultrasound Examination: Testicular ultrasound examinations will be performed according to the research center's procedure for evaluating testicular adrenal remnant tumors (TART). All male participants will undergo two ultrasound examinations: 1) after screening but before treatment; 2) at the end of treatment. Results will be recorded. All ultrasound examination results will be evaluated by investigators to identify any findings requiring immediate medical attention and will be interpreted by the center's ultrasound radiologist. The clinical significance of any ultrasound examination result will be determined by investigators, including after the center's readings are available.

[0243] Pharmacodynamic (PD) biomarker extraction:

[0244] Screening visit 1: Blood samples for PD biomarkers can be taken at any time after informed consent is signed and will not be used for inclusion criteria assessment.

[0245] Screening visit 2: Blood should be drawn in the morning before taking GC.

[0246] Visits 2-7: Blood will be drawn twice (approximately 1 hour apart) to detect PD biomarkers before the morning GC replacement dose. PD biomarker collection should be one of the first activities at the start of each visit. Visits should begin as early as possible in the morning (ideally between 7:00 and 8:00 AM) to minimize delays in morning GC administration, and the timing of each study visit should be as consistent as possible. The second set of PD biomarker collections should be no later than 11:00 AM.

[0247] Circadian rhythm assessment: During designated visits, participants will be admitted to the metabolic unit for a 24-hour circadian rhythm assessment. The assessment will be conducted at a designated location with 24-hour blood sampling capability. The assessment will be administered at approximately 22:00 during the study treatment period (days -7 to 1, 12 to 17, and 70 to 86). The study drug will be administered at approximately 22:00 during the study treatment period (days 12 to 17 and 70 to 86). Blood samples will be drawn every 4 hours to measure PK, ACTH, A4, 17-OHP, DHEA, 11-DOC, 11-OHA4, 11-ketoA4, 11-OHT, and 11-ketoT for 24 hours, starting at approximately 10:00, followed by sampling at 14:00, 18:00, 22:00 before administration, 02:00, 06:00, and 10:00. Except at 2:00 AM (when participants are allowed to sleep), saliva will be collected simultaneously with blood to measure A4, 17-OHP, 11-OHA4, 11-ketoA4, 11-OHT, 11-ketoT, and testosterone. Additionally, blood will be drawn once at 6:00 AM to measure testosterone, DHEA-S, and 21-deoxycortisol.

[0248] Security assessment

[0249] Physical Examination: A comprehensive physical examination will be conducted, and weight and waist circumference will be measured at the times specified in the activity plan. Height and body mass index (BMI) will be measured once during screening. The examination includes the head (external), eyes, ears, nose, throat, lungs, cardiovascular system, abdomen, musculoskeletal system, skin, lymph nodes, central nervous system (CNS), and other body systems (where applicable).

[0250] Physical examinations for symptoms may be performed as unplanned assessments in response to adverse events or other available safety data.

[0251] Vital signs: Vital signs (resting blood pressure and standing blood pressure, resting respiratory rate and resting body temperature) will be measured according to standard operating procedures.

[0252] Standard blood pressure should be measured after lying down and resting for 5 minutes. Participants should lie down for 1 hour and then measure their standing blood pressure and standing pulse, followed by 5 minutes of standing for 2 to 5 minutes.

[0253] Electrocardiogram (ECG): ECGs will be taken at the time points specified in the activity plan. The ECG assessment should be a standard 12-lead ECG, repeated three times (with intervals of 1 to 3 minutes between each). Participants must be in a resting position for at least 10 minutes without significant stimulation (noise, television, etc.). If there are clinical indications (e.g., palpitations, dizziness), an ECG other than the planned assessment should be taken according to the protocol.

[0254] The ECG parameters to be evaluated include a summary of the examination results and measurements of pulse rate, the time interval between the Q and T waves (QT), the QT corrected for the Fridericia formula (QTcF), the time interval between the P and R waves (PR), and the QRS complex interval (QRS duration) based on ECG machine readings.

[0255] All ECG assessments should be performed initially by the investigator to identify any findings requiring immediate medical attention, and then read by the central ECG reader. The clinical significance of any ECG findings should be determined by the investigator, including after central readings are available. Any abnormal values ​​that may be significant should be confirmed by the central ECG reader. Any ECG measurement determined to be clinically significant (occurring after ICF signing) should be recorded as an adverse event (AE). Such abnormalities will be monitored until the end of the study, or until any abnormality deemed related to the investigational drug is resolved.

[0256] Clinical safety laboratory testing: Clinical laboratory tests, their timing, and frequency will be disclosed in the activity plan. Safety laboratory tests should be performed by the central laboratory. Reference ranges will be established based on the central laboratory's guidelines. Investigators must review laboratory reports, document this review, and record any clinically significant changes occurring during the study as adverse events (AEs). Laboratory reports must be archived along with the source documents. During participation in the study, all laboratory tests deemed to have clinically significant abnormal values ​​should be repeated until the values ​​return to normal or baseline levels, or until the investigator or medical monitor deems them no longer clinically significant. If these values ​​do not return to normal / baseline levels within a timeframe deemed reasonable by the investigator, the cause should be determined and the sponsor notified.

[0257] Clinical safety laboratory tests include the following: blood urea nitrogen (BUN); potassium; creatinine; sodium; calcium; random blood glucose; fasting blood glucose; fasting lipid profile; aspartate aminotransferase / serum glutamate-oxaloacetate transaminase (AST / SGOT); alanine aminotransferase / serum glutamate-pyruvate transaminase (ALT / SGPT); alkaline phosphatase; total bilirubin and direct bilirubin; total protein; uric acid; chloride; phosphate; magnesium; albumin; indirect bilirubin; amylase; lipase.

[0258] The laboratory tests required for the protocol are summarized in Table 2:

[0259]

[0260]

[0261]

[0262] 11-OHA4 = 11β-hydroxyandrostenedione; 11-DOC = 11-deoxycorticosterone; 11-ketoT = 11-ketotestosterone; 11-OHT = 11-hydroxytestosterone; 17-OHP = 17-hydroxyprogesterone; A4 = androstenedione; ACTH = adrenocorticotropic hormone; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; COVID = coronavirus disease; DHEA = dehydroepiandrosterone; DHEAS = dehydroepiandrosterone sulfate; ECG = electrocardiogram; EOS = study ended; FSH = follicle-stimulating hormone; HbA1C = glycated hemoglobin White; HBsAg = Hepatitis B surface antigen; HCG = Human chorionic gonadotropin; HIV = Human immunodeficiency virus; INR = International Normalized Ratio; LH = Luteinizing hormone; MCH = Mean corpuscular hemoglobin; MCV = Mean corpuscular volume; PK = Pharmacokinetics; PT = Prothrombin time; PTT = Activated partial thromboplastin time; RBC = Red blood cells; SGOT = Serum glutamate-oxaloacetate transaminase; SGPT = Serum glutamate-pyruvate transaminase; SHBG = Sex hormone-binding globulin; T4 = Thyroxine; TSH = Thyroid hormone; WOCBP = Women of reproductive age.

[0263] a) An analysis of liver chemical abnormalities detected by liver function tests and an analysis of drug discontinuation based on evidence of liver injury will be conducted, and the results must be reported to the sponsor as soon as possible (except for studies on liver function impairment or cirrhosis).

[0264] b. If alkaline phosphatase levels are elevated, consider fractionation.

[0265] Unless local regulations or IRB / IEC require serological testing, local urine testing will be the standard for this program.

[0266] Pregnancy testing: Pregnancy testing (urine or serological testing as required by local regulations) should be performed as per the activity plan. Pregnancy testing (urine or serological testing as required by local regulations) should be performed 14 days after the relevant systemic exposure and within the timeframe of contraception used by female participants. Additional serum or urine pregnancy tests may be performed as deemed necessary by the investigator or as required by local regulations to determine if a participant is not pregnant at any point during the study period.

[0267] Adverse events (AEs), serious adverse events (SAEs), and other safety reports

[0268] An adverse event (AE) is an adverse medical condition or a worsening of a pre-existing medical condition that occurs after or during exposure to a drug, regardless of whether it is causally related to the drug, and occurs from the time the informed consent form is signed until the last follow-up contact.

[0269] Therefore, an AE can be any adverse or unexpected sign (including abnormal laboratory test results), symptom, or disease (new or worsening) that occurs during a clinical study, even if the investigational drug has not yet been used.

[0270] Treatment-associated adverse events (TEAEs) are adverse events that occur or worsen after administration of an investigational drug.

[0271] The investigator and their designated personnel are responsible for detecting, documenting, and recording events that meet the definition of AE or SAE, and for following up on all AEs or SAEs, regardless of whether these events are considered related to the investigational drug or investigational procedures, or whether they lead to the participant discontinuing treatment with CRN04894. This includes events reported by the participant (or, where appropriate, reported by a caregiver, agent, or legally authorized representative of the participant).

[0272] Timeframe and frequency of AE and SAE information collection: All AEs and SAEs will be collected from the date of informed consent until 4 weeks after the last administration of the investigational drug. When an AE / SAE occurs, the investigator is responsible for collecting and reviewing all documents related to the event (e.g., hospital progress notes, laboratory reports, and diagnostic reports). Subsequently, the investigator should record all relevant AE / SAE information in the eCRF and report all SAEs on a paper SAE report form. All SAEs should be recorded and reported immediately to the sponsor or its designated personnel, and in any case, the reporting time should not exceed 24 hours after the first discovery. The investigator should submit any updated SAE data to the sponsor within 24 hours of obtaining it. The investigator is not obligated to actively seek information about AEs or SAEs after the study ends. However, if the investigator becomes aware of any SAE, including death, at any time after a participant withdraws from the study, and the investigator believes the event is reasonably related to the investigational drug or study participation, the investigator must immediately notify the sponsor.

[0273] Timeframe and frequency of AE and SAE information collection: All AEs and SAEs will be collected from the date of ICF signing until 4 weeks after the last administration of the study drug. When an AE / SAE occurs, the investigator is responsible for collecting and reviewing all documents related to the event (e.g., hospital progress notes, laboratory reports, and diagnostic reports).

[0274] Then, the researcher should record all relevant AE / SAE information in the eCRF and report all SAEs on the paper SAE report form.

[0275] All SAEs should be logged and reported immediately to the sponsor or its designated personnel, and under no circumstances should more than 24 hours have passed since the first discovery of an AE. Researchers should submit any updated SAE data to the sponsor within 24 hours of obtaining it.

[0276] Researchers are not obligated to proactively seek out information about adverse events (AEs) or study-associated injuries (SAEs) after the study has concluded. However, if a researcher becomes aware of any SAE, including death, at any time after a participant has withdrawn from the study, and the researcher believes the event is reasonably relevant to the investigational drug or the study participation, the researcher must immediately notify the sponsor.

[0277] Methods for detecting adverse events (AEs) and subacute emergencies (SAEs): When detecting AEs and / or SAEs, care should be taken to avoid introducing bias. Open-ended, unguided verbal questioning of participants is the preferred method for inquiring about the occurrence of AEs.

[0278] Follow-up of AEs and SAEs: After the initial AE / SAE report, the investigator is required to proactively follow up with each participant during subsequent visits / contacts. All SAEs and AEs of particular concern will be followed up until symptoms subside, the condition stabilizes, the event is alternatively explained, or the participant is lost to follow-up.

[0279] Researchers are obligated to perform or arrange supplemental measurements and / or assessments, as indicated by medical evidence or at the request of the sponsor or its designee, to elucidate the nature and / or causation of the AE or SAE as comprehensively as possible. This may include additional laboratory tests or investigations, histopathological examinations, or consultations with other healthcare professionals.

[0280] If a participant dies during the study or during a recognized follow-up period, the investigator should provide the sponsor or its designated representative with copies of any autopsy results (including histopathological results) whenever possible.

[0281] Regulatory reporting requirements for SAEs: Investigators must promptly notify sponsors of SAEs to ensure their legal obligations and ethical responsibilities regarding the safety of subjects and the safety of investigational drugs in clinical studies.

[0282] Sponsors have a legal responsibility to report the safety of the investigational drug in clinical trials to local and other regulatory bodies. Sponsors must comply with national regulations regarding the submission of safety reports to regulatory agencies, Institutional Review Boards (IRBs) / Independent Ethics Committees (IECs), and investigators.

[0283] Upon receiving the investigator safety report from the sponsor describing the SAE or other specific safety information (e.g., an SAE summary or list), the investigator should review it and file it along with the Investigator's Handbook (IB) / Instructions for Use or other documents, and notify the IRB / IEC as appropriate, as required by local regulations.

[0284] Researcher safety reports must be prepared for suspected unintended serious adverse reactions (SUSAR) in accordance with local regulatory requirements and sponsor policies, and forwarded to researchers when necessary.

[0285] Pregnancy: After the start of the study drug, all pregnancy details of female participants and (if indicated) female partners of male participants should be collected until the time period for reporting pregnancy coincides with the time period for contraception after intervention.

[0286] Although pregnancy itself is not considered an AE or SAE, any pregnancy complications or selective termination of pregnancy for medical reasons will be reported as an AE or SAE.

[0287] Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital malformation, ectopic pregnancy) are considered SAEs and will be reported accordingly.

[0288] Participants / pregnant female partners will be followed up to determine pregnancy outcomes. Researchers will collect follow-up information from participants / pregnant female partners and their newborns and forward this information to the sponsor.

[0289] Any pregnancy-related serious adverse event (SAE) that occurs after the study will be reported to the sponsor if the investigator believes it is reasonably related to the investigational drug. While the investigator is not obligated to proactively seek such information from previous participants / pregnant female partners, he or she can learn about SAEs through voluntary reporting.

[0290] Any female participant who becomes pregnant during the study will have to stop using the study drug or withdraw from the study.

[0291] Adverse events of particular concern (AESIs): Adverse events of particular concern (AESIs) are adverse events of special medical or scientific significance for the sponsor. In this study, the following event was considered an AESI: adrenal insufficiency.

[0292] Statistical considerations

[0293] General considerations: Descriptive statistics will be used to summarize continuous endpoints, including the number of non-missing observations, arithmetic mean, standard error, median, first and third quartiles, minimum, and maximum values. The number and percentage of participants at each level will be used to summarize categorical or ordinal endpoints. Unless otherwise stated, missing or unreported categorical results will be included in the summaries, with the number of participants in the entire analysis set as the denominator.

[0294] Safety analysis: Safety endpoints included study drug exposure, adverse events, clinical laboratory tests, vital signs, and 12-lead electrocardiogram. Unless otherwise stated, safety endpoints were aggregated at the planned dose level for each cohort and the overall population.

[0295] Drug exposure: CRN04894 treatment exposures will be aggregated by planned dose level for each cohort. The exposure aggregate will include the number of administrations, duration of treatment, and actual dose received.

[0296] Adverse events: Adverse events will be summarized by planned dose level for each cohort and overall. Adverse events will be coded according to MedDRA version 25.0 or later.

[0297] TEAE is defined as an adverse event (AE) that occurs or worsens during or after the first administration of the study drug. If the timing of the AE cannot be determined, TEAE refers to an adverse event that occurs on or after the first day of administration of the study drug. Non-treatment-related adverse events will not be included in the summary but will be included in the list.

[0298] A summary table of AEs will be displayed, detailing the number and percentage of participants, as well as the number of events in the following categories:

[0299] At least one case of TEAE;

[0300] At least one TEAE related to the investigational drug;

[0301] At least one severe TEAE;

[0302] At least one case of critical TEAE;

[0303] At least one serious TEAE related to the investigational drug;

[0304] At least one case of TEAE leading to treatment termination.

[0305] Treatment-related adverse events (AEs) are defined as AEs that are "related" to the study drug. Any adverse event (AE) that does not demonstrate a relationship is considered related.

[0306] The incidence of TEAEs will be expressed using counts, percentages, and the number of events calculated by system organ classification (SOC) and preferred term (PT). SOCs will be sorted in descending order of frequency of occurrence, and PTs within each SOC will be sorted in descending order of frequency of occurrence based on the percentage of AEs across all participants. If a participant has multiple events associated with a specific SOC or a PT within a SOC, that participant will be counted only once in that SOC and / or PT. Separate summaries for each category in the overall AE summary table will be created separately by SOC and PT.

[0307] In addition to the summaries of AEs listed by SOC and PT, the following will be sorted in descending order of PT frequency based on the percentage of AEs across all participants:

[0308] TEAE;

[0309] Treatment-related TEAEs; and

[0310] Severe TEAE.

[0311] The following additional list will also be provided:

[0312] SAE list;

[0313] List of TEAEs that lead to treatment interruption;

[0314] List of serious TEAEs; and

[0315] Death list.

[0316] Clinical laboratory tests: At each clinical visit, all consecutive hematological and clinical chemistry laboratory parameters will be descriptively summarized, along with corresponding changes compared to baseline. Other consecutive clinical laboratory tests will also be summarized in the same manner. The number and percentage of participants with values ​​outside the normal range (normal, low, and high) will also be summarized at each visit.

[0317] A time curve will be plotted showing the mean and standard error of the changes in relevant laboratory test results relative to the baseline.

[0318] All laboratory test results will be listed, including planned and unplanned results, and results that exceed the normal reference values ​​will be noted in the list.

[0319] Vital signs, weight, and waist circumference: Vital signs include resting blood pressure (resting and standing), resting respiratory rate, and resting body temperature. A descriptive summary of vital signs, weight, and waist circumference will be provided at each clinical visit. A time curve of waist circumference change relative to baseline, using the mean and standard error, will be plotted.

[0320] All vital signs, weight, and waist circumference measurements will be included in the list, including both planned and unplanned results.

[0321] Electrocardiogram (ECG): Standard 12-lead ECG data will be collected according to the schedule outlined in the activity plan. Results of all parameters (heart rate, QT, QTcF, PR interval, and QRS) at each visit and their changes relative to baseline will be presented. Assessment results will also be summarized at each visit. The average of three replicates will be used for summarization.

[0322] All ECG measurement data, raw triplet results, and evaluation results (including planned and unplanned results) will be listed.

[0323] Primary efficacy analysis: The primary efficacy endpoint was defined as the change in serum A4 levels relative to baseline at the morning of week 12 (before 11:00 AM). Analysis of covariance (ANCOVA) will be used to analyze the change in A4 relative to baseline. The model will use baseline values ​​as covariates and sex and dose cohorts as fixed effects. Sensitivity analyses may be performed, such as modeling the percentage change relative to baseline, including other baseline features in the ANCOVA model, and performing nonparametric tests; details will be provided in the SAP report. Changes in A4 relative to baseline at each post-baseline visit will be presented as box plots. Descriptive statistics will be presented as the overall planned dose level of A4 for each cohort and at each visit, and the corresponding change relative to baseline.

[0324] Sample Size Determination: The sample size will be determined based on actual circumstances. Formal sample size and efficacy calculations will not be performed for the efficacy endpoints of this study. This study will recruit a maximum of approximately 30 participants. Each cohort will recruit at least 6 participants, with a maximum of 6 additional participants per cohort, for a final maximum of 12 evaluable participants per cohort. Interim Analysis: For either cohort 1 or cohort 2, an analysis for SRC will be prepared after 3 or more participants in a given cohort have completed 2 weeks of administration, including PD, PK, efficacy, and safety endpoints. After all participants in cohort 2 have completed their treatment period or prematurely discontinued study treatment, analyses of efficacy and safety endpoints for both cohorts are planned to support regulatory interaction and decision-making.

[0325] Initial analysis of queue 1

[0326] The initial analysis summarized data from four participants (n=4) in cohort 1 who received 80 mg of CRN04894 QD. These included three female participants (n=3) and one male participant (n=1).

[0327] The demographic and baseline characteristics of the participants in Cohort 1 are shown in Table 3 below:

[0328]

[0329]

[0330] n=2

[0331] *in equivalents of hydrocortisone

[0332] Table 4 below shows the initial analysis of changes in morning serum A4, morning serum 17-OHP, morning serum testosterone in women, morning serum testosterone in men, and the percentage change in morning serum A4 / testosterone ratio in men relative to baseline in cohort 1. These changes relative to baseline were also analyzed in... Figure 1 , Figure 2 , Figure 4 , Figure 5 and Figure 10 It is described in the text.

[0333]

[0334]

[0335] Initial analysis and discussion of queue 1

[0336] We recruited patients with typical CAH (aged ≥18 to 75 years, ≥16 years) in the United States who had received stable-dose glucocorticoid replacement therapy for at least 6 months and were given 80 mg orally once daily with CRN04894 for 12 weeks, followed by a 4-week washout period. Four participants (3 women, median age 34 years (range 25–42 years)) completed 6 weeks of treatment, and two participants completed 12 weeks of treatment.

[0337] The baseline morning A4 levels of these participants ranged from 116 to 604 ng / dL (normal reference range for women is 30–200 ng / dL and for men is 40–150 ng / dL). In all participants, CRN04894 resulted in a rapid and significant reduction in A4 levels within 2 weeks, which remained low throughout the treatment period: at weeks 2, 6, and 12, the reductions were (mean ± SD) 86% ± 10% (n = 4); 90% ± 9% (n = 4); and 88% ± 15% (n = 2), respectively. Furthermore, at all follow-up visits, all A4 levels remained below the upper limit of normal. <ULN)。

[0338] The baseline 17-OHP levels of these participants ranged from 4740 to 6905 ng / dL (normal reference ranges were <220 ng / dL for men and <80 ng / dL [follicles] and <285 ng / dL [corpus luteum] for women). In all participants, CRN04894 resulted in a rapid and significant reduction in 17-OHP within two weeks, which was maintained throughout the treatment period: at weeks 2, 6, and 12, the reductions were (mean ± SD) 96% ± 2% (n = 4); 97% ± 0.3% (n = 4); and 83% ± 22% (n = 2), respectively.

[0339] In the three female participants, baseline morning testosterone levels were 114 ± 104 ng / dL (mean ± SD, RR 8–60 ng / dL), which decreased by (mean ± SD) 61% ± 53% (n = 3), 65% ± 56% (n = 3), and 97% ± 1% (n = 2) at weeks 2, 6, and 12, respectively. At baseline, the A4 / T ratio in male patients was 0.3 (normal < 0.2), which remained normal at follow-up at 0.08 (week 2) and 0.06 (week 6). Two female participants in this cohort achieved their first menstruation in over two years during treatment with CRN04894.

[0340] The mean baseline morning ACTH range was 155 to 1009 pg / mL (normal reference range: 7.2–63 pg / mL). Slight fluctuations in ACTH levels were observed during treatment, with no consistent trend: -25% ± 57% (n = 4) at week 2, 51% ± 87% (n = 4) at week 6, and -13% ± 67% (n = 2) at week 12.

[0341] Diaries and questionnaires

[0342] Menstrual cycle diary for female patients

[0343]

[0344] Patient-Reported CAH Severity Item Questionnaire

[0345] Subject ID: _______________ Visit ID: ______ Visit Date: ___________

[0346] Please select the option below that best describes any acne condition you are currently experiencing:

[0347] □ No acne

[0348] □ Mild acne

[0349] □ Moderate acne

[0350] □ Severe acne

[0351] Please select the option that best describes the severity of your current congenital adrenal hyperplasia.

[0352] □ None

[0353] □ Mild

[0354] □ Moderate

[0355] □ Severe [Female Only]: Please select the option that best describes your current facial hair growth.

[0356] No facial hair growth

[0357] Mild facial hair growth

[0358] □ Moderate facial hair growth

[0359] □ Severe facial hair growth

[0360] Patient-Reported Changes in CAH Item Questionnaire

[0361] Subject ID: _______________ Visit ID: ______ Visit Date: ___________ How is your acne condition now compared to when the study started?

[0362] □ Significant improvement

[0363] □ Moderate improvement

[0364] □ Mild improvement

[0365] □ No change

[0366] □ Mild aggravation

[0367] □ Moderately worsened

[0368] □ Significantly worsened

[0369] How severe is your congenital adrenal hyperplasia now compared to when you started your study?

[0370] □ Significant improvement

[0371] □ Moderate improvement

[0372] □ Mild improvement

[0373] □ No change

[0374] □ Mild aggravation

[0375] □ Moderately worsened

[0376] □ Significantly worse [Women only]: How is your facial hair growth now compared to when you started the study?

[0377] □ Significant improvement

[0378] □ Moderate improvement

[0379] □ Mild improvement

[0380] □ No change

[0381] □ Mild aggravation

[0382] □ Moderately worsened

[0383] □ Significantly worsened

[0384] Treatment satisfaction questionnaire for adults

[0385] protocol: Location ID: PI: Subject ID:

[0386] Treatment satisfaction questionnaire

[0387] Please select the option box below that best represents your answer to the following questions and statements:

[0388]

[0389]

[0390] Treatment satisfaction questionnaire for people under 18 years old

[0391] protocol: Location ID: PI: Subject ID:

[0392] Treatment Satisfaction Questionnaire (Parents / Caregivers)

[0393] Completed by the parents / caregivers of participants aged 16–17 in this study.

[0394] Please select the option box below that best represents your answer to the following questions and statements:

[0395]

[0396]

Claims

1. A method of treating a subject with congenital adrenal hyperplasia (CAH), comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof:

2. A method for treating hyperandrogenemia in a subject with CAH, comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof:

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

4. The method according to any one of claims 1-3, 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 1-3, 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 1-3, 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 1-3, wherein, The compound of formula (I) or a 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 1-3, wherein, The compound of formula (I) or a 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 1-3, 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 1-3, 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 1-10, wherein, The compound of formula (I) or a 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 an amount of formula (I) of compound (I) or a pharmaceutically acceptable salt thereof equivalent to about 40 mg.

13. The method according to any one of claims 11-12, wherein, The unit dosage form is an oral unit dosage form.

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

15. The method according to any one of claims 1-13, 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 1-15, wherein, CAH is caused by 21-hydroxylase deficiency.

17. The method according to any one of claims 1-16, wherein, The subjects also received glucocorticoid replacement therapy.

18. The method according to any one of claims 1-16, wherein, The subjects were simultaneously treated with hydrocortisone, prednisolone, prednisone, or methylprednisolone.

19. The method according to any one of claims 1-16, wherein, The subjects also received mineralocorticoid replacement therapy.

20. The method according to any one of claims 1-16, wherein, The subjects were also receiving fludrocortisone treatment.

21. The method according to any one of claims 1-20, wherein, The treatment included reducing the serum level of androstenedione (A4) relative to baseline in the subjects.

22. The method according to claim 21, wherein, The subjects' serum A4 levels decreased by >75% relative to baseline.

23. The method according to claim 21, wherein, The subjects' serum A4 levels decreased by >80% relative to baseline.

24. The method according to claim 21, wherein, The subjects' serum A4 levels decreased by >85% relative to baseline.

25. The method according to claim 21, wherein, The subjects' serum A4 levels decreased by >90% relative to baseline.

26. The method according to any one of claims 1-20, wherein, Treatment included reducing the serum level of 17-hydroxyprogesterone (17-OHP) in the subject relative to baseline.

27. The method according to claim 26, wherein, The serum 17-OHP level in the subjects decreased by >75% relative to baseline.

28. The method according to claim 26, wherein, The serum 17-OHP level in the subjects was reduced by >80% relative to baseline.

29. The method according to claim 26, wherein, The serum 17-OHP levels of the subjects decreased by >85% relative to baseline.

30. The method according to claim 26, wherein, The serum 17-OHP levels of the subjects decreased by >90% relative to baseline.

31. The method according to claim 26, wherein, The serum 17-OHP level in the subjects was reduced by >95% relative to baseline.

32. The method according to any one of claims 1-20, wherein, The treatment included lowering the serum testosterone level in the subject relative to baseline.

33. The method according to claim 32, wherein, The subjects' serum testosterone levels decreased by >50% relative to baseline.

34. The method according to claim 32, wherein, The subjects' serum testosterone levels decreased by >60% relative to baseline.

35. The method according to claim 32, wherein, The subjects' serum testosterone levels decreased by >70% relative to baseline.

36. The method according to claim 32, wherein, The subjects' serum testosterone levels decreased by >80% relative to baseline.

37. The method according to any one of claims 32-36, wherein, The subjects were female.

38. The method according to any one of claims 1-37, wherein, Treatment includes reducing the serum levels of one or more of the following in the subject, relative to baseline: 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 21-36, wherein, The baseline was measured in the early morning.

40. The method according to any one of claims 1-39, wherein, Treatment includes reducing the size of the adrenal glands.

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

42. The method according to any one of claims 1-39, wherein, Treatment includes lowering hemoglobin A1C (HbA1C) levels.

43. The method according to any one of claims 1 and 3-39, wherein, The subject had hyperandrogenemia.

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

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

46. ​​The method according to any one of claims 1-39, wherein, The subject had hirsutism.

47. The method according to claim 46, wherein, The subjects reported that their hirsutism improved after administration of compound (I) or a pharmaceutically acceptable salt thereof.

48. The method according to any one of claims 1-39, wherein, The subject suffered from menstrual disorders.

49. The method according to claim 48, wherein, The subjects reported that their menstrual disorders improved after administration of compound (I) or a pharmaceutically acceptable salt thereof.

50. The method according to any one of claims 1-39, wherein, The subject had a testicular adrenal remnant tumor (TART).

51. The method according to claim 50, wherein, The subjects' TART was improved upon administration of compound (I) or a pharmaceutically acceptable salt thereof.

52. A pharmaceutical composition for treating a subject suffering from CAH, wherein, The composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof:

53. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a subject with CAH:

54. A pharmaceutical composition for treating hyperandrogenemia in subjects with CAH, wherein, The composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof:

55. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating hyperandrogenism in a subject with CAH:

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