Clinecelfont administration regimen for treating congenital adrenal hyperplasia

Abstract

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders that result in enzyme deficiencies that alter the production of adrenal steroids, due to 21-hydroxylase deficiency (a condition in which little or no cortisol biosynthesis occurs). A method is provided for administering 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-propa-2-inyl-1,3-thiazole-2-amine, or a pharmaceutically acceptable salt thereof, to adult subjects with congenital adrenal hyperplasia.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 455,752, filed March 30, 2023, which is incorporated herein by reference in its entirety.

[0002] Field of Invention Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders that result in enzyme deficiencies that alter the production of adrenal steroids, due to 21-hydroxylase deficiency (a condition in which little or no cortisol biosynthesis occurs). One clinical manifestation of the absence of cortisol is the lack of feedback inhibition of pituitary adrenocorticotropic hormone (ACTH) secretion. Elevated ACTH levels lead to adrenal hyperplasia, and enzyme mutations cause shunting of cortisol precursor steroids into an alternative pathway. Most notably, shunting of androgens leads to masculinization and other developmental complications in females, and excessive accumulation of ACTH is associated with the formation of testicular adrenal tumors in males. Furthermore, since the same enzyme (21-hydroxylase) is used in the pathway for mineralocorticoid biosynthesis, many of these patients also suffer from aldosterone deficiency, which can lead to dehydration and death due to salt depletion. Based on newborn screening, the prevalence of classical 21-hydroxylase-deficient CAH in the general U.S. population has been recorded as 1:10,000–1:20,800. [Background technology]

[0003] Currently, exogenous corticosteroids are the standard treatment for patients with classic CAH. This treatment is used to correct cortisol deficiency and reduce excessive ACTH levels and androgen excess. However, the doses and durations of steroid use required to suppress ACTH typically exceed the normal physiological levels used for cortisol replacement alone (as in patients with Addison's disease). This increased exposure to glucocorticoids can lead to iatrogenic Cushing's syndrome, increased cardiovascular risk factors, glucose intolerance, reduced growth rate, and decreased bone mineral density in CAH patients.

[0004] Clinical trials have shown that orally active compounds that block CRF1 (e.g., 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-propa-2-inyl-1,3-thiazole-2-amine (compound A)) provide a reduction from baseline in 17-hydroxyprogesterone (17-OHP) and androstenedione levels at levels that are thought to allow the use of lower, more physiological doses of glucocorticoids (e.g., hydrocortisone) in patients with CAH. The structure of compound A is shown below: [ka] (Compound A)

[0005] There are significant unmet needs regarding methods for addressing CAH. This disclosure addresses these and other needs, as will be apparent from the following disclosures. [Overview of the Initiative] [Means for solving the problem]

[0006] In adult subjects with congenital adrenal hyperplasia (CAH), 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-propa-2-inyl-1,3-thiazole-2-amine, or a pharmaceutically acceptable salt thereof, was used as an adjunct to glucocorticoid therapy: [ka] (Compound A) A method for administering a compound A is provided, the method comprising administering to the subject a first amount of compound A or a pharmaceutically acceptable salt thereof over a first period of time, and subsequently administering to the subject a second amount of compound A or a pharmaceutically acceptable salt thereof over a second period of time, wherein the second amount is equal to approximately 200 mg of free base of compound A (qPM).

[0007] A method for treating congenital adrenal hyperplasia (CAH) in an adult subject already being treated with glucocorticoid therapy, the method comprising: a first amount of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-propa-2-inyl-1,3-thiazole-2-amine or a pharmaceutically acceptable salt thereof to the subject: [ka] (Compound A) A method is also provided which includes administering compound A over a first period, and subsequently administering to the subject a second amount of compound A or a pharmaceutically acceptable salt thereof over a second period, wherein the second amount is equal to approximately 200 mg of free base of compound A (qPM).

[0008] These and other aspects of the present invention will become apparent from the following detailed description. For this purpose, various references describing certain background information, procedures, compounds, and / or compositions in more detail are given herein, each of which is incorporated herein by reference in whole. [Modes for carrying out the invention]

[0009] Detailed explanation In the following description, certain specific details are shown to provide a complete understanding of the various embodiments. However, those skilled in the art will understand that the invention may be carried out without these details. In other examples, well-known structures are not shown or described in detail to avoid unnecessarily obscuring the description of the embodiments above. Unless the context otherwise requires, throughout this specification and the subsequent claims, the word “comprise” and its variations (e.g., “comprises” and “comprising”) should be interpreted as “including, but not limited to.” Furthermore, the headings provided herein are for convenience only and do not construe as defining the scope or meaning of the claimed invention.

[0010] Throughout this specification, reference to "one embodiment", "an embodiment", "some embodiments", or "a certain embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, appearances of the phrases "in one embodiment", "in an embodiment", "in some embodiments", or "in a certain embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0011] Also, as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0012] As used herein, in some embodiments, “pharmaceutically acceptable salt” refers to an acid addition salt with an inorganic or organic acid. A list of suitable salts can be found in WO 87 / 05297, Johnston et al., published September 11, 1987; Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418; and J. Pharm. Sci., 66, 2 (1977), each of which is incorporated herein by reference in its entirety. A reference relating to the preparation and selection of pharmaceutical salts in this disclosure is PH Stahl & CG Wermuth, “Handbook of Pharmaceutical Salts,” Verlag Helvetica Chimica Acta, Zurich, 2002, which is incorporated herein by reference in its entirety. Examples of the above organic or inorganic acids include, but are not limited to: Hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2 -Hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-octa-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, quinic acid, muconic acid, etc.In some embodiments, "pharmaceutically acceptable salts" refers to base addition salts with inorganic bases or organic bases. Examples of inorganic bases that can be used to prepare salts include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, manganese, aluminum hydroxide, carbonates, bicarbonates, phosphates, etc. Examples of organic bases that can be used to prepare salts include, but are not limited to, primary amines, secondary amines, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, etc. Specifically, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine can be mentioned.

[0013] As used herein, "about" means ±20% of the indicated value, and more specifically includes values of ±10%, ±5%, ±2%, and ±1% of the indicated value.

[0014] As used herein, "baseline" refers to the period immediately before the start of treatment. The state of the patient immediately before the start of treatment can be referred to as the baseline state of that patient.

[0015] As used herein, "adjusting administration", "altering administration", "adjusting dosing", or "altering dosing" are all synonymous and mean gradually reducing, decreasing or increasing the dose of a substance, stopping the administration of that substance to a patient, or using a different active agent in place of that substance.

[0016] As used herein, "administering to a patient" refers to the process of introducing a composition or dosage form to a patient via introduction means recognized in the art.

[0017] As used herein, “adult” refers to a subject who is at least 18 years of age.

[0018] As used herein, "bid" means two doses daily (administered approximately 12 hours apart).

[0019] As used herein, “co-administer” and its variations mean the administration of at least two drugs to a patient in succession, simultaneously, or consequently in close temporal proximity to one another (e.g., on the same day, or within the same week or 30-day period, or in close proximity so that each of at least two drugs can be detected simultaneously in plasma). When co-administered, two or more active agents may be co-formulated as part of the same composition or administered as separate formulations. This may also be referred herein as “concomitant” administration or its variations.

[0020] As used herein, “congenital adrenal hyperplasia” or “CAH” refers to a group of genetic disorders affecting the adrenal glands. Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive genetic disorders characterized by little to no cortisol biosynthesis. One clinical manifestation of the absence of cortisol is the lack of feedback inhibition of the CRF, which leads to dysregulation of the HPA axis. The most frequent form of the disease, accounting for approximately 95% of CAH cases, is 21-hydroxylase deficiency, caused by mutations in the CYP21A2 gene located on chromosome 6p21. 21-hydroxylase enzyme deficiency also causes a shunt of cortisol precursor steroids, resulting in excessive androgen (e.g., 17-hydroxyprogesterone, androstenedione, and testosterone) products. These mutations can range from complete loss of the enzyme activity required for cortisol synthesis in the adrenal cortex to varying degrees of partial loss, resulting in disease severity that is a direct consequence of the specific mutation. This continuum of 21-hydroxylase deficiency is broadly classified into salt-consuming and simple masculinizing forms, grouped as classical (or classic) CAH, while milder forms are known as non-classical (or non-classical) CAH (NCCAH) or "late-onset" CAH, which are usually diagnosed in late childhood or early adulthood. Patients with non-classical CAH are either homozygous or compound heterozygous and often possess the classical CAH allele. These patients have sufficient enzyme activity (>20-50% of normal), and as a result, they do not have salt-consuming or cortisol deficiency, have normal genitalia at birth, and many remain asymptomatic throughout life. In a less frequent form of the disease, accounting for 5% of cases, mutations in the 11β-hydroxylase gene CYP11B1 result in CAH (11β-OH CAH). Classical CAH is a rare disease; its incidence is estimated to be approximately 1 in 15,000 worldwide. Approximately 75% of patients with classical CAH have a salt-wasting form of the disease, characterized by severe enzyme deficiencies and insufficient levels of cortisol and aldosterone.Approximately 25% of patients with classic CAH have a simple masculinizing form in which cortisol synthesis is impaired, but enzyme activity is sufficient for adequate aldosterone production.

[0021] As used herein, the term “disorder” is intended to be generally synonymous with and interchangeable with the terms “disease,” “syndrome,” and “condition” (as in “medical condition”), all of which reflect an abnormal condition of one or more parts of the human or animal body that impairs normal function and is typically manifested by prominent signs and symptoms.

[0022] As used herein, “dose” means the measured amount of the active agent to be taken by a patient at one time. In certain embodiments where the active agent is not free base of compound A, the amount is the molar equivalent to the corresponding amount of free base of compound A. For example, drugs are often packaged in a pharmaceutically acceptable salt form, and the dose strength refers to the mass of the corresponding free base, the molar equivalent of compound A.

[0023] As used herein, “dosage regimen” means the initial dose of the active agent taken by the patient, and any subsequent dose intervals (in terms of time or symptoms) of the active agent taken by the patient, for example, about 100 mg to about 300 mg once daily, or about 20 mg to about 160 mg twice daily, for example, about 100 mg, about 150 mg, about 200 mg, about 250 mg, or about 300 mg once daily, or about 20 mg, about 40 mg, about 60 mg, about 80 mg, about 100 mg, about 120 mg, or about 160 mg twice daily. Additional doses of the active agent may differ from the initial dose taken. For example, the first dose can be in the range of approximately 20 mg to approximately 160 mg, for example, approximately 20 mg, approximately 40 mg, approximately 60 mg, approximately 80 mg, approximately 100 mg, approximately 120 mg, or approximately 160 mg, and the second dose can be in the range of approximately 100 mg to approximately 300 mg, for example, approximately 100 mg, approximately 150 mg, approximately 200 mg, approximately 250 mg, or approximately 300 mg.

[0024] As used herein, “dosage” refers to a prescribed number, quantity, and frequency of doses administered over a specific period of time.

[0025] As used herein, “effective amount” and “therapeutic amount” of a drug, compound, medicine, composition, or combination are amounts that are non-toxic when administered to a subject or patient (e.g., a human subject or patient) and are effective in producing a desired therapeutic effect. The exact therapeutic amount for a subject may depend, for example, on the size and health status of the subject, the nature and degree of the condition, the therapeutic agent or combination of therapeutic agents selected for administration, and other variables known to those skilled in the art. The effective amount for a given situation is determined by conventional experimentation and is within the scope of clinician judgment.

[0026] As used herein, “informing” means referring to or providing published material, for example, providing an active drug to a user along with published material; or presenting information orally, for example, by presentation at a seminar, conference, or other educational presentation, by conversation between a pharmaceutical sales representative and a medical care worker, or by conversation between a medical care worker and a patient; or showing information intended for the user to understand.

[0027] As used herein, “labeling” means all labels on or accompanying a pharmaceutical product or dosage form, or other means of written, printed, charted, electronic, linguistic or explicit communication.

[0028] As used herein, “medical care worker” means any healthcare professional who may need or have access to information about an active drug, including its dosage form, safety, efficacy, dosing, administration, or pharmacokinetics. Examples of medical care workers include physicians, pharmacists, physician's assistants, nurses, assistants, caregivers (which may include family members or guardians), emergency medical personnel, and veterinarians.

[0029] As used herein, “Medication Guide” means an FDA-approved patient label for a medicinal product that contains patient information on how to use the medicinal product safely, in accordance with the specifications set forth in 21 CFR 208 and other applicable regulations. A Medication Guide is scientifically accurate and based on and consistent with approved physician labeling for a medicinal product under 21 CFR 201.57, but its wording does not need to be identical to the corresponding section of the approved labeling. Medication Guides are typically available for medicinal products with specific risk management information.

[0030] As used herein, “patient,” “individual,” or “subject” means a mammal (including humans) to which treatment is desired, and generally refers to the recipient of such treatment.

[0031] As used herein, “Patient Information Sheet” means patient information that is part of the FDA-approved labeling regarding how to use a pharmaceutical product safely. It is an extension of the physician information that may be distributed to a patient when the pharmaceutical product is compounded, and provides consumer information about the product in easily understandable language. For example, it may describe benefits, risks, how to perceive risks, dosage, or administration.

[0032] As used herein, “pharmaceutically acceptable” refers to a substance that is not biologically or otherwise undesirable. That is, the substance can be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a harmful manner with any of the other components of the pharmaceutical composition (in which the substance is contained). When the term “pharmaceutically acceptable” is used to refer to a pharmaceutical carrier or excipient, it means that the carrier or excipient meets the required standards of toxicological and manufacturing testing, or is included in the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration. “Pharmacologically active” (or simply “active”), as in “pharmacologically active” derivative or analog, refers to a derivative or analog that has the same type of pharmacological activity as the parent compound, and to approximately the same degree. The term "pharmaceutically acceptable salt" includes acid addition salts formed with inorganic acids (e.g., hydrochloric acid or phosphoric acid) or organic acids such as acetic acid, oxalic acid, tartaric acid, and mandelic acid. Salts formed with free carboxyl groups can also be obtained from inorganic bases (e.g., sodium, potassium, ammonium, calcium, or ferric hydroxides) and organic bases such as isopropylamine, trimethylamine, histidine, and procaine.

[0033] As used herein, “product” or “pharmaceutical product” means the dosage form of the active ingredient, the published materials, and, if applicable, the packaging.

[0034] As used herein, “product information leaflet” means a medical label (prescription information) for a pharmaceutical product, a patient information leaflet for a pharmaceutical product, or a medication guide for a pharmaceutical product.

[0035] As used herein, “professional labeling” or “prescription information” means the official pharmacopoeia description of a pharmaceutical product approved by a regulatory authority (e.g., the FDA or EMEA) that controls the sale and distribution of the pharmaceutical product on the market, which includes a summary of essential scientific information required for the safe and effective use of the drug, such as indications and use; dosage and administration; who should take the drug; adverse events (side effects); instructions for use in special populations (e.g., pregnant women, children, the elderly); and patient safety information.

[0036] As used herein, “published material” means any medium that provides information, including printed, audio, video, or electronic media such as flyers, advertisements, product inserts, printed notices, internet websites, internet web pages, internet pop-up windows, radio or television broadcasts, compact discs, DVDs, audio recordings, or other recordings or electronic media.

[0037] As used in this specification, "qAM" means every morning.

[0038] As used herein, "qPM" means every night.

[0039] As used herein, “risk” means the probability or likelihood of an adverse reaction, injury or other undesirable outcome resulting from a medical procedure. “Acceptable risk” means the measure of the risk of harm, injury or disease resulting from a medical procedure that is tolerated by an individual or group. Whether a risk is “acceptable” depends on the benefits that the individual or group perceives they may receive in return for taking the risk, whether they accept all that scientific and other advice provides about the degree of that risk, and many other factors, both political and social. “Acceptable risk” of an adverse reaction means that the individual or group in society is willing to take or suffer the risk of the adverse reaction occurring because the probability of it occurring is small or the consequences are very minor, or the benefits (perceived or actual) of the active ingredient are very large. An “unacceptable risk” of an adverse reaction means that an individual or group in society is unwilling to take or be subjected to the risk of an adverse reaction occurring, weighted against the probability of the adverse reaction occurring, the consequences of the adverse reaction, and the benefits (perceived or actual) of the active ingredient. “At risk” means a state or condition in which a high level of risk or susceptibility is evident. Risk assessment consists of identifying and characterizing the nature, frequency, and severity of risks associated with the use of a product.

[0040] As used herein, “safety” means the incidence or severity of adverse events associated with the administration of the active agent (including adverse events associated with patient-related factors (e.g., age, sex, ethnicity, race, disease of the subject, abnormal renal or hepatic function, comorbidities, genetic characteristics (e.g., metabolic status, or environment)) and active agent-related factors (e.g., dose, plasma levels, duration of exposure, or concomitant medications)).

[0041] In adult subjects with congenital adrenal hyperplasia (CAH), 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-propa-2-inyl-1,3-thiazole-2-amine, or a pharmaceutically acceptable salt thereof, was used as an adjunct to glucocorticoid therapy: [ka] (Compound A) A method for administering a compound A is provided, the method comprising administering to the subject a first amount of compound A or a pharmaceutically acceptable salt thereof over a first period of time, and subsequently administering to the subject a second amount of compound A or a pharmaceutically acceptable salt thereof over a second period of time, wherein the second amount is equal to approximately 200 mg of free base of compound A (qPM).

[0042] A method for treating congenital adrenal hyperplasia (CAH) in an adult subject already being treated with glucocorticoid therapy, the method comprising: a first amount of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-propa-2-inyl-1,3-thiazole-2-amine or a pharmaceutically acceptable salt thereof to the subject: [ka] (Compound A) A method is also provided which includes administering compound A over a first period, and subsequently administering to the subject a second amount of compound A or a pharmaceutically acceptable salt thereof over a second period, wherein the second amount is equal to approximately 200 mg of free base of compound A (qPM).

[0043] In some embodiments, administering compound A or a pharmaceutically acceptable salt thereof refers to administering compound A or a pharmaceutically acceptable salt thereof with the subject's breakfast and dinner.

[0044] In some embodiments, the first amount is equal to about 100 mg of free compound A base in bid. In some embodiments, the first amount is equal to about 100 mg of free compound A base in qAM and about 100 mg of free compound A base in qPM.

[0045] In some embodiments, the first amount is equal to about 100 mg of compound A free base in qAM and about 200 mg of compound A free base in qPM.

[0046] In some embodiments, the first period is between one week and one year. In some embodiments, the first period is at least six months. In some embodiments, the first period is less than six months. In some embodiments, the first period is 24 hours. In some embodiments, the first period is less than 24 hours. In some embodiments, the first period is greater than six months. In some embodiments, the first period is about six months. In some embodiments, the first period is at least about one year. In some embodiments, the first period is greater than one year. In some embodiments, the first period is about one year.

[0047] In some embodiments, the second dose is administered because the first dose was missed. In some embodiments, the missed dose of the first dose is a qAM dose. In some embodiments, the second dose is administered on the same day as the missed dose of the first dose. In some embodiments, the missed dose of the first dose is a qPM dose. In some embodiments, the second dose is administered on the day following the missed dose of the first dose. In some embodiments, the second dose is adjusted to the first dose after the second period. In some embodiments, the second dose is adjusted to the first dose after the second period because the first dose was missed. In some embodiments, the second period is less than 24 hours. In some embodiments, the second period is about 12 hours. In some embodiments, the qAM dose of the first dose is a missed dose. In some embodiments, if the first dose of qAM is missed, the second dose is administered in the evening, and then the regular first dose administration schedule is restarted.

[0048] In some embodiments, the second period is between one week and one year. In some embodiments, the second period is at least six months. In some embodiments, the second period is less than six months. In some embodiments, the second period is 24 hours. In some embodiments, the second period is less than 24 hours. In some embodiments, the second period is greater than six months. In some embodiments, the second period is about six months. In some embodiments, the second period is at least one year. In some embodiments, the second period is greater than one year. In some embodiments, the second period is about one year.

[0049] In some embodiments, the method further includes adjustments for missed doses of the first dose. In some embodiments, the missed dose of the first dose is a qAM dose. In some embodiments, the missed dose of the first dose is a qPM dose. In some embodiments, the method further includes adjustments for missed doses of the second dose. In some embodiments, in the event of a missed dose, the missed dose is administered as soon as possible, even if it is immediately before the next scheduled dose, and then the regular dosing schedule is restarted.

[0050] In some embodiments, the glucocorticoid treatment is the daily dose of glucocorticoid administered to the subject.

[0051] In some embodiments, the daily dose of the glucocorticoid is administered once daily or through multiple doses. In some embodiments, the daily dose of the glucocorticoid is administered once daily. In some embodiments, the daily dose of the glucocorticoid is administered through multiple doses.

[0052] In some embodiments, the glucocorticoid is selected from hydrocortisone, prednisone, methylprednisolone, prednisolone, and dexamethasone, or a combination thereof.

[0053] In some embodiments, prior to the above administration of an amount equivalent to approximately 200 mg of compound A free base (qPM), the subject had previously received glucocorticoids at a target dose.

[0054] In some embodiments, the target dose of glucocorticoid treatment is ≤11 mg / m². 2 This is the equivalent of hydrocortisone per day.

[0055] In some embodiments, the target dose of glucocorticoid treatment is approximately 8 mg / m².2 / day~about 10mg / m 2 This is the equivalent of hydrocortisone per day.

[0056] In some embodiments, the target dose of glucocorticoid treatment is approximately 8 mg / m². 2 This is the equivalent of hydrocortisone per day.

[0057] In some embodiments, the glucocorticoid is hydrocortisone. In some embodiments, the glucocorticoid is methylprednisolone using a hydrocortisone dose equivalent conversion factor of 4×. In some embodiments, the glucocorticoid is prednisolone using a hydrocortisone dose equivalent conversion factor of 4×. In some embodiments, the glucocorticoid is prednisone using a hydrocortisone dose equivalent conversion factor of 4×. In some embodiments, the glucocorticoid is dexamethasone using a hydrocortisone dose equivalent conversion factor of 60×.

[0058] In some embodiments, the subjects showed adequate disease control prior to the administration of an amount equal to approximately 200 mg of compound A free base, which was approximately 200 mg of qPM.

[0059] In some embodiments, prior to the above administration of an amount equal to approximately 200 mg of compound A free base, the subjects had shown adequate disease control and had been administered glucocorticoids at the target dose.

[0060] In some embodiments, the subjects demonstrated adequate disease control when their androstenedione levels were ≤120% of the subject's baseline or ≤upper normal number (ULN) relative to the subject's age and sex.

[0061] In some embodiments, the subjects demonstrated adequate disease control in the opinion of the principal investigator.

[0062] In some embodiments, the method further includes monitoring the subject for adequate disease control, where if disease control is insufficient and the glucocorticoid treatment is at or above the target dose for the subject, the amount of compound A or a pharmaceutically acceptable salt thereof is adjusted to an amount equal to approximately 100 mg of compound A free base bid.

[0063] In some embodiments, the method further includes monitoring the subject for adequate disease control, where if disease control is insufficient and the glucocorticoid treatment is at or above the target dose for the subject, the amount of compound A or a pharmaceutically acceptable salt thereof is adjusted to an amount equal to approximately 100 mg of compound A free base in qAM and an amount equal to approximately 200 mg of compound A free base in qPM.

[0064] In some embodiments, the subjects showed inadequate disease control when their androstenedione levels exceeded 120% of their baseline or the upper limit of normal (ULN) for the subject's age and sex.

[0065] In some embodiments, the subjects exhibited inadequate disease control in the opinion of the principal investigator.

[0066] In some embodiments, the target dose of glucocorticoid treatment is ≤11 mg / m². 2 This is the equivalent of hydrocortisone per day.

[0067] In some embodiments, the target dose of glucocorticoid treatment is approximately 8 mg / m². 2 / day~about 10mg / m 2 This is the equivalent of hydrocortisone per day.

[0068] In some embodiments, the target dose of glucocorticoid treatment is approximately 8 mg / m². 2 This is the equivalent of hydrocortisone per day.

[0069] In some embodiments, the glucocorticoid is hydrocortisone. In some embodiments, the glucocorticoid is methylprednisolone using a hydrocortisone dose equivalent conversion factor of 4×. In some embodiments, the glucocorticoid is prednisolone using a hydrocortisone dose equivalent conversion factor of 4×. In some embodiments, the glucocorticoid is prednisone using a hydrocortisone dose equivalent conversion factor of 4×. In some embodiments, the glucocorticoid is dexamethasone using a hydrocortisone dose equivalent conversion factor of 60×.

[0070] In some embodiments, compound A is a free base.

[0071] In some embodiments, compound A is administered with food.

[0072] In some embodiments, compound A is administered to the subject in a ingested state.

[0073] In some embodiments, the CAH is classical congenital adrenal hyperplasia.

[0074] In some embodiments, the CAH is a non-classical congenital adrenal hyperplasia.

[0075] Examples of embodiments of the present disclosure are provided in the following embodiments. The following embodiments are presented for illustrative purposes only and to assist those skilled in the art in using the present disclosure. These embodiments are not intended to limit the scope of the present disclosure in any other way. [Examples]

[0076] Examples Example 1 A randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of Compound A in adult subjects with classical congenital adrenal hyperplasia, followed by an open-label treatment. Specifically, this is a Phase 3 randomized, double-blind, placebo-controlled trial to evaluate the efficacy, safety, and tolerability of Compound A versus placebo administered b.i.d. with breakfast and dinner (dosing approximately 12 hours apart) over 24 weeks in approximately 165 adult subjects with classical CAH due to 21-hydroxylase deficiency. Eligible subjects are randomly assigned to two treatment groups (Compound A 100 mg b.i.d. or placebo) in a 2:1 ratio (active drug:placebo). After a 24-week randomized treatment period, there is a 6-month open-label treatment period during which all subjects receive Compound A 100 mg b.i.d. At month 12, subjects who did not reduce their glucocorticoid dose to ≤ 11 mg / m 2 / day are randomized again (2:1) to receive 100 mg every morning (q.A.M.) and 200 mg every night (q.P.M.) or continue with 100 mg b.i.d. in a blinded fashion. Subjects who reduced their glucocorticoid dose to ≤ 11 mg / m 2 / day continue to receive 100 mg b.i.d. in an open-label fashion. At month 18, subjects review the appropriate section of the informed consent form and confirm whether they will participate in an optional open-label extension (OLE) treatment period for continued access to Compound A.

[0077] During the above OLE, subjects adjust their glucocorticoid dose to be appropriate and tolerable to achieve the lowest glucocorticoid dose that maintains adequate disease control (in the opinion of the study physician). The above glucocorticoid dose reduction does not require a dose reduction below 8 mg / m 2 / day hydrocortisone equivalent.

[0078] All subjects initiated at 18 months and continuing in OLE will initially receive a bid of compound A 100 mg. If the above subjects have inadequate disease control despite receiving glucocorticoid treatment at their target dose (in the opinion of the investigator), the above compound A dose may be increased to qAM 100 mg and qPM 200 mg. After the 24-month visit, an alternative dosing regimen of qPM 200 mg once daily may be considered by the investigator.

[0079] Screening period (from week 4 to day 1) Subjects will be screened for up to four weeks (from week -4 to day -1) to determine eligibility, according to the evaluation schedule. A second visit (at home or at the testing site) will be made during the screening period to collect blood samples (for hormone measurement). The screening period may be extended up to two weeks (if necessary) for the results of the two screening visits and hormone tests. Subjects must be stable for at least one month prior to screening, with a hydrocortisone dose equivalent (Table 1) adjusted for body surface area (BSA) >13 mg / m². 2 They must receive a hyperphysiological glucocorticoid regimen defined as [number] days. [Table 1] See Auchus and Arlt, J Clin Endocrinol Metab. 2013 Jul; 98(7):2645-55; Speiser et al., J Clin Endocrinol Metab. 2018 Nov 1; 103(11):4043-88. The glucocorticoid regimen should be optimized by the treating physician to achieve control of adrenal androgen levels and to minimize the glucocorticoid dose to an extent appropriate to the individual medical needs and treatment goals of the subject.

[0080] Rescreening is permitted if the subject fails to meet all eligibility requirements and is returned for rescreening. Subjects who fail screening twice will not be rescreened again without prior permission from the medical monitor.

[0081] Randomized, double-blind, placebo-controlled treatment period (from day 1 to week 24) 4-week glucocorticoid stabilization period (from day 1 to week 4) During the first four weeks of the trial, subjects should maintain their stable glucocorticoid regimen, except for sick-day guidelines (see, e.g., El-Maouche D et al., J Clin Endocrinol Metab. 2018 Jun 1; 103(6):2336-2345).

[0082] On day 1 (baseline), subjects collect a urine sample at home in the morning (all urination from late night the night before the trial until the first morning urination after waking up on the day of the trial) and bring it to the laboratory for measurement of androgen metabolite levels. They withhold their morning glucocorticoid administration and bring it to the laboratory themselves so that a blood sample can be obtained before receiving that morning glucocorticoid administration; then, subjects receive their morning glucocorticoid administration at the laboratory, and another blood sample is taken approximately 2 hours after administration to establish baseline hormone levels before and after glucocorticoid administration. Subjects should fast from the night before so that fasting blood tests and oral glucose tolerance tests can be performed, but drinking water should be encouraged to avoid any hypovolemic conditions.

[0083] Subjects will be randomized on day 1 in a 2:1 ratio (active drug:placebo). Randomization will be stratified by total daily glucocorticoid dose, glucocorticoid type, and sex. Starting on day 1 (baseline), the investigational drug will be administered at home with the subject's dinner; thereafter, the investigational drug will be administered bid with the subject's breakfast and dinner (with approximately 12-hour intervals between doses).

[0084] 8-week glucocorticoid reduction period (from week 4 to week 12) During this period, unless the subject has any signs or symptoms suggesting clinically relevant glucocorticoid deficiency or unacceptable symptoms of androgen excess, the subject will continue to receive 8 mg / m² up to week 12. 2 / day~10mg / m 2 They will undergo a gradual reduction (down-titration) of their glucocorticoid dose (in four steps or less) with the goal of reaching their target daily dose (hydrocortisone equivalent adjusted for BSA) (see below for further details on glucocorticoid dose reduction schedules).

[0085] At the 4-week visit, a more detailed assessment of the androgenic status will be performed using urine samples collected at home and blood samples collected at the study site before morning glucocorticoid and investigational drug administration and approximately 2 hours after administration, following a procedure similar to that for day 1. At this visit, the principal investigator will instruct the subject to the first stage of glucocorticoid dose reduction and arrange to contact the subject by telephone within one week of the study visit to assess how well the subject is tolerating the glucocorticoid dose reduction. If the principal investigator feels that clinical evaluation and / or laboratory tests are necessary during the telephone follow-up contact, these may be performed as unscheduled visits.

[0086] Subjects will have trial visits at week 6 (at home or at the trial site), week 9 (at home or at the trial site), and week 12 for trial evaluation, including blood sample collection to assess hormone levels and routine safety assessments.

[0087] At the 6-week visit, the principal investigator will instruct the subject to proceed to the second stage of glucocorticoid dose reduction (if applicable). If glucocorticoid dose reduction has been performed, the investigator will contact the subject by telephone within one week of the aforementioned visit to assess how well the subject is tolerating the dose reduction. The principal investigator will contact the subject again around 8 weeks to advise on the third step of glucocorticoid dose reduction (if applicable).

[0088] At the 9-week trial visit, the principal investigator will assess whether the subject is tolerating the third glucocorticoid dose reduction (if applicable). The principal investigator will contact the subject around 10 weeks to advise on the fourth stage of glucocorticoid dose reduction (if applicable), and if a glucocorticoid dose reduction is performed, arrange to contact the subject by telephone within one week of the trial visit to assess how well the subject is tolerating the glucocorticoid dose reduction.

[0089] If the subject experiencing any of the following signs or symptoms at any point during the glucocorticoid dose reduction process, the glucocorticoid dose should be returned to the previously tolerated dose rather than being further reduced. However, before the glucocorticoid dose reduction is discontinued due to symptoms or signs of orthostatic hypotension, the volume status should be optimized (e.g., with additional salt in the diet, salt tablets, or intravenous saline solutions). • Unexplained hyponatremia (serum sodium <135 mmol / L) • Orthostatic hypotension accompanied by a decrease of >20 mmHg in systolic blood pressure or >10 mmHg in diastolic blood pressure approximately 2 minutes after standing up (from a seated position), or severe symptoms of dizziness or lightheadedness upon standing. • Severe nausea, aversion to food, vomiting • Unacceptable symptoms of androgen excess (e.g., male-pattern hirsutism, acne, amenorrhea).

[0090] The reduction of glucocorticoid doses between weeks 4 and 12 should be carried out, even if it results in a transient increase in androstenedione levels, as long as the increase is asymptomatic and acceptable to the subject.

[0091] At the 12-week visit, based on a detailed examination of the subject's hormone levels collected up to that visit and on a clinical assessment, the principal investigator will determine an appropriate dose of glucocorticoid to continue beyond 12 weeks (a reduced dose, if permissible, or the previous [higher] dose) to achieve adequate control of androgen levels (i.e., androstenedione is ≤120% of the subject's baseline or ≤ the upper limit of normal [ULN] for age and sex).

[0092] 12-week glucocorticoid optimization period (weeks 12 to 24) Subjects will continue the glucocorticoid regimen as instructed by the principal investigator at week 12, and will return to the study site at weeks 16 (at home or at the study site), 20 (at home or at the study site), and 24 during the glucocorticoid optimization period. At these visits, the principal investigator will review laboratory results since the previous study visit and determine whether the glucocorticoid regimen needs adjustment to achieve adequate control of androgen levels (i.e., androstenedione ≤ 120% of the subject's baseline or ≤ ULN for age and sex).

[0093] At the 24-week visit, subjects will undergo a similar procedure to day 1 for further androgen assessment, using urine samples collected at home and blood samples collected at the study site before and approximately two hours after administration of glucocorticoids and the investigational drug in the morning. Subjects should fast from the previous night, but should be encouraged to drink water to avoid any hypovolemia. A glucose tolerance test will be performed (the investigational drug will be administered with the glucose load, not with food).

[0094] Open-label treatment period (from 24 weeks to 12 months) For the purposes of this study, months are defined as four-week intervals.

[0095] Starting on the evening of the 24th week visit (after all 24-week evaluations have been completed), all subjects will receive a 100 mg bid of the active investigational drug (compound A) with breakfast and dinner. Subjects should continue the glucocorticoid regimen identified by the principal investigator at 24 weeks. Subjects and the principal investigator remain blinded to the treatment group assignment of subjects from the double-blind period onward.

[0096] 1-month glucocorticoid stabilization period (from week 24 to month 7) During the first month of open-label treatment with compound A, subjects should maintain a stable glucocorticoid regimen (except for sick day guidelines).

[0097] A 3-month glucocorticoid reduction period (from the 7th to the 10th month) In months 7 (at home or at the trial site), 8, and 9 (at home or at the trial site), the principal investigator will determine the dosage to be 8-10 mg / m² by month 10. 2 With the goal of achieving the target physiological dose per day, the glucocorticoid dose will reach 11 mg / m² at 7 months. 2In subjects with levels still greater than 1 / day, the glucocorticoid dose should be reduced (unless there are safety concerns regarding glucocorticoid deficiency). The glucocorticoid dose should be reduced by approximately 10% to 20% at each visit (months 7, 8, and 9), unless androstenedione levels are controlled (i.e., androstenedione is ≤120% of the subject's baseline or ≤ULN for age and sex) and the subject is not experiencing any signs or symptoms suggesting clinically relevant glucocorticoid deficiency or unacceptable symptoms of androgen excess. The glucocorticoid dose reduction should be 8 mg / m². 2 No dose reduction below the hydrocortisone equivalent per day is required. After each of the above glucocorticoid dose reduction stages, the above location should contact the subject by telephone (within one week) to assess how well the subject tolerates the glucocorticoid dose reduction. The subject will have trial visits at 8, 9, and 10 months for trial evaluation, including the collection of blood samples for hormone levels.

[0098] 2-month glucocorticoid maintenance period (from month 10 to month 12) Subjects will undergo study evaluations at 10 months (at home or at the study site) and 12 months, as outlined in the evaluation schedule. During this period, the goal should be to maintain a stable glucocorticoid dose; however, the above dose may be adjusted according to standard treatment (e.g., to achieve appropriate androgen level control for each subject's treatment goals).

[0099] At the 12-month visit, subjects will undergo further androgen assessment using urine samples collected at home and blood samples collected at the test site before and approximately two hours after administration of glucocorticoids and the investigational drug in the morning. Subjects should fast overnight (subjects should be encouraged to drink water to avoid any hypovolemia). A glucose tolerance test will be performed at the 12-month visit (the investigational drug will be administered with a glucose load, not with food).

[0100] Open-label or double-blind active drug-control treatment (from month 12 to month 18) The glucocorticoid dose at 12 months was 11 mg / m². 2 6-month glucocorticoid maintenance period (from month 12 to month 18) for subjects taking less than / day. At 12 months, the glucocorticoid dose was 11 mg / m². 2 Subjects receiving less than / day will continue the active investigational drug at a 100 mg bid until month 18, with trial visits at month 14 (at home or at the study site), month 16 (at home or at the study site), and month 18. The goal during this period is to maintain a stable glucocorticoid dose while controlling androstenedione levels (i.e., androstenedione is ≤120% of the baseline for the subject or ≤ULN for age and sex), although the dose may be adjusted according to standard treatment.

[0101] At the 18-month follow-up visit, subjects will undergo further androgen assessment using urine samples collected at home and blood samples collected at the study site before morning glucocorticoid and investigational drug administration, and approximately two hours after administration. Subjects should fast overnight (subjects should be encouraged to drink water to avoid any hypovolemia).

[0102] The glucocorticoid dose at 12 months was 11 mg / m². 26-month glucocorticoid reduction / optimization (from month 12 to month 18) for subjects exceeding [number] days. At 12 months, glucocorticoid dose > 11 mg / m² 2 Subjects will be re-randomized (2:1) to either adjust their active investigational drug dose to qAM 100 mg and qPM 200 mg, or to continue with the active investigational drug at a 100 mg bid; the investigational drug will be blinded so that all re-randomized subjects receive the same number of capsules. Subjects should maintain a stable glucocorticoid regimen (except for sick day guidelines) for the first month until the 13-month visit. At the 13-month visit, subjects will undergo further androgen assessment using urine samples collected at home and blood samples collected at the study site before morning glucocorticoid and investigational drug administration and approximately 2 hours after administration.

[0103] At months 13, 14 (at home or at the trial site), and 16 (at home or at the trial site), the principal investigator will administer 8–10 mg / m² by month 18. 2 The glucocorticoid dose is reduced to achieve the target physiological dose per day. The glucocorticoid dose should be reduced by approximately 10-20% at months 13, 14, and 16, unless androstenedione levels are controlled (i.e., androstenedione is ≤120% of the subject's baseline or ≤ULN for age and sex) and the subject experiences no signs or symptoms suggesting clinically relevant glucocorticoid deficiency or unacceptable symptoms of androgen excess. The glucocorticoid dose reduction should be 8 mg / m². 2 / day No dose reduction below the hydrocortisone equivalent is required. After each of the above glucocorticoid dose reduction stages, the above location should contact the subject by telephone (within one week) to assess the extent to which the subject tolerates the glucocorticoid dose reduction.

[0104] At the 18-month follow-up visit, subjects will undergo further androgen assessment using urine samples collected at home and blood samples collected at the study site before morning glucocorticoid and investigational drug administration, and approximately two hours after administration. Subjects should fast overnight (subjects should be encouraged to drink water to avoid any hypovolemia).

[0105] Open-label extension (OLE) treatment period (from the 18th month onward) At 18 months, subjects review the relevant sections of their informed consent forms to determine whether they wish to participate in voluntary OLE.

[0106] During the above OLE, subjects will adjust their glucocorticoid dose to be appropriate and tolerable in order to achieve the lowest glucocorticoid dose that maintains adequate disease control (in the opinion of the principal investigator). The above glucocorticoid dose reduction is 8 mg / m². 2 / day No dose reduction below the hydrocortisone equivalent is required. After each glucocorticoid dose reduction, the above location should contact the subject by telephone (within one week) to assess how well the subject tolerates the glucocorticoid dose reduction.

[0107] All subjects initiated at 18 months and continuing in OLE will initially receive an open-label compound A 100 mg bid. If the above subjects have inadequate disease control despite receiving glucocorticoid treatment at their target dose (in the opinion of the investigator), the compound A dose may be increased to qAM 100 mg and qPM 200 mg (including at 18 months, after laboratory results become available). If the increased doses of qAM 100 mg and qPM 200 mg are not adequately tolerated, the dose may be reduced to a 100 mg bid. After the 24-month visit, an alternative dosing regimen of qPM 200 mg once daily may be considered by the investigator. The compound A dose should generally only be adjusted at or shortly thereafter at the study visit (after laboratory results become available).

[0108] In situations of inadequate disease control, if the glucocorticoid dose is at or above the target dose, an increase in the glucocorticoid dose should generally only be considered after the compound A dose has been maximized for the subject. Changes to the glucocorticoid and compound A doses should generally be observed at least one month apart to assess the effect of each change.

[0109] During the OLE study, trial visits are scheduled every three months until month 24, and every six months thereafter. The 21st month visit can be conducted at home. At the 24th month visit and subsequent 12-month visits, subjects will have blood samples taken at the study site before and approximately two hours after the administration of morning glucocorticoids and the investigational drug. Subjects should fast overnight (subjects should be encouraged to drink water to avoid any hypovolemic conditions). A glucose tolerance test will also be performed at month 24 and every 12 months thereafter (the investigational drug will be administered with the glucose load, not with food).

[0110] Subjects will remain in the OLE until compound A becomes commercially available, until the sponsor chooses to discontinue the development of compound A for CAH, until the sponsor chooses to discontinue the trial, or until the subject meets one of the above withdrawal criteria.

[0111] Tracking period The final post-treatment visit takes place approximately one month after the subject's final administration of the investigational drug.

[0112] Trial evaluation and trial visit scheduling Efficacy, safety, and pharmacokinetics (PK) should be evaluated at scheduled times throughout the trial. Wherever possible, all trial visits (including baseline and follow-up) should be scheduled at approximately the same time in the morning to standardize the time allocated for evaluating efficacy, safety, and drug exposure.

[0113] In the double-blind, placebo-controlled portion of the above study, all visits after day 1 during the glucocorticoid stabilization and glucocorticoid reduction periods have a visit range of +5 days, and all visits during the glucocorticoid optimization period have a visit range of ±5 days. In the open-label treatment period, visits from month 7 to month 10 have a visit range of ±5 days, and visits from month 12 to month 18 have a visit range of ±7 days. In the above OLE, visits have a visit range of ±14 days. If a subject's glucocorticoid regimen is adjusted due to sick day guidelines, the subject should restart their glucocorticoid administration regimen at least 3 days before their next scheduled hormone panel assessment, and this 3-day range takes precedence over all other visit ranges.

[0114] The objectives of the test include: • To evaluate the efficacy of compound A (100 mg twice daily [bid]) in reducing the daily glucocorticoid dose while maintaining adrenal androgen control, compared to placebo. • To evaluate the efficacy of compound A in reducing adrenal steroid levels after the first four-week treatment period, compared to placebo. • To evaluate the effect of compound A on clinical endpoints associated with hyperphysiological glucocorticoid administration compared to placebo. • Evaluate the plasma concentrations of compound A and its metabolites. • Evaluate the safety and tolerability of compound A. • Evaluate alternative administration regimens for compound A in subjects who have not reduced their glucocorticoid dose by 12 months.

[0115] Evaluation criteria: The effectiveness criteria that can be evaluated may include the following: • Daily glucocorticoid regimens expressed as hydrocortisone equivalents adjusted for body surface area (BSA) (mg / m²) 2 / day). • Hormone measurements: 17-hydroxyprogesterone (17-OHP) (serum; ng / dL), androstenedione (serum; ng / dL), testosterone (serum; ng / dL), adrenocorticotropic hormone (ACTH) (plasma; pg / mL), cortisol (serum; μg / dL), luteinizing hormone (LH) (serum; IU / L), follicle-stimulating hormone (FSH) (serum; IU / L), progesterone (serum; ng / mL), plasma renin activity (measured upright) (ng / mL / hour). • Urinary androgen metabolite levels (androsterone and etiocholanolone). • Metabolic assessment (fasting lipid panel, homeostasis model assessment of insulin resistance based on fasting glucose and insulin levels [HOMA-IR], glycated hemoglobin [HbA1c], glucose tolerance test). • Dual-energy X-ray absorptiometry (DXA) scan (bone mineral density and body composition). Blood pressure. • Male-pattern hirsutism and acne scale (female subjects only). • Testicular ultrasound (to detect residual adrenal tissue) (male subjects only). • Menstrual cycle questionnaire (only in fertile female subjects who are not using hormone therapy or intrauterine contraceptive devices). Bone markers: serum osteocalcin, serum bone-specific alkaline phosphatase, serum C-terminal telopeptide, urinary N-terminal telopeptide.

[0116] Patient-reported outcomes that can be evaluated include the 36-Item Short Form Health Survey (SF-36), EQ-5D-5L, Multidimensional Assessment of Fatigue (MAF), Psychological General Well-Being Index (PGWBI), and the Medical Outcomes Study 12-Item Sleep Scale (MOS-12).

[0117] Possible pharmacokinetic criteria to be evaluated include: Blood samples to assess the plasma concentrations of compound A and its metabolites will be collected throughout the study.

[0118] Safety and tolerability will be monitored throughout the above tests and may include the following evaluations: • Adverse events (including glucocorticoid-related events) • Clinical testing • Vital signs • Body weight / Body Mass Index (BMI) and waist circumference • Physical examination 12-lead electrocardiogram · Brief Psychological Symptom Rating Scale (BPRS) • Colombia Suicide Severity Scale (C-SSRS)

[0119] Table 2 summarizes the open-label extension (OLE) treatment duration protocols. [Table 2-1] [Table 2-2]

[0120] The various embodiments described above may be combined to provide further embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications referenced herein and / or enumerated in the application data sheets are incorporated herein by reference in their entirety. Aspects of the above embodiments may be modified if necessary to provide further embodiments by adopting concepts from various patents, applications, and publications.

[0121] These and other modifications may be made to the embodiments described above in light of the detailed description above. In general, the terms used in the following claims should not be construed as limiting the claims to the specific embodiments disclosed herein and herein, but rather as encompassing all conceivable embodiments, along with the entire scope of equivalents to which such claims are granted. Thus, the claims are not limited by this disclosure.

Claims

1. In adult subjects with congenital adrenal hyperplasia (CAH), 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-propa-2-inyl-1,3-thiazole-2-amine, or a pharmaceutically acceptable salt thereof, was used as an adjunct to glucocorticoid therapy: 【Transformation 6】 (Compound A) A method for administering a compound A, the method comprising administering to the subject a first amount of compound A or a pharmaceutically acceptable salt thereof over a first period of time, and subsequently administering to the subject a second amount of compound A or a pharmaceutically acceptable salt thereof over a second period of time, wherein the second amount is equal to q. p. m. about 200 mg of free base of compound A.

2. A method for treating congenital adrenal hyperplasia (CAH) in an adult subject already being treated with glucocorticoid therapy, the method comprising: a first amount of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-propa-2-inyl-1,3-thiazole-2-amine or a pharmaceutically acceptable salt thereof: 【Transformation 7】 (Compound A) A method comprising administering compound A over a first period, and subsequently administering to the subject a second amount of compound A or a pharmaceutically acceptable salt thereof over a second period, wherein the second amount is equal to q. p. m. about 200 mg of free base of compound A.

3. The method according to any one of the claims, wherein the first amount is equal to about 100 mg of free base b, i, and d of compound A.

4. The method according to claim 3, wherein the first period is between one week and one year.

5. The method according to claim 1 or 2, wherein the first amount is equal to q. A. M. about 100 mg of free base of compound A and q. P. M. about 200 mg of free base of compound A.

6. The method according to claim 5, wherein the first period is between one week and one year.

7. The method according to any one of claims 1 to 6, wherein the second period is between one week and one year.

8. The method according to any one of the claims, wherein the glucocorticoid treatment is a daily dose of glucocorticoid administered to the subject.

9. The method according to claim 8, wherein the daily dose of the glucocorticoid is administered once daily.

10. The method according to claim 8, wherein the daily dose of the glucocorticoid is administered through multiple doses.

11. The method according to any one of claims 8 to 10, wherein the glucocorticoid is selected from hydrocortisone, prednisone, methylprednisolone, prednisolone, and dexamethasone, or a combination thereof.

12. The method according to any one of claims 8 to 11, wherein the glucocorticoid is hydrocortisone.

13. The method according to any one of claims 8 to 12, wherein, prior to the administration of an amount equal to approximately 200 mg of free base of compound A, the subject had previously received a target dose of glucocorticoids.

14. The target dose for glucocorticoid treatment is ≤11 mg / m². ２ The method according to claim 13, wherein the amount is the equivalent of hydrocortisone per day.

15. The target dose for glucocorticoid treatment is approximately 8 mg / m². ２ / day ~ approx. 10mg / m ２ The method according to claim 13, wherein the amount is the equivalent of hydrocortisone per day.

16. The target dose for glucocorticoid treatment is approximately 8 mg / m². ２ The method according to claim 13, wherein the amount is the equivalent of hydrocortisone per day.

17. The method according to any one of the claims, wherein, prior to the administration of an amount equal to approximately 200 mg of free base of compound A, the subject showed adequate disease control.

18. The method according to any one of claims 13 to 17, wherein prior to the administration of an amount equal to approximately 200 mg of free base of compound A, the subject had shown adequate disease control and had been administered glucocorticoids at the target dose.

19. The method according to claim 17 or 18, wherein the subjects demonstrated adequate disease control when their androstenedione levels were ≤120% of the subject's baseline or ≤upper normal number (ULN) with respect to the subject's age and sex.

20. The method according to any one of the claims, further comprising monitoring the subject for adequate disease control, wherein if disease control is insufficient and the glucocorticoid treatment is at or above the target dose for the subject, the amount of compound A or a pharmaceutically acceptable salt thereof is adjusted to an amount equal to about 100 mg of compound A free base b. i. d.

21. The method according to any one of claims 1 to 19, further comprising monitoring the subject for adequate disease control, wherein if disease control is insufficient and the glucocorticoid treatment is at or above the target dose for the subject, the amount of compound A or a pharmaceutically acceptable salt thereof is adjusted to an amount equal to q. A. M. about 100 mg of free base of compound A and an amount equal to q. P. M. about 200 mg of free base of compound A.

22. The method according to any one of claims 1 to 19, further comprising monitoring the subject for adequate disease control, wherein if disease control is insufficient and the glucocorticoid treatment is at or exceeds the target dose for the subject, the amount of compound A or a pharmaceutically acceptable salt thereof is adjusted to an amount equal to approximately 200 mg of free base of compound A q. p. m.

23. The method according to any one of claims 20 to 22, wherein the subjects showed inadequate disease control when their androstenedione levels were >120% of the subject's baseline or >upper normal number (ULN) for the subject's age and sex.

24. The target dose for glucocorticoid treatment is ≤11 mg / m². ２ The method according to any one of claims 20 to 22, wherein the amount is the equivalent of hydrocortisone per day.

25. The target dose for glucocorticoid treatment is approximately 8 mg / m². ２ / day ~ approx. 10mg / m ２ The method according to any one of claims 20 to 22, wherein the amount is the equivalent of hydrocortisone per day.

26. The target dose for glucocorticoid treatment is approximately 8 mg / m². ２ The method according to any one of claims 20 to 22, wherein the amount is the equivalent of hydrocortisone per day.

27. The method according to any one of the claims, wherein compound A is a free base.

28. Compound A is administered together with food, according to the method according to any one of the claims.

29. The method according to any one of the claims, wherein the CAH is a classical CAH.

30. The method according to any one of the claims, wherein the CAH is a non-classical CAH.

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