Drug administration plan for clinecelfont to treat congenital adrenal hyperplasia in children

Abstract

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders that result in a deficiency in the enzyme that alters adrenal steroid production due to 21-hydroxylase deficiency, in which cortisol biosynthesis occurs little to no. 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 children 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 / 464,697, filed 8 May 2023, which is incorporated herein by reference in its entirety.

[0002] Technical field This application relates to a method of 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 children with congenital adrenal hyperplasia. [Background technology]

[0003] Background of the present invention Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders that result in an enzyme deficiency that alters adrenal steroid production, caused by a 21-hydroxylase deficiency, leading to a condition in which cortisol biosynthesis occurs little to no. One clinical manifestation of the absence of cortisol is the lack of feedback inhibition of pituitary adrenocorticotropic hormone (ACTH) secretion. Increased ACTH levels lead to adrenal hyperplasia, and the enzyme mutation causes shunting of cortisol precursor steroids into alternative pathways. Most notably, androgen conversion leads to masculinization and other developmental complications in females, and excessive accumulation of ACTH leads to the formation of residual adrenal tumors in the testes in males. Furthermore, since the same enzyme (21-hydroxylase) is used in the pathway of mineralocorticoid biosynthesis, some such patients suffer from aldosterone deficiency, which can lead to dehydration and death due to salt depletion. In the general U.S. population, the prevalence of classical 21-hydroxylase-deficient CAH based on newborn screening has been recorded as 1:10,000 to 1:20,800.

[0004] Children from birth to adolescence, and especially women, are considered the most vulnerable group of CAH sufferers and represent a subgroup of patients with the most unmet medical needs. Excessive androgen production in these young patients leads to precocious puberty and adrenaline, altered skeletal maturation patterns, short stature due to premature growth plate fusion, and marked hirsutism and acne problems. Survival is adequately ensured by steroid replacement strategies based on physiological administration of glucocorticoids (e.g., hydrocortisone) and mineralocorticoids (e.g., fludrocortisone), but these doses are often insufficient to suppress ACTH accumulation and the overproduction of progestogens and androgens (e.g., 17-hydroxyprogesterone [17-OHP], androstenedione, and testosterone). Uncontrolled symptoms of androgen excess significantly impact the daily functioning and development of such patients.

[0005] 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 dosage and duration of steroid use required to suppress ACTH are usually considerably higher than the normal physiological levels used with cortisol replacement alone (similar to patients with Addison's disease). Increased exposure to glucorticoids can lead to iatrogenic Cushing's syndrome, increased cardiovascular risk factors, glucose intolerance, reduced growth rate, and decreased bone mineral density in CAH patients.

[0006] Orally active compounds that block CRF1, such as 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), have been clinically demonstrated to reduce 17-hydroxyprogesterone (17-OHP) and androstenedione levels from baseline in patients with CAH, at levels that are thought to allow for the use of physiologically high doses of glucocorticoids (e.g., hydrocortisone) at lower doses. The structure of compound A is shown below: [ka] [Overview of the project] [Problems that the invention aims to solve]

[0007] There is a significant, unmet need regarding methods for addressing CAH. This disclosure addresses these and other needs, as will be evident from the following disclosures.

[0008] overview 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, may be used as an adjunct to glucocorticoid therapy in children with congenital adrenal hyperplasia (CAH). [ka] A method for administering a subject is provided, comprising the step of administering compound A, or a pharmaceutically acceptable salt thereof, to the subject daily in two doses, a first dose and a second dose, wherein the second dose is greater than the first dose.

[0009] Furthermore, as an adjunct to glucocorticoid therapy in children 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, may be used. [ka] A method for administering a compound A is provided, comprising the steps of administering to a 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 administered in two doses, consisting of a first dose and a second dose, and the second dose is greater than the first dose.

[0010] Furthermore, a method for treating congenital adrenal hyperplasia (CAH) in pediatric subjects already treated with glucocorticoid therapy, wherein the subjects are given 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, in two doses consisting of a first dose and a second dose. [ka] A method is provided which includes the step of administering a daily dose, wherein the second dose is greater than the first dose.

[0011] Also, a method for treating congenital adrenal hyperplasia (CAH) in pediatric subjects already treated with glucocorticoid therapy, comprising administering to the subject a first amount of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazole-2-amine, or a pharmaceutically acceptable salt thereof

Chemical formula

[0012] Furthermore, 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazole-2-amine for use in a method for treating congenital adrenal hyperplasia (CAH) in pediatric subjects already treated with glucocorticoid therapy

Chemical formula

[0013] Furthermore, the compound 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 in the manufacture of a pharmaceutical product for treating congenital adrenal hyperplasia (CAH) in pediatric subjects already treated with glucocorticoid therapy: [ka] or the use of its pharmaceutically acceptable salt, (1) The step of administering to the subject a first amount of compound A, or a pharmaceutically acceptable salt thereof, over a first period of time, (2) The procedure then includes administering to the subject a second amount of compound A, or a pharmaceutically acceptable salt thereof, over a second period of time. The second amount is provided to be administered in two doses, consisting of a first dose and a second dose, wherein the second dose is greater than the first dose.

[0014] These and other aspects of the present invention will become apparent by reference to the following detailed description. For this purpose, various references describing in more detail certain background information, procedures, compounds, and / or compositions are described herein, each incorporated herein in its entirety by reference. [Modes for carrying out the invention]

[0015] Detailed explanation The following description includes certain specific details to provide a full understanding of the various embodiments. However, those skilled in the art will understand that the invention can be carried out without these details. In other examples, well-known structures are not shown or described in detail to avoid unnecessarily ambiguous descriptions of embodiments. Unless the context requires otherwise, throughout this specification and the subsequent claims, the word “comprise” and its variations, e.g., “comprises” and “comprising,” should be interpreted in an open, comprehensive sense, i.e., “including, but not limited to.” Furthermore, the headings presented herein are for convenience only and do not describe the scope or meaning of the claimed invention.

[0016] Throughout this specification, any reference to “one embodiment,” “an embodiment,” “some embodiment,” or “a particular embodiment” means that the specific features, structures, or characteristics described in relation to the embodiment are included in at least one embodiment. Therefore, not all occurrences of the phrases “in one embodiment,” “in some embodiment,” “in some embodiment,” or “in a particular embodiment” throughout this specification necessarily refer to the same embodiment. Furthermore, specific features, structures, or characteristics may be combined in one or more embodiments in any preferred manner.

[0017] Furthermore, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly indicates otherwise.

[0018] Where 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 WO87 / 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 for the preparation and selection of the pharmaceutical salts of 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. 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, and 1,2-ethanolic acid. These include 2-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphor acid, camphor sulfonic 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, and the like. In some embodiments, "pharmaceutically acceptable salt" refers to a base addition salt with an inorganic or organic base.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, and phosphates. Organic bases that can be used to prepare salts include, but are not limited to, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, specifically including, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.

[0019] As used herein, “approximately” means ±20% of the stated value, and more specifically, includes values ​​of ±10%, ±5%, ±2%, and ±1% of the stated value.

[0020] As used herein, “baseline” refers to the period immediately preceding the initiation of treatment. The patient’s condition immediately preceding the initiation of treatment may be referred to as the patient’s baseline condition.

[0021] As used herein, “adjusting administration,” “altering administration,” “adjusting dosing,” and “altering dosing” are all equivalent and mean gradually reducing, decreasing, or increasing the dose of a substance, discontinuing the administration of a substance to a patient, or using a different active agent in place of that substance.

[0022] As used herein, “administering to a patient” means the process of introducing a composition or dosage form to a patient via an introduction method approved in the art.

[0023] As used herein, "bid" refers to two doses per day. In some embodiments, the two daily doses are spaced approximately 12 hours apart.

[0024] As used herein, “co-administer” and its variations mean administering at least two drugs to a patient consecutively, simultaneously, or subsequently, in close proximity to each other in time (for example, on the same day, or over a period of one week or 30 days, or in close enough proximity that each of the 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 to as “concomitant” administration or its variations.

[0025] 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 in which cortisol biosynthesis is little to no. One clinical manifestation of the absence of cortisol is the lack of feedback inhibition in the CRF, which leads to dysregulation of the HPA axis. The most common form of the disorder, 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 leads to the conversion of cortisol precursor steroids into excessive androgen (e.g., 17-hydroxyprogesterone, androstenedione, and testosterone) products. These mutations can range from complete deficiency of the enzyme activity required for cortisol synthesis in the adrenal cortex to various partial deficiencies, which result in disease severity that is a direct consequence of the specific mutation. This consecutive 21-hydroxylase deficiency is broadly classified into salt-wasting and simple masculinizing forms, and has been categorized into classical (or classical) CAH and a less severe form known as non-classical (or non-classical) CAH (NCCAH) or "late-onset" CAH, which is usually diagnosed in late childhood or early adolescence. Patients with non-classical CAH are either homozygous or compound heterozygous, often with the classical CAH allele. These patients have sufficient enzyme activity (>20-50% of normal), so they do not have salt-wasting or cortisol deficiency, have normal genitalia at birth, and many remain asymptomatic throughout their lives. In the 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 the 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 the simple masculinizing form, in which cortisol synthesis is impaired, but enzyme activity is sufficient to adequately produce aldosterone.

[0026] As used herein, the term “disorder” is generally synonymous with and intended to be interchangeable with the terms “disease,” “syndrome,” and “condition” (as in a medical condition), all of which reflect any abnormal condition of one of the body or parts of a human or animal that impairs normal function and typically presents with prominent signs and symptoms.

[0027] As used herein, “dose” means the measured amount of the active agent that a patient takes in one sitting. In certain embodiments where the active agent is not compound A free base, the amount is the molar equivalent to the corresponding amount of compound A free base. For example, in many cases the drug is packaged in a pharmaceutically acceptable salt form, and the dose in relation to potency refers to the mass of the molar equivalent of compound A, which is the corresponding free base.

[0028] As used herein, “dosage regimen” means the initial dose of the active agent taken by the patient and any subsequent doses of the active agent taken by the patient at intervals (times or symptomatically), 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 may be in the range of approximately 20 mg to 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 may 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.

[0029] As used herein, “dosage” refers to a prescribed dose, a specific amount, number of times, and frequency of doses over a specific period of time.

[0030] Where used herein, “effective dose” and “therapeutic dose” of a drug, compound, pharmacokinetic, composition, or combination are amounts that are non-toxic and effective in producing some desired therapeutic effect when administered to a subject or patient (e.g., a human subject or patient). The exact therapeutic dose for a subject may depend, for example, on the subject’s size and health condition, the nature and degree of the condition, the therapeutic agent or combination of therapeutic agents selected for administration, and other variable factors known to those skilled in the art. The effective dose for a given situation is determined by conventional experimentation and is within the scope of clinician judgment.

[0031] As used herein, “informing” means referring to or providing publicly available material, for example, providing the user with the publicly available material; or presenting information orally, for example, by a presentation at a seminar, conference, or other educational presentation, by a conversation between a pharmaceutical sales representative and a healthcare professional, or by a conversation between a healthcare professional and a patient; or showing the user the information intended for the purpose of understanding.

[0032] As used herein, “display” means any written, printed, graphic, electronic, linguistic, or illustrative means of communication present on or accompanying any label or other means of communication present on or accompanying any medicinal product or dosage form.

[0033] As used herein, “healthcare professional” means a person in the healthcare field who may need or have access to information about an active drug, including its dosage form, including information about safety, efficacy, administration, or pharmacokinetics. Examples of healthcare professionals include physicians, pharmacists, physician assistants, nurses, support staff, caregivers (which may include family members or guardians), emergency medical personnel, and veterinarians.

[0034] As used herein, “Pharmacotherapy Guides” means other applicable regulations, including FDA-approved patient labeling of a medicinal product in accordance with the specifications set forth in 21 CFR 208, and information on how patients should use the medicinal product safely. Pharmacotherapy Guides are scientifically accurate and based on and consistent with the approved physician labeling for that medicinal product under 21 CFR 201.57, although their wording does not need to be identical to the corresponding section of the approved labeling. Pharmacotherapy Guides are typically available for medicinal products with specific risk management information.

[0035] As used herein, “patient,” “individual,” or “subject” means a mammal, including humans, that is in need of treatment, and generally refers to the recipient of such treatment.

[0036] As used herein, “Patient Information Sheet” means information about how a patient should use a medical product that is part of an FDA-approved label. It is an extension of a medical label that provides consumer-oriented information about a medical product in language used by the general public, which may be distributed to a patient when the product is administered, and may, for example, describe the benefits, risks, and how to recognize the risks, dosage, or administration.

[0037] As used herein, “children” refers to subjects who are about 17 years of age or younger (i.e., at birth). In some embodiments, children are adolescents, i.e., subjects who are about 12 to about 17 years of age. In some embodiments, children are children, i.e., subjects who are about 2 years of age or younger but less than 12 years of age. In some embodiments, children are infants, i.e., subjects who are about 1 month of age or younger but less than 2 years of age. In some embodiments, children are newborns, i.e., subjects who are about 1 month of age or younger (i.e., at birth).

[0038] As used herein, “pharmaceutically acceptable” means a material that is not biologically or otherwise undesirable, i.e., that can be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interactions in a harmful manner with any of the other components of the composition in which it is contained. When the term “pharmaceutically acceptable” is used to refer to a pharmaceutical carrier or excipient, it implies that the carrier or excipient meets the required standards of toxicology and manufacturing testing, or that it is included in the Inactive Ingredient Guide provided by the U.S. Food and Drug Administration. “Pharmacologically active” (or “active”) derivative or analog means a derivative or analog that has the same type of pharmacological activity as the parent compound and is approximately equivalent in degree.

[0039] As used herein, the terms “pharmaceutically acceptable carrier” or “pharmaceutically acceptable additive” include all biologically or otherwise undesirable solvents, co-solvents, complexing agents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents and absorption retarders, etc. The use of such media and pharmaceuticals relating to pharmaceutically active substances is well known in the art. Any conventional media or agent is intended for use in therapeutic formulations unless it is incompatible with the active ingredient. Co-active ingredients may also be incorporated into these formulations. Furthermore, various additives may be included, such as those commonly used in the art. These compounds and other such compounds are described in the literature, e.g., Merck Index, Merck & Company, Rahway, NJ. Considerations for including various components in pharmaceutical compositions are described, for example, in Gilman et al. (Eds.) (2010); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 12th Ed., The McGraw-Hill Companies.

[0040] As used herein, “product” or “pharmaceutical product” means the dosage form of the active agent, the published materials, and, if applicable, the packaging.

[0041] As used herein, “product information leaflet” means the physician’s labeling (prescription information) for a pharmaceutical product, the patient’s information leaflet for that pharmaceutical product, or the pharmacotherapy guide for that pharmaceutical product.

[0042] Where used herein, “medical labeling” or “prescription information” means the official description of a pharmaceutical product approved by a regulatory authority (e.g., the FDA or EMEA) that controls the sale and distribution of pharmaceutical products on the market, which includes a summary of essential scientific information necessary 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.

[0043] As used herein, “Published Materials” means any media that provides information, including printed, audio, visual, or electronic media such as flyers, advertisements, product instructions, printed notices, internet websites, internet web pages, internet pop-up windows, radio or television broadcasts, compact discs, DVDs, audio recordings, or other recording media or electronic media.

[0044] As used herein, "qAM" means once a day in the morning.

[0045] As used herein, "qPM" means once daily in the evening.

[0046] Where used herein, “risk” means the probability or likelihood of an adverse reaction, injury, or other undesirable outcome arising from a medical procedure. “Acceptable risk” means the measure of the risk of harm, injury, or disease arising from a medical procedure that an individual or group would consider acceptable. Whether a risk is “acceptable” depends on the benefits that the individual or group understands they may gain in exchange for taking that risk, whether they are willing to accept any scientific or other advice offered about the magnitude of that risk, and many other factors (both political and social). The “acceptable risk” of an adverse reaction means that the probability of that adverse reaction occurring is small, or the consequences are very minor, or the benefits of the active ingredient (whether understood or real) are very large, so that an individual or group in society is willing to take or accept the risk that the adverse reaction may occur. An “unacceptable risk” of an adverse reaction means that an individual or group in society is unwilling to take or comply with the risk of that adverse reaction occurring, given the importance placed on the probability of that adverse reaction occurring, the consequences of that adverse reaction, and the benefits (whether understood or actual) of the active ingredient. “Risk present” means a situation or condition represented by a high level of risk or susceptibility. Risk assessment consists of identifying and characterizing the nature, frequency, and severity of risks associated with product use.

[0047] As used herein, “safety” means the incidence or severity of adverse events associated with the administration of the active agent, including adverse effects associated with patient-related factors (e.g., age, sex, ethnicity, race, target disease, renal or hepatic abnormalities, 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).

[0048] 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, may be used as an adjunct to glucocorticoid therapy in children with congenital adrenal hyperplasia (CAH). [ka] A method for administering a subject is provided, comprising the step of administering compound A, or a pharmaceutically acceptable salt thereof, to the subject daily in two doses, a first dose and a second dose, wherein the second dose is greater than the first dose.

[0049] Furthermore, a method for treating congenital adrenal hyperplasia (CAH) in pediatric subjects already treated with glucocorticoid therapy, wherein the subjects are given 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, in two doses consisting of a first dose and a second dose. [ka] A method is provided which includes the step of administering a daily dose, wherein the second dose is greater than the first dose.

[0050] In some embodiments, administration of compound A, or a pharmaceutically acceptable salt thereof, refers to administration of compound A, or a pharmaceutically acceptable salt thereof, with food. In some embodiments, compound A, or a pharmaceutically acceptable salt thereof, is administered with food. In some embodiments, administration of compound A, or a pharmaceutically acceptable salt thereof, with food, shows a positive food effect. In some embodiments, when compound A, or a pharmaceutically acceptable salt thereof, is administered to a fed subject, an increased or positive food effect is observed. In some embodiments, administration of compound A, or a pharmaceutically acceptable salt thereof, results in an increased or positive food effect, thereby, compared to a fasted state, when orally administered to a fed state, C max An increase in AUC is observed.

[0051] In some embodiments, administering compound A, or a pharmaceutically acceptable salt thereof, refers to administering compound A, or a pharmaceutically acceptable salt thereof, along with the subject's breakfast and dinner.

[0052] In some embodiments, the subject's weight is greater than or equal to approximately 55 kg.

[0053] In some embodiments, the first dose is equivalent to approximately 100 mg qAM of free compound A base. In some embodiments, the first dose is equivalent to approximately 0 mg qAM of free compound A base.

[0054] In some embodiments, the second dose is equivalent to approximately 200 mg qPM of free compound A base. In some embodiments, the second dose is equivalent to approximately 300 mg qPM of free compound A base.

[0055] In some embodiments, the subject's body weight is greater than or equal to approximately 55 kg, and the first dose is equivalent to approximately 100 mg qAM of free compound A base. In some embodiments, the subject's body weight is greater than or equal to approximately 55 kg, and the first dose is equivalent to approximately 0 mg qAM of free compound A base. In some embodiments, the subject's body weight is greater than or equal to approximately 55 kg, and the second dose is equivalent to approximately 200 mg qPM of free compound A base. In some embodiments, the subject's body weight is greater than or equal to approximately 55 kg, and the second dose is equivalent to approximately 300 mg qPM of free compound A base. In some embodiments, the subject's body weight is greater than or equal to approximately 55 kg, and the first dose is equivalent to approximately 100 mg qAM of free compound A base, and the second dose is equivalent to approximately 200 mg qPM of free compound A base. In some embodiments, the subject's body weight is greater than or equal to approximately 55 kg, and the first dose is equivalent to approximately 0 mg qAM of free compound A, while the second dose is equivalent to approximately 200 mg qPM of free compound A. In some embodiments, the subject's body weight is greater than or equal to approximately 55 kg, and the first dose is equivalent to approximately 0 mg qAM of free compound A, while the second dose is equivalent to approximately 300 mg qPM of free compound A.

[0056] In some embodiments, subjects weighing more than or equal to approximately 55 kg were administered a first dose equivalent to approximately 0 mg qAM of compound A free base and a second dose equivalent to approximately 200 mg qPM of compound A free base, demonstrating adequate disease management, and were administered a first dose equivalent to approximately 100 mg qAM of compound A free base and a second dose equivalent to approximately 200 mg qPM of compound A free base. In some embodiments, subjects weighing more than or equal to approximately 55 kg were administered a first dose equivalent to approximately 100 mg qAM of compound A free base and a second dose equivalent to approximately 200 mg qPM of compound A free base, as well as a target dose of glucocorticoids, demonstrating adequate disease management.

[0057] In some embodiments, subjects weighing more than or equal to approximately 55 kg were administered a first dose equivalent to approximately 0 mg qAM of compound A free base and a second dose equivalent to approximately 300 mg qPM of compound A free base, demonstrating adequate disease management, and were administered a first dose equivalent to approximately 100 mg qAM of compound A free base and a second dose equivalent to approximately 200 mg qPM of compound A free base. In some embodiments, subjects weighing more than or equal to approximately 55 kg were administered a first dose equivalent to approximately 100 mg qAM of compound A free base and a second dose equivalent to approximately 300 mg qPM of compound A free base, and were administered glucocorticoids at a target dose, demonstrating adequate disease management.

[0058] In some embodiments, subjects demonstrated adequate disease management when their androstenedione levels were ≤120% of the subject's baseline or ≤upper normal (ULN) for the subject's age and sex.

[0059] In some embodiments, the subjects demonstrated appropriate disease management in the opinion of the principal investigator.

[0060] In some embodiments, subjects weighing more than or equal to approximately 55 kg were administered compound A, or a pharmaceutically acceptable salt thereof, in two doses consisting of a first dose and a second dose, where the second dose was greater than the first dose, over a first period. The subjects were administered compound A, or a pharmaceutically acceptable salt thereof, as two daily doses, each containing an equal amount of compound A free base. In some embodiments, each dose is equivalent to approximately 100 mg of compound A free base.

[0061] In some embodiments, the subjects weigh approximately 20 kg to 55 kg.

[0062] In some embodiments, the first dose is equivalent to approximately 50 mg of free compound A base. In some embodiments, the first dose is equivalent to approximately 0 mg of free compound A base.

[0063] In some embodiments, the second dose is equivalent to approximately 100 mg of free compound A base. In some embodiments, the second dose is equivalent to approximately 150 mg of free compound A base.

[0064] In some embodiments, the subject weighs approximately 20 kg to 55 kg, and the first dose is equivalent to approximately 50 mg of free compound A base. In some embodiments, the subject weighs approximately 20 kg to 55 kg, and the first dose is equivalent to approximately 0 mg of free compound A base. In some embodiments, the subject weighs approximately 20 kg to 55 kg, and the second dose is equivalent to approximately 100 mg of free compound A base. In some embodiments, the subject weighs approximately 20 kg to 55 kg, and the second dose is equivalent to approximately 150 mg of free compound A base. In some embodiments, the subject weighs approximately 20 kg to 55 kg, and the first dose is equivalent to approximately 50 mg of free compound A base, while the second dose is equivalent to approximately 100 mg of free compound A base. In some embodiments, the subjects weigh approximately 20 kg to 55 kg, the first dose is equivalent to approximately 0 mg of free compound A base, and the second dose is equivalent to approximately 100 mg of free compound A base. In some embodiments, the subjects weigh approximately 20 kg to 55 kg, the first dose is equivalent to approximately 0 mg of free compound A base, and the second dose is equivalent to approximately 150 mg of free compound A base.

[0065] In some embodiments, subjects weighing approximately 20 kg to 55 kg had demonstrated adequate disease management and were administered a first dose equivalent to approximately 50 mg qAM and a second dose equivalent to approximately 100 mg qPM of compound A free base, prior to the administration of a first dose equivalent to approximately 0 mg qAM of compound A free base and a second dose equivalent to approximately 100 mg qPM of compound A free base. In some embodiments, subjects weighing approximately 20 kg to 55 kg had demonstrated adequate disease management and were administered a first dose equivalent to approximately 50 mg qAM and a second dose equivalent to approximately 100 mg qPM of compound A free base, along with a target dose of glucocorticoids, prior to the step of administering a first dose equivalent to approximately 0 mg qAM and a second dose equivalent to approximately 100 mg qPM of compound A free base.

[0066] In some embodiments, subjects weighing approximately 20 kg to 55 kg had demonstrated adequate disease management and were administered a first dose equivalent to approximately 50 mg qAM and a second dose equivalent to approximately 100 mg qPM of compound A free base, as well as a target dose of glucocorticoids, before administering a first dose equivalent to approximately 0 mg qAM and a second dose equivalent to approximately 150 mg qPM of compound A free base. In some embodiments, subjects weighing approximately 20 kg to 55 kg had demonstrated adequate disease management and were administered a first dose equivalent to approximately 50 mg qAM and a second dose equivalent to approximately 100 mg qPM of compound A free base, as well as a target dose of glucocorticoids, before administering a first dose equivalent to approximately 0 mg qAM and a second dose equivalent to approximately 150 mg qPM of compound A free base.

[0067] In some embodiments, subjects demonstrated adequate disease management when their androstenedione levels were ≤120% of the subject's baseline or ≤upper normal (ULN) for the subject's age and sex.

[0068] In some embodiments, the subjects demonstrated appropriate disease management in the opinion of the principal investigator.

[0069] In some embodiments, subjects weighing approximately 20 kg to 55 kg were administered compound A or a pharmaceutically acceptable salt thereof in two doses, where the second dose was greater than the first dose, over a first period. Prior to this administration, the subjects were administered compound A or a pharmaceutically acceptable salt thereof as two daily doses, each containing an equal amount of free compound A base. In some embodiments, each dose is equivalent to approximately 50 mg of free compound A base.

[0070] In some embodiments, the subject weighs approximately 10 kg to 20 kg.

[0071] In some embodiments, the first dose is equivalent to approximately 25 mg of free compound A base. In some embodiments, the first dose is equivalent to approximately 0 mg of free compound A base.

[0072] In some embodiments, the second dose is equivalent to approximately 50 mg of free compound A base. In some embodiments, the second dose is equivalent to approximately 75 mg of free compound A base.

[0073] In some embodiments, the subject weighs approximately 10 kg to 20 kg, and the first dose is equivalent to approximately 25 mg of free compound A base. In some embodiments, the subject weighs approximately 10 kg to 20 kg, and the first dose is equivalent to approximately 0 mg of free compound A base. In some embodiments, the subject weighs approximately 10 kg to 20 kg, and the second dose is equivalent to approximately 50 mg of free compound A base. In some embodiments, the subject weighs approximately 10 kg to 20 kg, and the second dose is equivalent to approximately 75 mg of free compound A base. In some embodiments, the subject weighs approximately 10 kg to 20 kg, and the first dose is equivalent to approximately 25 mg of free compound A base, while the second dose is equivalent to approximately 50 mg of free compound A base. In some embodiments, the subject weighs approximately 10 kg to 20 kg, the first dose is equivalent to approximately 0 mg of free compound A base, and the second dose is equivalent to approximately 50 mg of free compound A base. In some embodiments, the subject weighs approximately 10 kg to 20 kg, the first dose is equivalent to approximately 0 mg of free compound A base, and the second dose is equivalent to approximately 75 mg of free compound A base.

[0074] In some embodiments, subjects weighing approximately 10 kg to 20 kg had demonstrated adequate disease management and were administered a first dose equivalent to approximately 25 mg qAM and a second dose equivalent to approximately 50 mg qPM of compound A free base, as well as a target dose of glucocorticoids, before administering a first dose equivalent to approximately 0 mg qAM and a second dose equivalent to approximately 50 mg qPM of compound A free base.

[0075] In some embodiments, subjects weighing approximately 10 kg to 20 kg had demonstrated adequate disease management and were administered a first dose equivalent to approximately 25 mg qAM and a second dose equivalent to approximately 50 mg qPM of compound A free base, as well as a target dose of glucocorticoids, before administering a first dose equivalent to approximately 0 mg qAM and a second dose equivalent to approximately 75 mg qPM of compound A free base.

[0076] In some embodiments, subjects demonstrated adequate disease management when their androstenedione levels were ≤120% of the subject's baseline or ≤upper normal (ULN) for the subject's age and sex.

[0077] In some embodiments, the subjects demonstrated appropriate disease management in the opinion of the principal investigator.

[0078] In some embodiments, subjects weighing approximately 10 kg to 20 kg were administered two doses of compound A or a pharmaceutically acceptable salt thereof, where the second dose was greater than the first dose, over a first period. Prior to this administration, subjects were administered compound A or a pharmaceutically acceptable salt thereof as two daily doses, each containing an equal amount of compound A free base. In some embodiments, each dose is equivalent to approximately 25 mg of compound A free base.

[0079] In some embodiments, the method further includes adjusting for a lost qAM dose. In some embodiments, the method further includes adjusting for a lost qPM dose. In some embodiments, in the event of a lost dose, the amount of the lost dose is administered as soon as possible, even immediately before the next scheduled dose, and then the normal dosing schedule is resumed.

[0080] Furthermore, as an adjunct to glucocorticoid therapy in children 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, may be used. [ka] A method for administering compound A is provided, comprising the steps of administering to a 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 administered in two doses, consisting of a first dose and a second dose, and the second dose is greater than the first dose. In some embodiments, the method further comprises subsequently administering to the subject a third amount of compound A, or a pharmaceutically acceptable salt thereof, over a third period of time, wherein the third amount is administered in a qPM dose.

[0081] Furthermore, a method for treating congenital adrenal hyperplasia (CAH) in pediatric subjects already treated with glucocorticoid therapy, wherein the subject is given 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. [ka] A method is provided comprising the steps of administering a subject 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 administered in two doses, consisting of a first dose and a second dose, with the second dose being greater than the first dose. In some embodiments, the method further comprises the step of administering to the subject a third amount of compound A, or a pharmaceutically acceptable salt thereof, over a third period, wherein the third amount is administered in a qPM dose.

[0082] Furthermore, the compound 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 is for use in a method of treating congenital adrenal hyperplasia (CAH) in pediatric subjects already treated with glucocorticoid therapy: [ka] or a pharmaceutically acceptable salt thereof, the method is (1) The step of administering to the subject a first amount of compound A, or a pharmaceutically acceptable salt thereof, over a first period of time, (2) The procedure then includes administering to the subject a second amount of compound A, or a pharmaceutically acceptable salt thereof, over a second period of time. The compound or a pharmaceutically acceptable salt thereof is provided, wherein the second amount is administered in two doses, consisting of a first dose and a second dose, the second dose being greater than the first dose. In some embodiments, the method further comprises (3) subsequently administering to a subject a third amount of compound A or a pharmaceutically acceptable salt thereof over a third period, wherein the third amount is administered in a qPM dose.

[0083] Furthermore, the compound 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 in the manufacture of a pharmaceutical product for treating congenital adrenal hyperplasia (CAH) in pediatric subjects already treated with glucocorticoid therapy: [ka] or the use of its pharmaceutically acceptable salt, (1) The step of administering to the subject a first amount of compound A, or a pharmaceutically acceptable salt thereof, over a first period of time, (2) The procedure then includes administering to the subject a second amount of compound A, or a pharmaceutically acceptable salt thereof, over a second period of time. A method of use is provided in which the second amount is administered in two doses, consisting of a first dose and a second dose, wherein the second dose is greater than the first dose. In some embodiments, the method further comprises (3) administering to the subject a third amount of compound A, or a pharmaceutically acceptable salt thereof, over a third period, wherein the third amount is administered in a qPM dose.

[0084] In some embodiments, administration of compound A, or a pharmaceutically acceptable salt thereof, refers to administration of compound A, or a pharmaceutically acceptable salt thereof, with food. In some embodiments, administration of compound A, or a pharmaceutically acceptable salt thereof, with food exhibits a positive food effect. In some embodiments, when compound A, or a pharmaceutically acceptable salt thereof, is administered to a fed subject, an increased or positive food effect is observed. In some embodiments, administration of compound A, or a pharmaceutically acceptable salt thereof, results in an increased or positive food effect, thereby, when orally administered to a fed state, compared to a fasted state, C max An increase in AUC is observed.

[0085] In some embodiments, administering compound A, or a pharmaceutically acceptable salt thereof, refers to administering compound A, or a pharmaceutically acceptable salt thereof, along with the subject's breakfast and dinner.

[0086] In some embodiments, the subject weighs more than or equal to approximately 55 kg.

[0087] In some embodiments, the first amount is equivalent to approximately 100 mg bid of free base of compound A. In some embodiments, the first amount is equivalent to approximately 100 mg qAM of free base of compound A and approximately 100 mg qPM of free base of compound A.

[0088] In some embodiments, the second amount is equivalent to approximately 100 mg qAM of free compound A and qPM equivalent to approximately 200 mg of free compound A. In some embodiments, the third amount is equivalent to approximately 200 mg qPM of free compound A. In some embodiments, the third amount is equivalent to approximately 300 mg qPM of free compound A.

[0089] In some embodiments, the first period is approximately one week to approximately one year.

[0090] In some embodiments, the second period is at least about one week.

[0091] In some embodiments, the third period is at least about one week.

[0092] In some embodiments, the subjects weigh approximately 20 kg to 55 kg.

[0093] In some embodiments, the first amount is equivalent to approximately 50 mg bid of free base of compound A. In some embodiments, the first amount is equivalent to approximately 50 mg qAM of free base of compound A and approximately 50 mg qPM of free base of compound A.

[0094] In some embodiments, the second amount is equivalent to approximately 50 mg qAM of free compound A base and approximately 100 mg qPM of free compound A base.

[0095] In some embodiments, the third amount is equivalent to approximately 100 mg qPM of free base of compound A. In some embodiments, the third amount is equivalent to approximately 150 mg qPM of free base of compound A.

[0096] In some embodiments, the first period is approximately one week to approximately one year.

[0097] In some embodiments, the second period is at least about one week.

[0098] In some embodiments, the third period is at least about one week.

[0099] In some embodiments, the subject weighs approximately 10 kg to 20 kg.

[0100] In some embodiments, the first amount is equivalent to approximately 25 mg bid of free base of compound A. In some embodiments, the first amount is equivalent to approximately 25 mg qAM of free base of compound A and approximately 25 mg qPM of free base of compound A.

[0101] In some embodiments, the second amount is equivalent to approximately 25 mg qAM of free compound A base and approximately 50 mg qPM of free compound A base.

[0102] In some embodiments, the third amount is equivalent to approximately 50 mg qPM of free compound A base. In some embodiments, the third amount is equivalent to approximately 75 mg qPM of free compound A base.

[0103] In some embodiments, the first period is approximately one week to approximately one year.

[0104] In some embodiments, the second period is at least about one week.

[0105] In some embodiments, the third period is at least about one week.

[0106] In some embodiments, the first period is between one week and one year. In some embodiments, the first period is between approximately one week and approximately 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 greater than six months. In some embodiments, the first period is approximately six months. In some embodiments, the first period is at least one year. In some embodiments, the first period is greater than one year. In some embodiments, the first period is approximately one year.

[0107] In some embodiments, the second period is at least about one week. In some embodiments, the second period is between one week and one year. In some embodiments, the second period is between about one week and about 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 more 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 less than one year. In some embodiments, the second period is about one year. In some embodiments, the third period is at least about one week. In some embodiments, the third period is between one week and one year. In some embodiments, the third period is between about one week and about one year. In some embodiments, the third period is at least six months. In some embodiments, the third period is less than six months. In some embodiments, the third period is longer than 6 months. In some embodiments, the third period is about 6 months. In some embodiments, the third period is at least 1 year. In some embodiments, the third period is greater than 1 year. In some embodiments, the third period is less than 1 year. In some embodiments, the third period is about 1 year.

[0108] In some embodiments, the second period begins immediately after the end of the first period. In some embodiments, the second period begins within one day after the end of the first period. In some embodiments, the second period begins within one week after the end of the first period. In some embodiments, the second period begins within one month after the end of the first period. In some embodiments, the second period begins within six months after the end of the first period. In some embodiments, the second period begins approximately one day after the end of the first period. In some embodiments, the second period begins approximately one week after the end of the first period. In some embodiments, the second period begins approximately one month after the end of the first period. In some embodiments, the second period begins approximately six months after the end of the first period.

[0109] In some embodiments, the third period begins immediately after the end of the second period. In some embodiments, the third period begins within one day after the end of the second period. In some embodiments, the third period begins within one week after the end of the second period. In some embodiments, the third period begins within one month after the end of the second period. In some embodiments, the third period begins within six months after the end of the second period. In some embodiments, the third period begins approximately one day after the end of the second period. In some embodiments, the third period begins approximately one week after the end of the second period. In some embodiments, the third period begins approximately one month after the end of the second period. In some embodiments, the third period begins approximately six months after the end of the second period.

[0110] In some embodiments, the method further includes adjusting for a lost qAM dose. In some embodiments, the method further includes adjusting for a lost qPM dose. In some embodiments, in the event of a lost dose, the amount of the lost dose is administered as soon as possible, even immediately before the next scheduled dose, and then the normal dosing schedule is resumed.

[0111] In some embodiments, glucocorticoid therapy is defined as the daily dose of glucocorticoid administered to the subject.

[0112] In some embodiments, the daily dose of glucocorticoids is administered once or multiple times daily.

[0113] In some embodiments, the glucocorticoid is selected from hydrocortisone, prednisone, methylprednisolone, prednisolone, dexamethasone, and fludrocortisone, or a combination thereof. In some embodiments, the glucocorticoid is selected from hydrocortisone, prednisone, methylprednisolone, prednisolone, and dexamethasone, or a combination thereof. In some embodiments, the glucocorticoid is hydrocortisone. In some embodiments, the glucocorticoid is prednisone. In some embodiments, the glucocorticoid is methylprednisolone. In some embodiments, the glucocorticoid is prednisolone. In some embodiments, the glucocorticoid is dexamethasone. In some embodiments, the glucocorticoid is fludrocortisone.

[0114] In some embodiments, prior to administration of compound A, or a pharmaceutically acceptable salt thereof, the subject had received a target dose of glucocorticoids.

[0115] In some embodiments, the subject had received a target dose of glucocorticoids prior to the step of administering a second amount of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject had received a target dose of glucocorticoids prior to the step of administering a second amount of compound A, or a pharmaceutically acceptable salt thereof, over a second period.

[0116] In some embodiments, the subject had received a target dose of glucocorticoids prior to the step of administering a third amount of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject had received a target dose of glucocorticoids prior to the step of administering a third amount of compound A, or a pharmaceutically acceptable salt thereof, over a third period.

[0117] In some embodiments, the target dose of glucocorticoid treatment is ≤11 mg / m². 2 This is per day (hydrocortisone equivalent).

[0118] In some embodiments, the target dose of glucocorticoid treatment is approximately 8 mg / m². 2 / day~about 10mg / m 2 This is per day (hydrocortisone equivalent).

[0119] In some embodiments, the target dose of glucocorticoid treatment is approximately 8 mg / m². 2 This is per day (hydrocortisone equivalent).

[0120] In some embodiments, the glucocorticoid is hydrocortisone. In some embodiments, the glucocorticoid is methylprednisolone, and a hydrocortisone dose equivalent conversion factor of approximately 4 is used. In some embodiments, the glucocorticoid is prednisolone, and a hydrocortisone dose equivalent conversion factor of approximately 4 is used. In some embodiments, the glucocorticoid is prednisone, and a hydrocortisone dose equivalent conversion factor of approximately 4 is used. In some embodiments, the glucocorticoid is methylprednisolone, and a hydrocortisone dose equivalent conversion factor of approximately 5 is used. In some embodiments, the glucocorticoid is prednisolone, and a hydrocortisone dose equivalent conversion factor of approximately 5 is used. In some embodiments, the glucocorticoid is prednisone, and a hydrocortisone dose equivalent conversion factor of approximately 5 is used. In some embodiments, the glucocorticoid is dexamethasone, and a hydrocortisone dose equivalent conversion factor of approximately 26 to 80 is used. In some embodiments, the glucocorticoid is dexamethasone, and a hydrocortisone dose equivalent conversion factor of approximately 60 is used. In some embodiments, the glucocorticoid is dexamethasone, and a hydrocortisone dose equivalent conversion factor of approximately 80 is used.

[0121] In some embodiments, the subjects demonstrated adequate disease control prior to the step of administering compound A, or a pharmaceutically acceptable salt thereof.

[0122] In some embodiments, the subject had insufficient efficacy before the step of administering a second amount of compound A, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject had insufficient efficacy before the step of administering a second amount of compound A, or a pharmaceutically acceptable salt thereof, over a second period.

[0123] In some embodiments, the subjects demonstrated adequate disease control prior to the step of administering a third amount of compound A, or a pharmaceutically acceptable salt thereof.

[0124] In some embodiments, prior to the step of administering compound A, or a pharmaceutically acceptable salt thereof, the subjects had demonstrated adequate disease control and had been administered glucocorticoids at a target dose.

[0125] In some embodiments, prior to the step of administering a second amount of compound A, or a pharmaceutically acceptable salt thereof, the subject had insufficient efficacy and had been administered a target dose of glucocorticoids. In some embodiments, prior to the step of administering a second amount of compound A, or a pharmaceutically acceptable salt thereof over a second period, the subject had insufficient efficacy and had been administered a target dose of glucocorticoids.

[0126] In some embodiments, prior to the step of administering a third amount of compound A, or a pharmaceutically acceptable salt thereof, the subject had demonstrated adequate disease control and had been administered a target dose of glucocorticoids.

[0127] In some embodiments, subjects demonstrated adequate disease management when their androstenedione levels were ≤120% of the subject's baseline or ≤upper normal (ULN) for the subject's age and sex.

[0128] In some embodiments, subjects were sufficiently effective if their androstenedione levels were ≤120% of the subject's baseline or ≤upper normal number (ULN) for the subject's age and sex.

[0129] In some embodiments, the subjects demonstrated adequate disease management in the opinion of the principal investigator. In some embodiments, the subjects had sufficient efficacy in the opinion of the knowledge-responsible investigator. In some embodiments, the subjects demonstrated adequate disease management in the opinion of the prescriber or healthcare professional. In some embodiments, the subjects had sufficient efficacy in the opinion of the prescriber or healthcare professional.

[0130] In some embodiments, the method further includes monitoring the subject for adequate disease control and adjusting the amount of compound A or a pharmaceutically acceptable salt thereof if disease control is insufficient and glucocorticoid therapy is at or above the target dose for the subject.

[0131] In some embodiments, subjects demonstrated inadequate disease control when their androstenedione levels were >120% of the subject's baseline or >upper normal (ULN) for the subject's age and sex.

[0132] In some embodiments, subjects exhibited insufficient efficacy if their androstenedione levels were >120% of the subject's baseline or >upper normal (ULN) for the subject's age and sex.

[0133] In some embodiments, the subjects demonstrated inadequate disease control in the opinion of the principal investigator. In some embodiments, the subjects had inadequate efficacy in the opinion of the knowledge-based investigator. In some embodiments, the subjects demonstrated inadequate disease control in the opinion of the prescribing physician or healthcare professional. In some embodiments, the subjects had inadequate efficacy in the opinion of the prescribing physician or healthcare professional.

[0134] In some embodiments, compound A, or a pharmaceutically acceptable salt thereof, is a pharmaceutically acceptable salt of compound A. In some embodiments, compound A, or a pharmaceutically acceptable salt thereof, is the free base of compound A. In some embodiments, the free base of compound A is crystalline. In some embodiments, the free base of compound A is in the crystalline form as described in International Patent Application Publication No. WO2021 / 111179.

[0135] In some embodiments, compound A, or a pharmaceutically acceptable salt thereof, is administered in a pharmaceutical composition further comprising one or more pharmaceutically acceptable additives. In some embodiments, the methods and uses described herein include administering a pharmaceutical composition which is the formulation described herein in Example 2. In some embodiments, the methods and uses described herein include administering a pharmaceutical composition which is the formulation described in WO2020 / 115555.

[0136] In some embodiments, the pharmaceutical composition (a) Compound A, or a pharmaceutically acceptable salt thereof; (b) one or more of the following: sweeteners, antioxidants, and flavoring agents; and (c) Liquid vehicle This is an oral liquid dosage form containing [ingredient].

[0137] In some embodiments, the pharmaceutical composition contains about 1 w / v% to about 50 w / v% of compound A or a pharmaceutically acceptable salt thereof, based on the weight of free base. In some embodiments, the pharmaceutical composition contains about 1 w / v% to about 10 w / v% of compound A or a pharmaceutically acceptable salt thereof, based on the weight of free base. In some embodiments, the pharmaceutical composition contains about 5 w / v% of compound A or a pharmaceutically acceptable salt thereof, based on the weight of free base. In some embodiments, the pharmaceutical composition contains about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 w / v% of compound A or a pharmaceutically acceptable salt thereof, based on the weight of free base, or within any of the above ranges.

[0138] In some embodiments, the pharmaceutical composition contains a sweetener. The sweetener is a formulation component added to improve the taste. In some embodiments, the pharmaceutical composition contains about 0.01 w / v% to about 1.5 w / v% of the sweetener. In some embodiments, the pharmaceutical composition contains about 0.1 w / v% to about 0.5 w / v% of the sweetener. In some embodiments, the pharmaceutical composition contains about 0.15 w / v% of the sweetener. In some embodiments, the pharmaceutical composition contains about 0.1, 0.2, 0.3, 0.4, or 0.5 w / v% of the sweetener, or within any of the above ranges.

[0139] In some embodiments, the sweetener is selected from saccharin, sucrose, sucralose, aspartame, dextrose, fructose, maltitol, mannitol, sorbitol, and avantame. In some embodiments, the sweetener is saccharin.

[0140] In some embodiments, the pharmaceutical composition contains antioxidants. Antioxidants are formulation components added to improve stability by preventing oxidation. In some embodiments, the pharmaceutical composition contains about 0.01 w / v% to about 1.5 w / v% of antioxidants. In some embodiments, the pharmaceutical composition contains about 0.1 w / v% to about 0.5 w / v% of antioxidants. In some embodiments, the pharmaceutical composition contains about 0.17 w / v% of antioxidants. In some embodiments, the pharmaceutical composition contains about 0.1, 0.2, 0.3, 0.4, or 0.5 w / v% of antioxidants, or within any of the above ranges.

[0141] In some embodiments, the antioxidant is selected from butylated hydroxytoluene, vitamin E TPGS, butylated hydroxyanisole, ascorbic acid, lecithin, tert-butylhydroquinone, and citric acid. In some embodiments, the antioxidant is butylated hydroxytoluene.

[0142] In some embodiments, the pharmaceutical composition contains a flavoring agent. A flavoring agent is a formulation component added to mask the taste sensation with an aroma. In some embodiments, the pharmaceutical composition contains about 0.01 w / v% to about 0.5 w / v% of a flavoring agent. In some embodiments, the pharmaceutical composition contains about 0.05 w / v% to about 0.2 w / v% of a flavoring agent. In some embodiments, the pharmaceutical composition contains about 0.10 w / v% of a flavoring agent. In some embodiments, the pharmaceutical composition contains a flavoring agent in the range of about 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.2 w / v%, or any of the above values.

[0143] In some embodiments, the flavoring agent is selected from FONA orange flavoring agent, FONA juicy flavoring agent, FONA grape flavoring agent, Firmenich SA lemon flavoring agent, Firmenich Tetrarome orange flavoring agent, IFF cherry flavoring agent, and IFF grape flavoring agent. In some embodiments, the flavoring agent is FONA orange flavoring agent. In some embodiments, the flavoring agent is orange flavoring agent.

[0144] The liquid vehicle is a solvent capable of dissolving, or partially dissolving, compound A or a pharmaceutically acceptable salt thereof for the purpose of delivery as an orally administered solution. In some embodiments, the pharmaceutical composition contains about 50 w / v% to about 99.9 w / v% of the liquid vehicle. In some embodiments, the pharmaceutical composition contains about 90 w / v% to about 99 w / v% of the liquid vehicle. In some embodiments, the pharmaceutical composition contains about 92 w / v% to about 97 w / v% of the liquid vehicle. In some embodiments, the pharmaceutical composition contains about 94.6 w / v% of the liquid vehicle. In some embodiments, the pharmaceutical composition contains about 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99 w / v% of the liquid vehicle, or within any of the above ranges.

[0145] In some embodiments, the liquid vehicle is selected from medium-chain triglycerides, propylene glycol dicaprylate / dicaproate, glycerin, propylene glycol, polyethylene glycol, olive oil, soybean oil, corn oil, and transcutol. In some embodiments, the liquid vehicle is a medium-chain triglyceride. In some embodiments, the medium-chain triglyceride is Labrafac® Lipophile WL1349.

[0146] In some embodiments, the pharmaceutical composition further comprises a surfactant, which is a formulation component added to improve solubility or emulsion properties. In some embodiments, the pharmaceutical composition contains about 1 w / v% to about 50 w / v% of the surfactant. In some embodiments, the pharmaceutical composition contains about 10 w / v% to about 30 w / v% of the surfactant. In some embodiments, the pharmaceutical composition contains about 20 w / v% of the surfactant. In some embodiments, the pharmaceutical composition contains about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 w / v% of the surfactant, or within any of the above ranges.

[0147] In some embodiments, the surfactant is selected from oleoyl polyoxyl-6 glyceride, linoleoyl polyoxyl-6 glyceride, polysorbate 80, polysorbate 20, vitamin E polyethylene glycol succinate, Gelucire, lauroyl polyoxyl-32 glyceride, sodium lauryl sulfate, poloxamer, corn oil PEG-6 ester, and hydrogenated palm oil / palm kernel oil PEG-6 ester. In some embodiments, the surfactant is oleoyl polyoxyl-6 glyceride. In some embodiments, oleoyl polyoxyl-6 glyceride is LABRAFIL® M 1944CS.

[0148] In some embodiments, the pharmaceutical composition contains about 50 w / v% to about 90 w / v% of a liquid vehicle. In some embodiments, the pharmaceutical composition contains about 70 w / v% to about 80 w / v% of a liquid vehicle. In some embodiments, the pharmaceutical composition contains about 75 w / v% of a liquid vehicle. In some embodiments, the pharmaceutical composition contains about 74.6 w / v% of a liquid vehicle. In some embodiments, the pharmaceutical composition contains about 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 w / v% of a liquid vehicle, or within any of the above ranges.

[0149] In some embodiments, the liquid vehicle is selected from medium-chain triglycerides, propylene glycol dicaprylate / dicaproate, glycerin, propylene glycol, polyethylene glycol, olive oil, soybean oil, corn oil, and transcutol. In some embodiments, the liquid vehicle is a medium-chain triglyceride. In some embodiments, the medium-chain triglyceride is Labrafac® Lipophile WL1349.

[0150] In some embodiments, this pharmaceutical composition, (a) Compound A or a pharmaceutically acceptable salt thereof (b) Sweeteners (c) Antioxidants (d) Flavoring agents, and (e) Liquid vehicle Includes.

[0151] In some embodiments, the pharmaceutical composition further comprises a surfactant.

[0152] In some embodiments, this pharmaceutical composition, (a) Compound A or a pharmaceutically acceptable salt thereof, in a weight basis of approximately 4 w / v% to 6 w / v% of free base. (b) Sweeteners in an amount of approximately 0.1 w / v% to approximately 0.2 w / v% (c) Antioxidants in an amount of approximately 0.1 w / v% to 0.2 w / v% (d) Flavoring agents in amounts of approximately 0.05 w / v% to approximately 0.2 w / v%, and (e) Liquid vehicle of approximately 92 w / v% to approximately 97 w / v% Includes.

[0153] In some embodiments, this pharmaceutical composition, (a) Approximately 5 w / v% of compound A or a pharmaceutically acceptable salt thereof, by weight of free base. (b) Approximately 0.15 w / v% sweetener (c) Approximately 0.17 w / v% antioxidant (d) Approximately 0.1 w / v% of flavoring agents, (e) A liquid vehicle of approximately 94.6 w / v% Includes.

[0154] In some embodiments, this pharmaceutical composition, (a) Compound A or a pharmaceutically acceptable salt thereof, in a weight basis of approximately 4 w / v% to 6 w / v% of free base. (b) Sweeteners in an amount of approximately 0.1 w / v% to approximately 0.2 w / v% (c) Antioxidants in an amount of approximately 0.1 w / v% to 0.2 w / v% (d) Flavoring agent in an amount of approximately 0.05 w / v% to approximately 0.2 w / v% (e) Surfactants in an amount of approximately 15 w / v% to approximately 25 w / v%, and (f) Liquid vehicle of approximately 70 w / v% to approximately 80 w / v% Includes.

[0155] In some embodiments, this pharmaceutical composition, (a) Approximately 5 w / v% of compound A or a pharmaceutically acceptable salt thereof, by weight of free base. (b) Approximately 0.15 w / v% sweetener (c) Approximately 0.17 w / v% antioxidant (d) Approximately 0.1 w / v% of flavoring agents (e) A surfactant of approximately 20 w / v%, and (f) A liquid vehicle of approximately 75 w / v% Includes.

[0156] In some embodiments, this pharmaceutical composition, (a) Compound A or a pharmaceutically acceptable salt thereof (b) Saccharin (c) Butylated hydroxytoluene (d) FONA orange flavoring agent, and (e) Medium-chain triglycerides Includes.

[0157] In some embodiments, the pharmaceutical composition further comprises oleoyl polyoxyl-6 glyceride.

[0158] In some embodiments, this pharmaceutical composition, (a) Compound A or a pharmaceutically acceptable salt thereof, in a weight basis of approximately 4 w / v% to 6 w / v% of free base. (b) Saccharin at approximately 0.1 w / v% to 0.2 w / v% (c) Approximately 0.1 w / v% to 0.2 w / v% butylated hydroxytoluene (d) Approximately 0.05 w / v% to approximately 0.2 w / v% of FONA orange flavoring agent, (e) Medium-chain triglycerides of approximately 92 w / v% to 97 w / v% Includes.

[0159] In some embodiments, this pharmaceutical composition, (a) Approximately 5 w / v% of compound A or a pharmaceutically acceptable salt thereof, by weight of free base. (b) Approximately 0.15 w / v% saccharin (c) Approximately 0.17 w / v% butylated hydroxytoluene (d) Approximately 0.1 w / v% of FONA orange flavoring agent, and (e) Medium-chain triglycerides at approximately 94.6 w / v% Includes.

[0160] In some embodiments, this pharmaceutical composition, (a) Compound A or a pharmaceutically acceptable salt thereof, in a weight basis of approximately 4 w / v% to 6 w / v% of free base. (b) Saccharin at approximately 0.1 w / v% to 0.2 w / v% (c) Approximately 0.1 w / v% to 0.2 w / v% butylated hydroxytoluene (d) Approximately 0.05 w / v% to 0.2 w / v% of FONA orange flavoring agent (e) Oleyl polyoxyl-6 glyceride in an amount of approximately 15 w / v% to approximately 25 w / v%, and (f) Medium-chain triglycerides of approximately 70 w / v% to 80 w / v% Includes.

[0161] In some embodiments, this pharmaceutical composition, (a) Approximately 5 w / v% of compound A or a pharmaceutically acceptable salt thereof, by weight of free base. (b) Approximately 0.15 w / v% saccharin (c) Approximately 0.17 w / v% butylated hydroxytoluene (d) Approximately 0.1 w / v% FONA orange flavoring agent (e) Approximately 20 w / v% oleyl polyoxyl-6 glyceride, and (f) Approximately 75 w / v% medium-chain triglycerides Includes.

[0162] In some embodiments, the pharmaceutical composition contains compound A as a free base.

[0163] In some embodiments, the pharmaceutical composition is formulated in unit dosage forms, and compound A or a pharmaceutically acceptable salt thereof is present in an amount of about 5 mg / mL to about 200 mg / mL based on the weight of free base. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is present in a unit dosage form in an amount of about 75 mg / mL to about 150 mg / mL based on the weight of free base. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is present in a unit dosage form in an amount of about 50 mg / mL based on the weight of free base. In some embodiments, compound A or a pharmaceutically acceptable salt thereof is present in a unit dosage form in an amount of about 100 mg / mL based on the weight of free base.

[0164] In some embodiments, the liquid pharmaceutical composition has a viscosity between about 1 and about 50 centipoise at about 25°C.

[0165] In some embodiments, CAH is classical congenital adrenal hyperplasia.

[0166] In some embodiments, CAH is non-classical congenital adrenal hyperplasia.

[0167] Examples of embodiments of the present disclosure are provided in the following embodiments. These embodiments are presented for illustrative purposes only and to assist those skilled in the art in using the present disclosure. The embodiments are not intended to limit the scope of the present disclosure in any way. [Examples]

[0168] (Example 1) Phase 3 Compound A Pediatric Study This is a phase 3, randomized, double-blind, placebo-controlled trial to evaluate the efficacy, safety, and tolerability of compound A compared to placebo, administered twice daily (bid) with breakfast and dinner for 28 weeks in approximately 81 children with classical congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Eligible subjects were randomly assigned in a 2:1 ratio (activity:placebo) to either compound A (25 mg bid in oral liquid for subjects 10-<20 kg, 50 mg bid in oral liquid for subjects 20-<55 kg, or 100 mg bid in oral capsules for subjects ≥55 kg) or a suitable placebo (oral liquid placebo for subjects <55 kg and oral capsule placebo for subjects ≥55 kg). Dose assignment from day 1 to week 28 was based on the subject's body weight on day 1. After a 28-week placebo-controlled treatment period, there is a 24-week open-label treatment period during which all subjects receive compound A at a dose based on their weight at week 28.

[0169] At 12 months (week 52), subjects have the option to participate in an open-label extension (OLE). During the OLE, subjects will continue to receive compound A at a dose based on their body weight, unless their efficacy is insufficient (in the opinion of the principal investigator), in which case the compound A dose may be increased by doubling the evening dose. At 12 months, subjects may also choose to switch compound A formulations (oral liquid or capsules) based on their preference.

[0170] Screening period (from week 4 to day 1) Participants will undergo screening for up to four weeks (-4th week to -1st day) to determine eligibility. Before blood samples are collected during the screening period, participants will be required to take their evening glucocorticoid dose before 9:00 PM the previous night and to withhold their morning glucocorticoid and fludrocortisone doses (if applicable).

[0171] Randomized, double-blind, placebo-controlled treatment period (Day 1 to Week 28) For visits where blood samples are collected, subjects should take their evening glucocorticoid dose (if applicable) before 9:00 PM the previous night, and withhold their morning doses of glucocorticoids, fludrocortisone (if applicable), and the study drug (after day 1) until after the collection of pre-administered blood samples, with administration taking place between approximately 8:00 AM and 8:30 AM with breakfast. For blood tests obtained at the laboratory, subjects should bring their morning doses of glucocorticoids, fludrocortisone (if applicable), and the study drug (after day 1) together to the laboratory and take them there (administration taking place between approximately 8:00 AM and 8:30 AM with breakfast). Except for screening visits, subjects should fast from midnight the previous night until after the collection of pre-administered blood samples (multiple samples are possible), although drinking water is recommended to avoid any hypovolemic conditions. If the principal investigator believes that fasting until 08:00 is not feasible, subjects aged 6 years may have light snacks (multiple snacks are acceptable) if needed, but breakfast should be taken with the morning dose.

[0172] Glucocorticoid stabilization period On day 1, subjects weighing ≥20 kg and ≥6 years of age arrive at the study facility for continuous blood sampling procedures and administration, which takes place between approximately 08:00 and 08:30. Blood samples are obtained continuously over approximately 6 hours, with two baseline samples obtained at a total of six blood sampling points: approximately 15 minutes before the morning glucocorticoid administration, and again immediately before the morning glucocorticoid dose administration (administration takes place between approximately 08:00 and 08:30), as well as at 2, 3, 4, and 6 hours after the morning glucocorticoid administration. For subjects <6 years of age or weighing <20 kg, blood samples are collected only before the morning glucocorticoid administration (administration takes place between approximately 08:00 and 08:30). For all subjects, saliva samples for adrenal androgens and precursors will be collected in the early morning (06:00), approximately 08:00 before morning glucocorticoid administration, approximately 3 and 6 hours after morning glucocorticoid administration, and in the evening (within 30 minutes before evening glucocorticoid administration; before bedtime if the subject does not receive evening glucocorticoid administration). Saliva samples collected approximately 08:00 before administration, and 3 and 6 hours after administration, should be collected almost simultaneously with any corresponding blood sample (if applicable). Any midday glucocorticoid dose received by the subject should be taken after the blood and saliva samples collected 6 hours after administration. During the study, the precise timing of blood and saliva samples, as well as morning glucocorticoids, mineralocorticoids, and / or test drug doses (and breakfast), can be adjusted by ±1 hour if necessary to adapt to the facility and subject schedule, provided that this is performed consistently for each subject and the relative time between the sample(s) and dose(s) is maintained.

[0173] Participants are randomized on day 1 in a 2:1 ratio (activity:placebo). Randomization is stratified by puberty stage (Tanner breast or genital stage 1 or 2 to 3, 4, or 5) and sex. From the evening of day 1 visit (after all day 1 assessments have been completed) until the morning of week 28 visit, all participants receive a blinded study drug based on their day 1 weight (25 mg bid in oral liquid for participants 10-<20 kg, 50 mg bid in oral liquid for participants 20-<55 kg, or 100 mg bid in oral capsule for participants ≥55 kg). The study drug is administered as a bid with the participant's breakfast and dinner (approximately 12 hours between doses).

[0174] From day 1 to week 4, subjects should maintain a stable glucocorticoid regimen whenever possible, except for stress dosing required due to illness or other significant physical stress, in order to evaluate the direct effects of the study drug on adrenal androgens and precursors. Stress dosing of glucocorticoids (at any point during the study) may be done based on guidance provided by the principal investigator, the subject's attending physician, or guidelines provided in the protocol.

[0175] Glucocorticoid adjustment period At the 4-week visit, subjects weighing ≥20 kg and ≥6 years of age should arrive at the study facility for continuous blood sampling procedures and administration, with administration taking place between approximately 08:00 and 08:30 with breakfast. Blood samples should be obtained continuously over approximately 6 hours with two baseline samples (taken approximately 15 minutes before and again immediately before morning glucocorticoid and study drug administration, with administration taking place between approximately 08:00 and 08:30). Blood samples should also be obtained 2, 3, 4, and 6 hours post-administration. Pharmacokinetic (PK) blood samples should be obtained at the same time, except for one required pre-administration sample. For subjects <6 years of age or weighing <20 kg, blood sampling should only be performed before morning glucocorticoid and study drug administration (administration taking place between approximately 08:00 and 08:30 with breakfast). For all subjects, saliva samples for adrenal androgens and precursors will be collected in the early morning (06:00), 6 hours after morning glucocorticoid and test drug administration, and in the evening (within 30 minutes before evening glucocorticoid administration; before bedtime if the subject does not receive evening glucocorticoid administration). Saliva samples taken approximately 08:00 before administration and 3 and 6 hours after administration should be collected almost simultaneously with any corresponding blood sample (if applicable). Any midday glucocorticoid dose received by the subject should be taken after the blood and saliva samples collected 6 hours after administration. During the study, the exact timing of blood and saliva samples, as well as morning glucocorticoid, mineralocorticoid, and / or test drug administrations, may be adjusted by ±1 hour to accommodate facility and subject schedules, as long as the relative time between sample(s) and dose(s) is maintained.

[0176] From week 4 to week 28, the glucocorticoid dose should be adjusted according to their androstenedione (A4) levels, with the aim of controlling A4, i.e., controlling it to ≤120% of the baseline value or ≤upper limit of normal (ULN) at week 28, according to either sex and age (for Tanner stage 1) or adolescent stage (for Tanner stages 2-5), with a dose of 8-10 mg / m². 2The goal is to reach the target daily dose (in hydrocortisone dose equivalent adjusted for body surface area [BSA]). The calculation of the glucocorticoid dose in hydrocortisone equivalent adjusted for BSA on day 1 and week 28 is based on height and weight measurements on day 1 and week 28, respectively. BSA is updated at week 16 if height measurements are available at week 16.

[0177] Glucocorticoid dose adjustments can be made in as little as one step, or up to four steps, depending on the starting and target glucocorticoid doses and the amount of dose adjustment at each step. Decreasing glucocorticoid doses should follow guidelines, starting with the most non-physiological glucocorticoid types and timing of reduction. Unless A4 levels are controlled and there is no evidence of glucocorticoid deficiency, the target glucocorticoid dose should be 8–10 mg / m². 2 The dose should be within the range of / day. The investigator may lower the dose below this range if he or she determines that this is appropriate in light of the actual challenges considered in clinical practice in relation to the available dose potency, but is not obligated to do so. Prior to any glucocorticoid dose reduction, the investigator will use a standardized checklist to assess the subject for any symptoms suggestive of glucocorticoid deficiency and will make arrangements for follow-up as necessary after the dose reduction.

[0178] The first glucocorticoid dose adjustment step, approximately at week 6 (or when the week 4 lab results become available), should be guided by the change in A4 from baseline at week 4. Suggested guidelines are provided in the table below, however, the exact adjusted amount may differ from these guidelines based on the actual clinical challenges considered regarding available dose potencies. The principal investigator should contact the patient / guardian once the week 4 lab results are available to provide guidance on the amount of the first glucocorticoid dose adjustment. Guidance for the first glucocorticoid dose adjustment step is summarized in Table 1 below. [Table 1]

[0179] Follow-up observational blood tests (with saliva sample collection) should be scheduled at the 8th week, approximately 2 weeks later (either at home or at the test facility).

[0180] If necessary and when test results are available (at approximately the 10th, 14th, and 18th weeks), subsequent glucocorticoid dosage adjustment steps should be taken, and follow-up observational blood and saliva tests should be conducted at the 12th week (either at home or at the test facility, if the glucocorticoid dosage has been previously modified), the 16th week (either at home or at the test facility), and the 20th week (either at home or at the test facility, if the glucocorticoid dosage has been previously modified). The target amount of glucocorticoid dosage reduction at each step is approximately 1 - 4 mg / m 2 / day, but should be guided by the A4 level in the previous blood test and in accordance with the actual issues considered in clinical practice regarding the available administered drug potency. The guidance for subsequent glucocorticoid dosage adjustment steps is summarized in Table 2 below. [Table 2]

[0181] At all hospital visits, if A4 is >120% and >ULN of the baseline, the glucocorticoid dosage should be appropriately increased to maintain A4 control.

[0182] At the 28-week visit, subjects should withhold their morning glucocorticoid and study drug administration until pre-administered blood samples are collected, and administer the drugs with breakfast between approximately 08:00 and 08:30. For subjects weighing ≥20 kg and ≥6 years of age, an additional blood sample will be collected approximately 3 hours after the morning glucocorticoid and study drug administration. Saliva samples will be collected throughout the day for all subjects: approximately 06:00 and 08:00 before the morning glucocorticoid and study drug administration, 3 and 6 hours after administration, and within 30 minutes before the evening glucocorticoid administration (before bedtime if the subject has not taken an evening glucocorticoid dose). Any midday glucocorticoid dose received by the subject should be taken after a saliva sample collected 6 hours after administration.

[0183] Open-label treatment period (weeks 28-52) From the evening of the week 28 visit (after all week 28 evaluations have been completed) until the morning of the week 52 visit, all subjects will receive the investigational drug with breakfast and dinner, based on their week 28 weight (Compound A; 25 mg bid in oral liquid for subjects 10-<20 kg, 50 mg bid in oral liquid for subjects 20-<55 kg, or 100 mg bid in oral capsules for subjects ≥55 kg). Subjects and the principal investigator will remain blinded to the randomization of subjects to treatment groups throughout the entire study. From week 28 to week 32, subjects should maintain a stable glucocorticoid regimen whenever possible, except for stress doses if required due to illness or other significant physical stress. Blood samples will be collected at week 32 (at home or at the study site).

[0184] >11mg / m² at week 32 2In subjects receiving a daily glucocorticoid dose (in hydrocortisone dose equivalent adjusted for BSA [based on weight and height at 28 weeks]), further glucocorticoid dose adjustments should be made according to the same guidelines used during the placebo-controlled period, controlling A4 while maintaining a hydrocortisone dose equivalent of 8-10 mg / m² adjusted for BSA at 52 weeks. 2 This should be done with the aim of achieving the target dose per day. The calculation of the glucocorticoid dose in terms of adjusted hydrocortisone equivalents for BSA at week 52 is based on height and weight measurements at week 52. BSA is updated at week 40 if height measurements are available at week 40.

[0185] The first glucocorticoid dose adjustment step during this period (if performed) should be guided by the serum A4 change at week 32 (compared to week 28) after the subject has received the open-label investigational drug and a stable glucocorticoid regimen (if possible) for 4 weeks. Suggested guidelines are provided below, however the exact adjusted dose may differ from these guidelines based on the actual challenges considered in clinical practice regarding available dose potencies. The guidance for the first glucocorticoid dose adjustment in the open-label extension is summarized in Table 3 below. [Table 3]

[0186] If the glucocorticoid dose is adjusted around week 34, follow-up blood tests (along with saliva sample collection) should be arranged approximately two weeks later, at week 36 (at home or in a laboratory).

[0187] If necessary, subsequent glucocorticoid dose adjustments should be made at approximately weeks 38 and 42 (or if test results are available), and follow-up blood and saliva tests should be performed at week 40 (at home or in a laboratory) and week 44 (at home or in a laboratory, if the glucocorticoid dose was previously adjusted during the open-label treatment period). The target amount of glucocorticoid dose reduction at each step is approximately 1–4 mg / m². 2 However, this should be guided by the actual challenges considered in clinical practice regarding A4 levels in preceding blood tests and available dosage potencies. Open-label extension subsequent glucocorticoid dose adjustment guidance is summarized in Table 4 below. [Table 4]

[0188] If A4 is >120% and >ULN of baseline at all visits, increase glucocorticoid dose appropriately to maintain A4 control.

[0189] At the 52-week visit, subjects should administer their morning glucocorticoid and study drug doses with breakfast between approximately 08:00 and 08:30, withholding them until pre-administered blood samples have been collected. For subjects weighing ≥20 kg and ≥6 years of age, an additional blood sample should be collected approximately 3 hours after the morning glucocorticoid and study drug administration. Saliva samples should be collected throughout the day for all subjects: approximately 06:00 and 08:00 before the morning glucocorticoid and study drug administration, 3 and 6 hours after administration, and within 30 minutes before the evening glucocorticoid administration (before bedtime if the subject has not taken an evening glucocorticoid dose). Any midday glucocorticoid dose received by the subject should be taken after a saliva sample has been collected 6 hours after administration.

[0190] Open-label extension for continued access to compound A (from week 52 onwards) During the OLE, unless the subject demonstrates insufficient efficacy (in the opinion of the principal investigator), the subject will continue to receive compound A at an appropriate dose based on their weight at each trial visit (25 mg bid if weight is 10 to <20 kg, 50 mg bid if weight is 20 to <55 kg, and 100 mg bid if weight is ≥55 kg), in which case the compound A dose may be increased by doubling the evening dose. If efficacy is insufficient at the specified weight-based dose, the dose may be increased (for example, 50 mg bid may be increased to 50 mg qAM and 100 mg qPM), but no further increases unless the subject falls into the next weight category. If the principal investigator assesses that a subject has insufficient efficacy and, in addition, the subject falls into the next weight category, the Compound A dose should initially be increased based on weight (rather than doubling the evening dose); efficacy should be assessed at the next scheduled study visit, and if efficacy remains insufficient, the evening dose may be doubled at that point. If the Compound A dose is increased due to insufficient efficacy, a follow-up study visit should be conducted approximately one month after the dose increase to assess efficacy, pharmacokinetics, and safety. This follow-up study visit is not required for subjects whose dose is increased due to falling into the next weight category. Changes to the Compound A dose should generally only be made at scheduled study visits (whether based on falling into the next weight category or due to insufficient efficacy).

[0191] At 12 months, subjects receiving compound A 50 mg bid or more may choose to switch compound A formulations (oral liquid or capsules) based on their preference. For example, if a subject received compound A 50 mg bid oral liquid from week 28 to 12 months but prefers capsules, they may switch to 50 mg bid capsules, provided they remain in the same weight category. Once this preference is established at 12 months, the formulation should remain the same for the remainder of the OLE (unless there are tolerance issues, in which case the subject can ideally return to the previous formulation within approximately one month).

[0192] During OLE, subjects have their glucocorticoid dose adjusted to be appropriate and acceptable to achieve the minimum glucocorticoid dose that maintains appropriate disease management (in the opinion of the principal investigator). The glucocorticoid dose reduction is 8 mg / m². 2 Dose reductions below the hydrocortisone equivalent per day are not required. After each glucocorticoid dose reduction, the principal investigator should contact the subject / guardian (within 2 weeks) to assess how well the subject is tolerating the glucocorticoid dose reduction. In situations of inadequate disease control, if the glucocorticoid dose is at or above the target, an increase in the glucocorticoid dose should generally only be considered after the compound A dose has been maximized for the subject. Changes in glucocorticoid and compound A doses should generally be spaced at least one month apart to assess the effect of each change.

[0193] Starting at month 12, trial visits during OLE will be conducted every six months. At each OLE trial visit (including visits approximately one month after dose increases due to insufficient efficacy), subjects should administer their morning glucocorticoid and study drug doses with breakfast between approximately 08:00 and 08:30, withholding administration until pre-administered blood samples have been collected. At month 24, and thereafter every 12 months, subjects weighing ≥20 kg and ≥6 years of age will have another blood sample collected approximately three hours after morning glucocorticoid and compound A administration. In addition, saliva samples will be collected from all subjects at 24 months, then every 12 months thereafter, and at early termination visits, over a 24-day period: approximately 06:00, 08:00, 3 and 6 hours after morning glucocorticoid and study drug administration, and within 30 minutes before evening glucocorticoid administration (or before bedtime if the subject has not taken an evening glucocorticoid dose). Any midday glucocorticoid dose received by the subject should be taken after a saliva sample has been collected 6 hours after administration.

[0194] Investigational drug, dosage, and mode of administration: From day 1 to month 12, Compound A will be administered with breakfast and dinner to the subject (25 mg bid in oral liquid for subjects weighing 10-<20 kg, 50 mg bid in oral liquid for subjects weighing 20-<55 kg, or 100 mg bid in oral capsule for subjects weighing ≥55 kg) (each dose will be spaced approximately 12 hours apart). During OLE, unless the subject's efficacy is insufficient (in the opinion of the principal investigator) (in which case the Compound A dose may be increased by doubling the evening dose), the Compound A dose should be based on the subject's weight at the time of the study visit (25 mg bid if weight is 10-<20 kg, 50 mg bid if weight is 20-<55 kg, and 100 mg bid if weight is ≥55 kg). At month 12, subjects participating in OLE may choose to switch Compound A formulations based on their preference. Each Compound A oral capsule contains 50 mg of Compound A. The oral solution contains 50 mg of compound A per 1 mL and is administered via a graduated oral administration syringe. Further guidance on modifications to compound A administration in OLE is provided in Table 5 below. [Table 5-1] [Table 5-2]

[0195] The evaluation criteria include: Effectiveness: • Hormone measurements: A4 (serum and saliva), 17-hydroxyprogesterone (hydroxyprogeterone) (17-OHP; serum and saliva), adrenocorticotropic hormone (ACTH) (plasma), luteinizing hormone (LH; serum), follicle-stimulating hormone (FSH; serum), testosterone (serum and saliva), cortisol (serum and saliva), plasma renin activity (PRA) (measured upright). • Daily glucocorticoid regimens expressed as hydrocortisone dose equivalents adjusted for BSA (mg / m²) 2 / day). • Weight and body mass index (in absolute and standard deviation scores [SDS] units) • Growth (assessed as Bayley-Pinneau predicted adult height, height, and height velocity in absolute and SDS units; only for growing subjects). • X-ray-based bone age (evaluated in absolute and SDS units, adjusted for chronological age; only for subjects not meeting adult height requirements). • Assessment of a fasting lipid panel and insulin resistance homeostasis model (HOMA-IR) based on fasting glucose and insulin levels. • Menstrual cycle questionnaire (only for women who have had their first period and are not using hormones or intrauterine devices). • Male-pattern hirsutism (for females only) and acne scale. • Testicular ultrasound (for detecting residual adrenal tumors, for males only). Patient and caregiver-reported outcomes: • EQ-5D-Y for ages 8-15; EQ-5D-5L for ages 16-17 • Pediatric Quality of Life Instrument (PedsQL) • PedsQL Family Impact Module Pharmacokinetics: Blood samples for evaluating the plasma concentrations of compound A and its metabolites will be collected throughout the study. others: • Drug palatability / ease of administration (Palatability is assessed by subjects ≥6 years of age, and ease of administration is assessed by caregivers for subjects <6 years of age) • Cytochrome P450 (CYP) 21A2 genotype determination Safety: • Adverse events (AEs) (including events requiring glucocorticoid administration during stress) • Clinical laboratory tests (chemistry, hematology, agglutination, fasting glucose, urinalysis) • Vital signs • Physical examination including height, weight, and Tanner stage. • 6- or 12-lead electrocardiogram (ECGs) • Simplified Psychiatric Symptom Assessment Scale, Pediatric Version • Columbia Suicide Severity Scale (for subjects aged 6 years or older only) It includes.

[0196] Trial endpoints and statistical analysis The primary endpoint is the change in serum A4 from baseline to week 4. The first important secondary endpoint is the change in serum 17-OHP from baseline to week 4. The second important secondary endpoint is the percentage change in daily glucocorticoid dose from baseline to week 28 (adjusted hydrocortisone dose equivalent [mg / m²] with respect to BSA). 2 At [day], serum A4 at week 28 is ≤120% of the baseline value or ≤ULN according to either sex and age (with respect to Tanner stage 1) or pubertal stage (with respect to Tanner stages 2–5). These endpoints are analyzed using covariance model analysis, including treatment group (compound A vs. placebo), stratification factors used for randomization, and baseline values ​​where appropriate. An overall type I error of 0.05 is controlled by sequentially testing the primary, first critical secondary, and second critical secondary endpoints in this order.

[0197] Secondary endpoints include: • Serum A4 at week 28 is ≤120% of the baseline value or ≤ULN according to either sex and age (for Tanner stage 1) or puberty stage (for Tanner stages 2-5), and simultaneously the physiological level of the daily glucocorticoid dose at week 28 is ≤11 mg / m² in hydrocortisone dose equivalent adjusted for BSA. 2 Achieved a reduction to [number] days. • Change in Body Mass Index (SDS) from baseline to week 28. • Changes in average 24-hour salivary 17-OHP from baseline to week 28. • Tolerability and palatability of the test drug at week 4. • The ratio of the change in bone age from baseline to 28 weeks to the change in chronological age from baseline to 28 weeks (in subjects that are not adult height). • Change in Bayley-Pinneau predicted adult height SDS from baseline to 52 weeks (in subjects not measuring adult height).

[0198] (Example 2) Liquid formulation for compound A Table 6 shows liquid formulations of compound A as a free base (at a concentration of 50 mg / mL). A typical manufacturing process example for preparing the liquid formulation is shown in international patent publication number WO2020 / 115555. [Table 6]

[0199] Further embodiments can be provided by combining the various embodiments described above. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned herein and / or enumerated in the application datasheet are incorporated herein by reference in their entirety. The aspects of the embodiments may be modified, if necessary, to provide further embodiments using various patent, application, and publication concepts.

[0200] 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 interpreted as limiting the claims to the specific embodiments disclosed herein and in the claims, but rather to include all conceivable embodiments, together with the entire scope of equivalents (to which such claims are granted). Thus, the claims are not limited by the above disclosure.

Claims

1. As an adjunct to glucocorticoid therapy in children 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, may be used. 【Chemistry 14】 A method for administering a compound A, comprising the steps of administering to a 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 administered in two doses, consisting of a first dose and a second dose, the second dose being greater than the first dose.

2. A method for treating congenital adrenal hyperplasia (CAH) in a pediatric subject already treated with glucocorticoid therapy, wherein the subject is given 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. 【Chemistry 15】 A method comprising the steps of administering a substance 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 administered in two doses, consisting of a first dose and a second dose, the second dose being greater than the first dose.

3. The method according to claim 1 or 2, wherein the weight of the subject is greater than or equal to approximately 55 kg.

4. The method according to claim 3, wherein the first amount is equivalent to approximately 100 mg b. i. d. of free base of compound A.

5. The method according to claim 3 or 4, wherein the second amount is equivalent to about 100 mg q. A. M. of free base of compound A and about 200 mg q. P. M. of free base of compound A.

6. The method according to any one of claims 3 to 5, wherein the first period is approximately one week to approximately one year.

7. The method according to any one of claims 3 to 6, wherein the second period is at least about one week.

8. The method according to claim 1 or 2, wherein the weight of the subject is approximately 20 kg to approximately 55 kg.

9. The method according to claim 8, wherein the first amount is equivalent to approximately 50 mg b. i. d. of free base of compound A.

10. The method according to claim 8 or 9, wherein the second amount is equivalent to about 50 mg q. A. M. of free base of compound A and about 100 mg q. P. M. of free base of compound A.

11. The method according to any one of claims 8 to 10, wherein the first period is approximately one week to approximately one year.

12. The method according to any one of claims 8 to 11, wherein the second period is at least about one week.

13. The method according to claim 1 or 2, wherein the weight of the subject is approximately 10 kg to approximately 20 kg.

14. The method according to claim 13, wherein the first amount is equivalent to approximately 25 mg b. i. d. of free base of compound A.

15. The method according to claim 13 or 14, wherein the second amount is equivalent to about 25 mg q. A. M. of free base of compound A and about 50 mg q. P. M. of free base of compound A.

16. The method according to any one of claims 13 to 15, wherein the first period is approximately one week to approximately one year.

17. The method according to any one of claims 13 to 16, wherein the second period is at least about one week.

18. The method according to any one of claims 1 to 17, wherein the glucocorticoid treatment is the daily dose of glucocorticoid administered to the subject.

19. The method according to claim 18, wherein the daily dose of the glucocorticoid is administered once daily.

20. The method according to claim 18, wherein the daily dose of the glucocorticoid is administered by multiple doses.

21. The method according to any one of claims 18 to 20, wherein the glucocorticoid is selected from hydrocortisone, prednisone, methylprednisolone, prednisolone, and dexamethasone, or a combination thereof.

22. The method according to any one of claims 18 to 21, wherein the glucocorticoid is hydrocortisone.

23. The method according to any one of claims 18 to 22, wherein the subject had received a target dose of glucocorticoids prior to the step of administering the second amount of compound A or a pharmaceutically acceptable salt thereof.

24. The method according to any one of claims 1 to 23, wherein the subject had insufficient efficacy prior to the step of administering the second amount of compound A, or a pharmaceutically acceptable salt thereof.

25. The method according to claim 24, wherein, prior to the step of administering the second amount of compound A, or a pharmaceutically acceptable salt thereof, the subject had been administered a target dose of glucocorticoids with insufficient efficacy.

26. The target dose for glucocorticoid treatment is ≤ 11 mg / m². ２ The method according to claim 23 or 25, wherein the amount is / day (hydrocortisone equivalent).

27. The target dose for glucocorticoid treatment is approximately 8 mg / m². ２ / day ~ approx. 10mg / m ２ The method according to claim 26, wherein the amount is / day (hydrocortisone equivalent).

28. The target dose for glucocorticoid treatment is approximately 8 mg / m². ２ The method according to claim 27, wherein the amount is / day (hydrocortisone equivalent).

29. The method according to any one of claims 25 to 28, wherein the subject had insufficient efficacy if the androstenedione level of the subject was ≤120% of the baseline of the subject or ≤upper normal number (ULN) for the age and sex of the subject.

30. The method according to any one of claims 1 to 29, wherein compound A, or a pharmaceutically acceptable salt thereof, is the free base of compound A.

31. The method according to any one of claims 1 to 30, wherein compound A, or a pharmaceutically acceptable salt thereof, is administered with food.

32. The method according to any one of claims 1 to 31, wherein the CAH is a classical CAH.

33. The method according to any one of claims 1 to 31, wherein the CAH is a non-classical CAH.

34. The compound 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 for use in a method of treating congenital adrenal hyperplasia (CAH) in pediatric subjects already treated with glucocorticoid therapy: 【Chemistry 16】 or a pharmaceutically acceptable salt thereof, wherein the method (1) The step of administering to the subject a first amount of compound A, or a pharmaceutically acceptable salt thereof, over a first period of time, (2) The procedure further comprises administering to the subject a second amount of compound A, or a pharmaceutically acceptable salt thereof, over a second period of time. A compound or a pharmaceutically acceptable salt thereof, wherein the second amount is administered in two doses, a first dose and a second dose, the second dose being greater than the first dose.

35. The compound or salt for use according to claim 34, wherein the weight of the subject is greater than or equal to approximately 55 kg.

36. The compound or salt for use according to claim 35, wherein the first amount is equivalent to about 100 mg b. i. d. of free base of compound A.

37. The compound or salt for use according to claim 35 or 36, wherein the second amount is equivalent to about 100 mg q. A. M. of free base of compound A and about 200 mg q. P. M. of free base of compound A.

38. The compound or salt for use according to any one of claims 35 to 37, wherein the first period is approximately one week to approximately one year.

39. The compound or salt for use according to any one of claims 35 to 38, wherein the second period is at least about one week.

40. The compound or salt for use according to claim 34, wherein the weight of the subject is approximately 20 kg to approximately 55 kg.

41. The compound or salt for use according to claim 40, wherein the first amount is equivalent to about 50 mg b. i. d. of free base of compound A.

42. The compound or salt for use according to claim 40 or 41, wherein the second amount is equivalent to about 50 mg q. A. M. of free base of compound A and about 100 mg q. P. M. of free base of compound A.

43. The compound or salt for use according to any one of claims 40 to 42, wherein the first period is approximately one week to approximately one year.

44. The compound or salt for use according to any one of claims 40 to 43, wherein the second period is at least about one week.

45. The compound or salt for use according to claim 34, wherein the weight of the subject is approximately 10 kg to approximately 20 kg.

46. The compound or salt for use according to claim 45, wherein the first amount is equivalent to about 25 mg b. i. d. of free base of compound A.

47. The compound or salt for use according to claim 45 or 46, wherein the second amount is equivalent to about 25 mg q. A. M. of free base of compound A and about 50 mg q. P. M. of free base of compound A.

48. The compound or salt for use according to any one of claims 45 to 47, wherein the first period is approximately one week to approximately one year.

49. The compound or salt for use according to any one of claims 45 to 48, wherein the second period is at least about one week.

50. The compound or salt for use according to any one of claims 34 to 49, wherein the glucocorticoid treatment is a daily dose of glucocorticoid administered to the subject.

51. The compound or salt for use according to claim 50, wherein the daily dose of the glucocorticoid is administered once daily.

52. The compound or salt for use according to claim 50, wherein the daily dose of the glucocorticoid is administered by multiple doses.

53. The compound or salt for use according to any one of claims 50 to 52, wherein the glucocorticoid is selected from hydrocortisone, prednisone, methylprednisolone, prednisolone, and dexamethasone, or a combination thereof.

54. The compound or salt for use according to any one of claims 50 to 53, wherein the glucocorticoid is hydrocortisone.

55. The compound or salt for use according to any one of claims 50 to 54, wherein the subject had received a target dose of glucocorticoids prior to the step of administering the second amount of compound A or a pharmaceutically acceptable salt thereof.

56. The compound or salt for use according to any one of claims 34 to 55, wherein the subject had insufficient efficacy prior to the step of administering the second amount of compound A or a pharmaceutically acceptable salt thereof.

57. The compound or salt for use according to claim 56, wherein, prior to the step of administering the second amount of compound A, or a pharmaceutically acceptable salt thereof, the subject had been administered a glucocorticoid at the target dose, which had insufficient efficacy.

58. The target dose for glucocorticoid treatment is ≤ 11 mg / m². ２ A compound or salt for use according to claim 55 or 57, wherein the amount is / day (hydrocortisone equivalent).

59. The target dose for glucocorticoid treatment is approximately 8 mg / m². ２ / day ~ approx. 10mg / m ２ The compound or salt for use according to claim 58, which is / day (hydrocortisone equivalent).

60. The target dose for glucocorticoid treatment is approximately 8 mg / m². ２ The compound or salt for use according to claim 59, which is / day (hydrocortisone equivalent).

61. The compound or salt for use according to any one of claims 56 to 60, wherein the subject had insufficient efficacy if the androstenedione level of the subject was ≤120% of the baseline of the subject or ≤ upper limit of normal (ULN) for the age and sex of the subject.

62. The compound or salt for use according to any one of claims 34 to 61, wherein compound A, or a pharmaceutically acceptable salt thereof, is the free base of compound A.

63. Compound A, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 34 to 62, wherein the compound or salt thereof is administered with food.

64. The compound or salt for use according to any one of claims 34 to 63, wherein the CAH is a classical CAH.

65. The compound or salt for use according to any one of claims 34 to 63, wherein the CAH is a non-classical CAH.

66. (1) A step of administering a first amount of compound A, or a pharmaceutically acceptable salt thereof, to a child already treated with glucocorticoid therapy over a first period of time, (2) The procedure further comprises administering to the subject a second amount of compound A, or a pharmaceutically acceptable salt thereof, over a second period of time. A compound, 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, in the manufacture of a pharmaceutical for treating congenital adrenal hyperplasia (CAH) in the subject, by a method in which the second amount is administered in two doses consisting of a first dose and a second dose, the second dose being greater than the first dose: 【Chemistry 17】 Or the use of its pharmaceutically acceptable salt.

67. The use according to claim 66, wherein the weight of the subject is greater than or equal to approximately 55 kg.

68. The use according to claim 67, wherein the first amount is equivalent to approximately 100 mg b. i. d. of free base of compound A.

69. The use according to claim 67 or 68, wherein the second amount is equivalent to about 100 mg q. A. M. of free base of compound A and about 200 mg q. P. M. of free base of compound A.

70. The use according to any one of claims 67 to 69, wherein the first period is approximately one week to approximately one year.

71. The use according to any one of claims 67 to 70, wherein the second period is at least about one week.

72. The use according to claim 66, wherein the weight of the subject is approximately 20 kg to approximately 55 kg.

73. The use according to claim 72, wherein the first amount is equivalent to approximately 50 mg b. i. d. of free base of compound A.

74. The use according to claim 72 or 73, wherein the second amount is equivalent to about 50 mg q. A. M. of free base of compound A and about 100 mg q. P. M. of free base of compound A.

75. The use according to any one of claims 72 to 74, wherein the first period is approximately one week to approximately one year.

76. The use according to any one of claims 72 to 75, wherein the second period is at least about one week.

77. The use according to claim 66, wherein the weight of the subject is approximately 10 kg to approximately 20 kg.

78. The use according to claim 77, wherein the first amount is equivalent to approximately 25 mg b. i. d. of free base of compound A.

79. The use according to claim 77 or 78, wherein the second amount is equivalent to about 25 mg q. A. M. of free base of compound A and about 50 mg q. P. M. of free base of compound A.

80. The use according to any one of claims 77 to 79, wherein the first period is approximately one week to approximately one year.

81. The use according to any one of claims 77 to 80, wherein the second period is at least about one week.

82. The use according to any one of claims 66 to 81, wherein the glucocorticoid treatment is the daily dose of glucocorticoid administered to the subject.

83. The use according to claim 82, wherein the daily dose of the glucocorticoid is administered once daily.

84. The use according to claim 82, wherein the daily dose of the glucocorticoid is administered by multiple doses.

85. The use according to any one of claims 82 to 84, wherein the glucocorticoid is selected from hydrocortisone, prednisone, methylprednisolone, prednisolone, and dexamethasone, or a combination thereof.

86. The use according to any one of claims 82 to 85, wherein the glucocorticoid is hydrocortisone.

87. The use according to any one of claims 82 to 86, wherein the subject had received a target dose of glucocorticoids prior to the step of administering the second amount of compound A, or a pharmaceutically acceptable salt thereof.

88. The use according to any one of claims 66 to 87, wherein the subject had insufficient efficacy prior to the step of administering the second amount of compound A, or a pharmaceutically acceptable salt thereof.

89. The use according to claim 88, wherein, prior to the step of administering the second amount of compound A, or a pharmaceutically acceptable salt thereof, the subject had been administered a glucocorticoid at the target dose, which had insufficient efficacy.

90. The target dose of glucocorticoid treatment is ≤ 11 mg / m ２ / day (hydrocortisone equivalent), the use according to claim 87 or 89.

91. The target dose for glucocorticoid treatment is approximately 8 mg / m². ２ / day ~ approx. 10mg / m ２ The use according to claim 90, which is / day (hydrocortisone equivalent).

92. The target dose for glucocorticoid treatment is approximately 8 mg / m². ２ The use according to claim 91, which is / day (hydrocortisone equivalent).

93. The use according to any one of claims 88 to 92, wherein the subject had insufficient efficacy if the androstenedione level of the subject was ≤120% of the baseline of the subject or ≤upper normal number (ULN) for the age and sex of the subject.

94. The use according to any one of claims 66 to 93, wherein compound A, or a pharmaceutically acceptable salt thereof, is the free base of compound A.

95. The use according to any one of claims 66 to 94, wherein compound A, or a pharmaceutically acceptable salt thereof, is administered with food.

96. The use according to any one of claims 66 to 95, wherein the CAH is a classical CAH.

97. The use according to any one of claims 66 to 95, wherein the CAH is a non-classical CAH.

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