Melanocortin receptor antagonist subtype 2 (MC2R) for the treatment of ACTH-dependent Cushing's syndrome.

Description

1 / 52 Melanocortin receptor antagonist subtype 2 (MC2R) for the treatment of ACTH-dependent Cushing's syndrome. CROSS-REFERENCE TO RELATED REQUESTS

[001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 457,144, filed April 5, 2023, which is incorporated herein by reference in its entirety. FIELD

[002] This document describes a melanocortin receptor subtype 2 (MC2R) antagonist and methods of using the MC2R antagonist in the treatment of ACTH-dependent Cushing's syndrome, which may result from a pituitary tumor (Cushing's disease) or an extrapituitary tumor (ectopic ACTH syndrome). FUNDAMENTALS

[003] Melanocortin receptors form a family of G protein-coupled receptors (GPCRs) (MC1R, MC2R, MC3R, MC4R, and MC5R) that are selectively activated by different melanocortin peptides, adrenocorticotropic hormone (ACTH), and α, β, and γ melanocyte-stimulating hormone (α-MSH, β-MSH, and γ-MSH), all of which are proteolytically derived from proopiomelanocortin hormone, or POMC. ACTH is a 39-amino acid peptide that constitutes the main regulator of adrenal glucocorticoid synthesis and secretion and presents Petition 870250089737, dated 02 / 10 / 2025, page 15 / 71 2 / 52 affinity only for MC2R. As a central actor in this hypothalamic-pituitary-adrenal (HPA) axis, ACTH is secreted in a circadian rhythm by the pituitary gland and in pulses in response to stressful stimuli. ACTH acts on the adrenal gland to stimulate the synthesis and secretion of cortisol, which, through negative feedback in the hypothalamic-pituitary axis, regulates ACTH secretion. In ACTH-dependent Cushing's syndrome, pituitary and extra-pituitary tumors secrete excess ACTH, unregulated by negative feedback, which stimulates excessive cortisol secretion. Modulation of MC2R is attractive for the treatment of ACTH-dependent Cushing's syndrome. SUMMARY

[004] This document describes methods for the treatment of adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome.

[005] In one aspect, a method for treating adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome in a human being is described in this document, comprising the once-daily oral administration of about 80 mg to about 160 mg of a compound having the structure of Compound 1, or a pharmaceutically acceptable salt thereof: Petition 870250089737, dated 02 / 10 / 2025, p. 16 / 71 3 / 52

[006] In some forms, humans with ACTH-dependent Cushing's syndrome have a pituitary adenoma.

[007] In some forms, the human being with ACTH-dependent Cushing's syndrome presents with an ectopic ACTH-secreting tumor. In some forms, the ectopic ACTH-secreting tumor is located in the lungs, pancreas, thyroid, thymus, intestine, adrenal gland, paralymphadenopathy, or combinations thereof.

[008] In some modalities, treatment of ACTH-dependent Cushing's syndrome involves reducing serum cortisol levels, reducing urinary cortisol levels, or both. In some modalities, treatment of ACTH-dependent Cushing's syndrome involves reducing human cortisol levels by at least 10% from baseline.

[009] In some modalities, the treatment of ACTH-dependent Cushing's syndrome involves reducing serum levels of cortisol, androstenedione, or combinations thereof. In some modalities, the treatment of the syndrome Petition 870250089737, dated 02 / 10 / 2025, page 17 / 71 ACTH-dependent Cushing's syndrome is characterized by a reduction in serum levels of cortisol, androstenedione, or combinations thereof, by at least 10% compared to baseline values.

[0010] In some modalities, treatment of ACTH-dependent Cushing's syndrome involves reducing levels of cortisol, androstenedione (A4), 17-hydroxyprogesterone (17-OHP), aldosterone, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), or combinations thereof. In some modalities, treatment of ACTH-dependent Cushing's syndrome involves reducing levels of cortisol, androstenedione (A4), 17-hydroxyprogesterone (17-OHP), aldosterone, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), or combinations thereof, by at least 10% from baseline.

[0011] In some modalities, treatment of ACTH-dependent Cushing's syndrome involves postponing or eliminating the need for removal of one or both adrenal glands.

[0012] In some embodiments, approximately 80 mg, approximately 120 mg, or approximately 160 mg of Compound 1, or a pharmaceutically acceptable salt thereof, is administered. In some embodiments, approximately 80 mg of Compound 1, or a pharmaceutically acceptable salt thereof, is administered. In some embodiments, approximately 120 mg of Compound 1, or a pharmaceutically acceptable salt thereof, is administered. In some Petition 870250089737, dated 02 / 10 / 2025, p. 18 / 71 In 5 / 52 embodiments, approximately 160 mg of Compound 1, or a pharmaceutically acceptable salt thereof, is administered. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily, at night.

[0013] Articles of manufacture are provided, which include packaging material, Compound 1, or a pharmaceutically acceptable salt thereof, within the packaging material, and a label indicating that Compound 1, or a pharmaceutically acceptable salt thereof, is used to modulate the activity of a melanocortin receptor (e.g., melanocortin receptor subtype 2 (MC2R)), or for the treatment, prevention or improvement of one or more symptoms of a disease or condition that would benefit from modulation of the activity of a melanocortin receptor (e.g., melanocortin receptor subtype 2 (MC2R)), such as ACTH-dependent Cushing's Syndrome.

[0014] Other objectives, characteristics, and advantages of the compounds, methods, and compositions described in this document will become apparent from the detailed description that follows. It should be understood, however, that the detailed description and specific examples, while indicating specific embodiments, are provided only by way of illustration, since various alterations and modifications within the spirit and scope of the present description will become apparent to those skilled in the art. Petition 870250089737, dated 02 / 10 / 2025, page 19 / 71, based on this detailed description. DETAILED DESCRIPTION

[0015] Adrenocorticotropic hormone (ACTH) is a 39-amino acid peptide synthesized by corticotrophic cells of the adenohypophysis through proteolytic cleavage of proopiomelanocortin (POMC) hormone. ACTH is the main regulator of the synthesis and secretion of adrenal glucocorticoids (GC; cortisol in humans and most other species; corticosterone in rodents). As a central player in this hypothalamic-pituitary-adrenal (HPA) axis, ACTH is secreted by the pituitary gland in response to stressful stimuli and acts on the adrenal gland to stimulate cortisol synthesis and secretion. This stimulation is mediated by a highly specific G protein-coupled receptor (GPCR), which is expressed almost exclusively in the adrenal cortex. The receptor is the melanocortin receptor 2 (MC2R) and, together with ACTH, is part of the melanocortin system.

[0016] The melanocortin system comprises a family of five GPCRs (MC1R, MC2R, MC3R, MC4R, and MC5R); its natural agonists, the melanocortin peptides α, β, and γ melanocyte-stimulating hormone (α-MSH, β-MSH, and γ-MSH) and ACTH; and the endogenous antagonists of melanocortin, agouti and agouti-related protein (AGRP). Melanocortin receptors (MCRs) exhibit different selectivities for endogenous agonist and antagonist peptides and are Petition 870250089737, dated 02 / 10 / 2025, page 20 / 71 7 / 52 expressed in various tissues, where they perform varied and discrete physiological functions (Gantz, I. and TM Fong, Am. J. Physiol. Endocrinol. Metab., 284: E468-E474, 2003).

[0017] It is possible to selectively modulate any of the MCRs, or combinations thereof. In some modalities, selective modulation of any of the MCRs relative to other MCRs, or combinations thereof, is useful in various clinical applications. In some modalities, selective modulation of any of the MCRs relative to other MCRs, or combinations thereof, reduces undesirable side effects in various clinical applications. In one aspect, the compounds described in this document are MC2R antagonists. In some modalities, the compounds described in this document are selective MC2R antagonists relative to other MCRs.

[0018] MC2R is a highly selective receptor for ACTH. Although ACTH can activate all five MCRs, at physiological levels, the sensitivity of the other receptors is not high enough to be activated, and ACTH selectively activates MC2R. It is important to note that the other natural agonists α-MSH, β-MSH, and γ-MSH have no affinity for MC2R (Gantz, I. and TM Fong, Am. J. Physiol. Endocrinol. Metab., 284: E468-E474, 2003). The main function of MC2R is to stimulate cells in the zona fasciculata of the adrenal cortex to synthesize and secrete cortisol. MC2R requires the protein Petition 870250089737, dated 02 / 10 / 2025, p. 21 / 71 8 / 52 GPCR accessory protein, MRAP (melanocortin receptor protein 2), needs to be successfully secreted onto the cell surface and also to function. MRAP is a small protein with a single transmembrane domain that forms an antiparallel homodimer in a stable complex with MC2R and is required for both MC2R expression on the cell surface and its ability to bind ACTH. MRAP can bind to either MCR and affect its activities, but is essential only for MC2R activity. ACTH binding to the MC2R / MRAP complex in adrenal cortex cells activates Gs to elevate intracellular cAMP levels, which in turn stimulates cortisol synthesis and secretion, regulating multiple steps of the steroidogenic pathway. Cushing's disease

[0019] Cushing's syndrome (CS) is a constellation of clinical findings caused by prolonged exposure to excess glucocorticoids. The clinical presentation is quite variable and may include muscle weakness, fatigue, easy bruising, weight gain, menstrual irregularities, and stretch marks. Facial rounding, plethora, and prominent fat deposits in the dorsal and supraclavicular areas are common. CS is associated with multiple cardiovascular, metabolic, skeletal, psychiatric, and dermatological comorbidities that significantly reduce quality of life and functional status. Mortality increases due to Petition 870250089737, dated 02 / 10 / 2025, page 22 / 71 9 / 52 cardiovascular and infectious complications. These comorbidities and associated mortality are reduced with effective early treatment.

[0020] Cushing's syndrome (CS) can be caused by excessive amounts of adrenocorticotropic hormone (ACTH), either from a pituitary tumor (called Cushing's disease, CD) or from a non-pituitary (i.e., ectopic) ACTH-secreting tumor (AS). In these cases, excessive cortisol production is driven by normal or elevated ACTH levels, which are not suppressed by the negative feedback of cortisol. Alternatively, CS can be caused by exogenous glucocorticoids or by autonomous cortisol-secreting adrenal tumors. In these cases, the negative feedback effect of glucocorticoids on normal pituitary corticotropic hormones leads to suppression of ACTH levels. This difference in ACTH levels is used to distinguish between these two etiological mechanisms.

[0021] Surgical resection of the causative lesion(s) is the ideal treatment for SC, with the potential to restore normal hypothalamic-pituitary-adrenal function. However, some patients cannot undergo surgery due to risk or if the tumor is occult. For others, such as those with metastatic disease or invasive pituitary lesions, surgery will not be curative. Furthermore, although transsphenoidal surgery leads to a Petition 870250089737, dated 02 / 10 / 2025, page 23 / 71 10 / 52 Initial normalization of cortisol levels in 70% to 90% of patients in the hands of experienced neurosurgeons, permanent cure rates are estimated at 60% to 70%. Recurrences of CD have been reported months to decades after surgical outcomes initially considered curative. Primary pharmacological treatment is necessary for all such patients, and adjuvant medical treatment is necessary for CD patients undergoing radiation, until the tumor is controlled.

[0022] Current medical treatment for any cause of CS may target the adrenal gland by inhibiting enzymes that lead to cortisol synthesis (osilodrostat, ketoconazole, levoketoconazole, metyrapone, and etomidate) or the glucocorticoid receptor (to antagonize the action of glucocorticoids: mifepristone). CD therapy also includes agents that inhibit ACTH secretion: cabergoline and pasireotide. These agents are associated with toxicities that may preclude long-term use at effective doses (e.g., hypogonadism in men or liver function abnormalities in patients using ketoconazole), and the need for multiple agents to treat severe hypercortisolism increases the risk of adverse events.

[0023] In healthy individuals and those with ACTH-dependent adrenal insufficiency, ACTH acts on the adrenal gland to stimulate the Petition 870250089737, dated 02 / 10 / 2025, page 24 / 71 11 / 52 Cortisol synthesis and secretion through MC2R activation. Cortisol is the body's main stress hormone, and excessive amounts can cause significant increases in mortality and morbidity. Corticotropic adenomas are small, usually slow-growing, benign tumors that typically become clinically evident due to the effects of excess glucocorticoids, not due to physical effects caused by tumor expansion. Crohn's disease (CD) occurs much more commonly in women, usually between 30 and 50 years of age. CD often takes many years to be diagnosed, with an estimated time to diagnosis of 38 months, and may be underdiagnosed in the general population, as many of its symptoms, such as lethargy, depression, obesity, hypertension, hirsutism, and menstrual irregularity, may be incorrectly attributed to other more common disorders.

[0024] First-line therapy for ACTH-dependent CS is surgical and involves removal of the ACTH-secreting tumor in the pituitary gland or, in severe cases, the adrenal glands themselves. Because surgery is often unsuccessful, contraindicated, or delayed, pharmacological therapy for these patients becomes necessary. Adrenal enzyme inhibitors (e.g., metyrapone and ketoconazole) prevent cortisol synthesis and may improve Petition 870250089737, dated 02 / 10 / 2025, page 25 / 71 12 / 52 The symptoms, but suffer from mechanistic side effects. For example, metyrapone is associated with hirsutism in women, and patients should be carefully monitored to avoid hypoadrenalism, hypokalemia, and hypertension. Ketoconazole often requires progressive dosage increases to maintain disease control, but this is limited by the drug's hepatotoxicity. Furthermore, it is a potent inhibitor of one of the most important enzymes in drug metabolism in the liver, CYP3A4, resulting in potential for negative drug interactions as a side effect. Mifepristone, a potent glucocorticoid receptor antagonist, is approved for the control of hyperglycemia in Cushing's syndrome, but is difficult to titrate and has significant disadvantages due to its potent antiprogesterone activity.

[0025] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used in the treatment of Cushing's syndrome. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used in the treatment of ACTH-dependent Cushing's syndrome. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is used in the treatment of Cushing's disease. Compound 1

[0026] Compound 1 refers to 6-(2-ethoxyphenyl)-3 Petition 870250089737, dated 02 / 10 / 2025, page 26 / 71 13 / 52 ((R)-2-ethyl-4-(1-(trifluoromethyl)cyclobutane-1carbonyl)piperazin-1-yl)-N-((S)-quinuclidin-3yl)picolinamide, which has the chemical structure shown below. ΠCF3θ (Compound 1) .

[0027] Compound 1 is also known as N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2-ethoxyphenyl)-3-[(2R)-2-ethyl-4-[1-(trifluoromethyl)cyclobutanecarbonyl]piperazin-lyl]pyridine-2-carboxamide. Pre-Clinical Studies

[0028] Compound 1 is a potent oral, non-peptidic, small-molecule antagonist of MC2R (Ki < 10 nM), with selectivity > 2,900 times greater than other subtypes of human melanocortin receptors. Compound 1 potently blocked ACTH binding to the receptor, ACTH-mediated G protein activation, and subsequent cAMP production. In a screening for potential off-target activities, it showed weak antagonist activity and no agonist activity against the 5-HTib receptor, with selectivity more than 2200 times greater for hMC2R than for 5-HTib.

[0029] In vitro studies have evaluated the metabolism of Petition 870250089737, dated 02 / 10 / 2025, p. 27 / 71 14 / 52 Compound 1 was found in plasma, liver microsomes, and / or a 9000 g fraction of liver homogenate supernatant (S9 liver) from various species (including humans). The main metabolic pathways known to be involved in the metabolic clearance of Compound 1 are oxidative metabolism, resulting in the formation of hydroxylated and demethylated metabolites. CYP3A4 plays a key role in catalyzing these reactions; CYP2D6 and CYP2C8 may also have a minor contribution. CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP2C19 were not involved.

[0030] Oral administration of Compound 1 suppressed, in a dose-dependent manner, the secretion of corticosterone (the murine equivalent of cortisol in humans) after 1 pg / kg of ACTH(1-24) at doses of 3 and 10 mg / kg in male and female rats. After administration of ACTH 1, 4, 24 and 48 hours after a single dose of Compound 1, there was a dose-dependent suppression of corticosterone only at 1 and 4 hours.

[0031] Disease models simulating states of excess ACTH and hypercortisolism included rats that received exogenous ACTH(1-24) via subcutaneous osmotic pump for 7 days and mice implanted with ACTH-secreting AtT-20 corticotrophic tumor cells; the animals received daily oral doses of placebo or Compound 1. In each model, corticosterone values ​​on Days 1 and 7 showed a significant dose-dependent reduction. Petition 870250089737, dated 02 / 10 / 2025, page 28 / 71 15 / 52 reaching a maximum of 92%, with dose-dependent adrenal gland atrophy. Compound 1 also reduced ACTH-stimulated aldosterone levels, but did not affect angiotensin-II-stimulated aldosterone, which is responsible for most aldosterone production. However, six days after discontinuation of the highest dose of Compound 1 (75 mg / kg for 15 days), AngII-stimulated aldosterone was suppressed, but sodium and potassium levels remained normal.

[0032] The general non-clinical safety of Compound 1 was evaluated in 28-day and 3-month repeated-dose general toxicity studies in rats and dogs, and in a series of in vitro and in vivo genotoxicity and safety pharmacology studies. Repeated-dose toxicity studies demonstrated effects on rat lungs and dog adrenal glands and liver, which were further evaluated. Target organs of toxicity identified in repeated-dose toxicity studies included (1) foamy macrophages in the lungs in the 28-day rat study and (2) adrenal and hepatic atrophy in the 3-month dog study. The findings in rat lungs were confirmed as inconsistent with drug-induced DLP. The findings in the adrenal gland and liver in dogs were shown to be attenuated with hydrocortisone supplementation, demonstrating that these findings were an extension of Petition 870250089737, dated 02 / 10 / 2025, page 29 / 71 16 / 52 pharmacology. No findings were observed that indicated a significant genotoxic risk or adverse effects on essential organ systems, including the cardiovascular, central nervous, and respiratory systems. Treatment methods

[0033] In certain aspects, this document describes methods for treating ACTH-dependent Cushing's syndrome (CS) in an individual. ACTH-dependent Cushing's syndrome comprises Cushing's disease (CD) and ectopic ACTH syndrome (EAS). In some modalities, treatment involves reducing cortisol levels. In some modalities, treatment involves reducing cortisol levels induced by endogenous ACTH. In some modalities, the individual is a human being.

[0034] In some modalities, the treatment of ACTH-dependent Cushing's syndrome involves reducing cortisol levels in humans. In some modalities, the methods involve reducing endogenous cortisol levels. In some modalities, endogenous cortisol levels are reduced in the blood, serum, saliva, or urine. In some modalities, the methods involve reducing cortisol. In some modalities, cortisol levels are reduced in the blood, serum, saliva, or urine. In some modalities, blood cortisol levels are reduced. In some modalities, serum cortisol levels are reduced. In Petition 870250089737, dated 02 / 10 / 2025, p. 30 / 71 17 / 52 In some modalities, treatment of ACTH-dependent Cushing's syndrome comprises reducing serum cortisol levels, reducing urinary cortisol levels, or both. In some modalities, salivary cortisol levels are reduced. In some modalities, urinary free cortisol (UCC) levels are reduced. In some modalities, cortisol secretory capacity is reduced as determined by an ACTH stimulation test. In some modalities, treatment of ACTH-dependent Cushing's syndrome comprises reducing cortisol levels in humans by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or more than 30% of baseline levels. In some modalities, treatment for ACTH-dependent Cushing's syndrome involves reducing cortisol levels in the blood, saliva, or urine by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or more than 30% of the baseline level.In some modalities, treatment of ACTH-dependent Cushing's syndrome involves reducing cortisol levels in the blood, urine, or both by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or more than 30% of baseline levels. In some modalities, treatment of ACTH-dependent Cushing's syndrome involves reducing cortisol levels in the blood by at least 10%, at least 15%, at least 20%, at least 25%, at least. Petition 870250089737, dated 02 / 10 / 2025, p. 31 / 71 18 / 52 In some modalities, treatment of ACTH-dependent Cushing's syndrome involves reducing serum cortisol levels by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or more than 30% of baseline levels. In some modalities, treatment of ACTH-dependent Cushing's syndrome involves reducing salivary cortisol levels by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or more than 30% of baseline levels. In some modalities, treatment of ACTH-dependent Cushing's syndrome involves reducing urinary cortisol levels by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or more than 30% of baseline levels. In some modalities, cortisol levels are reduced compared to cortisol levels before treatment.In some modalities, cortisol levels are reduced to those of a human being without one of the diseases described in this document. In other words, in some modalities, cortisol levels are restored to normal levels in humans.

[0035] In some modalities, treatment of ACTH-dependent Cushing's syndrome involves reducing the levels of at least one of the following in the individual: serum cortisol, androstenedione, or combinations thereof. In some modalities, treatment of ACTH-dependent Cushing's syndrome involves reducing serum cortisol levels, Petition 870250089737, dated 02 / 10 / 2025, p. 32 / 71 19 / 52 androstenedione or combinations thereof. In some modalities, serum cortisol or androstenedione levels are reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or more than 30% from baseline. In some modalities, treatment of ACTH-dependent Cushing's syndrome involves reducing serum cortisol, androstenedione, or combinations thereof by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or more than 30% from baseline.

[0036] In some modalities, treatment of ACTH-dependent Cushing's syndrome involves reducing levels of cortisol, androstenedione (A4), 17-hydroxyprogesterone (17-OHP), aldosterone, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), or combinations thereof. In some modalities, levels of any of cortisol, androstenedione (A4), 17-hydroxyprogesterone (17OHP), aldosterone, dehydroepiandrosterone sulfate (DHEAS), or dehydroepiandrosterone (DHEA) are reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, or more than 30% from baseline. In some modalities, the treatment of ACTH-dependent Cushing's syndrome involves reducing levels of cortisol, androstenedione (A4), 17-hydroxyprogesterone (17-OHP), aldosterone, dehydroepiandrosterone sulfate (DHEAS), or Petition 870250089737, dated 02 / 10 / 2025, page 33 / 71 20 / 52 dehydroepiandrosterone (DHEA) or combinations thereof, at least 10%, at least 15%, at least 20%, at least 25%, at least 30% or more than 30% of the baseline level.

[0037] In some modalities, treatment of ACTH-dependent Cushing's syndrome involves treating one or more symptoms of Cushing's syndrome. In some modalities, treatment of ACTH-dependent Cushing's syndrome involves reducing the growth of fat deposits (clavicle, nape of the neck, face, and trunk), excessive sweating, capillary dilation, thinning of the skin, muscle weakness, hirsutism, depression / anxiety, hypertension, osteoporosis, insulin resistance, hyperglycemia, heart disease, lethargy, obesity (including truncal, abdominal, or central obesity), menstrual irregularity, or combinations thereof. In some modalities, treatment of ACTH-dependent Cushing's syndrome involves reducing the growth of fat deposits (clavicle, nape of the neck, and face). In some modalities, treatment of ACTH-dependent Cushing's syndrome involves reducing excessive sweating.In some modalities, treatment of ACTH-dependent Cushing's syndrome includes reducing capillary dilation. In some modalities, treatment of ACTH-dependent Cushing's syndrome includes reducing skin thinning. In some modalities, treatment of ACTH-dependent Cushing's syndrome includes reducing... Petition 870250089737, dated 02 / 10 / 2025, page 34 / 71 21 / 52 Muscle weakness. In some modalities, treatment of ACTH-dependent Cushing's syndrome includes reduction of hirsutism. In some modalities, treatment of ACTH-dependent Cushing's syndrome includes reduction of depression / anxiety. In some modalities, treatment of ACTH-dependent Cushing's syndrome includes reduction of hypertension. In some modalities, treatment of ACTH-dependent Cushing's syndrome includes reduction of osteopenia, osteoporosis, or fracture risk. In some modalities, treatment of ACTH-dependent Cushing's syndrome includes reduction of insulin resistance, risk of hyperglycemia, diabetes mellitus, or need for glucose-lowering medications. In some modalities, treatment of ACTH-dependent Cushing's syndrome includes reduction of hypertension or need for blood pressure-lowering medications.

[0038] In some modalities, the treatment of EAS involves reducing potassium abnormalities in the blood or the risk of thrombosis.

[0039] In some modalities, treatment of ACTH-dependent Cushing's syndrome includes reduction of hyperglycemia. In some modalities, treatment of ACTH-dependent Cushing's syndrome includes reduction of heart disease. In some modalities, treatment of ACTH-dependent Cushing's syndrome includes reduction of Petition 870250089737, dated 02 / 10 / 2025, page 35 / 71 22 / 52 lethargy. In some modalities, treatment of ACTH-dependent Cushing's syndrome includes reduction of obesity. In some modalities, treatment of ACTH-dependent Cushing's syndrome includes reduction of menstrual irregularity, infertility, hirsutism, acne, or androgen-induced hair loss in women.

[0040] In some modalities, treatment of ACTH-dependent Cushing's syndrome involves delaying or eliminating the need for removal of one or both adrenal glands. Individuals

[0041] In some modalities, the individual is a human. In some modalities, the individual has a disease associated with excess ACTH. In some modalities, the individual presents with ACTH-dependent Cushing's syndrome.

[0042] In some forms, an individual with ACTH-dependent Cushing's syndrome presents with at least two of the following symptoms: (i) failure to suppress serum cortisol to < 1.8 pg / dL during a 1 mg Dexamethasone Suppression Test (DST); (ii) at least 4 consecutive values ​​of salivary bedtime cortisol > ULN, where each value was obtained within an interval of approximately 7 to 14 days; and (iii) at least 4 consecutive values ​​of 24-hour urinary free cortisol (UFC) > 1.3 x ULN, without any lower values, where each value was obtained within an interval of approximately 7 to 14 days. Petition 870250089737, dated 02 / 10 / 2025, p. 36 / 71 23 / 52 interval of about 7 to 14 days.

[0043] In some modalities, the individual presents elevated serum cortisol in the low-dose dexamethasone suppression test. In some modalities, the human presents a serum cortisol level of 1.8 mcg / dL or higher the morning after the nighttime administration of 1 mg of dexamethasone.

[0044] In some modalities, humans have a higher nocturnal salivary cortisol level than the ULN for a human. In some modalities, humans have a nocturnal salivary cortisol level that is at least 1.5, 2.0, 2.5 or more than the ULN. In some modalities, the ULN for the nocturnal salivary cortisol level is about 100 ng / dL.

[0045] In some modalities, humans have a 24-hour urinary free cortisol (UFC) level higher than the ULN for a human. In some modalities, humans have a 24-hour UFC of at least 1.3 or more than the ULN. In some modalities, humans have a 24-hour UFC of at least 1.5, 2.0, 2.5 or more than the ULN. In some modalities, humans exhibit a 24-hour UFC greater than approximately 50 mcg / day, 100 mcg / day, 150 mcg / day, 200 mcg / day or more on a 24-hour urinary cortisol test. In some modalities, the ULN for 24-hour urinary cortisol excretion is approximately 50 to 55 mcg / day. Petition 870250089737, dated 02 / 10 / 2025, pp. 37 / 71 24 / 52

[0046] In some embodiments, ACTH-dependent Cushing's syndrome comprises: (a) nocturnal serum cortisol >7.5 mg / dL, or salivary cortisol at bedtime > ULN, wherein cortisol levels are measured before commencement of treatment with Compound 1, or a pharmaceutically acceptable salt thereof; and (b) morning plasma ACTH > 10 pg / mL, wherein plasma ACTH is measured before commencement of treatment with Compound 1, or a pharmaceutically acceptable salt thereof.

[0047] In some forms, the human being with ACTH-dependent Cushing's syndrome presents with a pituitary tumor (pituitary adenoma) or corticotrophic adenoma. In some forms, the human being with ACTH-dependent Cushing's syndrome presents with a pituitary tumor (pituitary adenoma). In some forms, the human being with ACTH-dependent Cushing's syndrome presents with a corticotrophic adenoma. In some forms, the pituitary adenoma or corticotrophic adenoma is benign. In some forms, the treatment of ACTH-dependent Cushing's syndrome includes corticotrophic adenoma.

[0048] In other forms, the human being presents with an ectopic ACTH-secreting tumor. In some forms, the human being presents with an ACTH-secreting tumor in an organ that does not normally produce ACTH. In some forms, the ACTH-secreting tumor is located in the lungs, pancreas, thyroid, thymus, intestine, adrenal gland, paraganglia. Petition 870250089737, dated 02 / 10 / 2025, pp. 38 / 71 25 / 52 lymph nodes or a combination thereof. In some forms, the ACTH-secreting tumor is cancerous. In some forms, the ACTH-secreting tumor is benign. Dosage and administration

[0049] In one embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, is used in the preparation of medicaments for the treatment of ACTH-dependent Cushing's syndrome. Methods for treating ACTH-dependent Cushing's syndrome in an individual requiring such treatment involve administering pharmaceutical compositions that include at least Compound 1, or a pharmaceutically acceptable salt thereof, in amounts therapeutically effective to said individual.

[0050] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered orally to humans. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to humans on a continuous dosing schedule. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered to humans on a continuous daily dosing schedule.

[0051] The term continuous dosing regimen refers to administration at regular intervals. In some modalities, continuous dosing regimen refers to administration at regular intervals without any Petition 870250089737, dated 02 / 10 / 2025, pp. 39 / 71 26 / 52 interruption of the specific therapeutic agent medication.

[0052] The term continuous daily dosing regimen refers to the administration of a specific therapeutic agent every day, at approximately the same time. In some modalities, daily administration is once a day.

[0053] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily, at night.

[0054] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount equivalent to about 50 mg to about 200 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount equivalent to about 80 mg to about 160 mg of Compound 1.

[0055] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount equivalent to approximately: 80 mg, 120 mg, or 160 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount equivalent to approximately 80 mg of Compound 1. In some embodiments, Compound 1, or a salt Petition 870250089737, dated 02 / 10 / 2025, pp. 40 / 71 27 / 52 pharmaceutically acceptable of the same, is administered in an amount equivalent to about 120 mg of Compound 1. In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount equivalent to about 160 mg of Compound 1.

[0056] In certain cases, it is appropriate to administer at least one additional therapeutic agent in combination with Compound 1, or a pharmaceutically acceptable salt thereof. Adrenal Blockade and Replacement Therapy with Glucocorticoids

[0057] In a specific embodiment, Compound 1, or a pharmaceutically acceptable salt thereof, is co-administered with one or more additional therapeutic agents, wherein the one or more additional therapeutic agents are selected from a glucocorticoid, a mineralocorticoid, or a combination thereof. In some embodiments, the administration of Compound 1, or a pharmaceutically acceptable salt thereof, comprises a reduction in the exogenous glucocorticoid dose requirements for humans. Examples of glucocorticoids contemplated for co-administration include, but are not limited to, beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, etamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, or similar agents. Examples of mineralocorticoids contemplated for Petition 870250089737, dated 02 / 10 / 2025, pp. 41 / 71 28 / 52 co-administration includes, among others, fludrocortisone and similar drugs.

[0058] In some modalities of treatment for ACTH-dependent Cushing's syndrome, Compound 1, or a pharmaceutically acceptable salt thereof, is co-administered with a second therapeutic agent, wherein the second therapeutic agent is a glucocorticoid (i.e., blockade and replacement therapy). In some modalities, the glucocorticoid is beclomethasone, betamethasone, budesonide, cortisone, dexamethasone, etamethasoneb, hydrocortisone, methylprednisolone, prednisolone, prednisone, or triamcinolone. In some modalities of treatment for ACTH-dependent Cushing's syndrome, Compound 1, or a pharmaceutically acceptable salt thereof, is co-administered with a low-dose glucocorticoid. In some modalities, the low-dose glucocorticoid comprises less than or equal to 20 mg / day of cortisone equivalent. In some modalities, the low-dose glucocorticoid comprises less than or equal to 15 mg / day of cortisone equivalent.In some embodiments, the low-dose glucocorticoid comprises less than or equal to 10 mg / day of cortisone equivalent. In some embodiments, the low-dose glucocorticoid comprises less than or equal to 5 mg / day of cortisone equivalent.

[0059] In some treatment modalities of the syndrome Petition 870250089737, dated 02 / 10 / 2025, p. 42 / 71 29 / 52 of ACTH-dependent Cushing's syndrome, the method further comprises the administration of adrenal glucocorticoid replacement therapy if serum cortisol is < 5 pg / dL; wherein serum cortisol is measured in the early morning. In some embodiments, the early morning occurs between approximately 5:30 a.m. and approximately 8:00 a.m. In some embodiments, adrenal glucocorticoid replacement therapy comprises hydrocortisone. In some embodiments, hydrocortisone is administered at a physiological hydrocortisone replacement dose. In some embodiments, hydrocortisone is administered at a supraphysiological hydrocortisone replacement dose.

[0060] In some modalities of treatment for ACTH-dependent Cushing's syndrome, the method additionally includes the administration of mineralocorticoid replacement therapy. In some modalities, mineralocorticoid replacement therapy includes fludrocortisone. Pharmaceutical compositions

[0061] In some embodiments, Compound 1, or a pharmaceutically acceptable salt thereof, is formulated into pharmaceutical compositions. The pharmaceutical compositions are conventionally formulated using one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of the active compounds into preparations for pharmaceutical use. The appropriate formulation depends on the route of administration. Petition 870250089737, dated 02 / 10 / 2025, pp. 43 / 71 30 / 52 chosen administration. A summary of the pharmaceutical compositions described in this document can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), incorporated herein by reference for such description.

[0062] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units, such as capsules or tablets, each containing a predetermined amount of Compound 1, or a pharmaceutically acceptable salt thereof; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as a liquid oil-in-water emulsion or a liquid water-in-oil emulsion. Specific terminology

[0063] Unless otherwise indicated, the following terms used in this application have the definitions set out below. The use of the term including, as well as its other forms, such as includes, include and included, is not limiting. The section headings used Petition 870250089737, dated 02 / 10 / 2025, pp. 44 / 71 31 / 52 in this document are for organizational purposes only and should not be interpreted as limiting the subject matter described.

[0064] As used in this descriptive report and claims, the singular forms a, an, or include plural references unless the context clearly indicates otherwise. For example, the term a sample includes a plurality of samples, including mixtures thereof.

[0065] As used in this document, the term about a number refers to that number plus or minus 10% of that number. The term about a range refers to that range with a 10% reduction from its minimum value and a 10% increase from its maximum value.

[0066] The terms determine, measure, assess, gauge, test, and analyze are frequently used interchangeably in this document to refer to forms of measurement. The terms include determining whether an element is present or not (e.g., detection). These terms may include quantitative, qualitative, or both quantitative and qualitative determinations. Assessment may be relative or absolute. Detecting the presence of may include determining the quantity of something present, as well as determining whether it is present or absent, depending on the context.

[0067] The acceptable term, in relation to a formulation, composition or ingredient, as used in this document, Petition 870250089737, dated 02 / 10 / 2025, pp. 45 / 71 32 / 52 means that it does not present a persistent harmful effect on the overall health of the individual undergoing treatment.

[0068] The term modular, as used in this document, means interacting with a target, directly or indirectly, in order to alter its activity, including, by way of example, intensifying the target's activity, inhibiting the target's activity, limiting the target's activity, or prolonging the target's activity.

[0069] The term modulator, as used in this document, refers to a molecule that interacts with a target, directly or indirectly. Interactions include, but are not limited to, agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some modalities, a modulator is an agonist.

[0070] The terms administer, administration, administering, and the like, as used in this document, refer to methods that may be used to enable the dispensing of compounds or compositions to the desired site of biological action. Such methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical administration, and rectal administration. Those skilled in the art are familiar with the delivery techniques that may be used with the compounds and methods described. Petition 870250089737, dated 02 / 10 / 2025, pp. 46 / 71 33 / 52 in this document. In some embodiments, the compounds and compositions described in this document are administered orally.

[0071] The terms co-administration or similar, as used in this document, encompass the administration of selected therapeutic agents to a single patient and include treatment regimens in which the agents are administered by the same or different routes of administration, or at the same or different times.

[0072] The terms effective amount or therapeutically effective amount, as used in this document, refer to a sufficient quantity of an administered agent or compound that is capable of relieving, at least in part, one or more symptoms of the disease or condition being treated. The result includes the reduction and / or relief of the signs, symptoms, or causes of the disease, or any other desired alteration in a biological system. For example, an effective amount for therapeutic uses is the amount of the composition comprising a compound as described in this document necessary to provide a clinically significant reduction in the symptoms of the disease. An appropriate effective amount in each individual case may optionally be determined by techniques such as dose escalation studies.

[0073] The term pharmaceutical combination, according Petition 870250089737, dated 02 / 10 / 2025, pp. 47 / 71 34 / 52 used in this document refers to a product resulting from the mixture or combination of more than one active ingredient and includes both fixed and non-fixed combinations of these active ingredients. The term fixed combination means that the active ingredients, for example, Compound 1, or a pharmaceutically acceptable salt thereof, and a co-agent, are both administered to the patient simultaneously as a single entity or dosage. The term non-fixed combination means that the active ingredients, for example, Compound 1, or a pharmaceutically acceptable salt thereof, and a co-agent, are administered to the patient as separate entities, either simultaneously, concomitantly or sequentially, without specific time limits between administrations, provided that such administration provides effective levels of both compounds in the patient's body. This latter definition also applies to combination therapy, for example, the administration of three or more active ingredients.

[0074] The terms manufacturing article and kit are used synonymously.

[0075] The terms individual or patient encompass mammals. Examples of mammals include, without limitation, any member of the class Mammalia: humans, non-human primates such as chimpanzees, other apes and monkey species; farm animals such as cattle, horses, sheep, goats. Petition 870250089737, dated 02 / 10 / 2025, pp. 48 / 71 35 / 52 and swine; domestic animals such as rabbits, dogs and cats; laboratory animals including rodents such as rats, mice and guinea pigs, among others. In one aspect, the mammal is a human being.

[0076] The terms treat, treating or treatment, as used in this document, include relieving, abate or improving at least one symptom of a disease or condition, preventing further symptoms, inhibiting the disease or condition, for example, halting the development of the disease or condition, alleviating the disease or condition, causing regression of the disease or condition, alleviating a condition caused by the disease or condition or halting the symptoms of the disease or condition.

[0077] Throughout this application, various embodiments may be presented in a range format. It should be understood that the range description is merely for convenience and brevity and should not be interpreted as an inflexible limitation on the scope of the description. Therefore, the description of a range should be considered as having specifically described all possible subintervals as well as individual numerical values ​​within that range. For example, the description of a range from 1 to 6 should be considered as having specifically described subintervals such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numbers within that range, e.g., 1, 2, 3, 4, Petition 870250089737, dated 02 / 10 / 2025, pp. 49 / 71 36 / 52 and 6. This applies regardless of the interval width.

[0078] The section headings used in this document are for organizational purposes only and should not be interpreted as limiting the subject matter described. EXAMPLES

[0079] The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention. Example 1: Open-label, multiple ascending dose, phase lb / 2a exploratory study of Compound 1 in ACTH-dependent Cushing's syndrome.

[0080] A non-limiting example of a clinical trial with an ACTH antagonist in humans is described below. Study Description

[0081] This is an exploratory, open-label, uncontrolled, multiple-dose, first-contact Phase 11 / 2a study to evaluate the safety, tolerability, and pharmacokinetics (PC) of Compound 1 in participants with ACTH-dependent Cushing's syndrome (Cushing's disease or ectopic ACTH syndrome).

[0082] The study will require a 14-day hospital stay, during which participants will receive oral Compound 1 once daily for 10 days, followed by monitoring during a 4-day washout period. Vital signs will be obtained and Petition 870250089737, dated 02 / 10 / 2025, pp. 50 / 71 37 / 52 safety laboratory tests. Objectives

[0083] Primary objectives: To evaluate the safety and tolerability of Compound 1 in participants with ACTH-dependent Cushing's syndrome. To evaluate the pharmacokinetics of Compound 1 in participants with ACTH-dependent Cushing's syndrome.

[0084] Secondary objective: To document the change in morning serum cortisol (~05:30-08:00).

[0085] Exploratory objectives: To demonstrate the reduction of urinary free cortisol (UFC) in participants with ACTH-dependent Cushing's syndrome. To evaluate the effect of Compound 1 on ACTH, other adrenal steroids, clinical and biochemical characteristics. Outcomes

[0086] Primary outcome: Assessment of the safety and tolerability of Compound 1 in participants with ACTH-dependent Cushing's syndrome: • Daily assessment for adrenal insufficiency with morning serum cortisol, adrenal insufficiency questionnaire, in-person consultation • Measurement of complete blood count with differential, electrolytes, urea, glucose, creatinine, and liver function tests Petition 870250089737, dated 02 / 10 / 2025, pp. 51 / 71 38 / 52 • Insulin measurement and pituitary function tests pre- and post-treatment • Daily ECG assessments • Aldosterone and renin activity

[0087] Pharmacokinetic outcomes: • Peak plasma concentration on Day 1 and Day 10 (Cmax) • Time to reach Cmax on Day 1 and Day 10 (tmax) • Area under the plasma concentration versus time curve on Day 1 and Day 10 (AUC0-24) • Accumulation index for Cmax • Accumulation index for AUC • Terminal half-life

[0088] Secondary outcome: Change from baseline in serum cortisol in the early morning (~05:30-08:00) on Day 11.

[0089] Exploratory Outcomes: Except where otherwise indicated, all exploratory outcomes assess the change from baseline to Day 11. Change in CLU. 30% reduction in CLU. Change in morning plasma ACTH (~05:30-08:00). Change in the area under the plasma concentration-time curve over 24 hours (AUC) in serum cortisol, 11-oxygenated androgens (11-ketotestosterone [11KT] and 11β-hydroxyandrostenedione [11OHΔ4A]) and plasma ACTH. Petition 870250089737, dated 02 / 10 / 2025, pp. 52 / 71 39 / 52 Percentage of participants who normalize the upper limit of normal (ULN) of the CLU on Day 11. CLU on Days 10-11 as a percentage of the ULN. Correlation between baseline pituitary lesion size and CLU response.

[0090] Change in morning values ​​from baseline to Day 11 values ​​and percentage of each cohort with normal values ​​at baseline and Day 11 for the following variables: • Serum and urinary potassium (mEq / L) • Plasma glucose (mg / dL) and fructosamine (gmol / L) • Insulin sensitivity (Homeostatic Model Assessment of Insulin Resistance [HOMA-IR]) • Systolic blood pressure (mmHg) • Diastolic blood pressure (mmHg) • Weight (kg) and waist circumference (cm) Study population

[0091] Up to 40 participants, aged 18 to 75 years, screened with a confirmed diagnosis of active ACTH-dependent Cushing's syndrome (Cushing's disease or ectopic ACTH syndrome), to achieve 6 finishers for each dose cohort. Inclusion Criteria:

[0092] To participate in this study, participants must have active ACTH-dependent Cushing's syndrome. They Petition 870250089737, dated 02 / 10 / 2025, pp. 53 / 71 40 / 52 may be participants currently under the care of the research team who are awaiting surgery or radiotherapy, or who have failed surgery and / or are awaiting response to radiotherapy. Participants who do not meet the remission criteria within five days of resection of a possible ACTH-producing tumor will not be eligible to begin screening until 6 weeks after the date of surgery. Alternatively, they may be participants who will be admitted for evaluation of the cause of Cushing's syndrome.

[0093] To be eligible to participate in this study, the individual must meet all of the following criteria: provision of a signed and dated informed consent form; ability to understand and be willing to sign a written informed consent form; willingness to comply with all study procedures and interventions; ability to take oral medication; male or female sex, age between 18 and 75 years; COVID-19 vaccination according to current CDC recommendations; evidence supporting the diagnosis of Cushing's syndrome, defined as meeting 2 of the following 3 criteria performed up to 56 days prior to Day 1: (i) Failure to suppress serum cortisol to ≥1.8 pg / dL during a 1 mg Dexamethasone Suppression Test (DST) may be used in all participants except for women taking oral estrogen-containing medications, Petition 870250089737, dated 02 / 10 / 2025, pp. 54 / 71 41 / 52 (ii) at least 4 (at 7- to 14-day intervals) consecutive bedtime salivary cortisol values ​​> ULN, (iii) at least 4 (at 7- to 14-day intervals) consecutive 24-hour urinary free cortisol (UFC) values ​​> 1.3 x ULN without any lower values ​​(however, for participants with previously confirmed ACTH-dependent Cushing's syndrome who are awaiting surgery or radiotherapy, or who have failed surgery or are awaiting the effects of radiotherapy, a DST is not required and only one additional elevated UFC or bedtime salivary cortisol value is required within three weeks of Day 1); Evidence of active ACTH-dependent Cushing's syndrome within 14 days of Day 1, defined as: (i) nocturnal serum cortisol (approximately 11:00 PM–12:00 AM) >7.5 pg / dL, or salivary cortisol at bedtime > ULN, and (ii) morning plasma ACTH (~5:30 AM–8:00 AM) >10 pg / mL.Participants with documented ACTH-dependent Cushing's syndrome using short-acting steroidogenesis inhibitors (ketoconazole, levoketoconazole, osilodrostat, cabergoline, or metyrapone) may participate after a 14-day washout period if they meet other study inclusion criteria. Exclusion criteria:

[0094] An individual who meets any of the following criteria will be excluded from participation in this Petition 870250089737, dated 02 / 10 / 2025, pp. 55 / 71 42 / 52 study: pregnant or breastfeeding women; history of bilateral adrenalectomy; if you have ever had adrenal insufficiency while taking Compound 1 in this study; previous pituitary MRI findings of a lesion 3 mm from the optic chiasm; presence of any known malignancy; a CLU more than 5 times the ULN; mitotane use; use of prohibited prescription or non-prescription drugs and / or non-medicinal / alternative medicinal products within 7 days prior to screening and unwillingness to discontinue use of these substances during the study; use of medications that are strong inducers of cytochrome (CYP)3A4 within 30 days prior to enrollment; use of medications or food intake that are strong or moderate inhibitors of CYP3A4 within 14 days prior to enrollment; use of medications that are strong or moderate inducers of P-gp within 14 days prior to the first dose of the study drug;Use of medications that are strong or moderate P-gp inhibitors in the 14 days prior to the first dose of the study drug; use of any investigational drug in the last 30 days or for 5 half-lives, whichever is greater, before the day of administration of Compound 1; any condition that, in the opinion of the Investigator, may compromise the participant's adequate participation in this study; prior unsuccessful surgery for Cushing's syndrome in the previous 6 weeks; and abnormal baseline ECG of any of the following; Petition 870250089737, dated 02 / 10 / 2025, pp. 56 / 71 43 / 52 ways: (a) based on the average of triplicated ECGs, QTcF > 500 ms (or QTcF > 530 ms in participants with bundle branch block) repeated in a second set of ECGs at least 2 hours apart and confirmed by the Principal Investigator; (b) any ventricular tachyarrhythmia associated with symptoms of hemodynamic response; (c) prolonged ventricular tachycardia (lasting > 30 s) regardless of symptoms; (d) Torsades de pointes; (e) cardiac arrest; (f) pause > 5 s; (g) second-degree type II block or third-degree atrioventricular block; (h) clinically significant symptomatic bradycardia; (i) any supraventricular tachyarrhythmia associated with symptoms of hemodynamic response. Lifestyle considerations:

[0095] During this study, participants are asked to do the following: abstain from consuming bitter orange, grapefruit, pomelo, exotic citrus fruits, grapefruit hybrids, or more than 8 ounces (230 ml) of juice containing these fruits, beginning 7 days before the first dose of Compound 1 until after the final dose; abstain from consuming red wine, beginning 2 days before the first dose of Compound 1 until after the final dose; participants who use tobacco products will be instructed that the use of products containing nicotine will not be permitted within the Clinical Center; abstain from strenuous exercise during Petition 870250089737, dated 02 / 10 / 2025, pp. 57 / 71 44 / 52 for the entire duration of the study. General Study Design

[0096] This is an exploratory, open-label, uncontrolled, single-center, multiple ascending-dose phase 11 / 2a study to evaluate the safety, tolerability, pharmacokinetics, and signs of efficacy of Compound 1 (an ACTH receptor antagonist) in participants with active ACTH-dependent Cushing's syndrome.

[0097] Six people will participate in each dose cohort, as available consecutively. Participants may participate in more than one dose cohort. The study requires a 14-day hospitalization, during which participants will receive oral Compound 1 once daily for 10 days, followed by monitoring during a 4-day washout period. Vital signs and safety laboratory tests will be obtained on alternate days. Blood cortisol levels and 24-hour CLU will be the primary measures of efficacy signals. There will be a safety follow-up review between days 24 and 31. Justification for Dose

[0098] The initial dose of 80 mg is based on available toxicological and clinical data from studies with healthy volunteers. Lower doses are unlikely to adequately control serum and urinary cortisol in participants with Cushing's syndrome, in whom the levels Petition 870250089737, dated 02 / 10 / 2025, pp. 58 / 71 Baseline ACTH and cortisol levels (45 / 52) will be significantly higher than those observed in healthy volunteers. The proposed maximum daily dose is 160 mg. Based on the population pharmacokinetic model, this dose is projected to have mean steady-state Cmax and AUC0-24 of 2510 ng / mL and 31,800 ngxh / mL, respectively. Histopathological findings (i.e., lung, adrenal gland, and liver) observed in repeated-dose toxicity studies in rats and dogs generally occur only after repeated dosing and likely correlate with total exposure (AUC) rather than peak exposure (Cmax). Therefore, Compound 1 is expected to be safely administered to healthy participants with ACTH-dependent Cushing's syndrome at planned doses up to 160 mg. Intervention

[0099] Compound: 1 oral tablet once daily for 10 days. Three dose-escalating cohorts are planned: 80, 120, and 160 mg per day. The first cohort will receive an 80 mg dose. Subsequent cohorts may receive 120 and 160 mg. Participant duration: up to 45 days.

[00100] Sequential, open-label, fixed-dose cohorts of 10 days, with 6 participants: • Cohort 1: Compound 1 80 mg once daily • Cohort 2: Compound 1 120 mg once daily Petition 870250089737, dated 02 / 10 / 2025, pp. 59 / 71 46 / 52 • Cohort 3: Composite 1 160 mg once daily

[00101] Participants will receive Compound 1 at the dose appropriate for their cohort, once daily, for 10 days, at approximately 8 a.m. The tablets will be taken orally with 240 mL of water. The drug can be taken before or after breakfast, as the effect of food on absorption is minimal. Glucocorticoid Deficiency

[00102] Glucocorticoid deficiency is an adverse event of special interest (AEE) that may occur as a result of the pharmacological action of Compound 1. Glucocorticoid deficiency will be treated with glucocorticoid replacement at doses determined by the investigator. Mild to moderate glucocorticoid deficiency will not result in modification of the study drug, provided there is an immediate clinical response of any symptoms or signs related to glucocorticoid treatment, in the investigator's opinion.

[00103] Glucocorticoid deficiency was observed during treatment with Compound 1 in a previous study involving healthy volunteers, consistent with the pharmacological action of the drug under study. Therefore, it was identified as an adverse event in this study and may lead to dose-limiting toxicity.

[00104] Mild to moderate deficiency of Petition 870250089737, dated 02 / 10 / 2025, pages 60 / 71 47 / 52 glucocorticoid deficiency is defined as inappropriately low basal or ACTH-stimulated serum cortisol concentrations, with or without related concomitant symptoms or signs (e.g., nausea, anorexia, hyponatremia). In all participants with serum cortisol < 5 pg / dL in the early morning (~05:30-08:00), initiation of hydrocortisone (HC) therapy is recommended, regardless of symptoms.

[00105] Severe (hypotensive) glucocorticoid deficiency is defined as an acute deterioration in health status, including, among others, the above signs and symptoms, associated with absolute hypotension (systolic blood pressure < 100 mm Hg) or relative hypotension (systolic blood pressure > 20 mm Hg below usual), with features that resolve within 1 to 2 hours after parenteral administration of glucocorticoids (i.e., a marked resolution of hypotension within 1 hour and improvement of clinical symptoms within 2 hours).

[00106] Participants diagnosed with glucocorticoid deficiency will receive hydrocortisone (and other possible interventions) according to severity. Diagnosis and management of glucocorticoid insufficiency and supervision of hydrocortisone therapy will be overseen by the researcher, and participants will be treated according to the standard of care. Petition 870250089737, dated 02 / 10 / 2025, pages 61 / 71 48 / 52

[00107] Before initiating HC therapy, if possible, blood should be collected for measurement of serum cortisol, ACTH, aldosterone, renin activity, biochemistry (sodium, potassium, glucose) and any scheduled hormone assays.

[00108] For asymptomatic participants or those with mild symptoms, the HC dosage should be administered at a physiological HC replacement dose.

[00109] The dosage of the drug under study may be continued, under careful supervision, if one of the following scenarios occurs: (1) the participant is on physiological carbohydrate replacement and asymptomatic; OR (2) any symptoms or signs related to mild to moderate glucocorticoid deficiency respond promptly to treatment with glucocorticoids, as determined by the investigator. Screening Procedures

[00110] Cushing's syndrome will be determined by the results of the 1 mg dexamethasone suppression test, 4 or more elevated salivary cortisol levels at bedtime and / or 4 or more elevated CLU levels > 1.3 times the normal; OR by an elevated CLU or salivary cortisol value at 21 days, for patients whose Cushing's syndrome was confirmed within 56 days of inclusion.

[00111] Participants with active Cushing's syndrome will undergo the following screening activities. Petition 870250089737, dated 02 / 10 / 2025, pages 62 / 71 49 / 52 only after signing consent for this study: pregnancy test, 12-lead triplicate ECG and measurement of electrolytes, glucose, blood urea nitrogen, creatinine, alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transferase (GGT), complete blood count, nocturnal serum cortisol, pituitary magnetic resonance imaging and morning plasma ACTH. Study Assessments and Procedures

[00112] The study requires the collection of biospecimens before, during, and 10 days after administration of the study drug, Compound 1.

[00113] The physical examination will include measurement of height, weight, abdominal circumference, and vital signs (blood pressure, pulse, temperature, respiratory rate) using automated pulse and blood pressure monitoring with an appropriately sized cuff, assessment of the thyroid gland, heart and lung sounds, abdominal sounds, sensitivity, organ size, presence of abnormal adipose tissue deposits (dorsocervical, supraclavicular, temporal) or marked central adiposity, presence of acne, hirsutism, stretch marks or hyperpigmentation, muscle strength, and mini-mental state examination. BMI will be calculated once for the initial examination on Day 1.

[00114] Participants will receive instructions on how to complete an online questionnaire about symptoms of Petition 870250089737, dated 02 / 10 / 2025, pages 63 / 71 50 / 52 Adrenal insufficiency. Participants will complete a questionnaire about Cushing's syndrome. The questionnaire will ask the participant: In the last few days, how bothered have you been by the following symptoms? For each symptom, choose the answer that best matches your experience. Symptoms include: Mental confusion, Difficulty concentrating, Difficulty sleeping, Abdominal bloating or distension, Anxiety, Depression, and Irritability, and the answers are: Not at all, A little, Moderately, Extremely, and Very. Biospecimen Assessments

[00115] Screening, safety, and efficacy measures include complete blood count with differential, liver panel, GGT, ACTH, cortisol, androstenedione, 11-oxygenated androgens (11KT and 11OHΔ4A), 17-OH progesterone, dehydroepiandrosterone (DHEA), progesterone, testosterone, prolactin, IGF-1, growth hormone, intensive care panel, POMC-related peptides, fructosamine, insulin, LH, FSH, testosterone (men), estradiol (women), renin activity, aldosterone, and pharmacokinetics of Compound 1.

[00116] The total amount of blood collected during the 16 to 28 days of the study (including variable time for screening) is 279 mL.

[00117] Urine samples (cortisol, creatinine, Petition 870250089737, dated 02 / 10 / 2025, pages 64 / 71 51 / 52 potassium, sodium, volume): Collect urine for 24 hours, starting at approximately 8:00 AM on the study days. Correlative Studies for Research / Pharmacokinetic Studies

[00118] Plasma samples will be collected for measurement of plasma concentration of the study drug, as specified in the AOS (Table 1). Samples will be collected for pharmacokinetic evaluation on Day 1 and Day 10, pre-dose, and 0.25, 0.5, 1.0, 1.5, 2, 8, and 18 hours after dose administration. Pharmacokinetic sampling times within the first 120 minutes should be within ±5 minutes of the specified time; after this period, a window of ±30 minutes is allowed. Individual pharmacokinetic samples will be collected on Day 11 and Day 12 (approximately 24 and 48 hours after the last dose administration on Day 10, respectively) and on Day 14.

[00119] Although preferred embodiments of the present invention have been shown and described in this document, it will be obvious to those skilled in the art that such embodiments are provided only as examples. Numerous variations, alterations, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described in this document may be used in the practice of the invention. Petition 870250089737, dated 02 / 10 / 2025, pp. 65 / 71 52 / 52 The following claims are intended to define the scope of the invention, and the methods and structures within the scope of these claims and their equivalents are intended to be covered by them. Petition 870250089737, dated 02 / 10 / 2025, pp. 66 / 71

Claims

1 / 4 CLAIMS 1. A method for treating adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome in a human, characterized in that it comprises the once-daily oral administration of about 80 mg to about 160 mg of a compound having the structure of Compound 1, or a pharmaceutically acceptable salt thereof: (Compound 1).

2. Method, according to claim 1, characterized in that a human being with ACTH-dependent Cushing's syndrome presents a pituitary adenoma.

3. Method according to claim 1, characterized in that a human being with ACTH-dependent Cushing's syndrome presents an ectopic ACTH-secreting tumor.

4. Method according to claim 3, characterized in that the ectopic ACTH-secreting tumor is located in the lungs, pancreas, thyroid, thymus, intestine, adrenal gland, paralymphadenopathy, or combinations thereof.

5. Method, according to any of the claims 1 to 4, characterized in that the treatment of ACTH-dependent Cushing's syndrome comprises reducing serum cortisol levels, reducing urinary cortisol levels, or both.

6. Method, according to claim 5, characterized in that the treatment of ACTH-dependent Cushing's syndrome comprises reducing cortisol levels in humans by at least 10% relative to baseline values.

7. A method, according to any one of claims 1 to 6, characterized in that the treatment of ACTH-dependent Cushing's syndrome comprises reducing serum levels of cortisol, androstenedione, or combinations thereof.

8. Method, according to claim 7, characterized in that the treatment of ACTH-dependent Cushing's syndrome comprises reducing serum levels of cortisol, androstenedione, or combinations thereof by at least 10% relative to baseline values.

9. A method, according to any one of claims 1 to 6, characterized in that the treatment of ACTH-dependent Cushing's syndrome comprises reducing levels of cortisol, androstenedione (A4), 17-hydroxyprogesterone (17-OHP), aldosterone, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA) or combinations thereof.

10. Method according to claim 9, characterized in that the treatment of ACTH-dependent Cushing's syndrome comprises reducing the levels of cortisol, androstenedione (A4), 17-hydroxyprogesterone (17-OHP), aldosterone, dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), or combinations thereof, by at least 10% relative to the baseline value.

11. A method, according to any one of claims 1 to 10, characterized in that the treatment of ACTH-dependent Cushing's syndrome comprises postponing or eliminating the need for removal of one or both adrenal glands.

12. Method, according to any one of claims 1 to 11, characterized in that about 80 mg, about 120 mg or about 160 mg of Compound 1, or a pharmaceutically acceptable salt thereof, are administered.

13. A method according to any one of claims 1 to 11, characterized in that approximately 80 mg of Compound 1, or a pharmaceutically acceptable salt thereof, is administered.

14. Method, according to any one of claims 1 to 11, characterized in that approximately 120 mg of Compound 1, or a pharmaceutically acceptable salt thereof, are administered.

15. Method, according to any one of claims 1 to 11, characterized in that about 160 mg of Compound 1, or a pharmaceutically acceptable salt thereof, are administered.

16. Method, according to any one of claims 1 to 15, characterized in that Compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily, at night. Petition 870250089737, dated 10 / 02 / 2025, pp. 70 / 71