Disclosure: N. Reisch: Crinetics Pharmaceuticals, Diurnal, Lundbeck A/S, Neurocrine Biosciences, Recordati Rare Diseases, Spruce Biosciences. R.J. Auchus: Neurocrine Biosciences, Diurnal, Corcept Therapeutics, Recordati Rare Diseases, Crinetics Pharmaceuticals, Adrenas, Spruce Biosciences, Quest Diagnostics, Xeris Pharmaceuticals, Novo Nordisk, H Lundbeck A/S, Sparrow Pharmaceuticals. U. Srirangalingam: Crinetics Pharmaceuticals, Diurnal, H Lundbeck A/S. T.A. Bachega: Crinetics Pharmaceuticals, Spruce Biosciences, Novo Nordisk. A. Ayala: Crinetics. Y. Wu: Crinetics Pharmaceuticals. E. De La Torre Ames: Crinetics Pharmaceuticals. A. Krasner: Crinetics Pharmaceuticals. L. Kjems: Crinetics Pharmaceuticals. D.P. Merke: Diurnal, Neurocrine Biosciences, Adrenas Therapeutics through the National Institutes of Health Cooperative Research and Development Agreements. In classic congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency (21-OHD), normal steroidogenesis pathways are disrupted, leading to a decrease in cortisol and aldosterone levels and virilization due to excess adrenal androgens. Traditional biomarkers of disease activity include 17-hydroxyprogesterone (17-OHP) and androstenedione (A4). The adrenals produce 11β-hydroxyandrostenedione (11-OHA4), which is metabolized to the potent androgen 11-ketotestosterone (11-KT); these 11-oxygenated androgens substantially contribute to the total androgen burden in patients with CAH. Atumelnant, a first-in-class competitive and selective melanocortin type 2 receptor (adrenocorticotropic hormone receptor) antagonist, was assessed in a Phase 2, open-label, dose-finding study. Adults age ≥18-75 years with classic CAH taking stable doses of glucocorticoid (GC) replacement therapy (≥15 mg daily dose hydrocortisone equivalent) for ≥6 months and morning serum A4 level ≥1.5 times the upper limit of normal were enrolled in 3 dose cohorts of oral atumelnant, 40 mg, 80 mg, 120 mg once daily for 12 weeks. A total of 28 patients (40 mg, n=11; 80 mg, n=11; 120 mg, n=6) completed treatment; 54% were women; mean (range) age 31.3 (20-47) years; and mean (range) GC dose 28.9 (20-40) mg/day hydrocortisone equivalent. Baseline 11-OHA4 was mean (range) 997 (142-3128) ng/dL, and baseline 11-KT was mean (range) 303 (54-1292) ng/dL. At week 2, the mean (SE) percent change from baseline (CFB) in morning 11-OHA4 for the 40-, 80-, and 120-mg cohorts was −49% (9.8), −74% (6.9), and −85% (4.6), respectively; at week 12, CFB was −60% (10.8), −68% (11.4), and −82% (3.5), respectively. The mean (SE) percent CFB in morning 11-KT for the 40-, 80-, and 120-mg cohorts at week 2 was −40% (11.1), −56% (13.0), and −79% (7.3), respectively; at week 12, CFB was −58% (10.0), −58% (13.2), and −77% (7.2), respectively. In conclusion, atumelnant results in rapid and substantial reductions of 11-oxygenated androgens and the traditional biomarkers A4 and 17-OHP in patients with classic CAH. The reduction in total androgen burden may explain previously reported improvements in clinical outcomes within the 12-week time frame of this study. Presentation: Sunday, July 13, 2025

Disclosure: U. Srirangalingam: Crinetics, Diurnal Ltd, H Lundbeck A/S. D. Bruera: None. A. Ayala: Crinetics. Y. Wu: Crinetics. E. De La Torre Ames: Crinetics. A. Krasner: Crinetics. M.R. Gadelha: Camarus, Ipsen, Novo Nordisk, Recordati, Crinetics. N. Reisch: Crinetics, Diurnal Ltd, Lundbeck A/S, Neurocrine Biosciences, Recordati Rare Diseases, Spruce Biosciences. F. Costa-Barbosa: None. V. dos Santos Nunes-Nogueira: None. R.J. Auchus: Neurocrine Biosciences, Diurnal Ltd, Corcept Therapeutics, Recordati Rare Diseases, Crinetics, Adrenas, Spruce Biosciences, Quest Diagnostics, Xeris Pharmaceuticals, Novo Nordisk, H Lundbeck A/S, Sparrow Pharmaceuticals. T.A. Bachega: Crinetics, Spruce Biosciences, Novo Nordisk. Atumelnant (CRN04894) is a potent, once-daily, orally bioavailable, nonpeptide, first-in-class competitive and selective melanocortin type 2 receptor (MC2R, or adrenocorticotropic hormone receptor) antagonist being developed for the treatment of congenital adrenal hyperplasia (CAH). We report results from 3 of 4 cohorts of a 12-week, Phase 2, open-label, dose-finding study of atumelnant in patients with CAH (NCT05907291). Adults with classic CAH (21-hydroxylase deficiency) on a stable dose of glucocorticoid (GC) replacement (≥15 mg hydrocortisone equivalent) for ≥6 months and androstenedione (A4) level ≥1.5 times the upper limit of normal (ULN) were enrolled in 3 dose cohorts (40 mg, 80 mg, or 120 mg) and received oral atumelnant once daily for 12 weeks. The primary efficacy endpoint was change from baseline (CFB) to week 12 in early morning pre-GC serum A4. CFB in pre-GC serum 17-hydroxyprogesterone (17-OHP) levels and, in men, serum A4:testosterone were secondary and exploratory endpoints, respectively. Menstrual cycle diaries were completed by female patients throughout the study period. As of October 16, 2024, 28 patients (54% women; mean [range] age 31.3 [20-47] years; mean [range] GC dose 28.4 [20-40] mg/day [hydrocortisone equivalent]) had completed treatment (40 mg, n=11; 80 mg, n=11; 120 mg, n=6). Overall, baseline median (range) A4 was 1049 (116-2755) ng/dL (reference range [RR]; women 30-200 ng/dL; men 40-150 ng/dL) and baseline median (range) 17-OHP was 12,750 (453-44,000) ng/dL (RR: women <80 ng/dL [follicular], <285 ng/dL [luteal]; men, <220 ng/dL); there were no meaningful differences between groups in baseline values. At week 12, median (range) morning A4 was reduced from baseline by 65% (5.5%-94%), 80% (22%-99%), and 82% (54%-91%) and 17-OHP was reduced by 84% (1.8%-97%), 86% (21%-99%), and 70% (12%-95%) in the 40-, 80-, and 120-mg cohorts, respectively. At week 12, A4 was Presentation: Saturday, July 12, 2025

Adrenocorticotropic hormone 1-24 (ACTH[1-24]) has a similar effect as endogenous ACTH(1-39) to generate cortisol by targeting the MC2R receptor on the adrenal gland. A new investigational ACTH receptor antagonist drug is being developed to treat diseases of ACTH excess (e.g., Cushing's disease) by binding to the MC2R receptor. Administration of ACTH(1-24) was used in a Phase I clinical study to assess the ability of this drug candidate to suppress the cortisol response to ACTH stimulation. A hybrid immunoaffinity-LCMS assay measuring ACTH(1-24) with a concentration range of 10 to 400 pg/ml was developed to support the study. Consistent and acceptable A&P results were achieved. The assay development and qualification will be discussed.

Abstract Disclosure: R.J. Auchus: Consulting Fee; Self; Corcept Therapeutics, H Lundbeck A/S, Quest Diagnostics, Sparrow Pharmaceuticals, Neurocrine Biosciences, Novo Nordisk, Recordati Rare Diseases, Diurnal, Xeris Pharmaceuticals. Research Investigator; Self; Corcept Therapeutics, Adrenas Therapeutics, Neurocrine Biosciences, Diurnal, Spruce Biosciences. P.J. Trainer: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc.. K.J. Lucas: None. D. Bruera: None. J. Marko: Consulting Fee; Self; Crinetics Pharmaceuticals, Inc. A. Ayala: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. Y. Wu: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. C.T. Ferrara-Cook: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. E. De La Torre: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. A. Krasner: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. H. Lagast: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. R. Luo: Employee; Self; Crinetics Pharmaceuticals Inc.. Stock Owner; Self; Crinetics Pharmaceuticals Inc. T.A. Bachega: Research Investigator; Self; Spruce Biosciences. R.S. Struthers: Employee; Self; Crinetics Pharmaceuticals Inc.. Stock Owner; Self; Crinetics Pharmaceuticals Inc. S.F. Betz: Employee; Self; Crinetics Pharmaceuticals, Inc.. Stock Owner; Self; Crinetics Pharmaceuticals, Inc. U. Srirangalingam: Consulting Fee; Self; Diurnal, H Lundbeck A/S. Atumelnant (CRN04894) is a potent, once-daily, orally bioavailable, nonpeptide, first-in-class competitive and selective melanocortin type 2 receptor (MC2R, or ACTH receptor) antagonist being developed for the treatment of CAH and ACTH-Dependent Cushing’s Syndrome. Here we report initial results from an open-label, dose-finding phase 2 study of atumelnant in patients with CAH (NCT05907291). Patients (aged ≥18-75, ≥16 years in USA) with classical CAH on a stable dose of GC replacement for at least 6 months were enrolled and received once daily, oral atumelnant for 12 weeks. Key efficacy endpoints include early morning androstenedione (A4) and 17-hydroxyprogesterone (17-OHP) levels. Ten (10) participants have been enrolled and dosed. Data from the first 4 participants (3 females, median age 34 [range 25-42] years, methylprednisone 8 mg/day [hydrocortisone equivalent {HCeq} 32 mg/day, n=2], prednisone 10 mg/day [HCeq 40 mg/day, n=2]) who received 80 mg once daily, oral atumelnant are available. Baseline morning A4 levels in these participants ranged from 116 to 604 ng/dL (reference range [RR]: females 30-200 ng/dL; males 40-150 ng/dL). In these 4 participants, treatment with atumelnant resulted in rapid and profound A4 reductions within 2 weeks which were maintained for the duration of therapy. A4 reductions ranged from 74% to 99% throughout the study. There have been no instances of A4 being above the upper limit of normal on treatment with atumelnant. Baseline 17-OHP levels in these participants ranged from 4740 to 6905 ng/dL (RR: females <80 ng/dL [follicular], <285 ng/dL [luteal]; males <220 ng/dL). In these 4 participants, treatment with atumelnant resulted in rapid and profound 17-OHP reductions within 2 weeks which were maintained for the duration of therapy. 17-OHP reductions ranged from 68% to >99% throughout the study. Two female participants in this cohort menstruated for the first time in over 2 years. Mean baseline morning ACTH ranged from 155 to 1009 pg/mL (RR: 7.2-63 pg/mL), and while modest variations were seen with atumelnant, no consistent directional trend was observed. In conclusion, these data demonstrate rapid, profound, and sustained suppression of A4 and 17-OHP with 80 mg once daily, oral atumelnant. There were no serious or treatment-related adverse events and atumelnant was generally well-tolerated. This ongoing study will explore further the safety and efficacy of various doses of atumelnant. Support: Crinetics Pharmaceuticals, Inc. Presentation: 6/3/2024

Abstract Disclosure: A. Ayala: Employee; Self; Crinetics Pharmaceuticals Inc. C. LaCerte: Employee; Self; Crinetics Pharmaceuticals Inc. R. Luo: Employee; Self; Crinetics Pharmaceuticals Inc. C. Davidson: Employee; Self; Crinetics Pharmaceuticals Inc. J. Wang: Employee; Self; Crinetics Pharmaceuticals Inc. P. Trainer: Employee; Self; Crinetics Pharmaceuticals Inc. A. Krasner: Employee; Self; Crinetics Pharmaceuticals Inc. Clinical trials of cortisol-lowering drug candidates would benefit from user-friendly methods to measure cortisol in an outpatient setting. CRN04894 is a potent, orally bioavailable, MC2R antagonist in development for the treatment of ACTH-dependent Cushing’s syndrome and congenital adrenal hyperplasia. We have previously reported results from a randomized, double-blinded, placebo-controlled (6 active:3 placebo/cohort), multiple (10-day) ascending dose (40 to 80 mg/day) study in healthy volunteers. Declines in basal and ACTH-stimulated serum cortisol levels and a median reduction of 75% in 24-hr urinary-free cortisol (UFC) were seen in the 80 mg cohort. Asymptomatic glucocorticoid deficiency (defined as 08:00 serum cortisol of <5 µg/dL) was the most commonly observed adverse event. Here we report the comparison of salivary cortisol measurements with serum cortisol day curves and 24-hr UFC observed in this study. We evaluated cortisol and ACTH data from the three cohorts dosed once daily (QD) at 22:00 with either 40, 60, or 80 mg. Cortisol (salivary & serum) and ACTH day curves (results reported as the mean of 4 or 5 available samples collected at 22:00, 08:00, 12:00, 16:00 & 20:00) studies were undertaken on days -1, 1, 4, and 9. Mean serum cortisol was moderately correlated with 24-hr UFC:creatinine ratio (ug/g) (r = 0.495) and strongly correlated (r = 0.734) with mean salivary cortisol. There was across all three doses of CRN04894 a consistent magnitude ranking change in measured cortisol analytes: serum (free plus bound) < saliva < urine, with substantial changes being seen within 24 hours of initiation of CRN04894 and no loss of cortisol suppression over 9 days despite median ACTH changes of >1000% from baseline (60 & 80 mg doses). Time-matched individual saliva and serum cortisol values were used (without timepoint or visit restrictions) to explore the relationship between low serum cortisol and salivary levels. A saliva cutoff for cortisol deficiency was optimized for diagnostic accuracy (92.2%) using a serum cortisol value of <5 µg/dL as the reference. Four subjects had 08:00 serum cortisol <5 µg/dL and saliva cortisol data. All four cases were correctly identified as cortisol-deficient using a simultaneous saliva cortisol cutoff of <0.0491 µg/dL. In conclusion, CRN04894 effectively lowered cortisol measured in serum, saliva, and urine in healthy volunteers. Salivary cortisol measured by tandem mass spectrometry correlated well with serum cortisol day curves and may be useful in the diagnosis of biochemical cortisol deficiency in outpatient studies. Future studies will explore the use of salivary glucocorticoid measurement in patients with Cushing’s disease receiving CRN04894. Presentation: Saturday, June 17, 2023

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