Once daily atumelnant (CRN04894) enables lowering of glucocorticoid doses with sustained androgen reduction in adults with congenital adrenal hyperplasia

Umasuthan Srirangalingam; Dario Bruera; Rodrigues Adriane Maria; Alejandro Ayala; Yang Wu; la Torre Ames Eduardo De; Alan Krasner; Peter J. Trainer; Monica R. Gadelha; Nicole Reisch; Costa-Barbosa Flavia Amanda; Santos Nunes-Nogueira Vania dos; Richard J. Auchus; Tania A.S.S. Bachega

doi:10.1530/endoabs.118.PO89

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Endocrine Abstracts (2026) 118 PO89 | DOI: 10.1530/endoabs.118.PO89

IDSD2026 Poster Abstracts Poster Abstracts (93 abstracts)

Once daily atumelnant (CRN04894) enables lowering of glucocorticoid doses with sustained androgen reduction in adults with congenital adrenal hyperplasia

Umasuthan Srirangalingam ¹ , Dario Bruera ² , Adriane Maria Rodrigues ³ , Alejandro Ayala ⁴ , Yang Wu ⁴ , Eduardo De la Torre Ames ⁴ , Alan Krasner ⁴ , Peter J. Trainer ⁴ , Mônica R. Gadelha ⁵ , Nicole Reisch ⁶ , Flavia Amanda Costa-Barbosa ⁷ , Vania dos Santos Nunes-Nogueira ⁸ , Richard J. Auchus ⁹ & Tania A.S.S. Bachega ¹⁰

Author affiliations

¹Endocrinology & Diabetes, University College London Hospitals NHS Foundation Trust, London, UK; ²Hospital Misericordia, Córdoba, Argentina; ³Division of Endocrinology and Metabolism (SEMPR), Department of Internal Medicine, Hospital de Clínicas, Universidade Federal do Paraná, Curitiba, Brazil; ⁴Crinetics Pharmaceuticals, Inc., San Diego, California, USA; ⁵Centro de Pesquisa Clínica, Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro, RJ, Brazil; ⁶Medizinische Klinik and Poliklinik IV, Klinikum der Universität München, LMU München, Munich, Germany; ⁷Adrenal and Hypertension Unit, Division of Endocrinology and Metabolism, Department of Medicine, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil; ⁸Department of Internal Medicine, São Paulo State University (UNESP), Medical School, Botucatu, São Paulo, Brazil; ⁹Division of Metabolism, Endocrinology, and Diabetes and the Departments of Internal Medicine and Pharmacology, University of Michigan, Ann Arbor, Michigan, USA; ¹⁰Laboratorio de Hormonios e Genetica Molecular-LIM 42, da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil. Correspondence to: [email protected]

Background: Atumelnant (CRN04894) is a first-in-class, once-daily, oral, selective melanocortin type 2 receptor antagonist in development for the treatment of congenital adrenal hyperplasia (CAH). A 12-week, Phase 2, open-label study (NCT05907291) was conducted to evaluate the efficacy and safety of atumelnant in adults with classic CAH (21-hydroxylase deficiency).

Methods: Participants with morning A4 level ≥1.5 times the upper limit of normal were enrolled in 4 dose cohorts of once-daily, oral atumelnant. Cohorts 1-3 (40, 80, or 120 mg at bedtime) maintained stable glucocorticoid (GC) dosing (≥15 mg hydrocortisone equivalent) throughout the study. Cohort 4 (80 mg in the morning [AM]) had stable GC dosing (≥11 mg/m²/d hydrocortisone equivalent) prior to screening, and reduced GC dose stepwise to target <11 mg/m²/d. The primary efficacy endpoint was change from baseline (CFB) to Week 12 in early morning pre-GC serum A4. Percent CFB in GC daily dose was an exploratory endpoint for Cohort 4.

Results: Thirty-eight participants (55.3% women; mean [range] age 33.2 [20-64] years; mean [range] GC dose 27.1 [20-40] mg/d [hydrocortisone equivalent], median [range] A4 34.2 (4.03-96.19) nmol/l [reference range: women, 1.05-6.98 nmol/l; men, 1.40-5.24 nmol/l]) were enrolled (40-mg, n = 11; 80-mg, n = 11; 120-mg, n = 6; 80-mg AM with GC reduction, n = 10). Two participants discontinued, both from Cohort 4 (withdrew consent). At Week 12, median (range) percent CFB in morning serum A4 was: 40-mg, −65.2% (−94.3%, −5.5%); 80-mg, −80.1% (−98.7%, −21.6%); 120-mg, −81.6% (−91.4%, −53.5%); 80-mg AM, −74.9% (−89.7%, −26.6%). In Cohort 4, the mean (SE) percent change from baseline at Week 12 in GC daily dose was −17.6% (9.1%), with 7/8 participants (87.5%) achieving a physiologic daily GC dose at Week 12. In all, 31 participants had ≥1 treatment-emergent adverse event (TEAE); none were severe or serious. Sixteen participants experienced TEAEs related to treatment, but none led to treatment discontinuation.

Conclusions: In adults with classic CAH, GC dose reduction did not diminish the atumelnant-induced androgen reduction. Additionally, morning atumelnant dosing resulted in similar A4 reductions as those observed with evening administration. These results highlight the potential for ACTH antagonism to achieve control of androgen levels with physiologic doses of GC replacement.

Acknowledgements: Technical editorial and medical writing assistance were provided under the direction of the authors by Ryan Avenatti, PhD, Crinetics Pharmaceuticals, and Matthew Rich, PhD, from Citrus Health Group, Inc. (Chicago, Illinois); funding for this support was provided by Crinetics Pharmaceuticals, Inc. (San Diego, California).

Funding: Crinetics Pharmaceuticals, Inc. (San Diego, California).

Disclosures: US received consulting fees from Crinetics Pharmaceuticals, Diurnal Ltd, and H Lundbeck A/S and received consulting fees and research support from Neurocrine Biosciences. DB has nothing to disclose. AMR is a principal investigator for Crinetics Pharmaceuticals and Spruce Biosciences and has received speaker fees from Merck Brasil Company. AA, YW, EDlTA, AK, and PJT are employees of Crinetics Pharmaceuticals and own stocks and shares from Crinetics Pharmaceuticals. MRG has received speaker fees from Camarus, Crinetics, Novo Nordisk, and Recordati and has attended advisory boards for Crinetics Pharmaceuticals, Novo Nordisk, and Recordati. NR has received consulting fees from Crinetics Pharmaceuticals, Diurnal Ltd, H Lundbeck A/S, Neurocrine Biosciences, Spruce Biosciences and received conference travel support from Recordati Rare Diseases. FAC-B has nothing to disclose. VdSN-N has nothing to disclose. RJA contracted research support and consulting fees from Corcept Therapeutics, Crinetics Pharmaceuticals, Diurnal Ltd, H Lundbeck A/S, Neurocrine Biosciences, Recordati Rare Diseases, and Spruce Biosciences; contracted research support from Adrenas Therapeutics and Mineralys Pharmaceuticals; and received consulting fees from Novo Nordisk, Quest Diagnostics, Sparrow Pharmaceuticals, and Xeris Pharmaceuticals. TASSB is a principal investigator for Crinetics Pharmaceuticals and Spruce Biosciences and has received consulting fees from Novo Nordisk.