Atumelnant Reduces Key CAH Biomarkers, Hits Primary Phase 2 Endpoint

Alan Krasner, MD

Credit: Crinetics Pharmaceuticals

Topline results were positive in the Phase 2 TouCAHn trial investigating atumelnant, a novel oral adrenocorticotropic hormone (ACTH) receptor antagonist candidate, for the treatment of classic congenital adrenal hyperplasia (CAH) and ACTH-dependent Cushing’s syndrome.¹

Announced by Crinetics Pharmaceuticals, Inc., on January 10, 2025, atumelnant achieved rapid reductions in key CAH biomarkers, including an up to 80% reduction in mean androstenedione, while notably improving the clinical signs and symptoms of CAH.

“This Phase 2 study demonstrated that atumelnant was well-tolerated and resulted in a reduction of adrenal androgen levels so rapid and robust that it allowed patients to realize meaningful improvements in long-term, pre-existing medical challenges, even within the short 12-week treatment period of this study,” Alan Krasner, MD, chief endocrinologist of Crinetics, said in a statement.¹

Atumelnant is the first once-daily, oral ACTH receptor antagonist acting selectively at the melanocortin type 2 receptor (MC2R) on the adrenal gland. Excess ACTH-linked diseases can significantly impact physical and mental health.² Preclinical models have shown the strong binding affinity of atumelnant for MC2R in preclinical models, as well as the suppression of adrenal-derided glucocorticoids and androgens under the control of ACTH.¹

The open-label, global TouCAHn trial measured the efficacy, safety, and pharmacokinetics of atumelnant administered for 12 weeks in patients with CAH due to 21-hydroxylase deficient. A total of 28 patients with CAH receiving a stable dose of glucocorticoid replacement were enrolled across 3 dose cohorts.

Multiple primary endpoints for TouCAHn included the change from baseline in morning serum androstenedione (A4) levels and the incidence of treatment-emergent adverse events (TEAEs). Secondary endpoints included the change from baseline in morning serum 17-hydroxyprogesterone (17-OHP).

Once-daily atumelnant led to substantial and sustained statistically significant reductions in A4 levels at 12 weeks, meeting the key biomarker for disease control. Analyses showed individuals treated with atumelnant 40 mg (n = 11), with a mean A4 baseline level of 1213 ng/dL, achieved a reduction of –619 ng/dL (P = .0003). Those treated with atumelnant 80 mg (n = 11), with a mean A4 baseline level of 1231 ng/dL, achieved a reduction of –774 ng/dL (P <.0001).

Patients treated with the highest dose of atumelnant (120 mg; n = 6), with a mean A4 baseline level of 1064 ng/dL, achieved a reduction of –954 ng/dL (P <.0001), at the 12-week mark.

Atumelnant also significantly impacted CAH signs and symptoms, including a substantial reduction and normalization of testosterone in most female participants (n = 8 of 13), with 6 resuming menses. Atumelnant also demonstrated a consistent reduction in total adrenal volume across dose cohorts and a resolution of androgen-mediated polycythemia in 5 of 6 impacted patients.

Safety reports showed a tolerable profile of atumelnant, with no treatment-related severe or serious adverse events, regardless of disease severity or dose level. None of the participants in TouCAHn required dose reduction or trial discontinuation. Most adverse events were labeled mild to moderate, with the most common events including headache (n = 7) and fatigue (n = 5).

In the release, Crinetics announced plans to move forward with a global Phase 3 pivotal trial for this population, as well as preparation for a Phase 2b/3 trial in children with CAH.¹

“These exciting results show atumelnant not only lowered key biomarkers but also had a significant impact on the signs and symptoms of CAH that are important to the overall health of people living with this condition,” Scott Struthers, PhD, founder and chief executive officer of Crinetics, said in a statement.¹ “We are eager to move forward with a global Phase 3 pivotal trial for adults in CAH, as we simultaneously prepare to start a Phase 2b/3 trial in pediatric patients this year.”

References

1. _{Crinetics announces positive topline results from phase 2 trial of atumelnant in congenital adrenal hyperplasia (CAH. Crinetics Pharmaceuticals - Developing Therapies for Endocrine Diseases. January 10, 2025. Accessed January 10, 2025. https://crinetics.com/crinetics-announces-positive-topline-results-from-phase-2-trial-of-atumelnant-in-congenital-adrenal-hyperplasia-cah/.}
2. _{Bertagna X. Effects of Chronic ACTH Excess on Human Adrenal Cortex. Front Endocrinol (Lausanne). 2017;8:43. Published 2017 Mar 8. doi:10.3389/fendo.2017.00043}