Crinetics Reports Positive Early Results at ENDO 2024 for Atumelnant in CAH and ADCS Studies

Crinetics Pharmaceuticals, Inc. (Nasdaq: CRNX) has unveiled promising initial data from its second clinical product candidate, atumelnant (CRN04894), an innovative once-daily oral adrenocorticotropic hormone (ACTH) receptor antagonist. This information was presented during the Endocrine Society’s annual meeting (ENDO2024) and includes data from both a Phase 1b/2a trial in participants with ACTH-dependent Cushing’s syndrome (ADCS) and the Phase 2 TouCAHn study in individuals with congenital adrenal hyperplasia (CAH).

According to Scott Struthers, Ph.D., founder and CEO of Crinetics, understanding ACTH’s role in endocrine stress responses has been a century-long endeavor. However, human studies on ACTH antagonist drug candidates have been lacking until now. Struthers highlighted that achieving normal hormone levels is essential for those with CAH and ADCS, and the current data underscores atumelnant's capability to reduce critical disease drivers to healthy levels. He also praised the company’s discovery engine and the novel mechanisms of action designed for their medicines.

In the Phase 2 trial (TouCAHn), participants with classic CAH were given oral atumelnant daily and evaluated for safety and efficacy. The trial, which continues to enroll participants, includes three treatment cohorts with doses of 80 mg, 40 mg, and 120 mg. As of the cutoff date on May 21, 2024, data for the 80 mg dose included four participants with 12 weeks of treatment and two additional participants with six weeks of treatment. For the 40 mg dose, data was available for four participants over two weeks of treatment. The ongoing study is expected to deliver topline results in the latter half of 2024.

Key baseline biomarker levels for Cohort 1 subjects were:
- Androstenedione (A4) mean: 838 ng/dL
- 17-hydroxyprogesterone (17-OHP) mean: 9,880 ng/dL

Initial results demonstrated remarkable reductions in key adrenal steroids. All participants maintained A4 levels below the upper limit of normal (ULN) at two weeks, with continued reduction through 12 weeks. Specifically:
- A4 reductions from baseline mean:
- 91% at two weeks
- 93% at six weeks
- 96% at 12 weeks
- 17-OHP reductions from baseline mean:
- 97% at two weeks
- 95% at six weeks
- 94% at 12 weeks

No severe adverse events were reported, and all observed adverse events were mild to moderate and transient. Common treatment-emergent adverse events included fatigue, headache, and upper respiratory tract infection.

Dr. Umasuthan Srirangalingam of University College London Hospitals highlighted that atumelnant’s unique inhibition of ACTH directly at its receptor is a significant advancement compared to traditional treatments involving high doses of glucocorticoids.

In the ADCS trial, five participants completed a 10-day atumelnant treatment regimen (80 mg daily), showing rapid and substantial reductions in cortisol:
- All participants achieved normalization of 24-hour urine free cortisol levels during treatment.
- Improvements in serum cortisol were observed in all participants, with at least two clinical symptoms improving in each case.

Dr. Lynnette Nieman from the National Institutes of Health expressed optimism about atumelnant’s potential, noting the unmet needs in ADCS patient populations.

Atumelnant demonstrated good tolerability, with mild to moderate adverse events such as headache, nausea, and decreased appetite. The drug showed strong binding affinity for the melanocortin type 2 receptor (MC2R), effectively suppressing ACTH-controlled glucocorticoids and androgens in preclinical models.

Atumelnant is currently under Phase 2 development for CAH and ACTH-dependent Cushing’s syndrome, aiming to improve treatment options for these conditions. Crinetics Pharmaceuticals remains focused on the discovery and development of novel endocrine therapeutics, including ongoing efforts in various other endocrine indications.