Crinetics Pharmaceuticals announced positive topline results from its Phase 2 TouCAHn trial, evaluating atumelnant, a novel, once-daily oral adrenocorticotropic hormone (ACTH) receptor antagonist, for the treatment of classic congenital adrenal hyperplasia (CAH). The open-label, global study demonstrated significant reductions in key biomarkers and improvements in clinical symptoms in adults with CAH caused by 21-hydroxylase deficiency.
The TouCAHn trial enrolled 28 patients with classic CAH across three dose cohorts (40 mg, 80 mg, and 120 mg) who were on a stable dose of glucocorticoid replacement. The primary endpoint was the change from baseline in morning serum androstenedione (A4) levels, a key biomarker for disease control, and the incidence of treatment-emergent adverse events. Secondary endpoints included changes in morning serum 17-hydroxyprogesterone (17-OHP) levels.
Significant Biomarker Reductions
Treatment with atumelnant resulted in rapid, substantial, and sustained statistically significant reductions in A4 levels across all doses. Specifically, the A4 change from baseline at week 12 was -619 ng/dL (p=0.0003) in the 40 mg cohort (n=11, baseline A4 1,213 ng/dL), -774 ng/dL (p<0.0001) in the 80 mg cohort (n=11, baseline A4 1,231 ng/dL), and -954 ng/dL (p<0.0001) in the 120 mg cohort (n=6, baseline A4 1,064 ng/dL). Similar reductions were observed in 17-OHP levels, a confirmatory secondary biomarker of disease control.
Impact on CAH Signs and Symptoms
Atumelnant also had a significant impact on CAH signs and symptoms. In female participants, substantial reduction and normalization of testosterone were observed in the majority (8/13), with six of the eleven impacted participants resuming menses. Consistent reduction in total adrenal volume was observed across dose cohorts. Furthermore, resolution of androgen-mediated polycythemia was seen in five of the six impacted participants.
Safety and Tolerability
Atumelnant was generally well-tolerated, with no treatment-related severe or serious adverse events reported to date, irrespective of disease severity or dose level. No participants required dose reduction or discontinued from the trial. The most common treatment-emergent adverse events were headache (7/28) and fatigue (5/28).
Next Steps
"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," said Scott Struthers, Ph.D., founder and chief executive officer of Crinetics. The company is eager to move forward with a global Phase 3 pivotal trial for adults in CAH and simultaneously prepare to start a Phase 2b/3 trial in pediatric patients this year. Crinetics' internally discovered pipeline now has two drug candidates with positive late-stage data.
