Atumelnant Demonstrates Rapid and Sustained Biomarker Reduction in Phase 2 Trial in Adults with Congenital Adrenal Hyperplasia
Atumelnant treatment resulted in statistically significant reductions in serum androstenedione and 17-OHP as well as notable improvements in CAH symptoms.
Crinetics Pharmaceuticals has reported positive topline results from its phase 2 TouCAHn trial evaluating atumelnant, an investigational oral adrenocorticotropic hormone (ACTH) receptor antagonist, in adults with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency.
The results highlight significant reductions in key biomarkers and improvements in clinical symptoms, supporting the initiation of a pivotal global phase 3 trial for adults, according to the Crinetics news release.1
©Sebastian Kaulitzki/stock.adobe.com
Atumelnant is the first once-daily, oral ACTH receptor antagonist characterized by selective action at the melanocortin type 2 receptor (MC2R) on the adrenal gland, Crinetics noted.1
The open-label, 12-week phase 2 TouCAHn study enrolled 28 adults aged 18 years or older to age 75 with classic CAH on stable glucocorticoid replacement. Participants were assigned to one of 3 atumelnant dose cohorts (40 mg, 80 mg, or 120 mg once daily). The primary endpoints were changes in morning serum androstenedione (A4) levels and the incidence of treatment-emergent adverse events. Secondary endpoints included changes in morning serum 17-hydroxyprogesterone (17-OHP) levels.2
Key Findings
Atumelnant demonstrated rapid, substantial, sustained, and statistically significant reductions in A4 levels, a primary biomarker for CAH disease control, across all 3 dose groups. At week 12, mean reductions in A4 ranged from -619 ng/dL in the 40 mg cohort (P =.0003) to -954 ng/dL in the 120 mg cohort (P <.001). Similar reductions observed in 17-OHP levels further confirmed disease control, according to the news release.1
Investigators also reported significant effects on signs and symptoms of CAH among atumelnant-treated participants. Notably, women experienced significant reductions in testosterone, with normalization achieved in 8 of 13 individuals. Of the 11 participants with androgen-mediated menstrual irregularities, 6 resumed menses during the study. Additional benefits included consistent reductions in adrenal gland volume and resolution of androgen-mediated polycythemia in 5 of 6 affected individuals.1
“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.”
“There has been a long-standing interest in using a potent, selective antagonist of the ACTH receptor for the treatment of CAH and other diseases of ACTH excess, leading to the design of atumelnant by Crinetics scientists,” Alan Krasner, MD, chief endocrinologist of Crinetics, stated in the press statement. “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.”1
Atumelnant was generally well-tolerated, with no reports of treatment-related severe or serious adverse events (SAEs) across dose levels or disease severity, according to Crinetics. The most common AEs were mild to moderate headaches (25%) and fatigue (18%). No participants required dose reductions or discontinued treatment due to AEs. Across all dose groups, no clinically significant trends were observed in laboratory parameters, vital signs, electrocardiograms, or physical examinations.
The substantial reductions in A4 and 17-OHP observed in this study suggest that atumelnant has the potential to provide effective hormonal control in CAH while minimizing the need for supraphysiologic glucocorticoid doses, which have deleterious long-term effects on both physical and emotional health, said Crinetics. Improvements in androgen-mediated symptoms, such as testosterone normalization and resumption of menses, point to the potential for atumelnant to address the equally negative long-term complications of CAH. The once-daily oral formulation could help simplify treatment regimens for persons with the chronic hormonal dysregulation.
“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 the news release. “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.”
The company is also advancing atumelnant as a candidate for ACTH-dependent Cushing’s syndrome and has additional investigational compounds in earlier development stages.
