Ascendis Publishes Positive Pivotal Data from Achondroplasia Study

Rare Daily Staff

Ascendis Pharma reported that children with rare genetic condition achondroplasia treated with its experimental therapy TransCon CNP had significantly higher annualized growth velocity at Week 52 compared to placebo.

The results from the pivotal study, published in JAMA Pediatrics, also showed improved lower-limb alignment and body proportionality, and positive changes in health-related quality of life, as well as a safety and tolerability profile similar to placebo.

Achondroplasia is caused by a genetic mutation in the fibroblast growth factor receptor 3 (FGFR3). This results in an imbalance between the stimulatory and inhibitory signaling pathways that regulate bone growth. People living with ACH may experience serious complications and comorbidities due to inhibited skeletal development. Complications may include sleep apnea and respiratory problems, chronic back and leg pain from lower spine impingement, and sudden infant death from compression of the brain stem. Chronic ear infections due to eustachian tube problems can lead to hearing loss and speech delay. Children with ACH may also experience social and emotional challenges.

TransCon CNP (navepegritide) is an investigational prodrug of C-type natriuretic peptide (CNP) administered once weekly. It is designed to continuously inhibit the overactive FGFR3 pathway in achondroplasia by providing sustained exposure of active CNP to receptors on tissues throughout the body.

TransCon CNP is under priority review by the U.S. Food and Drug Administration as a potential treatment for children with achondroplasia. The agency is expected to act on the company’s application by Nov. 30. The therapy is also under review by the European Medicines Agency.

ApproaCH was a randomized, double-blind, placebo-controlled trial evaluating TransCon CNP in 84 children with achondroplasia ages 2 to 11. Participants were randomized 2-to-1 to receive TransCon CNP or placebo during the 52-week double-blind period, followed by an open-label extension through Week 104.

In addition to meeting the primary endpoint of annualized growth velocity superior to placebo, favorable impacts on body proportionality and leg bowing were reported at Week 52. Treatment with TransCon CNP decreased the upper-to-lower body segment ratio from baseline to Week 52 and improved tibial-femoral angle, mechanical axis deviation, and fibula-to-tibia length ratio from baseline to Week 52 compared to placebo.

In the trial, treatment with TransCon CNP resulted in numerical improvements in health-related quality of life compared to placebo, as measured across several Achondroplasia Child Experience Measure domains. The benefits of TransCon CNP were achieved without accelerating bone age or negatively affecting spinal curvature.

TransCon CNP demonstrated a safety and tolerability profile similar to placebo, with the majority of adverse events mild or moderate. Injection-site reaction rates were low, and no symptomatic hypotension or bone fractures were observed.

“To help guide their health care decisions, families want information beyond changes in height to understand how an intervention may affect the potential medical challenges of achondroplasia,” said Michael Hughes, chair of the Biotech Industry Liaison Committee at Little People of America. “Including these endpoints in blinded, controlled studies, as done in ApproaCH, begins to fill that gap, and our community looks forward to more research to deepen understanding in these areas.”