Children with Achondroplasia See Improved Annual Height Velocity with Investigational Prodrug

Children with achondroplasia (ACH), the most common form of hereditary short stature, experienced statistically significant improvements in their annual height velocity with the prodrug TransCon CNP, according to a study presented at ENDO 2023. Ascendis Pharma is investigating the drug in the Phase 2 ACcomplisH trial.

Researchers led by Ravi Savarirayan, MBBS, FRACP, MD, of the University of Melbourne in Australia, point out that ACH is caused by a variant of the FGFR3 gene, and C-type natriuretic peptide (CNP) promotes chondrocyte development by inhibiting the FGFR3 pathway. “TransCon CNP is an investigational prodrug of CNP, designed to provide sustained release of CNP supporting continuous CNP exposure and a once-weekly dosing regimen,” the authors write. “The ACcomplisH trial assessed TransCon CNP for the treatment of children with ACH aged 2 to 10 years.”

For this study, the researchers enrolled 57 participants in this multicenter, double-blind, randomized, placebo-controlled, dose-escalation trial. The children were randomized to TransCon CNP dosed at 6, 20, 50, and 100 μg CNP/kg/week across 4 cohorts or placebo in a 3:1 ratio, with the primary objectives of safety and annual height velocity (AHV) over a year. “TransCon CNP was well tolerated with no treatment discontinuations,” the authors write. “No serious treatment-emergent adverse events (TEAEs) were reported as related to TransCon CNP.”

The researchers also found that the effects on heigh velocity were dose-dependent, with 100 μg CNP/kg/week providing the most benefit. “TransCon CNP 100 μg CNP/kg/week resulted in significantly higher AHV vs placebo at 52 weeks (least square [LS] mean 5.42 vs 4.35 cm/year; p=0.022) resulting in improved ACH-specific height SDS from baseline vs placebo (LS mean 0.22 vs -0.08; p=0.028),” the authors write. “There was a dose-dependent treatment effect on AHV of 4.09 cm/year (6 μg CNP/kg/week) to 5.42 cm/year (100 μg CNP/kg/week; p=0.003).”

Based on these results, the researchers conclude that TransCon CNP is safe and well tolerated, and that the highest dose of the drug provided statistically significant improvement in AHV vs placebo. “These results support continued investigation of TransCon CNP for children with ACH in the ongoing Phase 2b ApproaCH trial (NCT05598320) including treatment impact on ACH-related complications,” the authors write.