Design of the ACcomplisH Trial: A Phase 2, Multicenter, Placebo-Controlled, Dose Escalation Trial Evaluating Safety, Efficacy, and Pharmacokinetics of Weekly TransCon CNP in Children With Achondroplasia

Abstract Background: Achondroplasia (ACH) is the most common skeletal dysplasia and frequent form of dwarfism. ACH caused by a gain-of-function mutation in fibroblast growth factor receptor 3 (FGFR3) gene results impairment endochondral ossification processes. C-type natriuretic peptide (CNP) promotes chondrocyte development through inhibition FGFR3 pathway, specifically activation NPRB. CNP desirable target as it known to increase without off-target effects (Bocciardi, 2007). TransCon long-acting prodrug designed optimize safety efficacy with once-weekly dose. The Phase 1 clinical trial demonstrated that doses up 150 μg CNP/kg were well-tolerated healthy adult male volunteers, no clinically significant trends observed laboratory assessments, vital sign measurements, ECG parameters, or physical examination findings. Methods: phase 2 ACcomplisH will be conducted at over 35 sites worldwide. primary objective evaluate compared placebo 12 months prepubertal children, aged 2-10 years old, ACH. Approximately 60 subjects randomized 3:1 receive either weekly placebo. Following screening verification genetic confirmation, remain within dose cohort for 52 weeks treatment. dosed 6 100 CNP/kg/week across 4 cohorts, an optional 5th 200 CNP/kg/week. An independent Data Monitoring Committee review data prior initiation higher cohort. endpoint annualized height velocity Key secondary endpoints examine change upper lower body segment ratio week 52, safety, pharmacokinetics (PK), quality life associated CNP. Conclusion: targeted underlying pathology FGFR3. No effective medicinal product currently available treatment provide sustained exposure This ongoing assess efficacy, PK administration