Navepegritide combined with lonapegsomatropin for the treatment of children with achondroplasia: 52-week results from the phase 2 COACH trial

OBJECTIVE: Navepegritide, a prodrug of C-type natriuretic peptide, has demonstrated improved growth and additional benefits, including lower limb alignment, in children with achondroplasia. The well-described mechanism of action of navepegritide in the growth plate is hypothesized to enhance its receptivity to lonapegsomatropin, a prodrug of somatropin, to provide benefits beyond those seen with monotherapies in achondroplasia. METHODS: In the proof-of-concept phase 2 COACH trial, children with achondroplasia aged 2 to 11 received weekly navepegritide and lonapegsomatropin. The primary efficacy endpoint was annualized growth velocity (AGV) at week 52 vs AGV with navepegritide monotherapy in the ApproaCH trial (NCT05598320). RESULTS: Twenty-one children were enrolled: 12 received no prior growth-promoting treatment (treatment-naive, TN) and 9 had been receiving navepegritide monotherapy for >1 year (navepegritide-experienced, NE). At week 52, TN children receiving navepegritide and lonapegsomatropin had a least squares mean AGV of 8.69 cm/year versus 5.95 cm/year for matched children who received navepegritide monotherapy, a difference of 2.74 cm/year (P < .0001). Observed mean AGV for TN children was 8.80 cm/year, a +3.89 cm/year increase from baseline (P = .0015). NE children had an observed mean AGV of 8.42 cm/year, a +3.28 cm/year increase from navepegritide-treated baseline (P < .0001). An improvement in body proportionality was observed and arm span increased substantially (+9.4 cm in TN and +7.9 cm in NE children), in line with gains in height. Treatments were well-tolerated with generally mild adverse events and no treatment discontinuations. CONCLUSIONS: In this prospective trial, the robust growth and anthropometric results suggest that by continuously relieving the pre-hypertrophic block in achondroplasia, navepegritide may make the growth plate more responsive to the strong complementary effect of lonapegsomatropin. TRIAL REGISTRATION DETAILS: ClinicalTrials.gov NCT06433557.