ORF47-06 - Navepegritide Combined with Lonapegsomatropin for the Treatment of Achondroplasia: An Open-Label Phase 2 Trial

Objective: Navepegritide, a prodrug of C-type natriuretic peptide (CNP) designed to provide continuous exposure to active CNP, has been shown to significantly increase growth in children with achondroplasia (ACH) compared with placebo, while demonstrating a similar safety and tolerability profile. Navepegritide counterbalances the constitutively active fibroblast growth factor receptor 3 signaling in ACH via activation of the natriuretic peptide receptor B pathway to improve growth plate function. Adding once-weekly lonapegsomatropin, a prodrug of somatropin (human growth hormone [hGH]), to once-weekly navepegritide is hypothesized to augment effects on endochondral bone formation.
Design and

Methods: In the open-label phase 2 COACH trial, children with ACH aged 2-11 years received navepegritide (100 μg/kg/week) and lonapegsomatropin (starting at 0.30 mg hGH/kg/week). The trial had 2 cohorts: treatment-naive (TN) children, who began both treatments on Day 1 and navepegritide-experienced (NE) children, who added once-weekly lonapegsomatropin to their weekly navepegritide monotherapy. The primary efficacy endpoint was the effect of navepegritide and lonapegsomatropin at Week 52 on annualized growth velocity (AGV) in the TN cohort compared to those who received navepegritide monotherapy in the ApproaCH trial (NCT05598320) using an ANCOVA model with weights estimated by inverse probability treatment weighting.

Results: 21 children were enrolled: 12 TN and 9 NE. In NE children, the mean exposure to navepegritide 100 μg/kg/week was 2.56 years. At Week 52, TN children had a least squares mean AGV of 8.69 cm/year vs 5.95 cm/year for navepegritide alone in ApproaCH: a difference of 2.74 cm/year (95% CI, 2.11-3.38 p< 0.0001). Statistically significant increases in linear growth from baseline to Week 52 occurred in the TN and NE groups. TN children had a mean increase from baseline in AGV of +3.89 cm/year (p=0.0015) and of +1.02 in ACH-specific height Z-score (p < 0.0001). NE children had a mean increase in AGV of +3.28 cm/year (p < 0.0001) and of +0.86 in ACH-specific height Z-score (p < 0.0001). At Week 52, AGV in both cohorts exceeded the 97th percentile for children of average stature. An improvement in body proportionality was observed after 52 weeks of treatment. Bone age remained consistent with chronological age at Week 52. Arm span increased substantially (by 9.4 cm in TN children and by 7.9 cm in NE children), in line with gains in height. Navepegritide and lonapegsomatropin were associated with a safety and tolerability profile consistent with that observed for monotherapies.

Conclusions: One year of once weekly navepegritide and lonapegsomatropin were well tolerated and augmented proportionate growth in children with ACH, suggesting that lonapegsomatropin, through a distinct mode of action, complements navepegritide's therapeutic effects in children with ACH.