Once-Weekly Navepegritide in Children With Achondroplasia: The APPROACH Randomized Clinical Trial.

Importance: Historically considered a skeletal dysplasia characterized by disproportionate short stature, achondroplasia is a condition with multisystemic effects due to the widespread expression of the fibroblast growth factor receptor 3 variant throughout the body, impacting muscle, neurological function, cardiorespiratory health, and health-related quality of life. Objective: To evaluate the efficacy, safety, and tolerability of once-weekly navepegritide, an investigational prodrug of C-type natriuretic peptide, while assessing benefits beyond growth that may have important implications for complications and health-related quality of life in children with achondroplasia. Design, Setting, and Participants: Enrollment for this pivotal phase 2b, randomized, double-blind, placebo-controlled trial (APPROACH) was conducted between March and August 2023 at 10 hospitals in Australia, Canada, Denmark, Ireland, New Zealand, Spain, and the US with randomized, blind treatment through 52 weeks and an open-label extension (ongoing). Eligible participants aged 2 to 11 years had achondroplasia confirmed by genetic testing, were naive to treatment with growth-promoting agents, and had their height recorded at least 6 months prior to randomization. Enrolled participants were stratified by age and sex. Those with radiographic evidence of closed growth plates, planned bone surgery, severe untreated sleep apnea, or medical conditions known to affect growth were excluded (n = 2 of 86); of 84 participants enrolled, all were analyzed for safety and efficacy outcomes, including 2 who discontinued treatment. Interventions: Navepegritide (100 μg/kg/wk) or placebo administered by once-weekly subcutaneous injection. Main Outcomes and Measures: The primary end point was annualized growth velocity at week 52. Other clinically important secondary measures included radiographically assessed skeletal outcomes and health-related quality of life, evaluated using Achondroplasia Child Experience Measures. Safety assessments included adverse events, clinical laboratory assessments, bone age, and immunogenicity. Results: Eighty-four participants were enrolled and assigned randomly in a 2:1 ratio to receive navepegritide (n = 57; mean [SD] age, 5.6 [2.6] years; 31 [54%] male) or placebo (n = 27; mean [SD] age, 6.0 [2.7] years; 14 [52%] male). All randomized participants were included in efficacy and safety analyses, although 2 patients in the navepegritide group discontinued treatment (one at week 26 and the other at week 34). The trial met its primary end point, demonstrating superiority of navepegritide in annualized growth velocity at week 52 vs placebo (least-squares mean treatment difference of 1.49 cm/y; 95% CI, 1.05 to 1.93; P < .001). Treatment resulted in improvements (least-squares mean treatment difference [95% CI]) in tibial-femoral angle (-1.81° [-3.16 to -0.47]), mechanical axis deviation (-2.78 mm [-4.71 to -0.86]), fibula to tibia length ratio (-0.016 [-0.024 to -0.008]), and Achondroplasia Child Experience Measures-Physical Functioning (-11.1 [-21.5 to -0.80] in children younger than 5 years). No serious adverse events were treatment-related, and no deaths occurred. Injection site reaction rates were low, and no symptomatic hypotension or fractures were observed. Conclusions: In this randomized clinical trial, navepegritide treatment resulted in statistically significantly higher annualized growth velocity in children with achondroplasia, with a similar safety and tolerability profile vs placebo. Moreover, navepegritide demonstrated additional potential health benefits beyond growth. Trial Registration: ClinicalTrials.gov Identifier: NCT05598320.