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

Area of Science:

• Pediatric Endocrinology
• Skeletal Dysplasias
• Clinical Trials

Background:

• Achondroplasia is a genetic skeletal dysplasia causing disproportionate short stature and multisystemic effects.
• Fibroblast growth factor receptor 3 (FGFR3) variant expression impacts various bodily functions.
• Current treatments focus on growth promotion, with limited options for broader health implications.

Purpose of the Study:

• To evaluate the efficacy, safety, and tolerability of navepegritide, a C-type natriuretic peptide prodrug.
• To assess benefits of navepegritide beyond linear growth in children with achondroplasia.
• To explore implications for achondroplasia complications and health-related quality of life.

Main Methods:

• A phase 2b, randomized, double-blind, placebo-controlled trial (APPROACH) involving 84 children aged 2-11 years.
• Participants received once-weekly subcutaneous injections of navepegritide (100 μg/kg/wk) or placebo for 52 weeks.
• Primary endpoint: annualized growth velocity; secondary endpoints: skeletal outcomes and quality of life (Achondroplasia Child Experience Measures).

Main Results:

• Navepegritide demonstrated statistically significant superiority in annualized growth velocity at week 52 compared to placebo (1.49 cm/y difference, P<.001).
• Improvements were observed in skeletal parameters (tibial-femoral angle, mechanical axis deviation, fibula-to-tibia ratio) and physical functioning scores.
• The treatment exhibited a similar safety and tolerability profile to placebo, with no treatment-related serious adverse events or deaths.

Conclusions:

• Navepegritide significantly enhances growth velocity in children with achondroplasia.
• The drug is safe and well-tolerated, with potential to improve skeletal parameters and physical functioning.
• Navepegritide offers promising therapeutic benefits extending beyond growth for achondroplasia management.