A phase 2b randomized trial found once-weekly navepegritide improved growth velocity, skeletal alignment, and physical functioning in children with achondroplasia.
A randomized clinical trial evaluated the efficacy and safety of once-weekly navepegritide, an investigational prodrug of C-type natriuretic peptide, in children with achondroplasia.1 Achondroplasia, historically defined as a skeletal dysplasia, is now understood as a multisystem condition involving muscle, neurological function, cardiorespiratory health, and quality of life.2 The trial aimed to assess whether sustained natriuretic peptide receptor-B activation could provide growth benefits and improvements in other clinically meaningful outcomes.
The phase 2b APPROACH trial enrolled 84 children aged 2 to 11 years across seven countries in a randomized, double-blind, placebo-controlled design. Participants were assigned 2:1 to receive weekly subcutaneous navepegritide 100 μg/kg or placebo. All randomized participants were included in the efficacy and safety analyses.
The study met its primary end point. At week 52, navepegritide demonstrated a statistically significant improvement in annualized growth velocity (AGV). The least-squares mean treatment difference was 1.49 cm/year. As reported by the investigators, “children treated with navepegritide achieved an LS mean AGV of 5.89 vs 4.41 cm/y for those treated with placebo.”
The treatment effect appeared by week 12 and persisted through week 52, with the greatest improvements observed in children aged 8 years and older.
Secondary outcomes demonstrated improvements in height z scores. For achondroplasia-specific height z score, the least-squares mean difference between groups at week 52 was 0.28. The study noted that “observed mean values for the achondroplasia-specific and CDC-based height z scores consistently increased from baseline to week 52” in the navepegritide group, while CDC-based height scores declined in the placebo group.
Exploratory radiographic measures showed improvements in skeletal alignment among children treated with navepegritide. At week 52, treatment was associated with:
According to the investigators, “improvements in lower limb alignment were observed with navepegritide compared to placebo at week 52.”
These findings suggest a potential reduction in long-term mechanical strain on lower-extremity joints and may influence future orthopedic outcomes.
Health-related quality of life was assessed using the Achondroplasia Child Experience Measures. Improvements favoring navepegritide were noted across all subscales. The largest change occurred in physical functioning among children younger than 5 years, with a least-squares mean difference of −11.1. Children with higher baseline burden demonstrated the greatest improvements.
The SF-10 Physical Summary Score did not differ between treatment groups at week 52.
Safety profiles were similar between navepegritide and placebo. Most adverse events were mild or moderate. The trial reported that “no serious adverse events were treatment-related, and no deaths occurred.” Injection-site reactions were infrequent and mild. No symptomatic hypotension occurred, and no fractures were reported. Transient, low-titer anti-CNP antibodies were detected in a small number of children but did not affect safety or efficacy.
In this 52-week study, once-weekly navepegritide improved growth velocity, skeletal alignment, and physical functioning in children with achondroplasia while maintaining a safety profile similar to placebo. The authors concluded that “navepegritide treatment resulted in statistically significantly higher annualized growth velocity…with additional potential health benefits beyond growth.” Long-term follow-up is ongoing to determine the durability of the benefit and long-term safety.
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