Achondroplasia management in the era of targeted therapies: a meta-analysis of C-type natriuretic peptide analogs.

CONTEXT: No prior meta-analysis has systematically assessed efficacy and safety of C-type natriuretic peptide (CNP) analogs within the context of evolving understanding of FGFR3 biology and achondroplasia natural history.

OBJECTIVE

To evaluate the safety and efficacy of CNP analogs in children with achondroplasia and contextualize clinical outcomes and natural history.

METHODS

Systematic review of randomized control trials and real-world studies evaluating the safety and efficacy of CNP analogs (vosoritide and navepegritide) in children aged <18 years with genetically confirmed achondroplasia was performed. Coprimary outcomes of interest were adverse events (AEs) and changes from baseline in annualized growth velocity (AGV) at the end of the trials. Secondary outcomes included changes from baseline in height Z-score, standing height, and upper-to-lower body segment (ULS) ratio.

RESULTS

Eleven studies (N = 542) were included, of which 4 RCTs (n = 326) with low overall risk of bias were meta-analyzed. Overall and serious AE rates were comparable between CNP analogs and placebo, except for higher relative risks of injection site reactions (1.65), urticaria (4.04), and swelling (3.57). C-type natriuretic peptide analogs significantly increased mean differences in AGV (1.36 cm/year; 95% CI: 1.05-1.68; P < .00001) and standing height (1.24 cm; 95% CI: 0.47-2.01; P = .002), without short-term effect on ULS ratio. Real-world studies demonstrated sustained growth benefits with infrequent serious AEs or treatment discontinuations.

CONCLUSION

C-type natriuretic peptide analogs provide slight but statistically meaningful improvements in linear growth in children with achondroplasia with acceptable short-term safety profile. Long-term studies are needed to define optimal timing of therapy on adult height, functional outcomes, and achondroplasia-related complications.