Vosoritide Shows Promise for Rare Genetic Growth Disorders Beyond Achondroplasia in Phase 2 Trial
Key Insights
Children with five genetic subtypes of short stature (search) experienced significant growth acceleration from 4.53 cm/year to 8.09 cm/year during vosoritide treatment in a phase 2 basket trial.
The study represents the first precision medicine approach for MAPK pathway growth disorders, with NPR2 (search) deficiency patients showing particularly robust responses without significant adverse events.
Long-term safety concerns emerged as five participants discontinued treatment due to orthopedic complications including slipped capital femoral epiphyses (search) and severe genu valgum (search), particularly in children with ACAN (search) mutations.
A phase 2 basket trial has demonstrated that vosoritide, currently approved for achondroplasia (search), significantly improves growth velocity in children with five different genetic causes of short stature (search), marking the first precision medicine approach for MAPK pathway growth disorders. The study, published in The Journal of Clinical Endocrinology & Metabolism, enrolled 30 children aged 3 to 11 years from August 2020 to February 2024.
Significant Growth Acceleration Observed
The trial showed remarkable efficacy across multiple genetic subtypes. During the 6-month observation period, participants grew at an average rate of 4.53 cm per year. Following initiation of once-daily 15 mg/kg subcutaneous vosoritide therapy, growth velocity increased to 8.09 cm per year (P < .0001), representing an improvement of 3.56 cm per year.
"Prior to our study, there were no precision medicine approaches to children with MAPK pathway growth disorders," said Andrew Dauber, MD, MMSc, chief of endocrinology at Children's National Hospital in Washington, D.C. "Growth hormone was the only option, and it does not address the underlying pathophysiology."
The study population included children with various genetic variants: 40% had ACAN (search) genetic variants, 23% had NPR2 (search) variants, and 37% had RASopathy (search). Among the 28 participants who completed the study (mean age 7.2 years, 27% girls), 17% had previously received growth hormone therapy.
Precision Medicine Success in NPR2 Deficiency
Age- and sex-adjusted annualized growth velocity z-scores improved from −1.34 during observation to 2.66 with vosoritide treatment (P < .0001). Mean height increased from −3.09 standard deviations at baseline to −2.52 standard deviations at 1 year (P < .0001).
Children with NPR2 (search) deficiency demonstrated particularly strong responses. "The cohort with NPR2 deficiency has done particularly well without any significant adverse events," Dauber noted. "NPR2 encodes the receptor for C-type natriuretic peptide and vosoritide, so these patients represent the best example of precision medicine in this study."
Safety Profile and Orthopedic Concerns
During the initial 12-month treatment period, injection site reactions were the most common adverse events, occurring in 40% of participants. Two serious adverse events occurred but were unrelated to vosoritide. No grade 4 or grade 5 adverse events were reported, and no participants discontinued treatment due to drug-related adverse events at one year.
However, long-term extension data revealed concerning orthopedic complications. Five participants discontinued vosoritide due to adverse events, including two who developed severe genu valgum (search) requiring surgery and later experienced slipped capital femoral epiphyses (search). Two additional participants discontinued due to significant genu valgum, while a fifth stopped therapy after developing slipped capital femoral epiphysis following coxa valga.
Clinical Implications and Future Directions
"Doctors should be cautious about using vosoritide outside of its approved indications due to this new risk we have identified of children developing slipped capital femoral epiphyses (search) with or without genu valgum (search)," Dauber warned. "The risk seems most pronounced in children with ACAN (search) gene mutations."
The findings represent a significant advancement in treating rare genetic growth disorders, as vosoritide is an analog of C-type natriuretic peptide (CNP) that directly targets the affected pathways. Unlike growth hormone, which provides general growth stimulation, vosoritide addresses the underlying pathophysiology in these specific genetic conditions.
Children's National Hospital is currently the only site worldwide conducting this type of research in pediatric endocrinology for novel clinical trials in growth disorders. The investigator-initiated study was funded by BioMarin Pharmaceutical.
Dauber emphasized that additional research is needed to develop screening methods for preventing orthopedic complications and to identify which children would benefit most from vosoritide therapy. The study also highlights the importance of comprehensive genetic evaluation for children with short stature (search), as many patients do not receive proper genetic testing to identify underlying causes.