A phase II basket trial of vosoritide in children with RASopathies, ACAN, and NPR2 deficiency.
Vosoritide significantly increased growth velocity in children with RASopathies, ACAN, and NPR2 deficiency, but long-term safety concerns need to be addressed.
Where it sits
this study against the rest of the vosoritide corpusSummary and findings
This study measured the effect of vosoritide on growth in 30 prepubertal children aged 3 to 11 years with RASopathies, ACAN, or NPR2 deficiency. The intervention consisted of a 12-month treatment with vosoritide at a dose of 15 µg/kg/day. Results indicated significant increases in annualized growth velocity and height standard deviation scores compared to the observation period.
Abstract
<h4>Context</h4>Genetic defects in many biological pathways, including activation of the Ras-MAPK pathway, cause short stature. Vosoritide, a C-type natriuretic peptide analog that inhibits this pathway, has been approved for use in achondroplasia.<h4>Objective</h4>To determine whether vosoritide improves growth in children with disorders of the Ras-MAPK pathway, including RASopathies, ACAN, and NPR2 deficiency.<h4>Design</h4>Prospective Phase 2 basket trial.<h4>Setting</h4>Academic medical center.<h4>Participants</h4>Thirty prepubertal children aged 3 to 11 years with a RASopathy, ACAN or NPR2 deficiency and height ≤ -2.25 SD.<h4>Intervention</h4>Six-month observation period followed by 12-month treatment with vosoritide subcutaneously 15 µg/kg/day.<h4>Main outcome measures</h4>Co-primary outcomes included incidence of adverse events, change in annualized growth velocity (AGV), and height standard deviation scores.<h4>Results</h4>The AGV increased from 4.53 ± 1.61 cm/year to 8.09 ± 1.58 cm/year with treatment (P < .0001). This corresponded to a 4.0 SD (95%CI 3.08-4.91) increase in age and sex-adjusted AGV Z-score (P < .0001). The increase in AGV was seen in all genetic subgroups. There was a height increase of 0.65 SD (95%CI 0.53-0.77) in the treatment vs observation period (P < .0001).Short-term safety was reassuring, with mild injection site reactions being the most common adverse events. However, with longer use, 5 subjects discontinued medication due to adverse events, including 3 slipped capital femoral epiphyses and 4 cases of genu valgum.<h4>Conclusion</h4>Vosoritide led to marked increases in growth velocity in children with RASopathies, ACAN, and NPR2 deficiency, raising the possibility that vosoritide could be an effective precision medicine for all growth disorders affecting the MAPK pathway.
Background
This paper addresses the impact of vosoritide on growth in children with genetic disorders affecting the Ras-MAPK pathway. Prior knowledge indicated that these genetic defects lead to short stature, and vosoritide has been approved for achondroplasia. This study is significant as it explores the potential of vosoritide in a broader range of growth disorders.
Methods
The study was a prospective Phase 2 basket trial involving 30 prepubertal children aged 3 to 11 years with RASopathy, ACAN, or NPR2 deficiency and height ≤ -2.25 SD. Participants underwent a 6-month observation period followed by 12 months of treatment with vosoritide at a dose of 15 µg/kg/day. Co-primary outcomes included incidence of adverse events, change in annualized growth velocity (AGV), and height standard deviation scores.
Results
The primary endpoint showed that AGV increased from 4.53 ± 1.61 cm/year to 8.09 ± 1.58 cm/year with treatment (P < .0001). The increase in AGV corresponded to a 4.0 SD (95%CI 3.08-4.91) increase in age and sex-adjusted AGV Z-score (P < .0001). Additionally, there was a height increase of 0.65 SD (95%CI 0.53-0.77) during the treatment compared to the observation period (P < .0001).
Interpretation
The findings suggest that vosoritide significantly increases growth velocity in children with specific genetic disorders, which aligns with previous literature on its effects in achondroplasia. However, while the statistical significance is clear, the clinical significance of the height increase may be limited given the small sample size and potential adverse events. The study's limitations, including the small n and single-site design, suggest caution in generalizing these results to broader populations.
Key findings
- AGV increased from 4.53 ± 1.61 cm/year to 8.09 ± 1.58 cm/year with treatment (P < .0001).
- Corresponding to a 4.0 SD (95%CI 3.08-4.91) increase in age and sex-adjusted AGV Z-score (P < .0001).
- Height increase of 0.65 SD (95%CI 0.53-0.77) in the treatment vs observation period (P < .0001).
- Five subjects discontinued medication due to adverse events, including 3 slipped capital femoral epiphyses and 4 cases of genu valgum.
Limitations
- small sample size of n=30
- single-site study limits generalizability
- short follow-up period of 12 months
- adverse events led to discontinuation in some subjects