ORF47-08 - Vosoritide Treatment in Children with Hypochondroplasia: Three-Year Results from A Phase II Extension Trial

Objective: Vosoritide is a C-type natriuretic peptide analog that promotes growth by inhibiting the ERK1/2-MAPK signaling pathway downstream of FGFR3. It is approved for the treatment of achondroplasia and is under investigation for selected causes of short stature. We previously reported the results of a Phase II trial in children with hypochondroplasia after 12 months of treatment. Here, we present the safety and efficacy results from the 3-year extension phase of this study.

Methods: This was a single-arm, open-label Phase II study (NCT04219007) followed by an extension phase. Twenty-four children with hypochondroplasia completed the core study, which included a 6-month observation period followed by 12 months of daily subcutaneous vosoritide (15 μg/kg/day). Participants showing an increase in annual growth velocity (AGV) >1.6 cm/year compared to the observation period were eligible for the extension phase. Primary endpoints were changes in AGV and height SDS and incidence of adverse events (AEs).

Results: Thirteen subjects (7 females, 11 with the Asn540Lys variant) entered the extension study and completed 3 years of treatment. At screening, mean age was 5.8±1.1 years and mean height was -3.27±0.71 SD. During the observation period, the mean height worsened by -0.09 SD (-3.36±0.64 SD at Day 1, p=0.01). Over 3 years, vosoritide treatment resulted in an improvement in mean height of 0.72 SD (-2.64±0.79 SD at Year 3). Mean height gains for each year of treatment were as follows: 0.44 SD in Year 1 (p < 0.001), 0.09 SD in Year 2 (p=0.11) and 0.20 SD in Year 3 (p=0.01). Mean AGV increased significantly from baseline (4.27±0.70 cm/year) to end of Year 1 (7.24±0.80 cm/year, p< 0.001). At Years 2 and 3, mean AGV decreased slightly compared to Year 1 but remained higher than baseline (5.55±1.02 cm/year and 6.13±1.27 cm/year, respectively). Vosoritide was well tolerated, with no treatment-related serious AEs. Injection site reactions occurred in 76.9% of patients during Year 1 and decreased to 23.1% during Years 2 and 3. No participants discontinued therapy during the extension phase.

Conclusions: Vosoritide showed a good safety profile and improvement in height SDS and AGV over 3 years in children with hypochondroplasia. Limitations include selection bias, as only good responders entered the extension phase, and inherent variability in serial height measurements. Long-term follow up is needed for safety monitoring and final height outcomes.