Regulatory Decision Summary for Voxzogo (vosoritide)

This New Drug Submission (NDS) for vosoritide (VOXZOGO, BMN 111) as a new active substance for the treatment of children with achondroplasia (ACH) whose epiphyses were not closed. The rationale for filing was based on vosoritide’s novel mechanism of action, which targeted the underlying pathophysiology of ACH by activating natriuretic peptide receptor-B (NPR-B) signaling and inhibiting fibroblast growth factor receptor 3 (FGFR3) downstream signaling, thereby promoting endochondral bone growth.

Vosoritide is indicated for increasing linear growth in patients with achondroplasia who are 4 months of age and older, and whose epiphyses are not closed. The diagnosis of achondroplasia should be confirmed by appropriate genetic testing. There are currently no pharmacological treatments for achondroplasia approved in Canada. Management is limited to supportive care and surgical interventions aimed at addressing medical complications associated with the condition. The evidence supporting the efficacy and safety of vosiritide varies by age group. For children aged 5 to <18 years, it is supported by direct data from pivotal and long-term studies, while for children aged 4 months to 5 years it is supported primarily by pediatric extrapolation and a phase 2 clinical trial.

In children with achondroplasia aged 5 to <18 years, vosoritide has demonstrated consistent and clinically meaningful efficacy. The pivotal placebo-controlled Phase 3 trial 111-301, together with its open-label extension 111-302, and the earlier dose-finding and long-term extension studies 111-202/205, provide robust evidence supporting the efficacy of vosoritide. In the pivotal trial, vosoritide treatment produced an LS mean increase of 1.57 cm/year in annualized growth velocity (AGV) compared with placebo (95% confidence interval [CI]: 1.22-1.93; p <0.0001). This result was consistently supported by the key secondary endpoint, Height Z-score. The observed improvement in growth velocity corresponds to approximately 75% of the normal growth rate expected for age-matched non-ACH children. No evidence of tachyphylaxis or waning treatment effect has been observed in the extension studies, supporting sustained efficacy with continued use.

Vosoritide directly targets the underlying molecular defect in ACH by modulating overactive FGFR3 signaling, providing a strong mechanistic foundation for the clinical benefits observed. While current evidence confirms meaningful gains in height parameters, further long-term data are needed to determine the therapy’s effect on final adult height.

The safety profile of vosoritide (15 μg/kg once daily) in children aged 5 to 15 years was generally favorable. Most adverse events were mild to moderate, with transient injection-site reactions being the most common. Events of hypotension occurred but were typically mild, asymptomatic, and did not require medical treatment. Importantly, no adverse events suggestive of worsening bone abnormalities, disproportional growth, or accelerated bone maturation were reported.

Evidence supporting efficacy in children >4 months to 5 years is based on pediatric extrapolation, supported by shared disease pathophysiology, comparable pharmacodynamic responses, and similar growth characteristics across age groups. Pharmacokinetic data further reinforce this approach, as exposure profiles were generally consistent between participants aged ≥5 years and those <5 years. Data from the randomized Phase 2 Study 111-206 and the extension Study 111-208, along with comparisons to external natural history datasets, show clinically meaningful improvements in linear growth in children aged 2 to 5 years and signal a positive treatment effect in infants >4 months to 2 years. Because the youngest patient studied in the clinical program was 4 months old, there are no clinical efficacy or safety data for infants younger than this age. As a result, together with dose-prediction uncertainties in this population, treatment is recommended only for children 4 months of age and older.

Although placebo-adjusted gains in very young infants were smaller, these findings must be interpreted in the context of naturally high variability in infant growth and the limited number of participants in this age group. Long-term follow-up suggests that benefits are sustained and may accumulate with early treatment initiation. However, efficacy evidence in children under 2 years, especially under 6 months, remains limited due to small sample sizes, shorter exposure, and the absence of demonstrated benefits on cranial morphology or sleep-related clinical outcomes. Confirmation of effects on final adult height and long-term functional outcomes remains necessary. Despite these uncertainties, vosoritide will represent the only available pharmacologic treatment capable of increasing growth in children with ACH.

The safety profile in children >4 months to 5 years was similar to that of older children. Higher adverse event (AE) rates in the younger cohort were primarily driven by mild, transient injection-site reactions, particularly in infants aged 0–6 months receiving 30 μg/kg. Hypotension events were infrequent, asymptomatic, and nonserious, though diastolic blood pressure changes were more common in the youngest participants. Slightly higher rates of rash and viral infections were observed compared with placebo. No new safety concerns were identified for patients >4 months to 5 years of age.

The totality of data provided in the submission suggests that vosoritide has a favorable benefit–risk profile for children with achondroplasia. Ongoing long-term studies will address remaining uncertainties regarding final adult height and to further substantiate the long-term clinical benefit. Specifically, Study 4134-2 (111-confirm) is expected to provide confirmatory evidence of the long-term efficacy and safety of vosoritide for the treatment of pediatric subjects with achondroplasia whose epiphyses are not closed; the final report is anticipated to be submitted to Health Canada for review late 2026.

The Risk Management Plan (RMP) for Voxzogo was reviewed by Health Canada and considered acceptable.

The chemistry and manufacturing information submitted for Voxzogo has demonstrated that the drug substance and drug product have been well characterized and can be consistently manufactured to meet the approved specifications.

The labelling material met all applicable regulations and guidance.

For further details about Voxzogo, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.