Summary Basis of Decision for Voxzogo

Clinical Pharmacology

Vosoritide, the medicinal ingredient in Voxzogo, is a modified type C natriuretic peptide. In patients with achondroplasia, endochondral bone growth is negatively regulated due to a gain-of-function mutation in fibroblast growth factor receptor 3 (FGFR3). The FGFR3 protein inhibits endochondral bone growth through the mitogen-activated protein kinase (MAPK) pathway. Binding of vosoritide to natriuretic peptide receptor-B antagonizes the FGFR3 downstream signaling of extracellular signal-regulated kinases 1 and 2 at the level of rapidly accelerating fibrosarcoma serine/threonine protein kinase of the MAPK pathway, and positively regulates endochondral bone growth through chondrocyte proliferation and differentiation.

The clinical pharmacology package for Voxzogo in the treatment of achondroplasia comprised seven clinical studies and three modelling reports. Vosoritide demonstrated predictable pharmacokinetics with no evidence of time-dependent changes or drug accumulation. Across studies, treatment with vosoritide produced consistent and sustained pharmacodynamic effects, including a favourable modulation of biomarkers associated with bone formation. Immunogenicity assessments indicated that the development of anti-drug antibodies did not impact the plasma pharmacokinetics of vosoritide.

The pharmacokinetic profiles were generally consistent between participants aged 5 years and older and those aged less than 5 years. However, during review, it was concluded that the provided population pharmacokinetic modeling could not reliably predict vosoritide exposure in the youngest and lightest patients (aged less than 2 years). Since the proposed posology initially lacked a lower age limit, and the youngest patient with observed data in the clinical program was 4 months old, there were no clinical efficacy or safety data for patients under 4 months of age. Consequently, Health Canada recommended restricting the indication to patients aged 4 months and older. Therefore, the approved dosing regimen is a once-daily subcutaneous administration in patients aged 4 months and older and weighing 5 kg or more. Doses are adjusted according to body weight to provide proportionally higher weight-normalized doses for younger/lighter patients and lower weight-normalized doses for older/heavier patients.

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

Clinical Efficacy

Patients aged 5 to less than 18 years

Voxzogo has demonstrated consistent and clinically meaningful efficacy in children aged 5 to less than 18 years with achondroplasia. The pivotal placebo-controlled Phase III Study 111-301 and its open-label extension Study 111-302, together with the earlier dose-finding Study 111-202 and its long-term extension Study 111-205, provide robust evidence supporting the efficacy of Voxzogo.

Study 111-301 was a pivotal, Phase III, randomized, placebo-controlled, double-blind, multicentre study evaluating the efficacy and safety of Voxzogo in children aged 5 to less than 18 years with genetically confirmed achondroplasia. One hundred and twenty-one participants were randomized 1:1 to receive Voxzogo 15 mcg/kg (60 patients) or placebo (61 patients) for 52 weeks. The study was conducted in 7 countries and enrolled children aged 5.1 to 13.1 years in the Voxzogo group and 5.1 to 14.9 years in the placebo group. The mean age at baseline was slightly lower in the Voxzogo group (8.35 years) compared with the placebo group (9.06 years), with a greater proportion of younger patients (aged 5 to less than 8 years) in the Voxzogo group compared with the placebo group (51.7% versus [vs.] 39.3%). Conversely, fewer patients aged 8 to less than 11 years were included in the Voxzogo group compared with the placebo group (28.3% vs. 39.3%). After the Week 52 visit (i.e., the last dose of study drug), patients in the Voxzogo and placebo groups were eligible to receive Voxzogo in Study 111-302. Study 111-302 is an ongoing Phase III open-label, multicentre, long-term, extension study to evaluate the efficacy and safety of Voxzogo in 119 patients from Study 111-301. Voxzogo, administered as a single subcutaneous dose of 15 mcg/kg, is given daily for a minimum of 5 years or until patients reach near final adult height, defined as evidence of growth plate closure and a reduced annualized growth velocity (less than 1.5 cm/year).

Study 111-202 was a pediatric, Phase II, open-label, dose-escalation study to assess the safety and tolerability of Voxzogo (ranging from 2.5 mcg/kg to 30 mcg/kg once daily) administered to 35 patients aged 5 to 14 years with genetically confirmed achondroplasia. Study 111-205 is an ongoing Phase II, multicentre, open-label, extension study designed to evaluate the long-term efficacy and safety of Voxzogo (15 mcg/kg or 30 mcg/kg once daily) in children who completed Study 111‑202.

In the pivotal Study 111-301, the primary endpoint was the change from baseline in annualized growth velocity at Week 52. Voxzogo 15 mcg/kg once daily resulted in a least-squares (LS) mean increase of 1.57 cm/year in annualized growth velocity compared with placebo (95% confidence interval [CI]: 1.22 to 1.93; p<0.0001). This represents a clinically relevant improvement, restoring a substantial portion of the approximately 2 cm/year growth deficit typically seen between children with achondroplasia and those of average stature. The treatment effect was further supported by consistent improvements in the key secondary endpoints, including height Z-score (LS mean difference of 0.28 standard deviation scores [95% CI: 0.17 to 0.39; p<0.0001]) and standing height (LS mean difference of 1.57 cm [95% CI: 1.21 to 1.93; p<0.0001]), confirming the robustness of the growth benefit.

Data from Study 111-202 and long-term data from Study 111-205 demonstrated that the increase in annualized growth velocity observed during the first year of Voxzogo therapy was maintained over multiple years of treatment without evidence of tachyphylaxis. Preliminary data suggest that Voxzogo may enable children with achondroplasia to achieve up to 75% of the normal growth velocity observed in age-matched peers, potentially leading to a meaningful cumulative gain in final adult height over time. Although data beyond 4 to 5 years of treatment remain limited, early findings indicate a sustained effect on linear growth. Improvements in body proportion ratios show a favourable trend, though longer-term data are needed to confirm proportional skeletal growth and final adult height.

Patients under 5 years of age

The evidence supporting the efficacy of Voxzogo in children under 5 years of age with achondroplasia is primarily based on pediatric extrapolation from the demonstrated treatment effect in children aged 5 years and older in the pivotal Phase III Study 111-301. This was supported by data from Study 111-206 and Study 111-208. Study 111-206 was a Phase II, 52-week, multicentre, randomized, double-blind, placebo-controlled study designed to assess the efficacy and safety of Voxzogo on growth in infants and young children (aged less than 5 years) with genetically confirmed achondroplasia. Study 111-208 is an ongoing, Phase II, open-label, multicentre extension study evaluating the long-term efficacy and safety of Voxzogo in children who completed Study 111-206.

Extrapolation from older children, who exhibit more stable growth patterns and in whom treatment effects can be measured with greater reliability, is supported by the shared underlying disease mechanism across age groups. This approach is considered scientifically justified, as Study 111-206 demonstrated similar trajectories in growth parameters and body proportionality between younger and older children. Furthermore, as outlined in the clinical pharmacology assessment, the pharmacological intervention with Voxzogo is consistent across age groups. Efficacy data from Study 111-206 and Study 111-208, supported by comparisons with external natural history datasets, demonstrate that Voxzogo provides a growth benefit in children aged 2 to 5 years with achondroplasia, and indicate a positive treatment effect in those under 2 years of age as well. Since 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 aged 4 months 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, evidence of efficacy in children under 2 years of age, especially under 6 months of age, 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, Voxzogo represents the only available pharmacologic treatment capable of increasing growth in children with achondroplasia.

Voxzogo was authorized under the Guidance Document: Notice of Compliance with Conditions (NOC/c) on the basis of the promising nature of the clinical evidence, and the need for further follow-up to confirm the clinical benefit. Ongoing long-term studies will address remaining uncertainties regarding final adult height and to further substantiate the long-term clinical benefit of Voxzogo. Specifically, Study 4134-2 is expected to provide confirmatory evidence of the long-term efficacy and safety of Voxzogo for the treatment of pediatric patients with achondroplasia whose epiphyses are not closed.

Indication

The New Drug Submission for Voxzogo was filed by the sponsor with the following proposed indication:

Voxzogo (vosoritide injection) is indicated for the treatment of achondroplasia in pediatric patients whose epiphyses are not closed.

To support safe and effective use of the product, Health Canada approved the following indication:

Voxzogo (vosoritide for injection) is indicated to increase linear growth in patients with achondroplasia who are 4 months of age and older whose epiphyses are not closed. The diagnosis of achondroplasia should be confirmed by appropriate genetic testing.

This indication is approved based on an improvement in annualized growth velocity. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

For more information, refer to the Product Monograph for Voxzogo, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Voxzogo was evaluated in a pooled safety dataset of 239 pediatric patients with achondroplasia who received Voxzogo at any dose across two Phase III and five Phase II clinical studies conducted globally. Specifically, the pooled safety dataset included the studies described in the Clinical Efficacy section as well as Study 111-209, a Phase II, stratified (based on age), randomized, controlled, open-label clinical study to investigate the safety of Voxzogo treatment in children aged 0 to less than 12 months with achondroplasia at risk of requiring cervicomedullary decompression surgery. During the Voxzogo clinical development program, 215 patients were treated for 12 months or longer and 98 patients were treated for 36 months or longer with any dose of Voxzogo. Only patients who started Voxzogo at 5 years of age or older showed treatment exposures longer than 48 months. The median duration of treatment in the clinical program was 32.7 months (range: 0 to 97.4 months) corresponding to 715.9 person-years of exposure. The clinical population was well balanced with respect to the sex of the participants (males: 51.5%; females: 48.5%). Overall, the majority of participants were White (71.5%) or Asian (20.1%, of whom 6.7% were Japanese) and not Hispanic or Latino (92.9%). Age ranged from 0.1 to 15.9 years. In total, 77 participants aged less than 5 years were treated with Voxzogo in the clinical development program: 43 participants in Study 111-206, 25 of whom continued in the extension Study 111-208, and 9 participants from Study 111-209. Of the 77 participants aged less than 5 years, 43 were aged less than 2 years and only 2 were aged less than 4 months (one aged 1.4 months and another aged 3.9 months) at treatment initiation. In the group aged 5 years and older, the majority of the participants (123 patients [75.9%]) were aged 5 years to less than 11 years and only 1 patient was aged 15 to less than 18 years at the start of treatment.

The safety profile of Voxzogo in pediatric patients was acceptable and generally similar between patients aged less than 5 years and patients aged 5 years and older. While almost all participants experienced at least one adverse event, the majority of adverse events were mild or moderate in severity. Only 12.1% of participants experienced Grade 3 or higher events. Injection site reactions were the most frequent adverse reaction observed across clinical studies, occurring in 50.6% of patients. It should be noted that the reporting methodology of injection site reactions differed across studies. All injection site reactions, regardless of the severity and duration, were reported as adverse events in 111-301, 111-202, and 111‑206, while only those that were of Grade 2 severity or higher, lasted more than 24 hours (excluding bruising), recurred or began more than 24 hours after the most recent injection, or had a change in duration or frequency over a period of time compared to previous injection site reaction, were reported as adverse events in the long-term extension studies. Although the rate of injection site reactions was higher in participants aged less than 2 years, all reactions resolved within a short period of time and without requiring medical attention.

Due to the vasodilatory effect of C-type natriuretic peptides, transient decreases in blood pressure were identified as another risk of Voxzogo. Transient decreases in blood pressure occurred in 14.6% of patients and were usually asymptomatic, non-severe, and self-limiting. In addition, a higher incidence of viral infections (18.0%), common in pediatric patients, was also observed among Voxzogo-treated patients in the main studies 111-301 and 111-206. Other common reactions reported in the clinical program included increased alkaline phosphatase (31.0%), vomiting (30.1%), rash (22.6%), arthralgia (17.2%), ear pain (17.2%), diarrhea (14.6%), dizziness (10.0%), and influenza (9.6%). All of these risks were considered manageable, non-serious, and adequately addressed through labelling and routine monitoring. No life-threatening or fatal treatment-related events were reported in the clinical program, and no participants discontinued the drug as a result of an adverse reaction.

Upon 6 years of treatment, no new safety signals were identified, and improvements in linear growth were not associated with accelerated bone maturation, disproportionate skeletal growth, or abnormal bone morphology. Conversely, the incidence of adverse effects decreased over time, suggesting a more favourable profile with longer treatment exposure.

Overall, the benefit-risk profile of Voxzogo in children with achondroplasia is considered favourable. Daily injections of Voxzogo were generally well tolerated in children aged 4 months and older at the proposed dosage. The adverse reactions associated with the treatment were non-serious and manageable; however, long-term safety risks, particularly on bone development and in special populations, should continue to be assessed. Due to the absence of clinical data in infants under 4 months of age and uncertainties regarding dose prediction in this group, treatment is recommended only for children aged 4 months and older.

Appropriate warnings and precautions are in place in the approved Product Monograph for Voxzogo to address the identified safety concerns.

For more information, refer to the Product Monograph for Voxzogo, approved by Health Canada and available through the Drug Product Database.

Vosoritide, the medicinal ingredient in Voxzogo, exhibits pharmacologic activity similar to endogenous human C-type natriuretic peptide. Vosoritide binds to the natriuretic peptide receptor (NPR)-B, resulting in antagonism of FGFR3‑mediated MAPK/ERK signaling. Subcutaneous administration was associated with an increase in body length, long bone lengths, growth plate thickness, and markers of collagen turnover in both healthy animals (rats, mice, and monkeys) and in a mouse model of achondroplasia.

Vosoritide is rapidly absorbed with a relatively short elimination half-life with no consistent sex differences. Adverse findings in repeat-dose studies in aged adult rats (26 weeks), juvenile rats dosed from postnatal day 7 (26 weeks), and cynomolgus monkeys treated for up to 26 weeks (juvenile/adolescent) and up to 44 weeks (sexually mature) were generally limited to exaggerated pharmacological effects on skeletal structures, including paw curvature, impaired limb movement, tail kinking, joint swelling, and hunched posture that were evident into the undosed recovery periods. These endpoints were considered the basis for no-observable-adverse-effect levels (NOAELs) in the relevant studies. The NOAEL in adult rats was 50 mcg/kg, equivalent to a systemic exposure 0.9-fold that seen in humans at the maximum recommended human dose (MRHD) of 30 mcg/kg/day based on area under the concentration-time curve from zero to the last quantifiable concentration (AUC_0‑t). The NOAEL in unweaned rats was 10 mcg/kg/day, equivalent to a systemic exposure 0.02-fold that seen in humans at the MRHD based on AUC_0-t. In cynomolgus monkeys, the NOAELs for the 26- and 44-week studies were 90 mcg/kg/day and 25 mcg/kg/day, respectively, equivalent to systemic exposures 0.73-fold and 0.1-fold that seen in humans at the MRHD based on AUC_0-t. In monkeys, a transient increase in heart rate and decrease in blood pressure correlated with recumbency or hypoactivity was noted in a safety pharmacology study and in a long-term repeat-dose study. Adverse central nervous system and respiratory effects were not detected in other safety pharmacology studies.

No reproductive or developmental toxicities were identified in fertility, embryofetal development, or pre- and postnatal development studies in rabbits and rats at doses of up to 240 mcg/kg/day and 540 mcg/kg/day, respectively. Similarly, no associated effects on reproduction or fertility were apparent in rats dosed daily from the age of 7 days. Vosoritide was detected in pooled fetal plasma at concentrations less than 1% of maternal levels from the preceding day and was quantifiable in the offspring of rats on postnatal day 1, and in milk on lactation day 14 with a milk-to-plasma ratio of 1% to 5% across all treated groups. Safety margins for general toxicity are at or below 1, reflecting exaggerated pharmacological effects in healthy animals rather than unanticipated target-organ toxicity; however, the applicability of these endpoints in healthy animals to those with fibroblast growth factor receptor 3 (FGFR3)-related achondroplasia is uncertain.

Appropriate warnings and precautionary measures are in place in the Product Monograph for Voxzogo to address the identified safety concerns.

For more information, refer to the Product Monograph for Voxzogo, approved by Health Canada and available through the Drug Product Database.

Characterization of the Drug Substance

Voxzogo (vosoritide) is a modified recombinant human form of C-type natriuretic peptide. The Voxzogo drug product is supplied as a lyophilized powder in a single-dose vial at three different strengths (0.4, 0.56, and 1.2 mg/vial) and is co-packaged with sterile water for reconstitution. The drug product is formulated as one of two vosoritide concentrations (0.8 mg/mL for the 0.4 and 0.56 mg/vial strengths and 2.0 mg/mL for the 1.2 mg/vial strength).

Detailed characterization studies were performed to provide assurance that vosoritide consistently exhibits the desired characteristic structure and biological activity.

Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within established limits and are considered to be acceptable. A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

The drug substance manufacturing process has been optimized and scaled up during development. The process changes introduced at each generation of the process were adequately described and comparatively addressed. Lot release, stability, and characterization data have also been used to support the comparability assessment.

Manufacturing Process of the Drug Substance and Drug Product and Process Controls

The vosoritide precursor (TAF-BMN 111 fusion protein) is produced in Escherichia coli cells. After fermentation, the cells are harvested via centrifugation and lysed via homogenization to yield inclusion bodies containing the TAF-BMN 111 fusion protein. The inclusion bodies are combined and the vosoritide is cleaved from the TAF-BMN 111 fusion protein via a low pH/high temperature step, and the resulting material is clarified by centrifugation and filtration. Downstream purification consists of anion exchange chromatography, a redox control step, cation exchange chromatography, and anion exchange membrane filtration. The vosoritide is then concentrated and buffer exchanged into acidified water for injection via cation exchange chromatography, followed by formulation and filtration into single-use storage bags. The drug substance can be held at 2 °C to 8 °C for up to seven days prior to blast freezing and storage.

The drug product manufacturing process begins with compounding and bioburden reduction filtration of the buffer solution and thawing of the drug substance, followed by pooling and dilution of the drug substance to a desired peptide concentration using filtered formulation buffer. The drug product solution then undergoes bioburden reduction filtration, inline sterile filtration, and aseptic filling. Filled vials are then partially stoppered, lyophilized, fully stoppered and crimped, subjected to visual inspection, and then stored at 2 °C to 8 °C until transfer to the secondary packaging site for labelling/packaging operations and assembly of the co-package. None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations. The compatibility of the medicinal ingredient with the excipients is supported by the stability data provided.

Changes to the manufacturing process made throughout the pharmaceutical development are considered acceptable upon review. The drug substance and drug product manufacturing processes were validated. During validation, all process parameters, in-process controls, release testing results, characterization results, and stability results met the pre-defined acceptance criteria. The impurity clearance was successfully demonstrated, and all hold times, sterile filtration and aseptic processes, and shipping were successfully validated. Based on these validations, the sponsor has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

Control of the Drug Substance and Drug Product

The control strategy for Voxzogo applies to both the drug substance and drug product, and involves control of materials, in-process controls of product quality attributes, control of process parameters, release and stability specifications, and facility and equipment controls. The release and stability specifications for the drug substance and drug product include assays for identity, quantity, biological activity, purity and impurities, safety, and compendial requirements. A two-tier reference standard program has been established, and the in-house analytical methods were appropriately validated.

Voxzogo is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 36-month shelf life at 2 °C to 8 °C for Voxzogo drug product is considered acceptable. Voxzogo may be stored at room temperature (below 30 °C) for up to 90 days, but not beyond the expiry date, and may not be returned to the refrigerator after being stored at room temperature.

The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.

The proposed packaging and components are considered acceptable.

Facilities and Equipment

An on-site evaluation (OSE) of the facilities involved in the manufacture and testing of the drug substance and drug product was not conducted as the review of the quality component of the New Drug Submission for Voxzogo was based primarily on the foreign review completed by the European Medicines Agency.

Adventitious Agents Safety Evaluation

The drug substance manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control. Pre-harvest culture fluid from each lot is tested to ensure absence of adventitious microorganisms (bioburden, mycoplasma, and viruses) and appropriate limits are set. Purification process steps designed to remove and inactivate viruses are adequately validated.

No raw materials or excipients of human or animal origin are used in the manufacture of Voxzogo.