Long-Term Safety and Efficacy Evaluation of Vosoritide in Pediatric Achondroplasia: A Phase 3 Open-Label Extension Study

The primary objective of this study is to evaluate the long-term **safety**, tolerability, and efficacy for growth in children with **achondroplasia** treated with BMN 111 (vosoritide). This is clinically relevant as it aims to address the growth deficiencies associated with achondroplasia, potentially improving the quality of life and health outcomes for affected children.

Secondary objectives include:

• Evaluate the pharmacokinetics of BMN 111.
• Assess the immunogenicity of BMN 111 and its impact on safety, pharmacokinetics, and efficacy measures.
• Evaluate body proportion ratios of the extremities.
• Assess the effect of BMN 111 on bone morphology and quality using X-ray and DXA.
• Evaluate changes in health-related quality of life using the Quality of Life in Short Stature Youth (QoLISSY) and the PedsQL questionnaires.
• Assess changes in functional independence as measured by the Wee-FIM clinician-reported outcome.
• Evaluate changes from baseline in bone metabolism biomarkers.
• Assess the effect of BMN 111 on final adult height.

The clinical trial involves a total of **80 participants** diagnosed with **achondroplasia**, a genetic disorder affecting bone growth. The study population includes both male and female subjects, with an age range starting from 2 years old. Participants were selected based on their completion of a prior study, Study 111-301, and the willingness of their parents or guardians to provide informed consent. The trial includes a vulnerable population, as it involves children. Participants are required to adhere to specific lifestyle considerations, such as undergoing regular pregnancy tests for females aged 10 years and older or those who have begun menstruation, and using contraception if sexually active. The trial aims to evaluate the long-term safety, tolerability, and efficacy of BMN 111 for growth in children with achondroplasia. The sponsor has not provided additional information regarding the general health status or specific lifestyle habits of the participants.

The clinical trial is a **Phase 3**, open-label, long-term extension study designed to evaluate the safety and efficacy of **BMN 111** in children with **achondroplasia**. The primary objective is to assess the long-term safety, tolerability, and efficacy for growth in children treated with **vosoritide**. The trial employs a non-randomized, open-label design, allowing all participants to receive the investigational product. The study is expected to run until December 31, 2030, with recruitment having commenced on September 30, 2019.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as completion of a prior study (Study 111-301) and the ability to provide informed consent. The trial includes regular follow-up visits to monitor safety and efficacy endpoints, such as changes in annual growth velocity (AGV), height Z-score, and body segment ratios. Safety assessments will include the incidence and severity of treatment-emergent adverse events (TEAEs), as well as clinical laboratory assessments, imaging, and other relevant evaluations. The end-of-study visit will conclude the participant's involvement, summarizing the overall outcomes and any adverse events experienced.

The expected length of participant involvement is up to 192 weeks, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. Participants are required to adhere to study procedures, including regular subcutaneous administration of **vosoritide** and compliance with follow-up assessments. Conditions for early termination include non-compliance with study procedures, development of exclusionary medical conditions, or withdrawal of consent by the participant or their guardian.

The clinical trial involves the administration of **Voxzogo**, a pharmaceutical product containing the active substance **vosoritide**. Voxzogo is available in three different dosages: 1.2 mg, 0.4 mg, and 0.56 mg, each formulated as a powder and solvent for solution for injection. The pharmaceutical form is a solution for injection, and the route of administration is subcutaneous use. The maximum daily dose for the 1.2 mg formulation is 2 mg, with a total maximum dose of 4.67 g over the treatment period. The 0.4 mg formulation has a maximum daily dose of 0.24 mg and a total maximum dose of 1.4 g, while the 0.56 mg formulation allows for a maximum daily dose of 0.8 mg and a total maximum dose of 2.34 g. The maximum treatment period for all formulations is 192 days. The active substance, vosoritide, is a modified recombinant human C-type natriuretic peptide, classified under the ATC code M05BX07. The product is manufactured by BioMarin International Limited and is designated as an orphan drug for the treatment of achondroplasia in pediatric patients.

In this clinical trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The study is designed to evaluate the long-term safety, tolerability, and efficacy of BMN 111 (vosoritide) in children with achondroplasia. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment regimen. The trial is conducted under the marketing authorization number EU/1/21/1577, with the product being authorized for use in the European Union. The study aims to provide comprehensive data on the effects of vosoritide on growth in children with achondroplasia, contributing to the understanding of its therapeutic potential.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoints include the change from baseline in Annualized Growth Velocity (AGV), height Z-score, and the upper to lower body segment ratio. These parameters will be measured to evaluate the impact of **vosoritide** on growth in children with achondroplasia. Secondary endpoints will focus on additional growth-related metrics, such as changes from baseline in the upper arm length to lower arm length ratio, upper leg length to knee to heel length ratio, and arm span to standing height ratio. Bone-related assessments will include bone age, bone age Z-score, bone mineral density (BMD), BMD Z-score, and bone mineral content (BMC). Quality of life will be evaluated using QoLISSY and PedsQL domain and total scores.

The collection and analysis of these efficacy parameters will be conducted at specified intervals throughout the trial. The trial is designed as a long-term extension study, with a maximum treatment period of 192 weeks. The study will utilize validated scales and clinical assessments to ensure the accuracy and reliability of the data collected. The efficacy assessments will be complemented by safety evaluations, including the incidence and severity of treatment-emergent adverse events (TEAEs), as well as clinical laboratory assessments, imaging, and other relevant clinical evaluations.