Evaluation of Long-Term Safety, Tolerability, and Efficacy of Vosoritide in Pediatric Patients with Achondroplasia: A Phase 2 Open-Label Extension Study

The primary objective of this study is to evaluate the long-term **safety** and tolerability of daily subcutaneous injections of BMN 111, also known as **vosoritide**, in children with **achondroplasia**. This is clinically relevant as it aims to ensure that the treatment is safe for long-term use in a pediatric population, addressing potential adverse effects and overall patient tolerance to the therapy.

Secondary objectives include:

• Evaluating the effect of BMN 111 on annualized growth velocity, which is crucial for understanding the treatment's impact on growth rate over time.
• Assessing the effect on growth parameters, providing insights into how the treatment influences various aspects of physical development.
• Investigating the effect on body proportions, including upper arm to forearm length, upper leg to lower leg length, and upper to lower body segment ratios, which are important for determining the treatment's impact on body symmetry and proportionality.
• Evaluating the effect on final adult height, which is significant for determining the long-term efficacy of the treatment in achieving normal or near-normal stature.

The clinical trial involves a total of **28 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 24 months of prior treatment with BMN 111 in a previous study. The trial includes a vulnerable population, as it involves children. Participants are required to maintain a stable lifestyle, including adherence to daily subcutaneous injections, and if sexually active, must use a highly effective method of contraception. The study ensures that all participants and their caregivers are willing and able to comply with study procedures, including the administration of daily injections. The trial does not specify any particular lifestyle considerations such as diet or physical activity beyond the requirements for study compliance.

The clinical trial is designed as a **Phase 2, open-label, extension study** to evaluate the long-term safety, tolerability, and efficacy of daily subcutaneous injections of **vosoritide** in children with **achondroplasia**. The trial aims to assess the safety profile through the incidence of adverse events, serious adverse events, laboratory test results, changes in vital signs, physical examinations, echocardiograms, X-rays/QCT results, and clinical hip assessments. Efficacy will be measured by changes in height growth velocity, height, final adult height, growth parameters, and body proportions, using anthropometric measurements and ratios.

The trial is expected to last until December 31, 2024, with participant involvement spanning a maximum treatment period of 192 weeks. Participants must have completed 24 months of prior treatment with BMN 111 in a previous study and meet specific inclusion criteria, such as the ability to provide informed consent and assent, willingness to use contraception if sexually active, and the ability to perform study procedures. Females aged 10 years or older or those who have begun menses must have a negative pregnancy test at the baseline visit and agree to additional tests during the study.

The sequence of study visits includes an initial screening visit to confirm eligibility, followed by regular follow-up visits to monitor safety and efficacy parameters. The end-of-study visit will conclude the participant's involvement, with comprehensive assessments to evaluate the long-term outcomes of the treatment. Conditions that may lead to early termination from the study include the occurrence of significant adverse events or the participant's inability to comply with study procedures.

The clinical trial involves the administration of **Voxzogo**, a pharmaceutical product containing the active substance **vosoritide**. Voxzogo is provided in two formulations: 0.56 mg and 1.2 mg 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 0.56 mg formulation is 0.4 mg, with a total maximum dose of 2.34 mg over the treatment period. For the 1.2 mg formulation, the maximum daily dose is 0.8 mg, with a total maximum dose of 4.67 mg. The treatment period extends up to 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 under the designation number EU/3/12/1094.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on evaluating the long-term safety, tolerability, and efficacy of daily subcutaneous injections of BMN 111 (vosoritide) in children with achondroplasia. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial is designed as an open-label extension study, allowing for the continuous assessment of the investigational product's effects over an extended period.

Efficacy in this clinical trial will be assessed by evaluating changes from baseline in several growth-related parameters in children with **Achondroplasia**. The primary efficacy endpoints include height growth velocity, height, final adult height, and body proportions. These parameters will be measured using anthropometric methods, which may include assessments of height, standing height, sitting height, weight, head circumference, and limb lengths. Additionally, body proportion measurements will be evaluated, such as the upper to lower body segment ratio, upper arm to forearm length ratio, upper leg to lower leg length ratio, and arm span to standing height ratio. Final adult height is defined as the height achieved at 16 years of age for females and 18 years of age for males. These measurements will be collected and analyzed to determine the efficacy of the treatment over the course of the study.