A Phase 3, Open-Label, Long-Term Extension Study to Evaluate the Safety and Efficacy of Vosoritide in Children with Hypochondroplasia

The primary objective of this study is to evaluate the long-term safety, tolerability, and efficacy of vosoritide treatment until final adult height in patients with hypochondroplasia who participated in previous studies 111-303 and 111-212. This assessment is clinically relevant to determine the sustained benefit-risk profile of vosoritide therapy throughout the entire growth period in this patient population.

The secondary objectives include:

• To evaluate the maintenance effect of vosoritide treatment on standing height and height Z-score

• To evaluate the long-term effect of vosoritide treatment on growth velocity and body proportions until final adult height

• To evaluate the long-term effect of vosoritide on bone age/chronological age ratio

• To evaluate the long-term effect of vosoritide on bone metabolism biomarkers

• To evaluate long-term changes in health-related quality of life, as measured by QoLISSY

This clinical trial enrolled a total of **65 participants** diagnosed with **hypochondroplasia**. The study population consisted of both **male and female** subjects in the **pediatric age range**. Participants were selected from prior studies 111-303 and 111-212, with eligibility requiring completion of the Week 52 visit in those studies and confirmation of **open epiphyses** as assessed by left hand anteroposterior X-rays using the Greulich and Pyle method. The trial population was classified as a **vulnerable population**. Female participants aged 10 years or older, or those who had begun menses, were required to have negative pregnancy testing at baseline and throughout the study. Sexually active participants were required to use highly effective contraceptive methods during the study period. Selection criteria included the ability and willingness of participants to perform all study procedures and the willingness of parents or caregivers to administer daily injections following appropriate training.

This is a Phase 3, open-label, long-term extension study designed to evaluate the safety, tolerability, and efficacy of **vosoritide** in pediatric patients with **hypochondroplasia**. The study will continue until participants reach **final adult height**. The investigational medicinal product, **Voxzogo**, is a solution for injection administered via **subcutaneous** route and is available in three dosage strengths: 0.4 mg, 0.56 mg, and 1.2 mg powder and solvent for solution for injection. The active substance is vosoritide, which is classified as a protein of other origin and holds **orphan drug** designation. The maximum daily dose ranges from 0.24 mg to 0.80 mg depending on the formulation used, with treatment periods extending up to 204 weeks for the higher dose formulations and 24 weeks for the lowest dose formulation. The study is categorized as a **paediatric formulation** trial and is not classified as a low-intervention clinical trial.

The primary objective is to assess the long-term safety, tolerability, and efficacy of vosoritide treatment until final adult height is achieved in participants who have completed the Week 52 visit of parent studies 111-303 or 111-212. The **primary endpoints** include the incidence of **treatment-emergent adverse events** over time until final adult height, change from baseline in height Z-score yearly until final adult height, and change from baseline in height yearly until final adult height. **Secondary endpoints** focus on change from baseline in height and height Z-score at Week 52 of Study 111-308. Baseline measurements are defined as those taken at the first dose of study drug, either vosoritide or placebo, in the parent study.

Eligible participants must have completed the Week 52 visit of studies 111-303 or 111-212 and have open **epiphyses** as assessed by left hand anteroposterior X-rays using the Greulich and Pyle method according to standard of care. Parent(s) or guardian(s) must provide written, signed **informed consent** after being informed about the nature of the study and prior to any study-related procedures. Female participants 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 pregnancy tests during the study. Sexually active participants must be willing to use a highly effective method of **contraception** throughout the study period. Participants must be willing and able to perform all study procedures as physically possible, and parent(s) or caregiver(s) must be willing to administer daily injections to the participants and complete the required training.

The estimated recruitment start date for the study is January 9, 2026, with an estimated end date of April 30, 2041. Participant involvement will extend from enrollment until final adult height is reached, which may vary depending on individual growth patterns and skeletal maturation. The study does not specify principal exclusion criteria in the available data. Daily subcutaneous injections will be administered by parent(s) or caregiver(s) following appropriate training. The study visits will include a baseline visit for enrollment and assessment, followed by regular follow-up visits to monitor safety, tolerability, and efficacy parameters including height measurements, height Z-scores, and adverse events. Participants will continue in the study until they achieve final adult height, at which point they will complete an end-of-study visit. Conditions that may lead to early termination from the study are not explicitly detailed in the provided information.

The investigational medicinal product utilized in this clinical trial is **vosoritide**, a protein-based active substance designated as an **orphan drug** (EU/3/12/1094). Vosoritide is supplied in three different dosage strengths under the trade name **Voxzogo**, manufactured by BioMarin International Limited. The product is presented as a **powder and solvent for solution for injection**, which is reconstituted to form a **solution for injection** prior to administration. All formulations are classified as **paediatric formulations** and are administered via the **subcutaneous route**.

Three distinct dosage strengths of Voxzogo are employed in this study to accommodate individual patient dosing requirements. **Voxzogo 0.4 mg** powder and solvent for solution for injection is administered at a maximum daily dose of 0.24 mg, with a maximum total dose of 175.20 mg over a treatment period of 24 weeks. **Voxzogo 0.56 mg** powder and solvent for solution for injection is administered at a maximum daily dose of 0.40 mg, with a maximum total dose of 2482.00 mg over a treatment period of 204 weeks. **Voxzogo 1.2 mg** powder and solvent for solution for injection is administered at a maximum daily dose of 0.80 mg, with a maximum total dose of 4964.00 mg over a treatment period of 204 weeks. The dosing regimen is determined based on individual patient characteristics and treatment phase within the long-term extension study.

This open-label, long-term extension study evaluates the safety, tolerability, and efficacy of vosoritide treatment in patients continuing from previous studies until final adult height is achieved. The study design allows for extended treatment duration to assess the sustained therapeutic effects and long-term safety profile of vosoritide in the target patient population. Participant compliance monitoring is conducted throughout the treatment period to ensure adherence to the prescribed dosing schedule and to capture any deviations from the protocol-specified administration regimen.

Efficacy will be assessed through multiple parameters measured from baseline until final adult height is achieved. The primary efficacy endpoints include change from baseline in height Z-score evaluated yearly until final adult height and change from baseline in height measured yearly until final adult height. Secondary efficacy endpoints comprise change from baseline in height at Week 52 of Study 111-308 and change from baseline in height Z-score at Week 52 of Study 111-308. Baseline measurements are defined as those obtained at the time of first dose of study drug in the parent study. Height and height Z-score serve as the primary measures for evaluating treatment efficacy over the long-term extension period. Assessment of open epiphyses will be performed using left hand anteroposterior X-rays according to the Greulich and Pyle method as per standard of care, which is relevant for determining eligibility for continued treatment until final adult height is reached.