Phase 2 Randomized Controlled Multicenter Study of Vosoritide in Pediatric Patients with Idiopathic Short Stature

The primary objective of this study is to evaluate the effect of three doses of **vosoritide** compared to placebo on annual growth velocity (AGV) after six months of treatment in children with **Idiopathic Short Stature (ISS)**. Additionally, the long-term phase aims to assess the impact of the therapeutic dose of vosoritide versus human growth hormone (hGH) on height and height Z-score after extended treatment. This is clinically relevant as it seeks to determine the optimal dosing strategy for enhancing growth in children with ISS, potentially offering an alternative to existing treatments.

Secondary objectives include:

• Evaluating the safety and tolerability of vosoritide.
• Assessing the effect of three vosoritide doses on linear growth after six months of treatment.
• Evaluating the effect of the therapeutic dose of vosoritide on growth up to final adult height (FAH).
• Assessing the pharmacokinetic (PK) profile of vosoritide.
• Evaluating the effect of vosoritide on pharmacodynamics (PD) and bone growth biomarkers.
• Assessing the effect of vosoritide on bone age relative to chronological age.
• Evaluating the effect of vosoritide on bone quality.

The clinical trial involves a total of **88 participants** diagnosed with **Idiopathic Short Stature (ISS)**. The study population includes both male and female subjects, aged between **3 and 10 years for females** and **3 and 11 years for males**. Participants were selected based on specific criteria, including a height Z-score of ≤ -2.25 standard deviations according to the Centers for Disease Control and Prevention (CDC) growth charts, and being at Tanner Stage 1 at the time of consent. The trial population is considered vulnerable due to the young age of the participants. Lifestyle factors such as diet and physical activity were not specified in the available data. The selection process ensured that participants met the age and health status requirements pertinent to the study's objectives.

The clinical trial is a **Phase II**, randomized, controlled, multicenter study designed to evaluate the efficacy and safety of **vosoritide** in children with **Idiopathic Short Stature (ISS)**. The trial employs a double-blind methodology to ensure unbiased results, with participants randomly assigned to receive one of three doses of vosoritide or a placebo. The study is divided into two phases: a dose-finding phase and a long-term phase. The dose-finding phase aims to assess the effect of three different doses of vosoritide compared to placebo on the annual growth velocity (AGV) over a six-month period. The long-term phase will evaluate the impact of the therapeutic dose of vosoritide versus human growth hormone (hGH) on height and height Z-score after extended treatment.

The trial is expected to last until July 2040, with recruitment starting in July 2025. Participants will be involved in the study for a maximum treatment period of 180 days. The study includes several key visits: an initial screening visit to confirm eligibility based on criteria such as height Z-score and Tanner Stage, followed by regular follow-up visits to monitor growth and safety parameters. The end-of-study visit will assess the primary and secondary endpoints, including changes in AGV, height, and height Z-score, as well as the incidence of treatment-emergent adverse events.

Participants are expected to be involved in the study for the full duration unless specific conditions necessitate early termination. These conditions include the occurrence of significant adverse events or non-compliance with the study protocol. The trial's primary endpoints focus on changes from baseline in AGV at six months and height and height Z-score at four years. Secondary endpoints include the incidence of adverse events, pharmacokinetic parameters, and changes in bone mineral density and bone age. The study is conducted under strict regulatory guidelines to ensure the safety and well-being of all participants.

The clinical trial involves the administration of **vosoritide**, a modified recombinant human C-type natriuretic peptide (rhCNP), as the experimental medication. Vosoritide is provided in the form of a **powder for solution for injection**. The pharmaceutical form is specifically designed for **subcutaneous use**. The dosing regimen is based on the participant's body weight, with the dosage expressed in micrograms per kilogram (µg/Kg). The maximum treatment period for vosoritide administration is 180 days. The trial includes two formulations of vosoritide: "Voxzogo 0.56 mg powder and solvent for solution for injection" and "Voxzogo 1.2 mg powder and solvent for solution for injection," both of which are pediatric formulations. The active substance in these formulations is vosoritide, and they are manufactured by BioMarin International Limited.

In addition to the experimental treatment, the study employs a **placebo** as a comparator. The placebo is used to evaluate the efficacy of vosoritide by providing a control group for comparison. The placebo is administered in a manner consistent with the experimental treatment to ensure blinding and maintain the integrity of the study design. The placebo is also provided in a form suitable for subcutaneous administration, ensuring consistency in the route of administration across all study arms.

Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol. This monitoring is crucial for maintaining the validity of the trial results and ensuring that the data collected accurately reflects the effects of the experimental treatment. The study is designed to assess the impact of vosoritide on growth parameters in children with idiopathic short stature, with the primary objective being the evaluation of the effect of different vosoritide doses compared to placebo on annual growth velocity (AGV) after six months of treatment.

The efficacy of **vosoritide** in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the change from baseline in annual growth velocity (AGV) at 6 months during the Dose-Finding Phase, and the change from baseline in height and height Z-score at 4 years during the Long-Term Phase. These measurements will provide insights into the impact of vosoritide on growth parameters in children with idiopathic short stature.

Secondary endpoints will further evaluate efficacy by examining various parameters. These include the incidence of treatment-emergent adverse events, changes from baseline in height Z-score at 6 months, and changes in height and height Z-score at each visit and at final adult height (FAH). Pharmacokinetic parameters such as Tmax, Cmax, AUC0-t, AUC0-inf, t1/2, CL/F, and Vz/F will also be assessed. Additionally, changes from baseline at prespecified timepoints in urine cyclic guanosine monophosphate (cGMP) and serum collagen type X marker (CXM) will be measured. Bone age relative to chronological age and changes in bone mineral density (BMD) and bone mineral content (BMC) as measured by dual-energy X-ray absorptiometry (DXA) will be evaluated at each visit.