Phase 2 Randomized Study of Vosoritide in Pediatric Patients with Turner Syndrome, SHOX Deficiency, and Noonan Syndrome Unresponsive to Somatropin

The primary objective of this study is to evaluate the effect of three doses of **vosoritide** compared to continued human growth hormone (hGH) on annual growth velocity (AGV) after six months of treatment in children with Turner Syndrome, Short Stature Homeobox-Containing Gene Deficiency, and Noonan Syndrome who have shown an inadequate response to hGH. This is clinically relevant as it aims to determine the efficacy of vosoritide in enhancing growth outcomes in these pediatric populations, potentially offering an alternative therapeutic option for those not responding adequately to hGH.

Secondary objectives include:

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

The clinical trial involves a total of **32 participants** diagnosed with **Turner Syndrome**, **Short Stature Homeobox-Containing Gene Deficiency**, or **Noonan Syndrome**. 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 a genetically confirmed diagnosis of the aforementioned conditions and a height Z-score of ≤ -2.00 standard deviations relative to the general population of the same age and sex. All participants are at Tanner Stage 1 and have been receiving continuous human growth hormone (hGH) treatment for at least one year prior to enrollment. The trial population is considered vulnerable, and participants are required to continue hGH treatment during the baseline growth phase and for two years post-randomization if assigned to the hGH arm. The study does not specify any particular lifestyle considerations such as diet or physical activity. The sponsor has not provided additional information regarding the general health status of the participants.

The clinical trial is a **Phase 2**, randomized, human growth hormone-controlled, multicenter basket study designed to evaluate the efficacy of **vosoritide** in children with Turner Syndrome, Short Stature Homeobox-Containing Gene Deficiency, and Noonan Syndrome who have shown an inadequate response to human growth hormone (hGH). The trial employs a **randomized, double-blind, controlled** design to ensure the reliability and validity of the results. The primary objective is to assess the change in annual growth velocity (AGV) after six months of treatment with three different doses of vosoritide compared to continued hGH therapy. The trial is expected to last until April 2030, with recruitment starting in February 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, genetic diagnosis, height Z-score, Tanner Stage, and prior hGH treatment. Following randomization, participants will enter the baseline growth phase, during which they will continue hGH treatment. Subsequent visits will occur at regular intervals to monitor growth parameters, adverse events, and laboratory assessments. The end-of-study visit will conclude the trial, with final evaluations of growth and safety outcomes.

The expected duration of participant involvement is up to 24 months post-randomization, with the possibility of early termination if specific conditions arise, such as significant adverse events or non-compliance with the study protocol. The trial will also assess secondary endpoints, including changes in height, height Z-score, and bone mineral density, as well as pharmacokinetic parameters and biochemical markers. The study aims to provide comprehensive data on the safety and efficacy of vosoritide in the target population.

The clinical trial involves the administration of **vosoritide**, a modified recombinant human C-type natriuretic peptide (rhCNP), which 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 expressed in micrograms per kilogram (µg/kg), with a maximum treatment period of 180 days. Vosoritide is also available under the trade name Voxzogo, in two different dosages: 1.2 mg and 0.56 mg, both as powder and solvent for solution for injection, also administered subcutaneously. The active substance vosoritide is classified as a protein of other origin and is designated as an orphan drug for this trial.

In addition to vosoritide, the trial includes the use of **somatropin**, a growth hormone, as a comparator treatment. Somatropin is available in various formulations, including Norditropin FlexPro, which is a solution for injection in a pre-filled pen, and Humatrope, which is provided as a powder and solvent for solution for injection. Both formulations are intended for subcutaneous administration. The dosing for somatropin is measured in milligrams per kilogram (mg/kg), with a maximum treatment period of 156 days. Somatropin is a structurally diverse substance of other origin and is not designated as an orphan drug in this study.

Participant compliance with the dosing schedule will be monitored throughout the trial. The trial aims to evaluate the effect of three different doses of vosoritide compared to continued human growth hormone (hGH) therapy on the annual growth velocity (AGV) after six months of treatment in children with Turner Syndrome, Short Stature Homeobox-Containing Gene Deficiency, and Noonan Syndrome who have shown an inadequate response to hGH.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline in Annualized Growth Velocity (AGV) at 6 months. This will be measured to evaluate the effect of three doses of **vosoritide** compared to continued human Growth Hormone (hGH) treatment. Secondary endpoints include the incidence of treatment-emergent adverse events, changes from baseline in height and height Z-score at 6 months, and changes in height, height Z-score, and 12-month interval AGV at 24 months. Additional secondary endpoints involve pharmacokinetic parameters such as Tmax, Cmax, AUC0-t, AUC0-inf, t1/2, CL/F, and Vz/F, as well as changes in urine cGMP and serum CXM at prespecified timepoints.

Bone age/chronological age changes at prespecified timepoints will also be evaluated, along with changes in bone mineral density (BMD) and bone mineral content (BMC) as measured by Dual-energy X-ray Absorptiometry (DXA). These assessments will include total body (less head) BMD Z-score, lumbar spine BMD Z-score, total body (less head) BMC, and lumbar spine BMC. The trial is designed to provide comprehensive data on the efficacy of **vosoritide** in children with Turner Syndrome, Short Stature Homeobox-Containing Gene Deficiency, and Noonan Syndrome who have shown an inadequate response to hGH. The study will follow a structured schedule for measuring and collecting data at various timepoints, ensuring a robust analysis of the efficacy parameters.