Evaluation of Vosoritide Safety and Efficacy in Infants and Young Children with Hypochondroplasia: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study
- Trial ID
- 2024-512261-14-00
- Protocol
- 111-212
- Sponsor
- Biomarin Pharmaceutical Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective is to assess the safety and tolerability of vosoritide compared with placebo in infants and young children diagnosed with hypochondroplasia and to determine its effect on linear growth, addressing the critical need for therapies that are both well‑tolerated and capable of improving stature in this population. Secondary objectives include:
- Evaluating the impact on height gain;
- Assessing overall growth parameters;
- Analyzing changes in body proportions;
- Measuring arm span;
- Determining bone quality using dual‑energy X‑ray absorptiometry (DXA);
- Characterizing the pharmacokinetic profile of the investigational product;
- Investigating pharmacodynamic biomarkers;
- Monitoring the incidence of otitis media;
- Monitoring the frequency of seizures.
Participants
The trial enrolled 39 participants diagnosed with Hypochondroplasia, a rare skeletal dysplasia, all of whom were infants aged from birth to less than 36 months at randomization; both male and female subjects were represented. Eligible individuals required a genetically confirmed FGFR3 pathogenic variant, a height Z‑score meeting disease‑specific thresholds (≤ −1.0 SDS for those < 12 months, ≤ −2.0 SDS for those 12–< 36 months), and a baseline weight of at least 3 kg, reflecting overall health status appropriate for the study. Recruitment involved screening for the genetic diagnosis, anthropometric criteria, and verification of parental or guardian consent and willingness to administer daily injections. Participants were otherwise generally healthy, with no specific diet or activity restrictions reported, and were classified as a vulnerable population due to their age and disease status.
Plans and Procedures
The study is a phase 2, multicenter, randomized, double‑blind, placebo‑controlled trial evaluating subcutaneous vosoritide (0.40 mg daily) versus matching placebo in infants and young children diagnosed with hypochondroplasia aged 0 to < 36 months. After obtaining written informed consent, participants undergo a screening visit to confirm eligibility, including genetic confirmation of an FGFR3 pathogenic variant and assessment of height Z‑score according to CDC growth charts. Eligible subjects are randomized on Day 1 (baseline visit) to receive either vosoritide or placebo, with daily administration by the caregiver throughout the 52‑week treatment period. Follow‑up visits are scheduled at regular intervals (e.g., weeks 4, 12, 24, 36, and 52) to monitor safety (adverse events, laboratory values, vital signs), assess pharmacokinetics, and measure efficacy endpoints such as change in height Z‑score, body proportion ratios, and bone density by DXA. The end‑of‑study visit occurs at Week 52, concluding the participant’s involvement of approximately one year. Primary outcomes include incidence of treatment‑emergent and serious adverse events and change from baseline in height Z‑score at Week 52; secondary outcomes assess growth velocity, anatomical ratios, bone health, and additional safety parameters.
Treatment
The investigational product is Voxzogo 0.56 mg powder and solvent for solution for injection, containing the active peptide vosoritide. It is formulated as a solution for injection and is administered by subcutaneous injection at a dose of 0.40 mg per administration. The dosing interval and total treatment duration follow the protocol‑specified schedule, and investigators will verify the administered volume against the prescribed dose at each visit to ensure compliance.
The control arm utilizes a matching placebo consisting of powder and solvent for solution for injection, without any active pharmaceutical ingredient. The placebo is prepared in an identical pharmaceutical form and is given subcutaneously using the same volume, dosing interval, and administration procedures as the active product to maintain blinding.
Both study treatments are supplied in single‑use vials. Study personnel will document each injection in the electronic case report form, perform a count of returned vials, and assess injection site observations to monitor participant adherence and detect any administration‑related events.
Efficacy
Efficacy will be assessed using several growth‑related and skeletal endpoints in infants and young children with hypochondroplasia. The primary efficacy parameter is the change from baseline to Week 52 in height Z‑score. Secondary efficacy parameters include change from baseline to Week 52 in absolute height, average growth velocity over the 6‑month interval at Week 52, upper‑to‑lower body segment ratio, arm span, total body and lumbar spine bone mineral density (BMD) Z‑scores measured by dual‑energy X‑ray absorptiometry (DXA), and total body and lumbar spine bone mineral content (BMC) by DXA. Additional secondary measures comprise pharmacokinetic (PK) profiles, change in circulating cGMP levels, incidence of otitis media, and seizure frequency.
Height and segmental measurements will be obtained using calibrated stadiometers and anthropometric tapes at baseline and at Week 52. DXA scans of the total body and lumbar spine will be performed at the same time points to determine BMD Z‑scores and BMC. Blood samples for PK and cGMP assessments will be collected pre‑dose and at scheduled visits, with analysis performed using validated laboratory assays. Otitis media incidence and seizure frequency will be recorded throughout the study period based on clinical observation and caregiver reporting. All efficacy data will be analyzed by comparing the change from baseline to Week 52 between the vosoritide and placebo groups, employing appropriate statistical methods for continuous and categorical outcomes.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participants must be 0 to < 36 months of age at randomization.
- Participants must have a confirmed genetic diagnosis of HCH (obtained via whole genome sequencing; presence of a FGFR3 pathogenic variant associated with HCH). Genetic confirmation of disease can be obtained either in Study 111-902 or during the Screening period of 111-212 (Appendix 4).
- Participants aged 0 to < 12 months must have a height Z-score of ≤ −1.0 SDS and participants aged ≥ 12 to < 36 months must have a height Z-score of ≤ −2.0 SDS in reference to the average stature of the same sex and age, as calculated using the Center for Disease Control and Prevention (CDC) growth charts (https://www.cdc.gov/growthcharts/zscore.htm) as assessed at Screening.
- Participant’s weight at the Day 1 visit (pre-treatment) must be ≥ 3 kg.
- Parent(s) or guardian(s) are willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to performance of any research-related procedure.
- Parent(s) or caregiver(s) are willing to administer daily injections to the participants and willing to complete the required training.
Exclusion Criteria
- Short stature condition other than HCH (eg, ACH, trisomy 21, pseudoachondroplasia).
- Have had regular long-term treatment (> 1 month) with oral corticosteroids in the 12 months prior to Screening.
- Have condition(s) requiring a daily inhaled steroid dose > 400 µg of inhaled budesonide per day or equivalent. Low-dose ongoing inhaled steroids for asthma, or intranasal steroids, are acceptable.
- Have had a fracture of the long bones or spine within 6 months prior to Screening.
- Require any investigational agent prior to completion of study period.
- Have received another investigational product or investigational medical device within 30 days prior to the Screening visit.
- Have used any other investigational product or investigational medical device for the treatment of HCH or short stature at any time
- Have aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3 × upper limit of normal (ULN or total bilirubin ≥ 1.5 × ULN at screening (except for participants with a known history of Gilberts).
- Have current malignancy, history of malignancy, or currently under work-up for suspected malignancy.
- Have known hypersensitivity to vosoritide or its excipients.
- Have a history of hip surgery or severe hip dysplasia.
- Have any of the following: • Hypothyroidism or hyperthyroidism, growth hormone deficiency, hypercortisolism or hypopituitarism, or other endocrine cause of short stature. • Insulin-requiring diabetes mellitus. • Autoimmune inflammatory disease (e.g., systemic lupus erythematosus, juvenile dermatomyositis, scleroderma). • Other chronic diseases that per investigator determination may be causative of a participant’s short stature, including conditions causing malnutrition (e.g., inflammatory bowel disease, cystic fibrosis, celiac disease, eating disorders). • Autonomic neuropathy.
- Have a history of clinically significant hip injury in the 30 days prior to Screening.
- Have a history of slipped capital femoral epiphysis or avascular necrosis of the femoral head.
- Have abnormal findings on baseline clinical hip exam or imaging assessments that are determined to be clinically significant.
- Have a condition or circumstance that places the participant at high risk for poor treatment compliance or for not completing the study.
- Have any concurrent disease or condition that will interfere with study participation or safety evaluations, for any reason.
- Have a history of any of the following: • Renal insufficiency defined as estimated glomerular filtration rate (eGFR) of < 60 ml/min/1.73 m2 using the revised Schwartz Pediatric Bedside eGFR formula. • Chronic anemia or hemoglobin (Hgb) < 10.0 g/dL (Screening lab test). • Recurrent symptomatic hypotension (i.e., dizziness, fainting, postural tachycardia) or recurrent symptomatic orthostatic hypotension.
- History of cardiac or vascular disease, including the following: • Cardiac dysfunction • Hypertrophic cardiomyopathy • Pulmonary hypertension • Congenital heart disease with ongoing cardiac dysfunction • Cerebrovascular disease • Aortic insufficiency or other clinically significant valvular dysfunction • Clinically significant atrial or ventricular arrhythmia
- Have an unstable medical condition likely to require surgical intervention during the study period.
- Have documented uncorrected vitamin D deficiency: 25-hydroxy-vitamin D ≤ 15 ng/mL (37.5 nmol/L). Note: participants with deficiency may receive supplementation and re-screen after 8 weeks.
- Taking any of the prohibited medications.
- Require current chronic therapy with antihypertensive medication or any medication that may compromise the safety or ability of the participant to participate in this clinical study.
- Have been treated with growth hormone, insulin-like growth factor 1 (IGF-1), or anabolic steroids in the 6 months prior to Screening, or long-term treatment (> 3 months) at any time.
- Please see protocol for complete details.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 21 Sept 2025 | 10 |
 Germany | Recruiting | 21 Sept 2025 | 10 |
 Italy | Recruiting | 21 Sept 2025 | 10 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Voxzogo 0.56 mg powder and solvent for solution for injection | Test | POWDER AND SOLVENT FOR SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 0.40 | 52 | PRD9189025 |
powder and solvent for solution for injection | Placebo | N/A | — | — | — | N/A |