Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of SAR442501 in Pediatric Participants With Achondroplasia

Study Overview
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Brief Summary
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This is a Phase 2, open-label, multicenter, study to evaluate safety, tolerability and efficacy of SAR442501 in children from birth up to 12 years of age with Achondroplasia.

Detailed Description
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Up to approximately 275 weeks: 3 weeks Screening + 52 weeks primary treatment period + up to approximately 216 weeks extended treatment period+ 4 weeks follow-up.

Official Title
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A Phase 2, Open-label, Multi-center, 2-stage Sequential Cohort, Dose Escalation Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of Subcutaneous SAR442501 in Pediatric Participants With Achondroplasia

Conditions
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Osteochondrodysplasia

Intervention / Treatment
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* Drug: SAR442501


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have ACH with a confirmed mutation in the FGFR3 gene Participants and/or parent(s) or legal representative(s) must be willing and able to perform all the study procedures to the best of their physical ability. Parent(s) or legal representative(s) capable of giving signed informed consent and participants capable of giving assent when applicable. Exclusion Criteria: Have hypochondroplasia (or the N540K mutation) or short stature condition other than ACH (eg, trisomy 21, pseudochondroplasia) Participants have received any dose of medications or investigational product, including human growth hormone, intended to affect participants' stature or body proportions within 6 months of enrollment (Week 0/Day 1/Visit 2). Have a history of growth plate closure. Long bone fracture within 3 months of enrollment (Week 0/Day 1/Visit 2) Current evidence of corneal or retinal disorder/keratopathy. Participants have had a previous surgical intervention involving the foramen magnum (Stage 2 only). Hyperphosphatemia. The above information is not intended to contain all considerations relevant to a potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 0 Days
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br> | Drug: SAR442501<br>* Solution for injection; Subcutaneous injection<br>|
| Experimental: Cohort 2<br> | Drug: SAR442501<br>* Solution for injection; Subcutaneous injection<br>|
| Experimental: Cohort 3<br> | Drug: SAR442501<br>* Solution for injection; Subcutaneous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events (AE), serious adverse events (SAE), and adverse events of special interest (AESI) during the treatment-emergent period |  | Baseline to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in annualized growth velocity (AGV) Zscore |  | Baseline to Week 26 and Week 52 | 
| Change in AGV (cm/year) |  | Baseline to Week 26 and Week 52 | 
| Change in height Z score |  | Baseline to Week 26 and Week 52 | 
| Change in upper-to-lower body segment ratio |  | Baseline to Week 26 and Week 52 | 
| Change in upper to lower extremity ratio |  | Baseline to Week 26 and Week 52 | 
| Change in sitting to standing height ratio (crown-to-rump length to total length for infants) |  | Baseline to Week 26 and Week 52 | 
| Change in arm span to height ratio |  | Baseline to Week 26 and Week 52 | 
| Change in upper arm to forearm length ratio |  | Baseline to Week 26 and Week 52 | 
| Change in upper leg to lower leg ratio |  | Baseline to Week 26 and Week 52 | 
| Change in head circumference to height ratio |  | Baseline to Week 26 and Week 52 | 
| Change in brainstem parameter | Change in surface area of the bony foramen magnum (cm2) as measured by head and neck Magnetic Resonance Imaging (MRI). | Baseline to Week 52 | 
| Change in skull parameter | Change in dimensions of skull base parameters, and degree of synchondroses fusion as measured by head and neck MRI. | Baseline to Week 52 | 
| Change in spine morphometric parameter | Change in grading of cord compression and cord constriction as assessed by head and neck MRI. | Baseline to Week 52 | 
| Change in volumetric parameter | Change in brainstem and spinal cord volume as measured by head and neck MRI. | Baseline to Week 52 | 
| Change in overall health-related quality of life score in the PedsQL Inventory Generic Core Scale | PedsQL Generic Core Scales, global score ranging from 0-100, with higher scores representing better outcomes | Baseline to Week 26 and Week 52 | 
| Change in fatigue score in the PedsQL Multidimensional Fatigue Scale | PedsQL Multidimensional Fatigue Scale, global score ranging from 0-100, with higher scores representing better outcomes | Baseline to Week 26 and Week 52 | 
| Change in present pain and worst pain rating (PPQ) score | Pediatric Pain Questionnaire (PPQ) score value between 0-4. The lower the better. | Baseline to Week 26 and Week 52 | 
| Change in mobility and symptom rating (STEMS) score | Screening Tool for Everyday Mobility and Symptoms (STEMS) score value between 1-5. The lower the better. | Baseline to Week 26 and Week 52 | 
| Change in developmental score in the Achondroplasia Developmental Recording Form | Achondroplasia Developmental Recording Form to record the age at which participants achieve developmental milestones. The earlier the better. | Baseline to Week 52 | 
| Assessment of pharmacokinetic (PK) parameter: plasma concentration of SAR442501 |  | Baseline to Week 26 and 52 | 
| Assessment of PK parameter: maximum plasma concentration observed (Cmax) |  | Baseline to Week 26 and 52 | 
| Assessment of PK parameter: time to reach Cmax (Tmax) |  | Baseline to Week 26 and 52 | 
| Assessment of PK parameter: Area under the plasma concentration versus time curve calculated using the trapezoidal method during a dose interval (AUC0-t) |  | Baseline to Week 26 and 52 | 
| Assessment of PK parameter: concentration observed before treatment administration during repeated dosing (Ctrough) |  | Baseline to Week 26 and 52 | 
| Assessment of pharmacodynamics (PD) parameter: change in collagen X biomarker (CXM) levels |  | Baseline to Week 26 and Week 52 | 
| Assessment of PD parameter: change in osteocalcin levels |  | Baseline to Week 26 and Week 52 | 
| Assessment of PD parameter: change in bone-specific alkaline phosphatase |  | Baseline to Week 26 and Week 52 | 
| Assessment of PD parameter: change in procollagen type 1 N-terminal propeptide (P1NP) levels |  | Baseline to Week 26 and Week 52 | 
| Assessment of PD parameter: change in collagen-type 1 C-Telopeptide (CTX) levels |  | Baseline to Week 26 and Week 52 | 
| Number of participants with treatment-emergent anti-drug antibodies (ADA) |  | Baseline to Week 26 and Week 52 | 
| Changes in neurological examination | Percentage of participants with changes (i.e. abnormal to normal or normal to abnormal) in neurological examination findings | Baseline through Week 26 and Week 52 |