Evaluation of SAR442501 for Safety, Tolerability, Pharmacokinetics, and Efficacy in Pediatric Achondroplasia: A Phase 2, Open-Label, Dose Escalation Study

The primary objective of this study is to assess the **safety** and **tolerability** of SAR442501 when administered subcutaneously in pediatric participants with achondroplasia. This is clinically relevant as it aims to ensure that the treatment is safe for use in children with this condition, which is characterized by abnormal bone growth leading to short stature and other skeletal anomalies.

Secondary objectives include:

• Evaluating changes in growth parameters and body proportionality.
• Assessing changes in the foramen magnum and clinical signs and symptoms of foramen magnum stenosis.
• Evaluating changes in health-related quality of life (QoL) using the Pediatric Quality of Life Inventory Generic Core Scale.
• Assessing changes in fatigue, pain, and mobility using the PedsQL Multidimensional Fatigue Scale, PedsQL Pediatric Pain Questionnaire, and STEMS, respectively.
• Collecting developmental milestone data using the Achondroplasia Developmental Recording Form.
• Evaluating the pharmacokinetic profile and immunogenicity of SAR442501.
• Characterizing changes from baseline in bone/collagen biomarkers.

The clinical trial involves a total of **24 participants** diagnosed with **achondroplasia**, a form of **osteochondrodysplasia**. The study population includes both male and female subjects, with an age range starting from 2 years old. Participants were selected based on the presence of a confirmed mutation in the FGFR3 gene, which is a key inclusion criterion. The trial does not specifically target a vulnerable population. Participants and their parent(s) or legal representatives must be willing and able to perform all study procedures to the best of their physical ability. The study does not specify any particular lifestyle considerations such as diet or physical activity. The general health status of participants is not detailed beyond the requirement of having achondroplasia.

The clinical trial is designed as a **Phase 2**, open-label, multi-center, 2-stage sequential cohort, dose escalation study. It aims to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of subcutaneous SAR442501 in pediatric participants with **achondroplasia**. The trial will involve a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a confirmed mutation in the FGFR3 gene and the ability of participants and their guardians to comply with study procedures. The trial is expected to commence recruitment on July 1, 2023, and conclude by September 1, 2027, with the maximum treatment period for participants set at 216 weeks.

Participants will be administered SAR442501, a **humanised monoclonal antibody derivative against fibroblast growth factor receptor 3**, via subcutaneous injection. The study will monitor the number of participants experiencing adverse events, serious adverse events, and adverse events of special interest during the treatment-emergent period as primary endpoints. Secondary endpoints will include changes in growth velocity, body segment ratios, and various pharmacokinetic and pharmacodynamic parameters. The trial will also assess changes in health-related quality of life scores and neurological examinations.

Study visits will be scheduled at regular intervals to monitor the participants' response to the treatment and to collect data on the primary and secondary endpoints. The end-of-study visit will mark the completion of the trial for each participant, where final assessments will be conducted. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The trial is not categorized as low intervention, and it is crucial to maintain the integrity of the research and development efforts throughout the study duration.

The clinical trial involves the administration of an **experimental medication** identified as SAR442501, which is a **humanised monoclonal antibody derivative against fibroblast growth factor receptor 3**. This investigational product is provided in the form of a **powder for solution for injection**. The medication is administered via **subcutaneous injection**. The dosing regimen specifies a maximum daily dose of 12 mg/kg and a maximum total dose of 24 mg/kg. The treatment period is capped at 216 days. The investigational product is not formulated specifically for pediatric use, although it is being tested in a pediatric population with achondroplasia. The product is developed by Sanofi Aventis Recherche et Développement (SAR) and holds an orphan drug designation under the number EU/3/21/2454.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of SAR442501. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol. The trial is designed as a Phase 2, open-label, multi-center, 2-stage sequential cohort, dose escalation study, specifically targeting pediatric participants diagnosed with achondroplasia.

Efficacy in this clinical trial will be assessed through a series of secondary endpoints designed to evaluate various growth and developmental parameters in pediatric participants with **Achondroplasia**. These endpoints include changes in annualized growth velocity (AGV) Z-score, AGV in centimeters per year, height Z-score, and several body segment ratios such as upper-to-lower body segment ratio, upper to lower extremity ratio, and sitting to standing height ratio. Additional assessments will focus on changes in arm span to height ratio, upper arm to forearm length ratio, upper leg to lower leg ratio, and head circumference to height ratio. Furthermore, changes in brainstem, skull, spine morphometric, and volumetric parameters will be evaluated.

Health-related quality of life will be measured using the PedsQL Inventory Generic Core Scale, while fatigue will be assessed with the PedsQL Multidimensional Fatigue Scale. Pain and mobility will be evaluated through changes in present pain and worst pain rating (PPQ) score and mobility and symptom rating (STEMS) score. Developmental progress will be recorded using the Achondroplasia Developmental Recording Form. Pharmacokinetic parameters such as plasma concentration of SAR442501, maximum plasma concentration observed (Cmax), time to reach Cmax (Tmax), area under the plasma concentration versus time curve (AUC0-t), and concentration observed before treatment administration (Ctrough) will also be assessed. Pharmacodynamic parameters will include changes in collagen X biomarker (CXM) levels, osteocalcin levels, bone-specific alkaline phosphatase, procollagen type 1 N-terminal propeptide (P1NP) levels, and collagen-type 1 C-Telopeptide (CTX) levels. The presence of treatment-emergent anti-drug antibodies (ADA) and changes in neurological examination will also be monitored.