Single Ascending Dose Study of SAR439459 in Adults With Osteogenesis Imperfecta (OI)

A Phase 1b, Single Ascending Dose, Randomized, Double-blind Study to Evaluate the Safety, Tolerability, and Activity of SAR439459 in Adults With Osteogenesis Imperfecta

SAR439459 is a human anti-Transforming growth factor β (TGFβ) monoclonal antibody. This phase 1 clinical study investigates the safety, tolerability, and activity of a single dose of SAR439459 in adult participants with OI.

Participants will receive a single IV dose of SAR439459 with safety, pharmacokinetic (PK), and pharmacodynamic (PD) assessments over 24 weeks.

There will be up to 3 dose cohorts. In addition to safety, tolerability, and PK assessments, bone mineral density (BMD) will be evaluated by dual-energy Xray absorptimetry (DXA) scan and a series of blood biomarkers will be monitored to document pharmacodynamic effects of the single dose of SAR439459.

The duration of the study for all participants will be approximately 29 weeks:

• Up to 5 weeks from initiation of screening to dose administration
• Treatment on Day 1
• Follow-up and observation of safety and PD for 24 weeks
• Final study visit at Week 24

Inclusion Criteria:

• Participants who are clinically categorized as Type I or IV osteogenesis imperfecta with a previously documented pathogenic genetic variant in human collagen type 1 alpha 1 gene (COL1A1) or human collagen type 1 alpha 2 gene (COL1A2).
• Participants who have experienced at least 1 bone fracture in the past 10 years OR 2 or more (≥2) fractures since the age of 18.
• Body weight ≥30.0 kg.
• Contraception for sexually active male participants or female patient; not pregnant or breastfeeding; no sperm donating for male participant.
• Signed written informed assent/consent.

Exclusion Criteria:

• Previously installed rods or metal hardware that would prevent bone mineral density evaluation of the lumbar spine (note: only two of the L1-L4 vertebrae are necessary for evaluation).

• History of moderate (25-40°) to severe (>40°) scoliosis assessed as Cobb angle (unless scoliosis does not impact assessment of bone mineral density in the lumbar vertebrae in the opinion of the investigator).

• Postmenopausal women who:

  • Are within 5 years of the onset of menopause (for example less than 5 years from their last menstruation or post-hysterectomy), however if the person has been on hormone replacement therapy for more than 1 year prior to enrollment, then they are eligible regardless of time from onset of menopause. The person must be willing to continue hormone replacement therapy throughout the study duration. OR
  • Were previously on hormone replacement therapy but have stopped within the past 5 years.

• History of treatment with denosumab, anti-sclerostin antibody, parathyroid hormone, bisphosphonates, or any other experimental therapy for OI within 6 months prior to any study baseline assessment.

• Known bleeding disorder.

• History of significant bleeding event that required hospitalization, surgery, or a blood transfusion that was possibly associated with increased bleeding tendency.

• Any major surgery within the last 28 days prior to investigational medicinal product (IMP) administration.

• Elective surgery or invasive procedure anticipated within 6 months after the IMP administration.

• Therapeutic doses of anticoagulants or antiplatelet agents (eg, 1 mg/kg bid of enoxaparin, 300 mg of aspirin daily, and 75 mg of clopidogrel daily or equivalent) within 7 days prior to the IMP administration.

• Any known central nervous system (CNS) or intraocular lesion that has a risk of bleeding.

• Prior history of skin cancers including melanoma, squamous cell carcinoma, or basal cell carcinoma.

• Clinically significant cardiac valvular disorder or symptomatic heart failure.

• Vitamin D (25-hydoxyvitamin D) <15 ng/dL; rescreening will be allowed after supplementation.

The above information is not intended to contain all considerations relevant to a potential participation in a clinical trial.