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

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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

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

Conditions
-----------------
Osteogenesis Imperfecta

Intervention / Treatment
-----------------
* Drug: SAR439459
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAR439459<br>Participants will receive a single dose of SAR439459 | Drug: SAR439459<br>* Powder for solution for infusion; IV infusion<br>|
| Placebo Comparator: Placebo<br>Participants will receive a single dose of placebo | Drug: Placebo<br>* Solution for infusion; IV infusion<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse events (AEs)/treatment-emergent adverse events (TEAEs) |  | From baseline to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of PK parameters: area under the curve (AUC) |  | From baseline to Week 24 | 
| Assessment of PK parameters: maximum serum concentration observed (Cmax) |  | From baseline to Week 24 | 
| Assessment of PK parameters: time to reach maximum concentration observed (tmax) |  | From baseline to Week 24 | 
| Titer of anti-SAR439459 antibodies (if detected) |  | From baseline to Week 24 | 
| Percent change from baseline in bone mineral density (BMD) |  | From baseline to Week 24 |