Study of Subretinally Injected SAR439483 Administered in Patients With Leber Congenital Amaurosis Caused by Biallelic Mutations in GUCY2D

Study Overview
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Brief Summary
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Primary Objective: To evaluate the safety and tolerability of ascending doses of SAR439483 administered as a unilateral subretinal injection in patients with Leber Congenital Amaurosis (LCA) caused by autosomal recessive guanylate cyclase 2D (GUCY2D) mutations (GUCY2D-LCA). Secondary Objective: To evaluate the efficacy of ascending doses of SAR439483 administered as a unilateral subretinal injection in patients with GUCY2D-LCA.

Detailed Description
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Study duration per participant is approximately 112 weeks including: an approximately 56-day screening/baseline period, an approximately 52-week study observation period including 1 treatment day, and an approximately 52-week safety follow-up period. The end of study visit will be approximately 260 weeks after the Investigational Medicinal Product (IMP) administration. After completion of the main study (DFI14738), participants may have the option to enroll in a separate long-term follow-up study, in which case they would no longer continue in DFI14738 and their end of study visit would be conducted at Week 52. The study is separated into 2 parts including a dose escalation phase (Part A) and a dose expansion phase (Part B). In Part B participants will be treated at the maximum tolerated dose (MTD) or maximum administered dose (MAD) determined from Part A.

Official Title
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A Phase 1/2 Dose Escalation Study of Subretinally Injected SAR439483 Administered in Patients With Leber Congenital Amaurosis Caused by Biallelic Mutations in GUCY2D

Conditions
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LCA, Leber Congenital Amaurosis, LCA1

Intervention / Treatment
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* Drug: SAR439483
* Drug: SAR439483 Diluent Solution
* Drug: Prednisone
* Drug: Triamcinalone Acetonide
* Drug: 1% Prednisolone
* Drug: Trimethoprim/polymyxin B


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Male or female participant with clinical diagnosis of Leber congenital amaurosis caused by biallelic mutations in the GUCY2D (retinal guanylate cyclase) gene with all of the following: a) Documented mutations in both alleles of the GUCY2D gene per testing in a CLIA-approved laboratory, b) For Cohort 1-3, best corrected visual acuity (BCVA) of 20/200 or worse in the eye to be injected; subsequent cohorts may include BCVA of 20/80 or worse in the eye to be injected, c) Photoreceptor (outer nuclear) layer structure identifiable on an optical coherence tomography (OCT) scan across the central retina. Age ≥18 years for Cohorts 1 through 4, and age ≥ 6 years and <18 years for Cohort 5. Male and female participants must follow the contraception requirements of the trial. Participants must agree to not donate blood, organs, tissues, cells or sperm for at least three months following SAR439483 administration. Exclusion criteria: Complicating systemic diseases (such as medical conditions causing immunosuppression) that would preclude the gene transfer, ocular surgery or planned study procedures. History of human immunodeficiency virus (HIV) infection. Pre-existing eye conditions in the study eye that would preclude the planned surgery or interfere with the assessment and interpretation of study endpoints: for example, glaucoma or optic neuropathy that has resulted in significant visual loss, corneal or lenticular abnormalities or opacities that would preclude view of the fundus or performance of the outcome measures, uveitis, retinopathy and maculopathy that in the opinion of the Investigator are causing significant visual loss. Presence of significant ocular abnormalities in the study eye that in the opinion of the Investigator would preclude the planned surgery, effective safety follow-up, or interfere with the interpretation of study endpoints (eg, glaucoma, corneal or significant lens abnormalities or opacities, pre-existing uveitis, intraocular infection, choroidal neovascularization). Any contraindication to the planned surgical procedure, such as contraindications to the use of anaesthesia or allergy to medications planned in the peri-operative period. Known allergy or hypersensitivity to any component of the investigational medicinal product (IMP), diagnostic agents used during the study or medications planned for use in the peri-operative period, particularly corticosteroids. Women who are pregnant (defined as positive beta-Human Chorionic Gonadotropin (HCG) blood or urine test), lactating or breastfeeding. Any ocular procedure, either planned or performed within 6 months of Day 1, which would interfere with the planned surgery or the interpretation of study endpoints in the opinion of the Principal Investigator (PI). Laboratory test abnormalities or abnormalities in electrocardiogram that in the opinion of the PI would make the participant unsuitable for participation in the study. Significant intercurrent illness or infection during the 28 days prior to enrollment. Current substance use disorder. Use of any investigational agent administered within 5 times the elimination half-life of that investigational agent prior to SAR439483 administration. Enrollment in any other clinical treatment study, for any condition, including those relating to GUCY2D-LCA, throughout the duration of the SAR439483 study participation. Use of anticoagulation therapy within two weeks prior to surgery. Use of immunosuppressive medications. Current, planned during the course of this trial, or past (within 5 times the elimination half-life of that therapy prior to SAR439483 administration) use of anti-viral therapy that would inactivate the investigational agent. Received gene therapy within the last 15 years. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 6 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAR439483<br>SAR439483 single dose according to an ascending dose design (dose escalation phase) or SAR439483 single dose (dose expansion phase) | Drug: SAR439483<br>* Pharmaceutical form:Solution for intraocular administration Route of administration: Subretinal injection<br>Drug: SAR439483 Diluent Solution<br>* Pharmaceutical form:Solution for parenteral use Route of administration: Subretinal injection<br>Drug: Prednisone<br>* Pharmaceutical form:Tablet Route of administration: Oral<br>Drug: Triamcinalone Acetonide<br>* Pharmaceutical form:Suspension Route of administration: Peri-ocular injection<br>Drug: 1% Prednisolone<br>* Pharmaceutical form:Suspension Route of administration: Drops<br>Drug: Trimethoprim/polymyxin B<br>* Pharmaceutical form:Solution Route of administration: Topical<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 (AEs) from baseline up to the end of the observation period | Number of participants with AEs will be summarized in each cohort and overall | From baseline to week 52 | 
| Number of participants with AEs from baseline up to the end of the safety follow-up period | Number of participants with AEs will be summarized in each cohort and overall | From baseline to week 260 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in best -corrected visual acuity (BCVA) | Change in BCVA from baseline in the treated and untreated eye (control) | Baseline to week 52 and Baseline to week 260 | 
| Change in sensitivity | Change in sensitivity from baseline in the treated eye and untreated eye (control) as measured by the full-field stimulus testing | Baseline to week 52 and Baseline to week 260 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GUCY2D