Phase I/IIA Study of SAR422459 in Participants With Stargardt's Macular Degeneration

Primary Objective:

To assess the safety and tolerability of ascending doses of SAR422459 in participants with Stargardt's Macular Degeneration (SMD).

Secondary Objective:

To evaluate for possible biological activity of SAR422459.

The total duration per participant was up to 52 weeks, which included 4 week screening period and 48 weeks study period.

At the end of the study, the participants were invited to enter in an open-label safety study (LTS13588-NCT01736592) for long-term follow-up visits including ophthalmological examinations and recording of adverse events (AEs) for up to 15 years.

Eligibility Criteria:
Inclusion Criteria:

* Signed and dated written informed consent obtained from the participant and/or the participant's legally acceptable representative.
* Diagnosis of SMD, with at least one pathogenic mutant ABCA4 allele on each chromosome.
* Women of childbearing potential must had a negative pregnancy test at Day -1, and agree to use an effective form of contraception for at least three months, or be surgically sterile or postmenopausal, with the last menstrual period being over two years prior to enrollment.
* Males must agree with their partner to use two forms of contraception for at least three months following SAR422459 administration.
* Participants must agree to not donate blood, organs, tissues or cells for at least three months following SAR422459 administration.
* Participants enrolled in France must be affiliated to or benefit from a social security regimen.

Specific Inclusion Criteria Participant Group A:

* Participants (18 years or older) with advanced SMD.
* Visual acuity less than or equal to (\<=) 20/200 in the worst eye.
* Severe cone-rod dysfunction with no detectable or severely abnormal full-field electroretinogram responses.

Specific Inclusion Criteria Participant Group B:

* Participants (18 years or older) with SMD.
* Visual Acuity \<=20/200 in the worst eye.
* Abnormal full-field electroretinogram responses.

Specific Inclusion Criteria Participant Group C:

* Participants (18 years or older) with SMD.
* Visual acuity \<=20/100 in the worst eye.
* Abnormal full-field electroretinogram responses.

Specific Inclusion Criteria Participant Group D:

* Symptomatic participants (from 6 years to 26 years old) with early or childhood-onset SMD (age at disease onset \[less than\] \<18 years) with at least one pathogenic mutant ABCA4 allele on each chromosome confirmed by direct sequencing and co-segregation analysis within the participant's family.
* Visual acuity of greater than or equal to (\>=) 20/200 in both eyes at the time of the screening visit.
* Participants were anticipated to experience rapid deterioration in visual function and/or retinal structure as determined by an annual progression rate in at least one of the following parameters occurring in at least one eye (assessments recorded up to 2 years prior to the screening visit date might be considered to document evidence of rapid deterioration):

  * Loss of \>=1 line of Snellen visual acuity (equivalent to 5 early treatment diabetic retinopathy study \[ETDRS\] letters).
  * Reduction in macular mean sensitivity of \>=1.2 decibels (dB) as assessed by microperimetry.
  * Reduction in macular mean sensitivity of \>=5 dB or reduction in hill of vision by greater than (\>)14 dB-sr as assessed by static perimetry.
  * Enlargement in the area of macular retinal pigment epithelial (RPE) atrophy by fundus autofluorescence at a rate of \>=0.5 millimeter square(mm\^2).
  * Enlargement in the area of central macular retinal thinning/photoreceptor loss by ocular coherence tomography at a rate of \>=0.5 mm\^2.
* All eligible participants must demonstrate an ability to understand, willingness to cooperate and ability to reliably perform required study procedures as judged and confirmed by the study investigator.

Specific inclusion criteria Participant Group E:

* Symptomatic participants (between 6 years and 17 years old) with early or childhood-onset SMD with at least one pathogenic mutant ABCA4 allele on each chromosome confirmed by direct sequencing and co-segregation analysis within the participant's family.
* Visual acuity of \>=20/100 in both eyes at the time of screening visit.
* Participants were anticipated to experience rapid deterioration in visual function and/or retinal structure as determined by an annual progression rate in at least one of the following parameters occurring in at least one eye (assessments recorded up to 2 years prior to the screening visit date were considered to document evidence of rapid deterioration):

  * Loss of \>=1 line of Snellen visual acuity (equivalent to 5 ETDRS letters).
  * Reduction in macular mean sensitivity of \>=1.2 dB as assessed by microperimetry.
  * Reduction in macular mean sensitivity of \>=5 dB or reduction in hill of vision by \>14 dB-sr as assessed by static perimetry.
  * Enlargement in the area of macular RPE atrophy by fundus autofluorescence at a rate of \>=0.5 mm\^2.
  * Enlargement in the area of central macular retinal thinning/photoreceptor loss by ocular coherence tomography at a rate of \>=0.5 mm\^2.
* All eligible participants demonstrated an ability to understand, willingness to cooperate and ability to reliably perform required study procedures as judged and confirmed by the study investigator.

Exclusion Criteria:

* Pre-existing eye conditions that would preclude the planned surgery or interfere with the interpretation of study outcome measures.
* Cataract surgery with intraocular lens implantation within 6 months of enrolment.
* Aphakia or prior vitrectomy in the study eye.
* Concomitant systemic diseases including those in which the disease itself, or the treatment for the disease, can alter ocular function.
* Any intraocular surgery or laser in either eye planned within 6 months of Day 0.
* Any contraindication to pupil dilation in either eye.
* Any known allergy to any component of the delivery vehicle or diagnostic agents used during the study, or medications planned for use in the perioperative period particularly topical, injected or systemic corticosteroids.
* Any injectable intravitreal treatment to the treated eye or intravitreal device in the treated eye within 6 months prior to screening.
* Any periocular injections of corticosteroids to the treated eye within 4 months prior to screening.
* Laboratory test abnormalities or abnormalities in electrocardiogram, chest X-rays that in the opinion of the Principal Investigator would make the participant unsuitable for participation in the study.
* Significant intercurrent illness or infection during the 28 days prior to enrolment.
* Pre-menopausal or non-surgically sterile women who were unwilling to use an effective form of contraception such as the contraceptive pill or intrauterine device.
* Alcohol or other substance abuse.
* Contraindications to use of anesthesia (local or general, as appropriate).
* Concurrent anti-retroviral therapy that would inactivate the investigational agent.
* History of any investigational agent within 28 days prior to SAR422459 administration.
* Participation in a prior ocular gene transfer therapy study.
* Enrolment in any other clinical treatment study throughout the duration of the SAR422459 study.
* Current or anticipated treatment with anticoagulant therapy or the use of anticoagulation therapy within the four weeks prior to surgery.
* A past medical history of human immunodeficiency virus or hepatitis A, B, or C infection.
* Women who were pregnant or were breastfeeding.
* History or signs consistent with unilateral amblyopia (strabismic, anisometropic, or stimulus deprivation).