Evaluation of Safety, Tolerability, and Preliminary Efficacy of Subretinal SB-007 Injection in Stargardt Disease with Bi-Allelic ABCA4 Mutations

The primary objective of this study is to evaluate the **safety**, **tolerability**, and preliminary **efficacy** of subretinal administration of SB-007 in subjects with Stargardt Disease type 1 (STGD1). This condition is characterized by bi-allelic mutations in the ATP Binding Cassette Subfamily A Member 4 (ABCA4) gene. The study aims to determine the appropriate dose selection for SB-007, which contains a replication-incompetent adeno-associated virus vector serotype 8 encoding the ABCA4 protein. The clinical relevance of this objective lies in addressing the unmet medical need for effective treatments for STGD1, a progressive retinal disorder leading to vision loss. No secondary objectives are specified for this study.

The clinical trial involves a total of **73 participants** diagnosed with **Stargardt Disease** type 1 (STGD1), confirmed genotypically to have bi-allelic ABCA4 gene mutations. The study population includes both male and female subjects, aged between 18 to 65 years. Participants were selected based on their ability to provide written consent, understand and comply with study procedures, and meet specific health criteria, including having clear ocular media and adequate pupillary dilation in the study eye. The trial population is not restricted by gender, and both genders are equally represented. Lifestyle considerations such as diet and physical activity are not specified, but participants must agree to use acceptable contraception measures if sexually active. The study does not provide additional information on the general health status or specific lifestyle habits of the participants.

The clinical trial is designed as a **Phase 1/2**, first-in-human, open-label, assessor-masked, randomized, controlled, dose escalation/expansion study. The primary objective is to evaluate the safety, tolerability, and preliminary efficacy of a subretinal injection of SB-007 in subjects with **Stargardt Disease** (STGD1) caused by bi-allelic autosomal recessive mutations in the ATP Binding Cassette Subfamily A Member 4 (ABCA4) gene. The trial is expected to run until September 2028, with recruitment starting in September 2025. Participants will be involved in the study for a duration of up to 96 weeks, with the primary endpoint being the assessment of safety and tolerability through the incidence and/or clinically significant changes in ocular and non-ocular adverse events.

The study will include several key visits: an initial screening visit to confirm eligibility, followed by a series of follow-up visits to monitor safety and efficacy outcomes. The inclusion criteria require participants to be between 18 and 65 years of age, have a confirmed diagnosis of Stargardt Disease type 1, and meet specific ocular health requirements. Women of child-bearing potential must have a negative pregnancy test at screening and agree to use contraception. The end-of-study visit will conclude the participant's involvement, assessing the final safety and efficacy outcomes.

Participants may be withdrawn from the study if they experience significant adverse events or if they are unable to comply with the study protocol. The study will employ a subretinal injection of SB-007, which contains a replication-incompetent adeno-associated virus vector. The trial will measure secondary endpoints such as changes in lesion size growth, retinal sensitivity, and visual acuity, using various imaging and assessment techniques. The study is not classified as low intervention and is categorized as a Category 2 trial, in line with EMA guidance on disclosure rules.

The clinical trial involves the administration of **SB-007**, an experimental medication designed for the treatment of Stargardt disease type 1 (STGD1). SB-007 is formulated as an **injection** and is delivered via **subretinal use**. The active substance in SB-007 is a replication-incompetent **adeno-associated virus vector serotype 8** encoding the **ABCA4 protein**, specifically targeting the N-region and C-region of the protein. This vector is intended to address the bi-allelic autosomal recessive mutations in the ATP Binding Cassette Subfamily A Member 4 (ABCA4) gene, which are responsible for the condition. The product is not a pediatric formulation and is classified as an orphan drug under the designation number EU/3/23/2788. The administration of SB-007 is conducted in vivo, and the gene transfer product type is categorized as advanced therapy type 3.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The trial is structured as a Phase 1/2, first-in-human, open-label, assessor-masked, randomized, controlled, dose escalation/expansion study. The primary objective is to evaluate the safety, tolerability, and preliminary efficacy of SB-007 to determine the appropriate dose selection for subjects with STGD1. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol. The study does not specify a maximum daily dose, total dose, or treatment period for SB-007, indicating that these parameters are likely determined based on individual participant response and safety assessments.

Efficacy in this clinical trial will be assessed through a series of secondary endpoints designed to evaluate the impact of the investigational product, SB-007, on patients with Stargardt Disease type 1 (STGD1). The parameters for efficacy evaluation include changes from baseline in lesion size growth, as measured by definitely decreased autofluorescence (DDAF) on fundus autofluorescence (FAF) imaging, and total lesion size growth, incorporating both DDAF and well-demarcated questionably decreased autofluorescence (QDAF) on FAF imaging. Additionally, changes in the ellipsoid zone area will be measured using spectral-domain optical coherence tomography (SD-OCT).

Further efficacy assessments will involve evaluating changes in retinal sensitivity through microperimetry, as well as changes in best-corrected visual acuity (BCVA) and low luminance visual acuity (LLVA) using the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. Contrast sensitivity scores will also be monitored. These assessments will be conducted at various timepoints throughout the study to determine the preliminary efficacy of SB-007 in comparison to untreated controls. The study is structured as a Phase 1/2, open-label, assessor-masked, randomized, controlled, dose escalation/expansion trial, with the primary focus on safety and tolerability, while also gathering preliminary efficacy data.