Long-Term Safety and Efficacy Assessment of Botaretigene Sparoparvovec in X-Linked Retinitis Pigmentosa with RPGR Gene Variants

The primary objective of this Phase 3 follow-up study is to evaluate the long-term **safety** and tolerability of AAV5-hRKp.RPGR in individuals with X-linked Retinitis Pigmentosa (RPGR-XLRP) caused by mutations in the RPGR gene. This is clinically relevant as it aims to ensure that the gene therapy does not pose significant risks to patients over an extended period. Additionally, the study seeks to assess the long-term **efficacy** of the treatment by measuring improvements in functional vision through vision-guided mobility assessment (VMA). This is crucial for determining the sustained therapeutic benefits of the gene therapy in enhancing patients' visual capabilities.

The clinical trial involves a total of **64 participants** diagnosed with **X-Linked Retinitis Pigmentosa** caused by mutations in the RPGR gene. The study population includes both male and female subjects, encompassing age ranges corresponding to categories 2 and 3, which typically include adolescents and adults. Participants were selected based on their previous completion of Study MGT-RPGR-021 and their willingness to reconfirm understanding and participation in the current study. The trial includes a vulnerable population, indicating that special considerations are in place to ensure their safety and ethical treatment. The study does not specify particular lifestyle considerations such as diet or physical activity. The selection criteria ensure that participants have a consistent baseline for assessing the long-term safety and efficacy of the treatment under investigation.

The clinical trial is designed to evaluate the long-term safety and efficacy of **botaretigene sparoparvovec** in individuals with X-linked **retinitis pigmentosa** caused by mutations in the RPGR gene. This is a Phase III, randomized, double-blind, controlled study. The trial is expected to commence on January 16, 2024, and conclude by December 19, 2029. Participants will be involved in the study for a maximum treatment period of one day, with follow-up assessments extending over several years to monitor long-term outcomes.

Study visits are structured to ensure comprehensive data collection and participant safety. The initial inclusion visit, or screening, will confirm eligibility based on the principal inclusion criteria, which include prior completion of Study MGT-RPGR-021 and a reconfirmation of understanding and willingness to participate. Following the inclusion visit, participants will undergo a series of follow-up visits to assess the primary endpoint, which is the change from baseline in binocular vision-guided mobility assessment (VMA) after bilateral subretinal delivery of the investigational product. Adverse events and laboratory assessments will also be monitored throughout the trial duration.

The end-of-study visit will mark the conclusion of participant involvement, where final assessments will be conducted to evaluate the long-term safety and efficacy of the treatment. Participants may be subject to early termination from the study if they experience significant adverse events, withdraw consent, or fail to comply with study procedures. The trial's methodology ensures rigorous data collection and participant safety, adhering to ethical standards and regulatory requirements.

The clinical trial involves the administration of several **experimental medications** and auxiliary treatments. The primary investigational product is **botaretigene sparoparvovec**, also known as JNJ-74765340, which is a gene therapy product delivered as a **solution for injection**. This product is administered via **subretinal use**. The dosing unit is in milliliters, with a maximum treatment period of one day. This product is designated as an orphan drug and is intended for the treatment of X-linked Retinitis Pigmentosa associated with variants in the RPGR gene.

**Cefazolin sodium** is used as an auxiliary treatment in the trial. It is administered in a pharmaceutical form identified as PHF00231MIG and is delivered via **subconjunctival use**. The administration of cefazolin sodium is a standard component of intraocular surgery to prevent infection, although it is not specifically approved for subconjunctival administration. The treatment period is limited to one day.

**Vancomycin** is another auxiliary treatment, also administered in a pharmaceutical form identified as PHF00230MIG via **subconjunctival use**. Similar to cefazolin sodium, vancomycin is used to prevent infection post-operatively in intraocular surgeries, with a treatment period of one day.

**Cefuroxime** is included as an auxiliary treatment, administered in the same pharmaceutical form as cefazolin sodium (PHF00231MIG) and via **subconjunctival use**. It serves the same purpose of infection prevention in intraocular surgeries, with a one-day treatment period.

**Dexamethasone acetate** is used to prevent local surgical inflammation and is administered in a pharmaceutical form identified as PHF00245MIG via **subconjunctival use**. The use of dexamethasone acetate is considered standard care in intraocular surgeries, with a treatment period of one day.

**Betamethasone acetate** is another corticosteroid used to prevent inflammation, administered in a pharmaceutical form identified as PHF00243MIG via **subconjunctival use**. It is part of the standard care in intraocular surgeries, with a treatment period of one day.

**Triamcinolone acetonide** is administered via **retrobulbar use** in a pharmaceutical form identified as PHF00243MIG. This administration route differs from the registered route in the marketing authorization, and the treatment period is one day.

**Omeprazole** is recommended for participants with risk factors for gastrointestinal toxicity, such as those taking non-steroidal anti-inflammatory drugs (NSAIDs). It is administered orally in a pharmaceutical form identified as PHF00094MIG. The treatment period for omeprazole is up to eight days, and it is used to mitigate the risk of gastric ulcers in patients undergoing prolonged systemic steroid therapy.

The efficacy of the clinical trial will be assessed by evaluating the change from baseline in binocular vision-guided mobility assessment (VMA) following bilateral subretinal delivery of **AAV5-hRKp.RPGR**. This primary endpoint is designed to measure the functional vision improvements in individuals with X-linked Retinitis Pigmentosa associated with variants in the RPGR gene. The VMA will serve as a key parameter to determine the efficacy of the treatment, providing insights into the participants' ability to navigate their environment using vision.