Phase 1/2 Study of Subretinal AAVB-081 Administration in Usher Syndrome Type 1B Retinitis Pigmentosa Patients

The primary objective of this study is to assess the **safety** and tolerability of subretinal administration of AAVB-081 in subjects with Usher Syndrome Type 1B (USH1B) Retinitis Pigmentosa. This is clinically relevant as it aims to establish a well-tolerated dose with an optimal risk-benefit profile, which is crucial for the development of effective and safe gene therapy treatments for this progressive retinal disorder.

Secondary objectives include evaluating the effect of AAVB-081 on retinal anatomy and function using standardized diagnostics routinely employed in ophthalmic clinics. This assessment is important for understanding the potential therapeutic impact of the treatment on visual function and retinal health in affected individuals.

The clinical trial involves a total of **6 participants** diagnosed with **Usher Syndrome Type 1B (USH1B) Retinitis Pigmentosa**. The study population comprises both male and female adults, aged between **18 to 50 years**. Participants were selected based on a molecular diagnosis of USH1B due to MYO7A mutations, confirmed by a Sponsor-approved CLIA laboratory. The trial includes individuals who are willing to adhere to the protocol, as evidenced by written informed consent. The health status of participants is characterized by their diagnosis of USH1B, and the trial does not specify additional lifestyle considerations such as diet or physical activity. The study population includes a vulnerable group, although specific details about this aspect are not provided. The sponsor has not disclosed further information regarding the general health status or lifestyle habits of the participants.

The clinical trial is designed as a **Phase 1/2 open-label, dose escalation, safety and efficacy study** to evaluate the subretinal administration of **AAVB-081** in subjects diagnosed with **Usher Syndrome Type 1B (USH1B) Retinitis Pigmentosa**. The primary objective is to assess the safety and tolerability of the treatment, as well as to determine a well-tolerated dose with an optimal risk-benefit profile. The trial is expected to commence recruitment on July 2, 2024, and is estimated to conclude by May 28, 2030.

Participants will be involved in a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18 to 50 years), molecular diagnosis of USH1B due to **MYO7A** mutations, and willingness to adhere to the protocol. Following the screening, participants will undergo a series of follow-up visits to monitor the incidence and severity of adverse events (AEs), including serious adverse events (SAEs) and dose-limiting toxicities (DLTs). These assessments will be conducted through physical examinations, vital signs, laboratory tests, and ophthalmic evaluations. The study will also measure humoral and cell-mediated immune responses to the viral vector and gene product, as well as vector shedding in biological samples.

The trial will involve the administration of **AAVB-081** via subretinal injection, with **prednisolone** provided as an auxiliary treatment for oral use. Participants are expected to remain in the study for the duration of the trial unless conditions arise that necessitate early termination, such as the occurrence of significant AEs or non-compliance with the study protocol. The study is not categorized as low intervention, given its integrated Phase I and Phase II nature, marking the first administration of the investigational product to humans.

The clinical trial involves the administration of **AAVB-081**, an experimental gene therapy product designed for the treatment of Usher Syndrome Type 1B (USH1B) Retinitis Pigmentosa. **AAVB-081** is a **solution for injection** that contains a dual **adeno-associated viral vector serotype 8**. This vector includes the 3'-MYO7A and 5'-MYO7A gene coding sequences, which are intended to replace the defective MYO7A gene in patients. The administration route is **intraocular**, specifically through **subretinal administration**. The dosing schedule is determined by the study protocol, focusing on dose escalation to assess safety and efficacy. Participant compliance is monitored through regular follow-ups and assessments as outlined in the trial protocol.

In addition to the experimental treatment, the study includes the use of **Prednisone** as a non-experimental treatment. Prednisone is a corticosteroid administered orally to manage inflammation and immune response associated with the gene therapy. The pharmaceutical form of Prednisone used in this trial is denoted as **PHF00245MIG**. The dosage and frequency of administration are aligned with standard clinical practices for corticosteroid use and are adjusted based on individual patient response and tolerability. Compliance with Prednisone administration is monitored through patient diaries and regular clinical evaluations.

The efficacy of the investigational product AAVB-081 in the clinical trial will be assessed through a series of primary endpoints. These endpoints include the incidence and severity of adverse events (AEs), serious adverse events (SAEs), and dose-limiting toxicities (DLTs). The assessment will be conducted using various methods such as physical examinations, vital signs monitoring, and laboratory tests including biochemistry, hematology, coagulation parameters, and urinalysis. Additionally, the humoral immune response to **AAV8** and **MYO7A** will be evaluated using serum samples, while vector shedding in serum and tears will be analyzed through PCR. The cell-mediated immune response to **AAV8** and **MYO7A** will be assessed using peripheral blood mononuclear cells (PBMCs).

Serial ophthalmic examinations will also be conducted to evaluate efficacy, including best-corrected visual acuity (BCVA), visual field perimetry, slit lamp examination, indirect ophthalmoscopy, intraocular pressure (IOP) measurements, and morphological alterations observed through optical coherence tomography (OCT). Additional assessments will include electroretinography (ERG) and fundus autofluorescence (FAF). The number and proportion of DLTs at each dose level will be recorded to further assess the efficacy of the treatment. These comprehensive evaluations will provide a detailed understanding of the treatment's impact on subjects with Usher Syndrome Type 1B (USH1B) retinitis pigmentosa.