A Study Comparing Two Doses of AGTC-501 in Male Subjects With X-linked Retinitis Pigmentosa Caused by RPGR Mutations (SKYLINE)

A Phase 1/2 Open-Label Dose Escalation Study to Evaluate the Safety and Efficacy of AGTC-501 (rAAV2tYF-GRK1-RPGR) and a Phase 2 Randomized, Controlled, Masked, Multi-center Study Comparing Two Doses of AGTC-501 in Male Subjects With X-linked Retinitis Pigmentosa Confirmed by a Pathogenic Variant in the RPGR Gene

This study will evaluate the safety and efficacy of a recombinant adeno-associated virus vector (rAAV2tYF-GRK1-RPGR) in patients with X-linked retinitis pigmentosa caused by RPGR mutations.

Approximately 12 participants, who were not part of the Phase 1/2 (HORIZON) study, will be enrolled into the dose expansion portion of the study. These participants will be randomized in a 1:1 ratio to 1 of 2 treatment groups (i.e., Group 1 [low dose] and Group 2 [high dose]). Each participant will receive the assigned dose of AGTC-501 in one eye on a single occasion.

Inclusion Criteria:

• Provide written informed consent or assent (per local regulation), prior to the conduct of any study-related procedure. Subjects who provide assent must have a parent, guardian, or legal representative provide written informed consent.
• Be between 8 and 50 years of age (inclusive) at the time of informed consent and assent (as applicable).
• Be male and have at least one documented pathogenic or likely pathogenic variant in the RPGR gene
• Have a clinical diagnosis of XLRP.
• Have a BCVA no better than 75 letters and no worse than 35 letters based on an ETDRS chart at each screening visit.
• Be able to perform all tests of visual and retinal function and structure in both eyes based on the subject's reliability, and fixation, per the investigator's discretion.
• Have detectable baseline mean macular sensitivity measured by (MAIA) microperimetry, as determined by the investigator and confirmed by the Central Reading Center (CRC).
• Have detectable EZ line in both eyes as assessed by SD-OCT and confirmed by the CRC.

Exclusion Criteria:

• Have other known disease-causing mutations documented in the subject's medical history or identified through a retinal dystrophy gene panel, that in the opinion of the investigator would interfere with the potential therapeutic effect of the study agent or the quality of the assessments.

• For subjects with herpes simplex virus (HSV):

  1. Have history of oral or genital herpes and unable and/or unwilling to utilize prophylactic antiviral medication.
  2. Have a history of ocular herpes.
  3. Have active oral or genital herpes or are currently receiving treatment for HSV infection.

• Have complicating systemic diseases (e.g., medical conditions causing immunosuppression, active systemic infection) that would preclude the gene transfer or ocular surgery.

• Have known sensitivity or allergy to systemic corticosteroids or other immunosuppressive medications.

• Have used anti-coagulant agents that may alter coagulation

• Have received any vaccination/immunization within 28 days prior to screening and/or during screening with the exception of the influenza vaccine, which is only exclusionary if they have received the influenza vaccine within 28 days prior to randomization.

• Have used systemic corticosteroids or other immunosuppressive medications within 3 months prior to screening and/or intend to use during screening.

• Have previously received any AAV gene therapy product, stem cell therapy, cell-based therapy, or similar biologics.

Ocular Exclusion Criteria (Either Eye):

• Have pre-existing eye conditions that would preclude the planned surgery, interfere with the interpretation of study endpoints, or increase the risk of surgical complications
• Have significant media opacity impacting evaluation of the retina or vitreous.
• Had intraocular surgery within 90 days of study treatment administration.
• Have any active ocular/intraocular infection or inflammation
• Have a history of steroid-induced raised IOP of >25 mmHg following corticosteroid exposure, despite topical IOP-lowering pharmacologic therapy.
• Have any artificial retinal implant or prosthesis.
• Have absence of clear ocular media and/or inadequate pupil dilation to facilitate good quality OCT images.
• Have any history of rhegmatogenous retinal detachment.
• Have myopia (spherical equivalent) exceeding -10 diopters (or axial length of >30 mm if PI deems it appropriate to measure) or presence of pathologic myopia in the study eye.
• Have passed the Low Contrast Ora-VNC™ mobility course in either eye or binocularly at any screening visit.