Clinical trial NCT06333249: A Study Comparing Two Doses of AGTC-501 in Male Subjects With X-linked Retinitis Pigmentosa Caused by RPGR Mutations (SKYLINE)
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: X-Linked Retinitis Pigmentosa
Keywords: XLRP
retinal degeneration
RPGR
adeno-associated virus
gene therapy
AAV
Lead sponsor: Beacon Therapeutics
Sponsor class: INDUSTRY
First posted: 2024-03-27
Enrollment: 14
Sex: MALE
Minimum age (years): 8
Maximum age (years): 50
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The purpose of the Phase 2 study is to evaluate the efficacy, safety, and tolerability of two doses of AGTC-501 in male subjects between 8 - 50 years of age (inclusive) with XLRP genetically confirmed by at least one pathogenic variant in the RPGR gene.

Approximately 12 subjects who meet the inclusion criteria, will be randomized in a 1:1 ratio to 1 of 2 treatment groups. Each subject will receive the assigned dose of AGTC-501 in the study eye; no treatment will be administered in the fellow eye. As treatment outcomes in pediatric vs. adult subjects may differ, randomization to dose groups will be stratified by age.

Each subject will receive a central subretinal injection of AGTC-501 at the assigned dose in the central macula of the study eye.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: The difference in the proportion of responding eyes between treated and control eyes in the low dose group and high dose group at 12 months, as measured by MAIA microperimetry, where response is defined as a 7dB or more improvement in at least 5 loci.
timeFrame: Day 0 - Month 12
Secondary outcomes:
measure: Proportion of responding eyes in treated eyes versus control eyes in the low dose group and the high dose group at Month 12 where responder is defined as an ORA-VNC mobility test score improvement of 2 or more luminance levels.
timeFrame: Day 0 - Month 12
measure: Proportion of responding eyes in treated versus control eyes in the low dose group and the high dose group at Month 12, as measured by MAIA microperimetry, where responder is defined as a 7 dB or more improvement in at least 5 loci within bleb.
timeFrame: Day 0 - Month 12
measure: Proportion of responding eyes in treated vs control eyes in the low dose group and the high dose group at Month 12, measured by MAIA microperimetry where responder is defined as 7 dB or more improvement in at least 5 loci within the central 16 loci
timeFrame: Day 0 - Month 12
measure: Difference in mean change from baseline in the central 36 loci (C36) mean sensitivity, as measured by MAIA microperimetry, in treated eyes versus control eyes in the low dose group and high dose group at Month 12.
timeFrame: Day 0 - Month 12
measure: Difference in mean change from baseline in "within bleb" mean sensitivity, as measured by MAIA microperimetry, in treated eyes versus control eyes in the low dose group and high dose group at Month 12.
timeFrame: Day 0 - Month 12
measure: Difference in mean change from baseline in central 10 degrees of vision on light adapted static perimetry, as measured by Octopus 900, in treated eyes versus control eyes in the low dose group and high dose group at Month 12.
timeFrame: Day 0 - Month 12
measure: Difference in mean change from baseline in BCVA, as measured by ETDRS or tumbling "E" chart, in treated eyes versus control eyes in the low dose group and high dose group at Month 12.
timeFrame: Day 0 - Month 12
measure: Proportion of responding eyes in treated versus control eyes in the low dose group and high dose group at Month 12 where responder is defined as a 10-letter vision gain as measured by ETDRS or tumbling "E" chart.
timeFrame: Day 0 - Month 12
measure: Difference in mean change from baseline in the EZ area, as measured by SD-OCT, in treated eyes versus control eyes in the low dose group and high dose group at Month 12 Visit.
timeFrame: Day 0 - Month 12
measure: Mean change from baseline in Impact of Vision Impairment (IVI) (Weih et al, 2002; Lamoureaux et al, 2007) or Impact of Vision Impairment for Children (IVI-C) (Cochrane et al, 2008) in the low dose group and high dose group at Month 12 Visit
timeFrame: Day 0 - Month 12
measure: Mean change from baseline in Patient Global Impressions of Change (PGI-C) and Patient Global Impressions of Severity (PGIS) in the low dose group and high dose group at Month 12 Visit.
timeFrame: Day 0 - Month 12
Other outcomes:
Locations:
city: Jacksonville
country: United States
facility: University of Florida
state: Florida
city: Boston
country: United States
facility: Boston Children's Hosptial
state: Massachusetts
city: Cincinnati
country: United States
facility: Cincinnati Eye Institute
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Portland
country: United States
facility: Casey Eye Institute
state: Oregon
city: Dallas
country: United States
facility: Retina Foundation of the Southwest
state: Texas
Study officials:
References: