Clinical trial NCT06275620: A Study Comparing Two Doses of AGTC-501 in Male Participants With X-linked Retinitis Pigmentosa Caused by RPGR Mutations (DAWN)
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 Participants With X-linked Retinitis Pigmentosa
Study type: INTERVENTIONAL
Overall status: ENROLLING_BY_INVITATION
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: 2024-02-23
Enrollment: 24
Sex: MALE
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This Phase 2 study is a non-randomized, open-label, study of the safety of AGTC-501 in participants with XLRP who have previously been treated with a full-length AAV vector-based gene therapy targeting RPGR protein.

Detailed description: This is a Phase 2, open-label, multicenter study to evaluate the safety of 2 doses of AGTC-501 administered as a single subretinal injection in participants with XLRP who have previously been treated with a full-length AAV vector-based gene therapy targeting RPGR protein.

The trial includes a screening period of up to 60 days and a 5 year study period.

Each participant will receive a single subretinal injection of one of two dose levels of AGTC-501 in their previously untreated eye. There will be 3 groups. Group 1 will receive the high dose and include up to 12 participants, Group 2 will receive the low dose and will include 6 participants, and Group 3 will include \~3-6 participants. Participants in Groups 1 and 2 will receive the standard corticosteroid regimen. A single subretinal injection of the high dose AGTC-501 will be administered to participants in Group 1 (n = 12), while participants in Group 2 (n = 6) will receive a single subretinal injection of low dose AGTC-501. Group 2 (low dose AGTC-501, Standard Steroid) will be dosed before moving to Group 3. After 6 Group 1 (high dose) study participants reach post-operative Month 1, all data will be reviewed by the DSMC. If no safety signals arise, additional participants, Group 3 (n \~ 3-6), will receive a single subretinal injection of the high dose with a modified course of corticosteroids.

Eligibility criteria: Inclusion Criteria:

* Be ≥12 years of age
* Have one eye previously treated with an AAV vector-based gene therapy designed to provide full-length functioning RPGR protein.
* Have a BCVA no better than 78 letters and no worse than 34 letters
* Be able to perform all tests of visual and retinal function and structure in both eyes based on the participant'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 the study eye as assessed by SD-OCT and confirmed by the CRC.

Exclusion Criteria:

* Have other known disease-causing mutations documented in the participant'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.
* 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
* 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.

Primary outcomes:
measure: The primary safety outcome is the number of participants experiencing Grade 3 or higher local (ocular) or non-ocular treatment-emergent adverse events, including treatment-emergent serious adverse events (SAEs).
timeFrame: Day 0 - Month 12
measure: The primary safety outcome is the proportion of participants experiencing Grade 3 or higher local (ocular) or non-ocular treatment-emergent adverse events, including treatment-emergent serious adverse events (SAEs).
timeFrame: Day 0 - Month 12
Secondary outcomes:
measure: The number of participants experiencing treatment-emergent AEs of ocular/non-ocular adverse events, including treatment-emergent serious AEs.
timeFrame: Day 0 - Month 12
measure: The proportion of participants experiencing treatment-emergent AEs of ocular/non-ocular adverse events, including treatment-emergent serious AEs.
timeFrame: Day 0 - Month 12
measure: Change from baseline in mean sensitivity across the whole grid, as measured by MAIA (Macular Integrity Assessment) microperimetry, assess photoreceptor function under low light
timeFrame: Day 0 - Month 12
measure: Response, as measured by MAIA (Macular Integrity Assessment) microperimetry, where response is defined as a greater than or equal to 7 decibel (dB) visual sensitivity improvement from baseline in at least 5 loci.
timeFrame: Day 0 - Month 12
measure: Change from baseline in full-field stimulus threshold (FST)
timeFrame: Day 0 - Month 12
measure: Change from baseline in Best Corrected Visual Acuity (BCVA) using Early-Treatment Diabetic Retinopathy Study (ETDRS) visual acuity
timeFrame: Day 0 - Month 12
measure: Change from baseline in Low Luminance Visual Acuity (LLVA) using Early-Treatment Diabetic Retinopathy Study (ETDRS) visual acuity
timeFrame: Day 0 - Month 12
measure: Proportion of responding eyes in treated versus control eyes at Month 12 where responder is defined as an improvement of at least 15-letters on low-luminance visual acuity (LLVA)
timeFrame: Day 0 - Month 12
measure: Change from baseline in ellipsoid zone (EZ) area measured by spectral domain optical coherence tomography (SD OCT)
timeFrame: Day 0 - Month 12
measure: Change from baseline in seven domain scores from a Michigan Retinal Degeneration Questionnaire (MRDQ)
timeFrame: Day 0 - Month 12
measure: Change from baseline in Ora-VNC (visual navigation course) mobility test score
timeFrame: Day 0 - Month 12
measure: Change from baseline in the MObility Standardized Test-Virtual Reality (MOST-VR) mobility course test score
timeFrame: Day 0 - Month 12
Other outcomes:
Locations:
city: Jacksonville
country: United States
facility: University of Florida
state: Florida
city: Miami
country: United States
facility: Bascom Palmer Eye Institute
state: Florida
city: Boston
country: United States
facility: Boston Children's Hospital
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: