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

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

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.

Study Overview

• Status: Enrolling by invitation
• Conditions: X-Linked Retinitis Pigmentosa
• Intervention / Treatment: Biological: AGTC-501 (high dose and standard corticosteroid regimen); Biological: AGTC-501 (low dose and standard corticosteroid regimen); Biological: AGTC-501 (high dose and modified corticosteroid regimen)

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.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida
    • Miami, Florida, United States, 33136
      • Bascom Palmer Eye Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • Cincinnati Eye Institute
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
  • Oregon
    • Portland, Oregon, United States, 97239
      • Casey Eye Institute
  • Texas
    • Dallas, Texas, United States, 75231
      • Retina Foundation of the Southwest

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 2 (Low Dose, Standard Corticosteroid); Following a pars plana vitrectomy, the previously untreated eye of participants (n=6) will receive a central subretinal injection at the low dose in the study eye at the Baseline visit; no treatment will be administered in the previously treated fellow eye. The corticosteroid taper for all treated participants in Groups 1 and 2 (high and low doses with standard corticosteroid regimen) will be a standard taper over the course of several weeks.	Biological: AGTC-501 (low dose and standard corticosteroid regimen); Adeno-associated virus vector expressing a human RPGR gene
Experimental: Group 3 (High Dose, Modified Corticosteroid); Following a pars plana vitrectomy, the previously untreated eye of participants (n=approximately 3-6) will receive a central subretinal injection at the high dose in the study eye at the Baseline visit; no treatment will be administered in the previously treated fellow eye. Participants in Group 3 (high dose, modified corticosteroid) will have a more rapid corticosteroid taper.	Biological: AGTC-501 (high dose and modified corticosteroid regimen); Adeno-associated virus vector expressing a human RPGR gene
Experimental: Group 1 (High Dose, Standard Corticosteroid); Following a pars plana vitrectomy, the previously untreated eye of participants (n=up to 12) will receive a central subretinal injection at the high dose in the study eye at the Baseline visit; no treatment will be administered in the previously treated fellow eye. The corticosteroid taper for all treated participants in Groups 1 and 2 (high and low doses with standard corticosteroid regimen) will be a standard taper over the course of several weeks.	Biological: AGTC-501 (high dose and standard corticosteroid regimen); Adeno-associated virus vector expressing a human RPGR gene

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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).	Day 0 - Month 12
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).	Day 0 - Month 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The number of participants experiencing treatment-emergent AEs of ocular/non-ocular adverse events, including treatment-emergent serious AEs.		Day 0 - Month 12
The proportion of participants experiencing treatment-emergent AEs of ocular/non-ocular adverse events, including treatment-emergent serious AEs.		Day 0 - Month 12
Change from baseline in mean sensitivity across the whole grid, as measured by MAIA (Macular Integrity Assessment) microperimetry, assess photoreceptor function under low light		Day 0 - Month 12
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.		Day 0 - Month 12
Change from baseline in full-field stimulus threshold (FST)	As assessed by full-field stimulus threshold (FST); FST measures the sensitivity of the visual field by testing for the lowest luminance flash which elicits a visual sensation perceived	Day 0 - Month 12
Change from baseline in Best Corrected Visual Acuity (BCVA) using Early-Treatment Diabetic Retinopathy Study (ETDRS) visual acuity		Day 0 - Month 12
Change from baseline in Low Luminance Visual Acuity (LLVA) using Early-Treatment Diabetic Retinopathy Study (ETDRS) visual acuity		Day 0 - Month 12
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)		Day 0 - Month 12
Change from baseline in ellipsoid zone (EZ) area measured by spectral domain optical coherence tomography (SD OCT)		Day 0 - Month 12
Change from baseline in seven domain scores from a Michigan Retinal Degeneration Questionnaire (MRDQ)		Day 0 - Month 12
Change from baseline in Ora-VNC (visual navigation course) mobility test score	As assessed by functional assessment Ora-VNC (visual navigation course) mobility course	Day 0 - Month 12
Change from baseline in the MObility Standardized Test-Virtual Reality (MOST-VR) mobility course test score	As measured by the MObility Standardized Test-Virtual Reality (MOST-VR) mobility course	Day 0 - Month 12

Collaborators and Investigators

• Sponsor: Beacon Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): November 14, 2023
• Primary Completion (Estimated): November 1, 2025
• Study Completion (Estimated): December 1, 2029

Study Registration Dates

• First Submitted: February 16, 2024
• First Submitted That Met QC Criteria: February 16, 2024
• First Posted (Actual): February 23, 2024

Study Record Updates

• Last Update Posted (Actual): October 30, 2024
• Last Update Submitted That Met QC Criteria: October 28, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: retinal degeneration; gene therapy; AAV; adeno-associated virus; XLRP; RPGR
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Eye Diseases; Eye Diseases, Hereditary; Retinal Diseases; Retinal Dystrophies; Retinal Degeneration; Retinitis; Retinitis Pigmentosa
• Other Study ID Numbers: AGTC-RPGR-001 DAWN

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No