Reviewed by Robert A. Sisk, MD, FACS
AGTC-501 (Applied Genetic Technologies Corporation), a novel gene therapy in development for the potential treatment of X-linked retinitis pigmentosa (RP), showed an acceptable safety profile and visual function improvements when administered in the study’s higher dose groups, according to Robert A. Sisk, MD, FACS, from the Cincinnati Eye Institute in Ohio.
Patients with X-linked RP, an inherited retinal disease that begins in childhood, are characterized by night blindness, progressive loss of peripheral vision, and eventual loss of central vision. Affected patients have access to only 1 approved treatment, voretigene neparvovec-rzyl (Luxturna; Spark Therapeutics) for RPE65, which represents about 1% of RP.
Sisk outlined the safety and efficacy findings of a phase 1/2 study of AGTC-501 gene therapy, a recombinant adeno-associated virus (AAV) 2 vector, for X-linked RP resulting from mutations in the RPGR gene, which accounts for 10% of RP cases.
This study was a 12-month open-label, dose-escalation trial that included 29 male patients aged 6 years and older with the RPGR mutation. All patients were treated with 1 subretinal injection in the study eye. The first 9 patients received peripheral retinal injections as part of a safety assessment, which was the primary outcome, and the rest of the patients were treated centrally.
The safety assessment also included immunologic responses to the AAV capsid and the RPGR proteins expressed, Sisk explained. Key secondary outcomes included visual function measured by microperimetry (Macular Integrity Assessment) and retinal structure seen on optical coherence tomography (OCT).
Safety and vision results with AGTC-501
The safety results showed that no serious adverse events were related to the treatment. The initial surgical approach resulted in 4 peripheral retinal detachments related to dosing targeting the peripheral retina. The detachments did not occur when the central retina was targeted.
Grade 1 to 2 intraocular inflammation developed in about 20% (5/29) of patients and all were reported as resolved.About one-third of the patients had intraocular pressure elevations related to corticosteroid use and all have resolved without IOP related morbidities. The immunologic results did not suggest safety concerns.
Regarding vision, in the 20 patients who received injections targeting the central retina, Sisk noted that “the mean visual acuity improved about 5 letters compared [with] the untreated fellow eyes.”
The microperimetry sensitivity improved at month 12 in all centrally dosed patients across the central 36 points, which corresponds to the most anatomically and functionally intact areas in the patient population, he explained. Sisk also noted that the FDA has accepted a change of 7 or more decibels in 5 or more loci in the central microperimetry as clinically meaningful.
During the course of the study, the investigators observed that patients without foveal ellipsoid zone (EZ) integrity before the treatment did not have improved microperimetry. When those patients were excluded from analysis, 50% of patients were responders to treatment. Another 2 patients also had significant improvements in microperimetry compared with the untreated fellow eye.
An analysis based on the status of the macular EZ showed that 7 of the 20 patients who were centrally treated had no EZ before or after the AGTC-501 injection. In the 13 patients with a macular EZ at baseline, 9 had recovery of the EZ at 3 to 6 months after treatment, and 6 of the 9 had an improved EZ at 12 to 18 months. In the other 4 of the 13 eyes with a macular EZ, all had incomplete EZ recovery at 12 months. Sisk reported positive associations between anatomic improvements in the EZ band and functional microperimetry sensitivities.
Optimizing outcomes with AGTC-501
In addition to avoiding treatment targeting the peripheral retina, patient selection is paramount to achieve the best results. “Advanced disease with absence of baseline microperimetry or a foveal EZ line precluded meaningful microperimetry or visual benefits,” Sisk said.
Clinical trials of AGTC-501 for the potential treatment of X-link RP are continuing. The Skyline trial (NCT03316560) is an expansion of this phase 1/2 clinical trial, and the Vista trial (NCT04850118) is a phase 2/3 safety and efficacy clinical trial
“The 12-month results of the study of AGTC-501 to treat X-linked RP showed acceptable safety outcomes and vision and microperimetry improvements at higher doses,” Sisk said. “In addition, we observed an encouraging anatomic correlate of EZ improvement.”
Robert Sisk, MD
This article is adapted from Sisk’s presentation at the American Academy of Ophthalmology 2021 annual meeting. Sisk is a consultant to AGTC.