AGTC-501 Efficacy Maintained in 18-Month Follow Up Data for X-linked Retinitis Pigmentosa

The RPGR gene-delivering rAAV-based therapy AGTC-501 (rAAV2tYF-GRK1-RPGR) demonstrated sustained efficacy and safety after 18 months of follow-up for patients with X-linked retinitis pigmentosa (XLRP), which is caused by RPGR mutations, according to findings from an ongoing, phase 1/2, open-label, dose escalation trial presented at the Association for Research in Vision and Ophthalmology (ARVO) 2022 Annual Meeting.

The efficacy of the subretinal AGTC-501 injection was assessed by optical coherence tomography (OCT) measurement of the foveal ellipsoid zone (EZ), which is a predictor of visual function and a common marker of disease progression in XLRP. The study enrolled 21 patients age ≥6 years with XLRP, 13 had visible foveal EZ at baseline and 8 did not have visible AZ at study entry. Following injection of AGTC-501 for those with visible EZ at baseline, 69% experienced EZ recovery 3 to 6 months following treatment (9 of 13). Of these patients, 67% had signs of EZ improvement (6 of 9) at 12 months that was sustained at 18 months. Those with no prior EZ did not experience a change following treatment with AGTC-501.

“These results indicate sustained durability of improved visual function over 18 months and suggest evidence of biological activity for this XLRP gene therapy,” principal investigator Paul Yang, MD, assistant professor of Ophthalmology at Oregon Health & Science University's Casey Eye Institute, said in a statement. “Because there are currently no approved treatment options for patients with XLRP, this data provides an important step toward a potential treatment for patients with vision loss due to XLRP.”

The study enrolled a total of 29 patients across 5 dose levels ranging from 4.0 x 10¹⁰ vg/ml to 3.2 x 10¹² vg/ml that were administered in the central or peripheral regions. Those who received a central dose of the treatment were analyzed for efficacy (n = 21) while those who were injected outside of the macula were not eligible for the macular structure and function-based end points (n = 8). The primary end point of the study was safety, with secondary end points focused on macular structure by OCT and function by macular integrity assessment (MAIA) microperimetry and best-corrected visual acuity (BCVA) by ETDRS.

There were 3 OCT case studies presented in the poster at the ARVO meeting of patients who responded to treatment with AGTC-501. In the first, an 18-year-old patient received AGTC-501 at 3.6 x 10¹¹ vg/ml and showed signs of EZ thickening and expansion, which led to improvements in macular autofluorescence. There were 24 months of follow up for this individual. In another example, a 45-year-old patient experienced EZ thickening with a 1.1 x 10¹² vg/ml dose and in the final case study a 26-year-old had expansion in visible EZ at 3.2 x 10¹² vg/ml, demonstrating EZ improvement across dose levels.

For secondary end points, there was a significant association observed between EZ and MAIA microperimetry improvement (P = .0212). Moreover, treated eyes with EZ improvement also had a higher incidence of stabilization in central foveal thickness (CFT) compared with eyes that did to have an EZ improvement, wherein CFT thinning was observed. "Significant association between EZ and MAIA improvement suggest that macular EZ may be a useful objective biomarker of the biological signal in gene therapy," the authors of the study wrote in their poster. "More stable CFT MIN thickness after surgery may be predictive of EZ recovery and improvement."

Most adverse events (AEs) observed in the study were mild to moderate in severity. The most frequently observed AEs were related to the subretinal injection and required vitrectomy procedures. Additionally, AEs were seen that were related to concomitant prophylactic steroid administration, which was intended to mitigation inflammation.

“We continue to be enthusiastic about our lead candidate AGTC-501. The data presented today combined with the prior 12-month data from this trial are a strong indicator of the potential of both AGTC-501 and our gene therapy platform,” Sue Washer, president and chief executive officer of AGTC, the company developing the gene therapy, said in a statement. “These data, coupled with other data from our ongoing clinical trials, reassure us that we are on the right path to bringing life-changing therapies for rare retinal diseases to patients and we look forward to sharing the three-month interim data from the SKYLINE phase 2 expansion portion of this trial in the second quarter of calendar 2022 and 24-month results from this phase 1/2 trial in the third quarter of calendar year 2022.”

In January 2022, AGTC announced that the phase 2 expansion of the phase 1/2 study, which is known as SKYLINE, had exceeded its enrollment goal, with 14 patients with XLRP receiving the treatment compared with the intended 12. Initial 3-month interim study results, including visual acuity, visual sensitivity, mobility, and safety are anticipated in the coming months (NCT03316560).