SKYLINE: AGTC-501 Reports Positive 24-Month Data in X-Linked Retinitis Pigmentosa

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Positive 24-month interim safety and efficacy results of the Phase 2 SKYLINE trial demonstrated the clinically tolerable and durable profile of AGTC-501 for patients with X-linked retinitis pigmentosa (XLRP).¹

Announced by Beacon Therapeutics on October 15, 2024, the analysis of the 24-month data found AGTC-501 generally safe and well-tolerated, while achieving a 57% response rate in analysis of retinal sensitivity in the high-dose cohort. These data were presented at the 128th Annual American Academy of Ophthalmology (AAO) Meeting.

“Our Phase 2 SKYLINE 24-month data reinforces AGTC-501’s favorable safety profile and robust improvements in mean retinal sensitivity,” said Lance Baldo, MD, chief executive officer of Beacon Therapeutics, in a statement.²

XLRP is an inherited retinal disease that can cause blindness by middle age and primarily affects an estimated 3.4 to 4.4 per 100,000 males with RPGR mutations in the United States, Europe, and Australia.³ Without treatment options available, AGTC-501 is an investigational gene therapy that expresses the full-length RPGR and could address all photoreceptor damage linked to XLRP, including rod and cone loss.

The Phase 2, randomized, controlled, multicenter SKYLINE study evaluated the safety, efficacy, and tolerability of AGTC-501 in patients with XLRP caused by RPGR mutations.¹ Eligible males with XLRP (n = 14) aged 8 to 50 years were randomized to low-dose (7.5 E + 10 vg/eye) or high-dose (6.8 E + 11 vg/eye) of AGTC-501.

Eligibility criteria included a best-corrected visual acuity (BCVA) between 35 and 75 ETDRS letters at each screening visit, detectable (1-12 db) baseline mean macular sensitivity measured by MAIA microperimetry, and detectable ellipsoid zone (EZ) line in both eyes.

For the primary analysis, the efficacy endpoint was the proportion of response by microperimetry between the study and fellow eye at Month 12. Secondary endpoints included the change from baseline at Month 12 in mean sensitivity by microperimetry (MAIA), full-field light sensitivity threshold (FST), mobility course scores, and BCVA, as well as safety.

At the SKYLINE baseline, the demographics and baseline characteristics of both study cohorts were well-matched. Safety data reported at Month 24 revealed no ocular serious adverse events (SAEs) related to AGTC-501.

Ocular treatment-emergent adverse events (TEAEs) were mostly non-serious, mild, or moderate in severity, with similar rates between the high-dose and low-dose cohorts. Most ocular TEAEs related to the AGTC-501 injection procedure were mild or moderate in severity.

Efficacy data at Month 24 revealed a greater response rate in the high-dose study cohort, compared with low-dose and fellow eyes, which remained consistent from Month 12. Approximately 57% (4 of 7) of patients treated with high dose AGTC-501 achieved a ≥7 dB improvement from baseline in ≥5 loci at Month 24. By comparison, only 25% (1 of 4) of patients treated with low-dose AGTC-501 achieved a response rate at Month 24.

The high-dose AGTC-501 cohort also experienced a robust improvement in mean retinal sensitivity at Month 24. Mean CPB in mobility maze score in the same period demonstrated a positive trend in the high-dose group, as 6 of 10 treated eyes demonstrated ≥1 level improvement in the maze test.

An ongoing follow-up will assess the long-term safety and durability of the response across 5 years. Beacon indicated the benefit-risk profile of AGTC-501 supports its ongoing clinical development for patients with XLRP caused by RPGR mutations.

“We will continue to assess the long-term safety and durability of AGTC-501 but are encouraged by the results we’ve seen in the SKYLINE trial to date,” Baldo added.²

References

1. _{Sisk RA, Birch DG, Yang P, Fulton AB, Curtiss D, Waheed NK. Subretinal AGTC-501 Gene Therapy for XLRP: Twenty-Four-Month Interim Results of the Phase 2 SKYLINE Trial. Poster presented at the American Academy of Ophthalmology (AAO) 2024 Meeting. Chicago, Illinois. October 18-21, 2024.}
2. _{Beacon Therapeutics announces positive 24-month data from phase 2 skyline trial of AGTC-501 in patients with X-linked retinitis pigmentosa. Beacon Therapeutics. October 15, 2024. Accessed October 19, 2024. https://www.beacontx.com/news-and-events/beacon-therapeutics-announces-positive-24-month-data-from-phase-2-skyline-trial-of-agtc-501-in-patients-with-x-linked-retinitis-pigmentosa/.}
3. _{Vinikoor-Imler LC, Simpson C, Narayanan D, Abbasi S, Lally C. Prevalence of RPGR-mutated X-linked retinitis pigmentosa among males. Ophthalmic Genet. 2022;43(5):581-588. doi:10.1080/13816810.2022.2109686}