Beacon Therapeutics published 24-month safety and efficacy data from the AGTC-501 HORIZON Trial in the American Journal of Ophthalmology
Beacon Therapeutics announces the publication of 24-month data from the Phase 1/2 HORIZON trial of laru-zova (AGTC-501), a treatment for X-linked retinitis pigmentosa (XLRP) caused by RPGR gene mutations, in the peer-reviewed American Journal of Ophthalmology.
The HORIZON study, a Phase 1/2 open-label, dose-escalation trial, rigorously evaluated the safety and efficacy of AGTC-501, a subretinal gene therapy utilizing a recombinant adeno-associated viral (rAAV) vector, in 29 male participants afflicted with XLRP. This debilitating inherited retinal dystrophy, primarily affecting males due to its X-linked inheritance, is predominantly caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. The study’s primary objective was to deliver a functional copy of the full-length RPGR gene to retinal cells via a modified AAV2tYF capsid, aiming to mitigate the progressive photoreceptor degeneration characteristic of XLRP.
AAV Vector and Gene Delivery:
AGTC-501 employs a specifically engineered rAAV2tYF vector, a modified version of the adeno-associated virus serotype 2, designed to enhance transduction efficiency and RPGR transgene expression within photoreceptor cells. This vector carries a codon-optimized gene therapy construct, designed to produce the full-length native RPGR protein, crucial for the comprehensive restoration of both rod and cone function. The delivery method utilized was subretinal injection, a surgical procedure enabling direct administration of the AAV vector to the space between the retinal pigmented epithelium (RPE) and photoreceptors.
Safety Profile:
The safety assessment revealed that all 29 participants experienced at least one treatment-emergent adverse event (TEAE), with the majority being mild and attributed to the subretinal injection procedure itself. However, a significant subset of participants experienced grade 3 TEAEs, and serious ocular adverse events (SAEs) occurred, including retinal detachment, subcapsular cataract, and glaucoma, all deemed related to the AGTC-501 intervention. Notably, the highest dose of AGTC-501 exhibited an unfavorable risk-benefit profile, as it induced concerning retinal pigment epithelial (RPE) changes in a substantial proportion of participants, leading to its exclusion from further clinical trials. Importantly, the immunological responses to the AAV vector and the delivered RPGR transgene did not raise significant safety concerns.
Efficacy Evaluation:
The efficacy of AGTC-501 was evaluated using mesopic microperimetry, a sensitive technique for assessing retinal sensitivity, a key indicator of visual function in retinitis pigmentosa. Preliminary efficacy was observed at the maximum tolerated dose (6.8 × 1011 vg/eye), with half of the participants demonstrating a clinically meaningful improvement in mesopic microperimetry mean sensitivity at the 24-month follow-up. This finding suggests that the AAV-mediated delivery of the full-length RPGR protein has the potential to confer functional benefits in XLRP patients.
Clinical Context and Significance:
XLRP is a severe and progressive retinal dystrophy that predominantly affects males, leading to night blindness, visual field loss, and eventual blindness. Mutations in the RPGR gene, which encodes a protein essential for the maintenance of photoreceptor cilia, are the primary cause of XLRP. AGTC-501 represents a promising gene therapy approach that aims to address the underlying genetic cause of XLRP by delivering a functional copy of the RPGR gene using an AAV vector. The study’s findings provide valuable insights into the safety and preliminary efficacy of AAV-mediated gene therapy for XLRP. While the maximum tolerated dose demonstrated potential benefits, the safety concerns associated with higher doses underscore the importance of meticulous dose optimization. Further long-term studies are warranted to comprehensively evaluate the safety and durability of AAV-mediated RPGR gene therapy as a potential treatment for XLRP.
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