Researchers at the Casey Eye Institute, Oregon Health & Science University (OHSU), Portland, USA, have provided formal results of a Phase 1/2 study, published at the American Journal of Ophthalmology (December, 2024, 10.1016/j.ajo.2024.11.021). Their paper presented an interim safety and efficacy results from an ongoing 5-year, open-label, non-randomized multicenter dose-escalation study, (termed “HORIZON” [NCT03316560]), using a recombinant adeno-associated viral (rAAV2tYF-GRK1-RPGR). The researchers recruited almost 30 X-linked retinitis pigmentosa (XLRP) patients receiving a full-length RPGR protein, aimed to report the number and proportion of adverse events (primary endpoint), with secondary endpoints of visual function (mesopic microperimetry; perimetry), visual acuity, changes of SD-OCT, FST, fundus imaging and quality-of-life questionnaires.
OHSU Casey Eye Institute, Portland, Oregon
XLRP, one of the most common forms of retinitis pigmentosa with mutations in one gene only, the RP GTPase regulator gene (RPGR gene), is thought to account for approximately 75% of XLRP recorded cases. The gene encodes a ciliary protein that regulates trafficking of proteins to the outer segment of photoreceptors. Males are more severely affected by the X-linked pathology with night blindness generally occurring within the first decade of life, followed by restriction of the visual field and loss of visual acuity leading to legal blindness in most patients by the fourth to fifth decade of life. Unlike other approaches in the gene therapy space, rAAV2tYF-GRK1-RPGR, correctly expresses the full length RPGR protein, thereby addressing the entirety of photoreceptor damage caused by XLRP, including both rod and cone loss.
Following the results of the Phase 1/2 trial, the mean age at presentation was 31.6 ±11.6 years (range: 15 to 55 years), all male (100.0%) and mostly white (89.7%). All twenty-nine (29) participants experienced at least one TEAE (Treatment-Emergent Adverse Events) however, the researchers reported that most of the events were mild in nature, and exhibited complete resolution, associated with the subretinal injection procedure itself rather than the study agent. In addition, the researchers showed the highest dose (1.99 × 1012 vector genomes/eye) exhibited an unfavourable risk benefit profile due to the development of RPE changes and therefore they decided not to continue this dose in future clinical trials. In terms of visual acuity, there were no significant visual acuity differences between the groups, while immunological findings did not raise any substantial safety concerns. The mean baseline ETDRS BCVA (of the centrally treated study eyes) was 60.6 letters (18-80 letters), compared to 63.3 letters (14-84 letters) after 24 months. In summary, the researchers, concluded that “the efficacy results, although preliminary, are promising” and the results “may provide clinically meaningful benefits for participants with XLRP, warranting further investigation in larger clinical trials”. Finally, the researchers reported that, “Skyline” (NCT06333249), a Phase 2 study with a randomized, masked, and controlled design, and “VISTA” (NCT04850118), a phase 2/3 study with a randomized controlled design, are currently planned to validate their findings. Once peer-reviewed data becomes available in due course, EURETINA will actively follow the outcomes and will highlight results in the EURETINA Brief.