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Phase 1 study results published in the Lancet report stable vision following a single dose gene therapy encoding anti-VEGF protein. 

Researchers at the University of Nevada, Reno School of Medicine and the Department of Ophthalmology, Weill Cornell Medical College, New York-Presbyterian Hospital, has published safety and efficacy data of “ixoberogene soroparvovec” (or “ixo-vec”) for neovascular age-related macular degeneration, using a prospective, two-year, multicentre phase 1 study.  The treatment is aimed to use a single-dose gene therapy encoding for the proven anti-VEGF protein, aflibercept.  According to the researchers, ixo-vec is the “first in vivo gene augmentation approach successfully administered intravitreally to deliver a standard-of-care therapeutic, aflibercept, targeting a prevalent, non-inherited ocular disorder, nAMD”.

The “holy grail” for anti-VEGF treatment without necessary repeat injections would be an enormous benefit for patients and clinicians. To pursue this objective, a phase 1 study recruited 30 patients with nAMD, assigned to four cohorts differing by ixo-vec dosages (2 × 1011 vs 6 × 1011 vector genomes (vg/eye)). Ixo-vec utilises a novel vector capsid, AAV2.7m8, carrying an aflibercept coding sequence under the control of a ubiquitous expression cassette. According to the researchers, previous preclinical studies of ixo-vec resulted in “long-term, stable expression of aflibercept at levels expected to be adequate to treat nAMD with no measurable effect on normal retinal structure or function observed following long-term VEGF suppression”.  The primary outcome for the phase 1 study was the type, severity, and incidence of ocular and systemic adverse events (AEs) and with secondary endpoints included vision, central subfield thickness (CST), and the number of supplemental injections. Thirty patients with nAMD were enrolled at nine study sites in the United States and the results of the trial reported that vision and CST remained stable throughout two years with annualized anti-VEGF injections reduced by 80% (10.0 mean annualized anti-VEGF injections to 1.9) in 2 × 1011 vg/eye and 98% (9.8 mean annualized anti-VEGF injections to 0.2) in 6 × 1011 vg/eye cohorts.   In addition, the study reported no systemic related AEs (adverse events) and the most common adverse event was anterior chamber cell, which was reported in 11 participants in the 6 × 1011 dose group and in 7 participants in the 2 × 1011 dose group.  Intraocular inflammation was responsive to topical corticosteroids, with no anterior chamber cells or vitreous cells observed in 2 × 1011 vg/eye patients at the end of the study.

In summary, the experimental treatment was generally well-tolerated, maintained vision, and improved anatomical outcomes in nAMD, with a substantial reduction in anti-VEGF injections. The report commented that a, “single administration of an in-office gene therapy, with vectorised protein with an already established clinical benefit, has the potential to revolutionize the management of common ocular disorders requiring ongoing, frequent therapeutic interventions”.