Anti-VEGF Neutralizing Protein Shows Promise in Age-related Macular Degeneration

Despite only reporting early phase 1 study results, the use of long-term intravitreous injections of AAV2-sFLT01 has shown to be not only safe but promise as a potential new therapy for chronic retinal or choroidal vascular diseases.

The treatment, a vascular endothelial growth factor (VEGF) neutralizing protein targeting adeno-associated viral (AAV) vectors, uses AAV as a carrier-gene and could significantly decrease the treatment burden for patients currently receiving monthly anti-VEGF injections.

Led by Jeffery Heier (pictured), MD, co-president, medical director, and director of retina research at Ophthalmic Consultants of Boston, the investigators targeted VEGF due to its key role in AMD development, noting that "intraocular injections of VEGF-neutralizing proteins reduce leakage, allowing fluid resorption and improvement in visual acuity" for patients with AMD.

Unfortunately, despite the benefits of VEGF-neutralizing injections, the treatment is uncomfortable for patients and requires repeated, usually monthly, intraocular injections to maintain visual gains. Heier and colleagues, intent on providing long-term VGEF suppression and reducing treatment burden, looked to the clinical success of AAV serotype2, as a means to provide more long-term anti-VEGF protein expression.

The study included 19 patients aged 50 or older (mean age 76.2 years) with advanced neovascular AMD and best corrected visual acuity (BCVA) of ≤ 20/100 (mean baseline 25.5) in the study eye, and evidence of intraretinal or subretinal fluid on the macula as diagnosed by optical coherence tomography (OCT). Each study participant received one intravitreous injection of AAV2-sFLT01 at 4 outpatient retina clinics.

Participants were placed into 4 dose-ranging cohorts by order of enrollment (n=3 each) and 1 maximum tolerated dose (MTD) cohort (n=7) as determined by responsiveness to previous anti-VEGF therapy in 12 months prior to study screening.

Each cohort received a single fixed volume 100 μL injection of AAV2-sFLT01. Cohort 1 received a dose of 2 × 10⁸ vg, cohort 2 received 2 × 10⁹ vg, cohort 3 received 6 × 10⁹ vg, and cohorts 4 and 5 receiving the MTD of 2 × 10¹⁰ vg. OCT scans were performed at baseline, day 7, and weeks 2, 4, 8, 12, 18, 26, 38, and 52 to determine central retinal lesion thickness (CRLT) and thickness of subretinal tissue and fluid.

Heier and colleagues reported "no dose-limiting toxic effects during the dose escalation phase" and no identified MTD. Only 2 out of the 19 patients (both receiving MDT) experienced adverse events (AEs) associated with treatment (pyrexia and intraocular inflammation). Other AEs reported by patients were deemed to be disease-related rather than treatment-related.

Eleven patients were classified as having fluid and expected to respond to anti-VEGF therapy. Dramatically positive effects of treatment were reported in 4 patients who showed significant reductions of central subfield thickness (CST) from baseline and “substantial” reduction of fluid sustained for a year, as well as improvement from baseline BCVA ≤10 letters. Two patients showed partial reductions in fluid, and 5 showed minimal reductions in fluid through week 52. Overall, 6 out of 11 patients showed significant to partial improvement under the treatment.

Elizabeth P Rakoczy MSc, PhD, with the Centre for Ophthalmology and Visual Sciences at the University of Western Australia in Perth, commented in an editorial that "AAV2-mediated gene delivery is a viable option for long-term drug production.”

“Antiangiogenic treatments have changed the world for wet-AMD sufferers who now have a reasonable chance of preserving their vision," Rakoczy told MD Magazine. "Not all patients respond to the treatment (up to 45%), but this non-response of wet-AMD patients to anti-VEGF therapies can be due to an exceptional imbalance between angiogenic and anti-angiogenic factors (lots of VEGF and no or very little [sFLT01]) and/or factors other than VEGF not being targeted."

Rakoczy noted that it is essential for researchers to better understand the pathogenesis of the condition, including the changing ratios of VGEF and sFLT01 during angiogenic therapy.

“The eye is an excellent target for gene therapy for both genetic and chronic conditions due to its confined space, and the limiting effects of the regina-blood barrier, which reduces the spread of injected AAV2 and produced medication,” Rakoczy said. Rakoczy, Heier, and colleagues, agree that the treatment holds promise for AMD sufferers, but that future clinical trials are needed.