Ixo-vec Gene Therapy Reduces Anti-VEGF Injections in nAMD

STOCKHOLM — Trial results are demonstrating positive findings for a single intravitreal injection gene therapy for patients with neovascular age-related macular degeneration (nAMD) who previously required frequent treatments.

Researchers speaking here at the American Society of Retina Specialists (ASRS) 2024 Annual Meeting reported that a single intravitreal injection of ixoberogene soroparvovec (Ixo-vec, Adverum Biotechnologies):

• significantly reduced the need for anti-vascular endothelial growth factor (anti-VEGF) injections by 90%-95% at 26 weeks,
• maintained vision and central subfield thickness (CST), and
• while local corticosteroid prophylactic regimens were sufficient to minimize inflammation.

Ixo-vec is a gene therapy that uses a modified virus (AAV2.7m8) to deliver the gene for aflibercept, an anti-VEGF protein. After a single intravitreal injection, aflibercept is continuously produced in the eye.

The therapy has shown promising results in phase 1 and phase 2 clinical trials and might represent a more effective and convenient treatment option for heavily treated nAMD patients, said Charles Wykoff, MD, PhD, a vitreoretinal surgical and medical specialist and director of research at Retina Consultants of Texas, Houston.

“Among the 115 patients treated to date, strong, consistent efficacy at controlling exudative disease activity has been demonstrated,” he said.

Adil Ibrahim, a medical retina consultant at Calderdale and Huddersfield NHS Foundation Trust, Huddersfield, England, who wasn’t involved in the study, told Medscape Medical News that current anti-VEGF treatments are easy to perform but come with risks like infection and inflammation, a rise in eye pressure, bleeding, and scratches on the lens of the eye.

In addition, anti-VEGF injections need to be repeated every 2-4 months for some patients, but others might require injections as often as every 4 weeks, he said. This causes an enormous burden on patients and the healthcare system. “Right now, particularly in the UK, clinics are swamped,” Ibrahim said. “If we can move to a one-off injection and treat the disease, it will reduce the disease burden massively.”

LUNA Study Design and Interim Analysis

The phase 1 open-label clinical trial, OPTIC, had shown promising results, with vision preservation and reduced macular fluid lasting up to 3 years after a single treatment. However, it had also shown high levels of intraocular inflammation.

The ongoing phase 2 LUNA study was designed to evaluate lower viral doses and find optimal steroid prophylactic regimens to manage potential inflammation.

LUNA is a multicenter, randomized, double-masked phase 2 trial that included 58 patients who completed 26 weeks of the trial. They had an average age of 76.6 years, had received a nAMD diagnosis 3 years earlier, had a visual acuity of 20/24, a CST of 350 microns, and had received an average of 10 annual anti-VEGF injections.

Patients were randomized to a single injection of two Ixo-vec doses, 6 × 10¹⁰ (6E10) and 2 × 10¹¹ (2E11) vector genomes (vg)/eye, and one of four steroid regimens, including local corticosteroids (topical difluprednate or intravitreal dexamethasone) with and without oral prednisone.

The study’s primary goals were to assess the safety profile through adverse event monitoring and to measure changes in best-corrected visual acuity at 52 weeks. Additionally, the trial evaluated changes in CST, the need for supplemental aflibercept injections, and the effectiveness of different corticosteroid regimens in controlling inflammation.

Wykoff presented an interim analysis at 26 weeks, which provided early insights into the therapy’s performance.

The treatment significantly reduced the need for supplemental anti-VEGF injections:

• A total of 76% of participants receiving the 6E10 dose and 83% receiving the 2E11 dose required no additional anti-VEGF injections at 26 weeks.
• There was also a 90% reduction in the frequency of anti-VEGF injections over the 26-week period for the 6E10 dose and a 95% reduction for the 2E11 dose in patients who required supplemental anti-VEGF injections.

Both Ixo-vec doses maintained visual acuity and CST with minor fluctuations through 26 weeks, “emphasizing the anatomic control achieved in this trial among patients with CST greater than 300 microns at baseline,” said Wykoff.

Inflammation Management

The therapy was well tolerated, with only mild to moderate related adverse events and no severe inflammatory complications.

The most common adverse events were dose-dependent anterior cellular inflammation and anterior pigmentary changes without impact on vision. Local corticosteroid prophylaxis effectively minimized inflammation in 91% of patients who had no or minimal inflammation during every visit through week 26.

Intravitreal dexamethasone alone did not provide adequate prophylaxis, but adding difluprednate drops meaningfully reduced intraocular inflammation rates. Oral prednisone did not provide additional benefits beyond topical and local steroids. Wykoff said these are two key learnings of the prophylactic regimens.

“We’ve come a long way in our understanding of how to deliver gene therapy safely, and this trial was designed to understand prophylactic regimens more comprehensively. What we have learned is that topical difluprednate was sufficient,” he said.

These results suggest that Ixo-vec could offer a long-lasting treatment option for nAMD patients, significantly reducing the burden of frequent injections while maintaining therapeutic efficacy. As the LUNA study continues, it will provide further data on Ixo-vec’s safety and effectiveness, which will be crucial for designing future phase 3 registrational studies.