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NEW YORK CITY -- A gene therapy for age-related macular degeneration (AMD) led to extended treatment-free intervals and durable improvement in visual acuity and retinal thickening, a preliminary trial showed.

ADVM-022 (ixoberogene soroparvovec) achieved sustained aflibercept expression and reduced the need for anti-VEGF injections by 80-90% as compared with baseline treatment intervals. Improvement in central subfield thickness (CST) occurred early and exhibited minimal fluctuation during 2 years of follow-up.

The treatment was well tolerated, as the most common adverse event was dose-dependent mild or moderate inflammation that responded to topical corticosteroids. Results also showed an interaction between baseline neutralizing antibodies (NAbs) and treatment effect, reported Dante Pieramici, MD, of California Retina Consultants in Bakersfield, during the American Society of Retina Specialists meeting.

"I think we've shown that there is some association between AAV vector transduction and subsequent protein expression that is impacted by the presence of neutralizing antibodies," said Pieramici. "We're going to continue with a phase II trial that will look at [two doses] in patients with neovascular AMD, and it will begin enrolling patients very soon."

The results in patients with AMD contrasted starkly with those from a phase II trial of ADVM-022 in diabetic macular edema (DME). As previously reported, the trial was stopped after three patients developed hypotony requiring surgical treatment, which was followed by severe, progressive vision loss. Additionally, almost all patients treated with ADVM-022 developed intraocular inflammation, which was severe in some cases.

During a Q&A session following the presentation, Scott Friedman, MD, of Florida Retina Consultants in Lakeland, asked whether the therapy, if it becomes available, would be appropriate for all patients or just those with low baseline NAbs.

"I think it still can work in patients who have higher levels of neutralizing antibodies," said Pieramici. "You might need a higher dose in these patients, perhaps. I think we'll learn more as we do more investigations. This is early data and as we get more data [from the phase II trial] and eventually phase III clinical trials we will be able to tell. Route of administration probably makes a difference, and you can probably dose it to a certain extent to overcome this."

Pieramici added that there is no way at this point to predict which patients will have elevated NAbs.

ADVM-022 comprises a proprietary vector capsid carrying an aflibercept coding sequence under the control of a proprietary expression cassette. Treatment consists of a single in-office intravitreal injection. Treatment goals are long-term efficacy, reduced frequency of anti-VEGF injections, and improved vision outcomes.

Pieramici reported updates results from the phase I involving 30 patients with treated neovascular AMD. Average age was in the late 70s.

Most of the patients have completed 2 years of follow-up. Data on all patients treated to date showed that a single injection of ADVM-022 achieved continuously therapeutic levels of aflibercept through 3 years.

Prior to enrolling in the trial, patients required nine to 10 intravitreal injections of anti-VEGF therapy annually. Treatment with ADVM-022 reduced treatment burden to 0.2 to 1.9 injections, representing annualized differences from baseline of 81-98%.

Patients treated with the two trial doses had stable visual acuity of +0.2- to +0.3 letters of improvement after 2 years. An analysis of best corrected visual acuity (BCVA) by baseline NAbs showed mean improvement at 2 years of +5 letters among patients with baseline NAbs levels <1:125, as compared with +0.2 for patients with higher baseline levels.

These doses also led to stable reductions in CST of 56 and 86 µm versus baseline. Consistent with the BCVA data, patients with lower baseline NAbs had more improvement in CST (-127 vs -86 µm). Patients with lower baseline NAbs had rapid improvement in CST followed by minimal fluctuation over 2 years of follow-up, said Pieramici. Higher baseline NAbs were associated with minimal change in CST and fluctuations throughout follow-up.

No patient developed vasculitis, retinitis, choroiditis, vascular occlusions, or endophthalmitis following intravitreal injection of ADVM-022. No clinically relevant episodes of low intraocular pressure occurred. The only serious adverse event was a single case of uveitis, which responded to topical corticosteroids.

Pieramici said investigators observed no evidence of a correlation between baseline NAbs and inflammation or other safety events.

Preparations are underway for the , which will evaluate the lower of OPTIC's ADVM-022 investigational doses as well as a new, even lower dose, according to Pieramici, who suggested that the sponsor had wanted to move forward with lower doses of the gene therapy and not evaluate a higher dose that was used in the DME trial.

"We all remember the DME patients, and it was so depressing when patients developed hypotony and a lot of inflammation, iris defects, ciliary body shut down, and that was only with the high dose," he said. "In the OPTIC trial, we didn't see these problems. Both doses seemed to be safe, so let's just stay away from the higher dose for safety reasons."

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