Neutralizing Antibodies to AAV Vector for AMD Gene Therapy May Boost Therapeutic Effect


The post-hoc analysis of the OPTIC trial explored the effects of neutralizing antibodies on patients treated with ADVM-002.

Findings from a post-hoc analysis of the phase 1 OPTIC trial show that patients with neovascular age-related macular degeneration (nAMD) with high levels of neutralizing antibodies (NAbs) to the adeno-associated viral vector used in the gene therapy ADVM-002 were more likely to have robust protein expression and sustained improvements in central subfield thickness, among other benefits.1

The findings were presented at the 2022 Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting, taking place in Denver, Colorado May 1-4, 2022 and virtually May 11-12, 2022.

"These new data give us important insight into the high levels of efficacy that wet AMD patients experience following treatment with ADVM-022, particularly among those whose baseline levels of NAbs are below 1:125," said Szilárd Kiss, MD, Bob and Dolores Hope – Robert M. Ellsworth, MD Distinguished Associate Professor in Ophthalmology and lead author of the study, in a statement.2 "We continue to seek ways to address critical areas of unmet needs in wet AMD patients and caregivers by decreasing the treatment burden from frequent anti-VEGF injections, which are the current standard of care.”

The phase 1 OPTIC trial assessed safety, tolerability, and efficacy of a single intravitreal injection of Adverum Bio’s ADVM-002 (AAV.7m8-aflibercept gene therapy) in patients with nAMD. The open-label, dose-ranging study included 30 participants assigned to 2 dose levels, 6x1011 vg of ADVM-022 (n=15) or 2x1011 vg of ADVM-022 (n=15), with NAbs inclusion criteria of <1:5 within 6 months prior to ADVM-002 treatment for cohort C1 (n=6) or <1:125 for cohorts C2-C4 (n=24).

As of the data cutoff, median follow-up ranged from 60 to 104 weeks for cohorts C4 through C1, respectively. Of those who received the first or second dose level, 89% and 67% had baseline NAbs of <1:125. At follow-up, 12/15 and 8/15 patients who received 6x1011 vg of ADVM-022 or 2x1011 vg of ADVM-022 remained anti-vascular endothelial growth factor (VEGF) injection-free, with mean annualized injection frequency reduced by 97% and 81% in each dose group, respectively. In those with NAbs <1:125, reductions in mean annualized anti-VEGF injection frequency were 97% and 93% in the 6x1011 and 2x1011 dose groups, respectively.

Among those with baseline NAbs <1:125, more robust aflibercept protein expression levels were observed as well as sustained improvements in central subfield thickness compared with those with a baseline NAbs of >1:125. No correlations with safety were observed based on baseline NAbs levels.

Although both doses were well-tolerated, patients in the 2x1011 vg/eye dose required less topical corticosteroid therapy to alleviate inflammation, and NAbs levels were generally not associated with occurrence or duration of inflammation.

Based on the previously presented findings from the OPTIC trial, Adverum plans to initiate a phase 2 clinical trial further examining the 2x1011 vg/eye dose of ADVM-002 as well as a new lower 6x1010 vg/eye dose, with new local and systemic steroid regimens. With a target enrollment of 70 patients with wet AMD, Adverum hopes to dose its first participant in Q3 of 2022.

Szilard K, Turpcu A, Bender K, et al. Phase 1 Study of Intravitreal (IVT) Gene Therapy with ADVM-022 for neovascular AMD (OPTIC Trial): the role of neutralizing antibodies (NAbs). Presented at: 2022 Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting; May 1-4, 2022, Denver, CO; May 11-12, 2022, virtual.
Adverum Biotechnologies Presents Additional Efficacy and Safety Data from the OPTIC Trial of ADVM-022 in Wet AMD at the ARVO 2022 Annual Meeting. News release. Adverum Bio. May 1, 2022.
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