Intravitreal gene therapy holds promise for novel wet AMD treatment


An in-office intravitreal therapy delivering a gene for aflibercept expression continues to demonstrate encouraging safety, tolerability, and efficacy in a phase 1 study of patients with neovascular age-related macular degeneration who require frequent injections to control their disease.

intravitreal gene therapy

Analyses of data from OPTIC, a dose-ranging phase 1 study, show that intravitreal AAV.7m8-aflibercept gene therapy (ADVM-022, Adverum)—a gene therapy vector designed to provide long-term aflibercept expression—shows promise for treating neovascular age-related macular degeneration (nAMD) with a greatly reduced injection burden compared with existing options, said Arshad M. Khanani, MD, MA.

“With data available from 21 patients across three dosing cohorts, ADVM-022 continues to be well-tolerated. Intraocular inflammation that primarily affects the anterior segment occurs, but it appears to be well managed with topical steroids,” said Khanani, director of clinical research, Sierra Eye Associates, Reno, Nevada. “The data from OPTIC also indicate that ADVM-022 has robust dose-related efficacy, suggesting that this intravitreal therapy has the potential to improve real-world vision outcomes in nAMD by addressing the unmet need for an in-office approach that will provide long-term control of VEGF driven disease activity.”

In a presentation for ARVO 2020, Khanani reported data for three of four patient cohorts in OPTIC. The results were based on analyses of data collected through April 1, 2020, and offered a first look at outcomes in cohort 3.

Study design

OPTIC is a 2-year multicenter study enrolling patients who were previously treated for nAMD and demonstrated a meaningful response but required frequent injections, explained Khanani, who is also a clinical associate professor of ophthalmology, University of Nevada, Reno.

Cohort 1 enrolled six patients who received ADVM-022 dose (6x1011vg/eye) with a 13-day course of oral steroid to prevent intraocular inflammation. Patients in cohorts 2 (n = 6) and 3 (n = 9) were treated with 2x1011 vg/eye ADVM-022 and a 13-day oral or a 6-week topical course of steroid, respectively. A single patient has been enrolled in Cohort 4 that is investigating the higher dose of ADVM-022 with topical steroid prophylaxis.

Patients are receiving a single injection of ADVM-022 and are given rescue treatment with intravitreal aflibercept based on strict protocol-defined criteria.

At enrollment, patients had received an average of over nine intravitreal anti-VEGF injections in the previous year and had a mean BCVA of approximately 65 letters. Mean central subfield thickness (CST) across the first three cohorts ranged from 308 to 472 µm, with patients in cohort 3 having the thickest average CST.

Primary outcomes

Safety and tolerability are being investigated as the primary outcomes in OPTIC. So far, ADVM-022 has been well tolerated, Khanani noted.

No patients experienced any serious or systemic adverse events attributed to the treatment. The most common adverse event has been low-grade intraocular inflammation. Two patients experienced elevated IOP that was successfully managed with topical treatment in one patient and resolved spontaneously in the second patient who was already on a topical IOP-lowering medication.

“There has been no clinical or fluorescein evidence of retinal vasculitis, retinitis or choroiditis,” Khanani said. “Although the duration of follow-up is shorter in cohort 3, we are encouraged that the longer prophylactic steroid eye op regimen is showing evidence of minimizing early ocular inflammation, with fewer ocular adverse events being reported.”

Functional and structural data

Results from cohort 1 showed that no patient needed rescue treatment. After a median follow-up of 60 weeks, BCVA had decreased by an average of 2.7 letters from baseline and mean CST improved by 26.2 µm.

“The loss of BCVA is attributed to a single patient who experienced a retinal detachment that was unrelated to the study treatment,” Khanani said.

Median follow-up of 36 weeks is available for cohort 2, and this subgroup had a mean decrease of 2.8 letters from baseline BCVA. Four of six patients remained rescue-free and BCVA among the rescue-free patients had improved by an average of 2.3 letters from baseline. Mean CST improved by 40.8 µm for the entire cohort and by 30.0 µm in the four eyes that were rescue-free.

Data were analyzed from the first five patients treated in cohort 3 who had completed 20 weeks of follow-up. At 20 weeks, four patients were rescue-free. BCVA was improved by 6.8 letters considering all five patients and by 8.8 letters for the rescue-free subgroup. Mean CST improved by 137.8 µm for the entire group and by 149.8 µm among rescue-free eyes.

Arshad M. Khanani, MD, MA
Khanani is a consultant to and receives grant support from Adverum.

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