Avacincaptad Pegol for GA Meets Primary Efficacy Endpoint in GATHER2 Trial

Arshad Khanani, MD

New data from the GATHER2 trial indicate avacincaptad pegol can slow the rate of geographic atrophy (GA) growth compared with sham treatment, with high statistical significance.

The pivotal, late-breaking findings were presented at the 2022 American Academy of Ophthalmology 2022 Annual Meeting in Chicago, Illinois.

“Both GATHER1 and GATHER2 studies have shown us that we see a treatment effect early with avacincaptad pegol that increases over time,” said Arshad Khanani, MD, Director of Clinical Research, Sierra Eye Associates at the presentation. “Avacincaptad pegol is the first, investigational therapy in GA to achieve the 12-month prespecified primary endpoint in 2 pivotal phase 3 studies."

The agent is a pegylated RNA aptamer designed to be a specific inhibitor of complement C5. The inhibition of C5 slows inflammation and cell death associated with the development and progression of GA. The C5 inhibition additionally has the potential to preserve the anti-inflammatory properties of C3a.

The phase 3 GATHER2 was a phase 3, international, multicenter, prospective, randomized, double-masked, sham-controlled study. It randomized 448 patients to receive either avacincaptad pegol monthly or sham injection.

Its primary endpoint was the mean rate of growth in GA area from baseline to month 12, using a slope analysis and square root transformation. The study in the second year then re randomized avacincaptad pegol treated patients to either monthly avacincaptad pegol or every-other-month. The sham group continued on the sham injection.

These findings are the first-time, primary month 12 results. Key inclusion criteria were considered standard for complement inhibitor trials, including age ≥50 years and best-corrected visual acuity (BCVA) between 20/25 and 20/320.

However, there were two key differences noted, including enrolling GA patients with non-center point involvement and GA in part had to be within 1500 μm from the foveal center. Center point involvement was determined by the Duke Reading Center using multimodal imaging.

When looking at treatment fidelity through year one, it was greater than 90% in both groups, or 91% in avacincaptad pegol 2 mg and 94% in sham. The injection fidelity rate was calculated by dividing the total number of administered injections by the total number of expected injections based on the number of enrolled patients.

Baseline patient demographics were balanced between each group. The mean age was 76.3 years and included 154 female patients (68.4%) in the avacincaptad pegol group compared with 76.7 years and 156 female patients (70.3%) in the sham group.

Moreover, baseline ocular characteristics were balanced. Khanani noted that most GA lesions were multifocal (178 [79.1%] in avacincaptad pegol and 178 [80.2%] in sham) with diffuse/banded hyperautofluorescence pattern (217 [96.4%] in avacincaptad pegol and 44 [19.8%] in sham).

The GATHER2 trial met the prespecified primary endpoint with a high degree of statistical significance at year. Investigators observed an early separation of treatment effect, which continued over time.

Data show a 14.3% growth rate reduction with avacincaptad pegol compared with sham. The difference observed was 0.056 mm (95% confidence interval [CI], 0.016 - 0.096; P = .0064).

The mean change from baseline analysis using observed data was consistent with the primary analysis, with an overall 17.3% reduction with avacincaptad pegol compared with sham. An early treatment effect was observed at month 6 (0.194 mm2; 95% CI, 0.044 - 0.345; P = .0115), which was is more than doubled at month 12 (0.405 mm2; 95% CI, 0.142 - 0.668; P = .0027).

In prespecified analysis, the benefit of avacincaptad pegol was observed in all prescified subgroups based on different baseline characteristics. This was determined to be consistent with the GATHER1 trial findings.

The study, “GATHER2 Pivotal Phase 3 Study Results: Efficacy of Intravitreal Avacincaptad Pegol in Geographic Atrophy,” was presented at AAO 2022.