GATHER2: Avacincaptad Pegol Significantly Slows GA Growth Over 12 Months

Primary results from the GATHER2 trial showed monthly C5 inhibition with avacincaptad pegol 2 mg (IZERVAY) significantly slowed the mean rate of geographic atrophy (GA) growth versus sham treatment over 12 months of study.¹

The investigative team, led by Arshad Khanani, MD, director of clinical research at Sierra Eye Associates, noted avacincaptad pegol 2 mg was well tolerated over 12 months of treatment, with no reported events of intraocular inflammation or endophthalmitis.

Given the limited number of US Food and Drug Administration (FDA)-approved treatments for GA, Khanani, and colleagues, suggested avacincaptad pegol has the potential to provide eye care professionals with a treatment that slows GA lesion growth and allows patients to maintain their quality of life.

“Although monthly injections can be a substantial burden to both patients and clinicians, the results of this study show that there is a treatment that can be used to slow the progression of the disease and the associated effect on the patient’s vision,” investigators wrote. “These data, together with the results of the GATHER1 study, suggest that avacincaptad pegol 2 mg might slow the progression of GA.”

An advanced form of age-related macular degeneration (AMD), GA is characterized by the loss of photoreceptors, retinal pigment epithelium, and choriocapillaris, and progression over time can lead to substantial, irreversible vision loss. Its pathology is considered multifactorial, but overactivity of complement cascade-mediated inflammation has been attributed to AMD pathogenesis, while dysregulation of the complement system has been linked to GA.

Granted approval by the FDA in August 2023 as the second therapy to treat GA, avacincaptad pegol is a specific inhibitor of complement C5 that slows the progression of disease by preventing the production of terminal, active C5 cleavage products (C3a and C3b).² The therapy was previously evaluated in the randomized, double-masked, sham-controlled phase 2/3 GATHER1 study, which met primary endpoints in both the avacincaptad pegol 2 mg and 4 mg groups.

Results from GATHER1 showed, compared with sham, avacincaptad pegol 2 mg had a 27% reduction, and avacincaptad pegol 4 mg had a 28% reduction in mean change in GA area over 12 months.³ The therapy showed a continued reduction in the progression of GA lesion growth over 18 months and was well-tolerated at both doses. Given this favorable benefit-risk profile, the randomized, double-masked, sham-controlled, phase 3 GATHER2 trial evaluated the efficacy and safety of intravitreal avacincaptad pegol 2 mg in patients with GA over 24 months.¹

Eligible participants were ≥50 years old with non-centerpoint-involving GA and best-corrected visual acuity (BCVA) between 20/25 (80 ETDRS letters) and 20/320 (25 ETDRS letters) in the study eye. These patients were randomly assigned 1:1 to monthly avacincaptad pegol 2 mg, administered as a 100 µL intravitreal injection, or sham for the first 12 months. Those involved in the study, including patients, investigators, study center staff, sponsor personnel, and data analysts, were masked to treatment allocation.

The primary GATHER2 trial endpoint was GA lesion size, measured by fundus autofluorescence at ≥3 time points: baseline, month 6, and month 12. This was analyzed using a slope analysis of square-root-transformed data, a request by the FDA, to determine the mean rate of GA growth from baseline to month 12. All efficacy analyses were conducted in the intention-to-treat populations, and the safety analyses were conducted in the safety population, consisting of all patients who received ≥1 dose of avacincaptad pegol.

Between June 2020 - July 2021, a total of 1422 patients were screened for eligibility and 448 were enrolled in GATHER2 and randomly assigned to avacincaptad pegol 2 mg (n = 225) or sham (n = 223). A single patient in the sham group did not receive treatment with an investigational product and was excluded from analyses. The study population included 154 (68%) females and 71 (32%) males in the avacincaptad pegol 2 mg group, and 156 (70%) females, and 66 (30%) males in the sham group.

Upon analysis, from baseline to month 12, the mean rate of square-root-transformed GA area growth was 0.336 mm per year with avacincaptad pegol 2 mg versus 0.392 mm per year with sham treatment. With an absolute difference in growth of 0.056 mm per year (95% CI, 0.016 - 0.096; P = .0064), these data represent a 14% difference between avacincaptad pegol 2 mg and sham treatment.

Regarding safety findings, ocular treatment-emergent adverse events in the study eye occurred in 110 (49%) patients in the avacincaptad pegol 2 mg group and 83 (37%) patients in the sham group. Investigators identified no events of endophthalmitis, intraocular inflammation, or ischemic optic neuropathy over 12 months in either treatment group.

Moreover, until month 12, macular neovascularization in the study eye occurred in 15 (7%) patients in the avacincaptad pegol 2 mg group and 9 (4%) patients in the sham group. Exudative macular neovascularization occurred in 11 (5%) patients in the avacincaptad pegol 2 mg group and 7 (3%) patients undergoing sham treatment.

A post-hoc analysis investigated persistent vision loss, defined as a loss of ≥15 ETDRS letters from baseline measured at any 2 constructive visits up to month 12. The findings revealed the risk probability was 3.1% for avacincaptad pegol 2 mg versus 7.7% for sham (hazard ratio [HR], 0.41; 95% CI, 0.17 - 1.00; logRank P = .042).

Based on these data, Khanani and colleagues suggested it possible to modify the trajectory of disease in eyes with GA treated with avacincaptad pegol, ultimately leading to preservation of the spared retina and lowering the risk of persistent vision loss.

“Taken together, these results suggest that avacincaptad pegol 2 mg, which achieved the 12-month primary objective in two pivotal phase 3 studies, effectively slowed GA growth, further corroborating the role of the complement pathway in the pathogenesis of GA,” they wrote.

References

1. _{Khanani AM, Patel SS, Staurenghi G, et al. Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2): 12-month results from a randomised, double-masked, phase 3 trial. Lancet. 2023;402(10411):1449-1458. doi:10.1016/S0140-6736(23)01583-0}
2. _{Kunzmann K. FDA approves Avacincaptad Pegol for geographic atrophy. HCP Live. August 5, 2023. Accessed October 30, 2023. https://www.hcplive.com/view/fda-approves-avacincaptad-pegol-geographic-atrophy.}
3. _{Jaffe GJ, Westby K, Csaky KG, et al. C5 inhibitor avacincaptad pegol for geographic atrophy due to age-related macular degeneration:
   a randomized pivotal phase 2/3 trial. Ophthalmology 2021;
   128: 576–86.}