Geographic atrophy remains the greatest unmet need in retina. The historical notion that GA progresses slowly was wrong and the concept has misled patients and their families. Numerous studies have confirmed patients afflicted with GA lose about one line of vision annually. At that rate, it doesn’t take many years before the ability to drive and other quality-of-life measures are irreversibly lost.
Fortunately, data from two recent Phase II clinical trials indicate the tide may be turning. First, inhibition of complement factor 3 (C3) with pegcetacoplan resulted in statistically significant reductions in GA growth, a directionality that appeared to increase with longer drug exposure and appeared to be dose dependent.1 Second and most recently, inhibition of C5 with avacincaptad pegol similarly resulted in statistically significant reductions in GA growth.2 Cumulatively, through one year, these datasets indicate that GA growth may be slowed by about one third with C3 or C5 inhibition.
Certainly these results must be verified through additional, larger studies, which are under way. The 2018 failure of lampalizumab in Phase III was particularly disappointing, and the shock waves have lingered in our field as there remains extensive speculation that targeting GA may be just too late in the disease process to prevent vision loss. While this may yet prove to be true, armed with these recent datasets and for the benefit of our patients, I believe and hope it is not.
My conversations with patients afflicted with GA have evolved from vague comments—“There is a lot of ongoing research”—to more specific details related to these Phase II trial results.
The advent of anti-VEGF therapies for exudative diseases was the dawn of a new era. I believe we are on the edge of another leap forward with validation of complement as a viable target to slow GA progression.
Ultimately, we must pivot toward intervention at earlier stages of the disease process, such as phenotypically variable intermediate AMD, with the goal of preventing progression to late-stage AMD, including both the neovascular and GA forms; analogous to preventing progression of severe nonproliferative diabetic retinopathy to proliferative disease with pharmacotherapy.
But for now, a welcome first step toward conquering this devastating disease would be to slow the thus far inexorable march to blindness inherent in a diagnosis of GA. RS
1. Liao DS, Grossi FV, El Mehdi D, et al. Complement C3 inhibitor pegcetacoplan for geographic atrophy secondary to age-related macular degeneration: A randomized phase 2 trial. Ophthalmology. 2019. In press. DOI: https://doi.org/10.1016/j.ophtha.2019.07.011.
2. IVERIC bio’s Zimura, a novel complement c5 inhibitor, met its primary endpoint and reached statistical significance in a phase 2b randomized, controlled clinical trial in geographic atrophy secondary to dry age-related macular degeneration. [Press release]. New York, NY; IVERIC bio; October 28, 2019. Available at: https://investors.ivericbio.com/news-releases/news-release-details/iveric-bios-zimurar-novel-complement-c5-inhibitor-met-its.