This is a breakthrough clinical trial for patients with late, nonexudative (dry) age-related macular degeneration. For the first time, we have been able to look at an entire dataset from a clinical trial on this population and demonstrate a dose-dependent benefit in significantly slowing the enlargement of geographic atrophy (GA). This phase 2 study population has been analyzed using several different strategies, and all the analyses show significant slowing of GA at the highest dose. We are not talking about a significant treatment effect in a subgroup, we are talking about the entire patient population, which represents a real-world population of patients with GA. The results are unambiguous.
In addition, this study is a great vindication for all the genetic research into complex human diseases. For a complex human disease, one of the strongest associations between any disease and its genetic locus exists between AMD and the complement factor H locus. The ultimate proof that genome-wide association studies are worthwhile rests in the ability to produce therapies that target a given genetic locus associated with human disease. With APL-2, we have unambiguously achieved this goal. Despite numerous obstacles, the clinical development team at Apellis has worked for the past 12 years and achieved these proof-of-concept study results. They started with a formulation of this drug known as POT-4, and in the phase 1 study, we saw a treatment effect, but the treatment effect was in the exudative form of AMD. We realized that this drug had a therapeutic role in AMD, we just needed a better formulation of the drug so it could be injected every month.
In this real-world phase 2 study, we enrolled patients with GA regardless of the fellow eye status and regardless of the autofluorescence patterns, and the only restriction was the size of the lesion. We included almost all patients as long as they saw better than 20/320. And, we included patients with exudative neovascularization in the fellow eye. In the past, a lot of these patients had been excluded from these clinical trials.
While the drug slowed the enlargement of GA in the study eye, there was also an increased risk of exudation in the study eye, which was easily treated with anti-VEGF therapy and did not affect vision and did not affect the outcome of the clinical trial. I am very excited by this result because it provides an important clue regarding the trigger that causes eyes to develop exudation from nonexudative lesions. In a separate study, we were able to identify nonexudative neovascular lesions months and months before they started leaking and before patients reported any vision changes.
In the APL-2 study population, I do not think APL-2 caused neovascularization to develop, but I do think the drug may have triggered pre-existing neovascularization to develop low level exudation. I am very excited because I think we have found a clue as to what causes the switch from nonexudative AMD to exudative neovascular AMD.
This is just a fascinating clinical trial. For the first time, we are taking most patients with GA and demonstrating that we can slow their disease progression. While some people may view the increased risk of exudation as a problem with the drug, I see it as a fascinating development that can be easily managed by identifying these eyes early with OCT angiography and treating the exudation early with anti-VEGF therapy when detected.
Philip J. Rosenfeld, MD, PhD
Bascom Palmer Eye Institute
University of Miami Miller School of Medicine, Florida
Disclosures: Rosenfeld reports he has been an investigator and is currently an investor in Apellis Pharmaceuticals.