Complement Factor Inhibitors for the Management of Patients with Geographic Atrophy from Dry AMD
Rishi Singh, MD
What up-and-coming therapies for dry AMD are you most excited about and why?
The therapies being investigated for dry age-related macular degeneration (AMD) that I am most excited about are the complement factor inhibitors. Geographic atrophy (GA) impacts approximately one million people in the United States alone. A key mediator of the progression to GA appears to be the complement pathway, which is partially responsible for our innate immune system responses such as phagocytosis and inflammation. Dysregulation of the pathway, particularly the alternative complement system, leads to an increased risk of development of GA. The entire complement pathway converges upon C3 which is being targeted now through an aptamer (APL-2) against C3 within the DERBY and OAK studies.
The FILLY Study was a phase 2 study investigating APL-2 delivered either monthly or bi-monthly to reduce the progression of GA compared to placebo. The study treatment protocol was conducted for 12 months, with an additional 6-month period of observation following the treatment period. The primary endpoint was the change in GA lesion size from baseline to month 12. The study demonstrated that, from baseline to 12 months, patients treated with bi-monthly APL-2 experienced a 20% reduction in growth compared to placebo, while patients treated with monthly APL-2 experienced a 29% reduction in progression. Despite being off treatment for the last 6 months of the study, there was no regression of the treatment effect.
Of concern from a safety standpoint was the conversion of some patients from nonexudative AMD to exudative AMD. The study showed what appears to be a dose-dependent conversion rate. Another possibility is that patients with quiescent exudative AMD (no fluid on optical coherence tomography at baseline) were enrolled in the study. Yet another possibility is that the inhibition of C3 caused a pseudoexudative state. Even after excluding the 26 patients who were identified during the study period as having exudative AMD, the study results still show a statistically significant inhibition in GA growth. The DERBY and OAK trials are now underway to evaluate this treatment in phase 3 and both are midway through enrollment. Careful evaluations are being performed to exclude patients with possible quiescent exudative AMD at baseline.
Other researchers are investigating the pathway as well. This week we saw data on complement inhibition of C5 by Iveric Bio (Zimura) showing an almost similar reduction in GA progression in patients treated within a phase 2 study. The reduction in the mean rate of GA growth over 12 months was 27.38% (p-value = 0.0072) for the Zimura 2 mg group compared to the corresponding sham control group and 27.81% (p-value = 0.0051) for the Zimura 4 mg group compared to the corresponding sham control group. Similar to the FILLY study, there was a higher number of apparent conversions to exudative AMD in the Zimura-treated patients. More data from this study are expected soon.
Certainly, these are exciting times for retina specialists as we can now reduce vision loss from exudative AMD and there are multiple potential treatments for GA on the horizon.
Dr. Rishi P. Singh is a retina specialist at the Cole Eye Institute, Cleveland Clinic and Associate Professor of Ophthalmology at Case Western Reserve University. He is the center director for the Cole Eye Center for Ophthalmic Bioinformatics.