Complement C3 Inhibitor Pegcetacoplan for Geographic Atrophy Secondary to Age-Related Macular Degeneration
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. 2020 Feb;127(2):186-195. doi: 10.1016/j.ophtha.2019.07.011. Epub 2019 Jul 16.
Geographic atrophy (GA), a late stage manifestation of age related macular degeneration is an irreversible cause of vision loss, and can be a particularly frustrating diagnosis for patients and physicians alike. At present, no effective treatment exists to help these patients. The underlying pathology leading to vision loss is atrophy of retinal pigment epithelium, photoreceptors and the underlying choriocapillaris. Research has pointed to the possible role of the immune system in disease progression in patients with GA. Specifically, it has been shown that that a buildup of C3b and its fragments on RPE, photoreceptors and capillary endothelial cell surfaces promote phagocytosis of these cells by microglia or macrophages. This led to the hypothesis that inhibition of C3 activation would help cells survive by evading phagocytosis, thus making C3 an attractive target for inhibition in therapies being assessed for treatment of GA. Filly is a phase 2 clinic trial (NCT02503332) designed to evaluate the efficacy, safety and tolerability of one such peptide inhibitor of C3, pegcetacoplan.
Filly is a randomized, sham-controlled study conducted over 46 sites in the US, Australia and New Zealand. To summarize, this study randomly assigned 246 patients with GA area size of 2.5mm2- 17.5mm2 in a 2:2:1:1 ratio to receive pegcetacoplan monthly (n=80), pegcetacoplan every other month (EOM) (n=80), sham (n=40) and sham EOM (n=40) for 12 months, with follow-ups at months 15 and 18. Fundus autofluorescence imaging was used to calculate the area and growth of GA at months 2, 6, 12 and 18. The primary outcome of interest was the mean change in the root mean square GA area from baseline to 12 months. Additionally, secondary outcomes of interest included mean change from baseline in the GA lesion area without the square root transformation, distance of the lesion from the fovea, BCVA, low-luminance BCVA and low-luminance VA deficit.
The results showed that patients treated with pegcetacoplan monthly had 29% smaller increase (p=0.008) and patients treated with pegcetacoplan EOM had 20% smaller increase (p=0.067) in square root GA lesion area from baseline when compared to patients treated with sham. The effect of pegcetacoplan was most notable between months 6 and 12. Specifically, post hoc analysis showed the greatest reductions in growth rate of square root GA lesion area in the pegcetacoplan monthly (45%, p< 0.001) and pegcetacoplan EOM (33%, p=0.009) groups between months 6 and 12. Additionally, this effect was noted to decline after cessation of treatment at 12 months, highlighting the need for continued therapy.
Overall, the safety profile of pegcetcoplan intravitreal injections was found to be comparable to those of other intravitreally administered medications. Two cases of culture positive endophthalmitis were reported in the pegcetacoplan treatment groups. Interestingly, a higher incidence of exudative CNV was noted in eyes treated with pegcetacoplan compared to eyes treated with sham. The authors hypothesize that when pegcetacoplan inhibits C3 activation it results in a decrease in the phagocytic attack on cells. As a result, the viable endothelium adjacent to the areas of GA are able to sprout new immature vessels. These immature vessels have an increased propensity to leak, thus explaining the higher rates of exudation in eyes treated with pegcetacoplan compared to sham.
One of the study limitations lies in the choice of central visual acuity as a functional outcome measure. As we know, central visual acuity does not fully capture the functional losses faced by patients with GA thereby limiting functional benefit assessment of this therapy. The authors acknowledge this limitation and moving forward plan to use additional functional assessments like reading speed and functional microperimetry. Another limitation stemmed from the fact that the treatment group patients who developed CNV, were discontinued on the pegcetacoplan therapy and treated with anti-VEGF instead. As a result, we are unable to examine the effect of pegcetacoplan in slowing growth of GA in patients who have concurrent CNV. Overall, however this was a well-designed Phase 2 trial which bears hope for patients with GA.