conference reporter

Geographic Atrophy in Age-Related Macular Degeneration: Novel Strategies Targeting the Complement System

by Carl D. Regillo, MD, FACS, FASRS

Overview

As seen at AAO 2022, there is hope that treatments targeting the complement system will soon be available for patients with geographic atrophy (GA). An advanced stage of dry age-related macular degeneration (AMD), GA progresses relentlessly and accounts for approximately 20% of the cases of legal blindness in North America.

Following these presentations, featured expert Carl D. Regillo, MD, FACS, FASRS, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Regillo’s clinical perspectives on these findings are presented here. 

Carl D. Regillo, MD, FACS, FASRS

Director, Retina Service
Wills Eye Hospital
Professor of Ophthalmology
Sidney Kimmel Medical College
Thomas Jefferson University
Philadelphia, PA

“There are certainly other targets and mechanisms of interest in dry AMD, but nothing up to this point has ever shown a benefit in the large-scale clinical trial setting. That is why there is so much excitement about blocking C3 or C5.”

Carl D. Regillo, MD, FACS, FASRS

In its earliest stages, dry AMD may not affect vision to any noticeable degree, but it puts patients at risk for significant vision loss because it can lead to either choroidal neovascularization (CNV) or GA. Antioxidant vitamins and minerals have a small benefit in reducing the risk of neovascular AMD but do not mitigate the risk of GA. Our patients are living longer, and GA is now a significant public health problem; it is not an orphan disease. Ultimately, as GA causes many individuals to become legally blind, we have been desperately looking for ways to try to treat it (ie, to either prevent it, stop it, or slow it down). 

Complement activation is considered to be a key potentially targetable mechanism in GA, with at least 2 different lines of evidence suggesting its potential role in the development and progression of AMD. First, abnormal complement protein deposition is observed in the drusen of AMD and in the perilesional areas of GA. Second, patients with GA often have genetic polymorphisms in genes that encode complement components. In particular, the discovery that CFH variants are major risk factors in AMD was a watershed moment. A defect in complement regulation by CFH and other abnormalities in the alternative pathway amplification process are thought to play an important role in the pathogenesis of AMD. 

There are certainly other targets and mechanisms of interest in dry AMD, but nothing up to this point has ever shown a benefit in the large-scale clinical trial setting. That is why there is so much excitement about blocking C3 or C5. There are currently 2 therapeutics that have demonstrated decreased rates of GA progression by blocking either C3 (ie, pegcetacoplan) or C5 (ie, avacincaptad pegol) in phase 3 trials.

At AAO 2022, we saw the 24-month data for C3 inhibition with pegcetacoplan in the phase 3 DERBY and OAKS studies. Charles C. Wykoff, MD, PhD, provided an overview of these data, reporting that pegcetacoplan slowed GA lesion growth, with increasing effects over time, reaching a 30% reduction in the monthly group and a 24% reduction in the every-other-month group during the 18- to 24-month period. Post hoc perilesional microperimetry results provided a signal of functional preservation with pegcetacoplan therapy that is consistent with less photoreceptor loss over time. In addition, the safety profile was generally consistent with those reported in trials of intravitreal therapeutics; an elevated incidence of exudative AMD was observed with pegcetacoplan treatment, but none of the exudative AMD conversions were serious adverse events and they generally did well with treatment.

We also saw the 12-month results of the second pivotal phase 3 trial (ie, GATHER2) for C5 inhibition with avacincaptad pegol, which showed a statistically significant benefit in slowing GA progression. At the conference, Arshad M. Khanani, MD, discussed the GATHER2 efficacy results and Jeffrey S. Heier, MD, discussed the GATHER2 safety results. Avacincaptad pegol achieved the 12-month prespecified primary end point, showing a significant 14.3% reduction in the mean rate of GA growth from baseline vs sham. The benefit was consistent across all prespecified study subgroups. Further, the safety profile of avacincaptad pegol was better compared with that reported in the GATHER1 trial. At month 12, there were no cases of intraocular inflammation, endophthalmitis, or ischemic optic neuropathy reported in either the avacincaptad pegol arm or the sham arm. CNV rates were 6.7% and 4.1% in the avacincaptad pegol group and the sham group, respectively. 

The background rate of secondary CNV in eyes with GA is approximately 2% to 3% per year. There are some patients who will just naturally convert, and these complement-targeted therapeutics thus far seem to be increasing the rate. Fortunately, for both drugs, the larger phase 3 studies showed the CNV rates to be lower than those reported in the smaller phase 2 studies, so that is good news. We do not know whether increased CNV rates are a class effect, unique to complement inhibition, but other agents targeting the complement system are in earlier phases of clinical development, so we expect that this will become clearer in the future. 

Virtually anything that we inject into the eye will cause some degree of inflammation, but we just like to make sure that the inflammation is mild and that it does not harm the eye permanently or have long-lasting effects on vision. There were no reports of inflammation events with avacincaptad pegol in the GATHER2 study at 12 months. In the DERBY and OAKS studies, over 24 months, the rate of intraocular inflammation was 0.24% per injection, which is acceptable and comparable to reported rates in studies of other intravitreal therapies.  

In summary, it is very exciting that we now have 2 therapeutics that have had successful phase 3 programs in demonstrating decreased rates of GA progression by blocking either C3 or C5. We are finally making some progress in the management of GA after many, many years. 

References

Ammar MJ, Hsu J, Chiang A, Ho AC, Regillo CD. Age-related macular degeneration therapy: a review. Curr Opin Ophthalmol. 2020;31(3):215-221. doi:10.1097/icu.0000000000000657

Armento A, Ueffing M, Clark SJ. The complement system in age-related macular degeneration. Cell Mol Life Sci. 2021;78(10):4487-4505. doi:10.1007/s00018-021-03796-9

Desai D, Dugel PU. Complement cascade inhibition in geographic atrophy: a review. Eye (Lond). 2022;36(2):294-302. doi:10.1038/s41433-021-01765-x

Heier JS. GATHER2 phase 3 safety results. Section VIII: first-time results of clinical trials. Session presented at: 2022 Annual Meeting of the American Academy of Ophthalmology (AAO 2022); September 30-October 3, 2022; Chicago, IL.

Holz FG, Strauss EC, Schmitz-Valckenberg S, van Lookeren Campagne M. Geographic atrophy: clinical features and potential therapeutic approaches. Ophthalmology. 2014;121(5):1079-1091. doi:10.1016/j.ophtha.2013.11.023

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(4):576-586. doi:10.1016/j.ophtha.2020.08.027

Kaszubski P, Ben Ami T, Saade C, Smith RT. Geographic atrophy and choroidal neovascularization in the same eye: a review. Ophthalmic Res. 2016;55(4):185-193. doi:10.1159/000443209

Khanani AM. GATHER2 phase 3 efficacy results. Section VIII: first-time results of clinical trials. Session presented at: 2022 Annual Meeting of the American Academy of Ophthalmology (AAO 2022); September 30-October 3, 2022; Chicago, IL.

Park YG, Park YS, Kim I-B. Complement system and potential therapeutics in age-related macular degeneration. Int J Mol Sci. 2021;22(13):6851. doi:10.3390/ijms22136851

Patel PN, Patel PA, Land MR, Bakerkhatib-Taha I, Ahmed H, Sheth V. Targeting the complement cascade for treatment of dry age-related macular degeneration. Biomedicines. 2022;10(8):1884. doi:10.3390/biomedicines10081884

Qin S, Dong N, Yang M, Wang J, Feng X, Wang Y. Complement inhibitors in age-related macular degeneration: a potential therapeutic option. J Immunol Res. 2021;2021:9945725. doi:10.1155/2021/9945725

Steinle NC, Pearce I, Monés J, et al. Impact of baseline characteristics on geographic atrophy progression in the FILLY trial evaluating the complement C3 inhibitor pegcetacoplan. Am J Ophthalmol. 2021;227:116-124. doi:10.1016/j.ajo.2021.02.031

Wykoff CC, Rosenfeld PJ, Waheed NK, et al. Characterizing new-onset exudation in the randomized phase 2 FILLY trial of complement inhibitor pegcetacoplan for geographic atrophy. Ophthalmology. 2021;128(9):1325-1336. doi:10.1016/j.ophtha.2021.02.025

Wykoff CC. Treatment of geographic atrophy secondary to AMD with pegcetacoplan: two-year outcomes from the randomized phase 3 DERBY and OAKS trials. Section VIII: first-time results of clinical trials. Session presented at: 2022 Annual Meeting of the American Academy of Ophthalmology (AAO 2022); September 30-October 3, 2022; Chicago, IL.


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