New Geographic Atrophy Treatment Shows Promise

Laird Harrison

July 22, 2018

VANCOUVER, Canada — An experimental treatment with an intravitreal complement C3 inhibitor (APL-2, Apellis Pharmaceuticals) slowed geographic atrophy in patients with age-related macular degeneration in FILLY (NCT02503332), the largest phase 2 trial of geographic atrophy to date.

"We're really motivated" by the results, said Nathan Steinle, MD, from California Retina Consultants in San Luis Obispo.

And although the treatment appeared to increase conversation to the neovascular form of the disease, the FILLY results were so positive "that we're going forward with phase 3 studies in both the United States and globally," he told Medscape Medical News.

Vascular endothelial growth-factor (VEGF) inhibitors have greatly improved the outlook for patients with neovascular, or wet, age-related macular degeneration, but treatments for geographic atrophy, or late-stage dry age-related macular degeneration, have so far disappointed.

To date, no drug has been approved that can halt or even slow geographic atrophy, Steinle reported here at the American Society of Retina Specialists (ASRS) 2018 Annual Meeting, where he presented 18-month data.

The complement system of immunity appears to play a key role in the development of geographic atrophy. Three complement pathways — lectin, classical, and alternative — trigger enzyme cascades that kill cells. The system also stimulates inflammation and attracts immune cells.

APL-2 is a synthetic cyclic peptide conjugated with a polyethylene glycol polymer that binds to complement C3 receptors, blocking all three pathways.

Another complement inhibitor, lampalizumab, was being developed by Genentech but failed to slow geographic atrophy in phase 3 trials, as reported by Medscape Medical News. However, lampalizumab targeted only the alternative complement pathway and took effect farther downstream in the complement cascade, Steinle explained.

To see whether APL-2 could succeed where lampalizumab failed, Steinle and his colleagues assessed 246 patients older than 50 years with geographic atrophy that ranged in area from 2.5 to 17.5 mm² at screening. All had best-corrected visual acuity of at least 24 letters. None had retina diseases other than age-related macular degeneration or any history of the neovascular type in the study eye.

Of the 165 patients randomly assigned to APL-2, 86 received injections monthly and 79 received injections every other month. Of the 81 patients assigned to sham therapy, 41 received injections monthly and 40 received injections every other month.

At 12 months, progression of geographic atrophy was 29% slower in the monthly APL-2 group than in the sham group (P = .008), and 20% slower in the bimonthly APL-2 group than in the sham group (P = .067).

Table 1. Change in Geographic Atrophy Area
Geographic Atrophy Area Monthly APL-2 Injections (n = 86) Bimonthly APL-2 Injections (n = 79) Pooled Sham Injections (n = 81)
Baseline mean, mm² 8.0 8.9 8.2
Change at 12 months, square root mm 0.25 0.28 0.35


With APL-2, progression was slower during the second half of the 12-month treatment period than during the first half. In the monthly APL-2 group, geographic atrophy progressed at only 47% of the rate in the sham group.

All treatments stopped after 12 months, but the patients were monitored for another 6 months.

From baseline to month 18, geographic atrophy progression was 16% less in the bimonthly APL-2 group than in the sham groups, although the difference was not significant (P = .097). In the monthly APL-2 group, progression was 20% less (P = .044).

Overall, progression in geographic atrophy in the sham groups was similar to progression reported in untreated patients in other studies, Steinle said.

And about 83% of patients in the FILLY trial had geographic atrophy in the fellow eye, which provided a second control group that could be used to assess the effectiveness of APL-2.

In these patients, differences in progression between the treated and untreated eyes were not significant.

Table 2. Difference in Progression Between Eyes in Patients With Geographic Atrophy in the Fellow Eye<
Treatment Group n Difference Between Eyes, % P Value
Monthly APL-2 injections 69 23 .083
Bimonthly APL-2 injections 63 10 >.1
Sham injections 72 0


Best-corrected visual acuity declined in all the groups during the 12-month treatment period, but the differences were not significant. The mean decrease in ETDRS letters was 3.3 in the monthly APL-2 group, 4.4 in the sham groups, and 5.8 in the bimonthly APL-2 group.

"In phase 3 we hope to see a difference," Steinle said.

There were 22 treatment-related ocular adverse events in the monthly APL-2 group, 11 in the bimonthly APL-2 group, and none in the sham group. There were three severe ocular events: two cases of endophthalmitis in the monthly APL-2 group and one in the bimonthly APL-2 group.

At 18 months, more new cases of neovascular age-related macular degeneration had developed in the APL-2 monthly and bimonthly groups than in the sham groups (20.9% vs 8.9% vs 1.2%). The patients with new exudation suffered some loss of vision and received treatment with a VEGF inhibitor.

In addition to geographic atrophy, Apellis Pharmaceuticals is evaluating APL-2 in clinical trials of systemic administration for paroxysmal nocturnal hemoglobinuria and related conditions.

Data from phase 3 trials will be crucial in evaluating APL-2, said Ajay Kuriyan, MD, from the University of Rochester Medical Center in New York.

"Phase 2 studies do show some promising results in terms of the decrease in geographic atrophy, but we still need a larger phase 3 trial," he explained. Phase 2 results were also promising for lampalizumab, he noted.

It is not a surprise that visual acuity did not improve in the FILLY patients because their maculas were already so damaged, he added.

Steinle reports financial relationships with Alimera Sciences, Genentech, Notal Vision, Regenerative Patch Technologies, Regeneron, Vortex Surgical, and Zeiss. Kuriyan reports financial relationships with Alimera, Allergan, Regeneron, Genentech, Bayer, and Second Sight.

American Society of Retina Specialists (ASRS) 2018 Annual Meeting. Presented July 21, 2018.

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