Pegcetacoplan for Treatment of Geographic Atrophy

Eleonora M. Lad, MD, PhD: David, tell us a little about pegcetacoplan and its clinical development in phase 3.

David R. Lally, MD: Pegcetacoplan is a pegylated aptamer that blocks part of the complement pathway. Specifically, it blocks C3 convertase from allowing C3 to go into C3a and C3b. The C3b component of the pathway leads to the MAC [membrane attack complex] formation and destruction of cells, so the complement system is very complex. It’s new to all retina specialists over the last few years, and I’m still trying to grapple with it at times. There are 3 different pathways: the classical, the alternative, and the lectin. All 3 pathways converge at this molecule C3. Pegcetacoplan takes the approach of blocking where these 3 pathways meet, to try to prevent the development of the MAC complex and destruction of these cells. We think this is part of the pathophysiology of geographic atrophy.

This drug has been studied extensively over the last few years. In a phase 2 trial called the FILLY trial, over 200 patients were randomized to 4 different groups. It was randomized in a 2:2, 1:1 fashion of a monthly injection or an every-other-month injection that was intravitreal of pegcetacoplan for 1 year vs sham injections monthly or every other month for 1 year. Patients were followed an additional 6 months. We saw that the primary outcome measure was defined as the change in geographic atrophy lesion size at 1 year on the fundus autofluorescence image. Eyes treated with pegcetacoplan monthly had a 29% reduction in the growth of that atrophic lesion, with the every-other-month group having a reduction of about 20% at 1 year. That was a very encouraging sign, to see the curves diverge at an early point, at 1 year. These patients live for quite a long time with this disease, far beyond 1 year.

Those studies were followed up with the pivotal phase 3 studies called OAKS and DERBY. These were very large multicenter, randomized, double-masked placebo-controlled trials. They were global studies, with sites all over the world that enrolled over 1200 patients. They were randomized in a similar fashion, 2:2, 1:1, to receive pegcetacoplan monthly injections for 2 years or every other month for 2 years, or sham injections for 2 years. The primary outcome measure was defined as the change in the area of the geographic atrophy lesion at 1 year.

In the primary analysis, we saw that the primary outcome at month 12, in the OAKS study, met its primary end point. The reduction was 22% in the geographic atrophy growth in the monthly group with a statistical P value. In the every-other-month group, it was a 16% reduction, which was statistically significant. These reductions in growth in OAKS were carried out through month 24, so when we look at month 24, it was a 22% reduction in the monthly group and 18% in the every-other-month group.

On the other hand, in the DERBY trial, which was a parallel trial, did not meet its primary end point at reducing the growth at 1 year. If we do a pooled analysis of both OAKS and DERBY, which was a prespecified analysis, it showed statistical significance that there was a positive effect, although the P value is nominal. This was exciting to see. For the first time, we had evidence in a phase 3 pivotal trial—with support from the phase 2 trial—that this medication may be slowing down, impacting, and influencing the speed of the disease for these patients. It was a very exciting thing to see.

Transcript edited for clarity