Pegcetacoplan for Geographic Atrophy: GALE Study

Dr. Kondapalli: A major difficulty with treatment of geographic atrophy is that, unfortunately, a lot of the visual endpoints that we’re really familiar with in some of the other diseases we don’t necessarily trust in geographic atrophy; the main one being visual acuity. Often, when patients have geographic atrophy, they have scotomas — essentially, they’re missing part of their vision — but they’re able to read past the scotoma, which makes visual acuity endpoints very difficult to base treatment decisions on.

It’s a little bit of a paradigm shift for us in the retina world because, when we think about other diseases like wet macular degeneration or diabetic macular edema, we’re able to very clearly see the improvement in best-corrected visual acuity based on ETDRS letters. But, in geographic atrophy, we really don’t have that ability. And, so, that’s one of the difficulties in talking to patients about their treatment options — it’s harder to define the preservation of vision because, obviously, best-corrected vision is often really difficult to measure in these patients.

Advantages of pegcetacoplan

There are couple of advantages to using pegcetacoplan, perhaps over other therapies, that come to mind.

The first is that, at baseline, there is stronger evidence that it slows the rate of geographic atrophy lesion growth at time points 12 months and 24 months. But, also, we have extension data now that show increasing efficacy over time.

The other benefit with pegcetacoplan is that it, on-label, can have a monthly versus every-other-month dosing interval. So, this allows some flexibility for our patients, which can be beneficial.

Efficacy and safety outcomes of the GALE study

The GALE study was an extension trial that looked at 3 years’ worth of data from patients taking pegcetacoplan. What’s nice is that it looked at not only efficacy but also safety.

What was interesting is that there was a 42% reduction in geographic atrophy lesion growth in those patients who had non-subfoveal lesions. So, remember, with pegcetacoplan, they enrolled patients with both subfoveal and non-subfoveal lesions. And, in the subgroup of patients who had non-subfoveal lesions, who we traditionally would think have better visual outcomes or better visual acuity, there was actually a substantial reduction in lesion growth.

Crossover from the sham arm

What’s also interesting in the GALE study is that they crossed over the patients who were in the sham arm, and these patients were able to get treated. And so, what happens to those patients who essentially go without treatment for 2 years, potentially patients who were holding off on treatment and then start treatment maybe 2 years down the road? What happens to those patients in terms of lesion growth, their visual acuity, their outcomes? Because perhaps a lot of us in the retinal community are thinking, do we treat a patient? Do we not treat a patient? And what happens if we delay treatment and then consider it later down the road? Do the patients still gain the benefit? And that’s something that excites me about the GALE study as well.

Increased rate of choroidal neovascularization

In terms of safety with pegcetacoplan, there are a few things to note. There is an increased rate of choroidal neovascularization that is thought to be dose-dependent, in the sense that it happens more often in those patients who are treated monthly versus every other month. However, we see this with other complement inhibitors as well. And, so, this is something that we have to consider in patients who we are treating with complement inhibition.

Retinal vasculitis in some cases

The rates of endophthalmitis were very similar to those seen with traditional anti-VEGF or other intravitreal injections. Of note, though, pegcetacoplan also was associated with retinal vasculitis or occlusive retinal vasculitis in certain situations. It’s still unclear what the cause of the retinal vasculitis was. The thought is that it might be the syringe, or rather the needle, that the medication was being drawn up with. The other possibilities are that it might be the PEGylation of the molecule itself, that patients perhaps have some sort of hypersensitivity reaction to it. It’s still yet to be determined. But the incidence of retinal vasculitis has been relatively low, about 0.01% per injection.

Microperimetry as a functional visual endpoint

One other advantage of pegcetacoplan that’s of interest is the fact that, in the OAKS trial, the investigators looked specifically at microperimetry. And, as I mentioned, in terms of geographic atrophy, it’s often very difficult to trust acuity as a good visual endpoint. Previous studies have shown that microperimetry is a useful functional vision measure that correlates best to geographic atrophy lesion growth. In post hoc analyses that were done of OAKS, at the junctional zone itself, there was better threshold sensitivity in the treatment arms and fewer new scotomatous defects detected with microperimetry.

There’s a decreased risk of losing the central four loci of microperimetry. We know for every one of those points lost, there’s a drop in best-corrected visual acuity. So, although we can’t necessarily say with confidence, in terms of the best-corrected visual acuity in patients with geographic atrophy, what’s interesting in the OAKS study and with pegcetacoplan is the fact that they looked at microperimetry. This gives me a little bit more confidence in terms of what’s actually happening with a patient’s functional vision, which helps me guide the discussion with the patient a little bit better as well.

And Izervay?

The 2-year data on ACP, or Izervay, which is another complement inhibitor, were recently presented, and what’s interesting is that it seems to be more effective with every-other-month versus every-month treatment. It is still not completely understood why less complement inhibition would lead to a greater reduction in lesion growth. There are some areas that still need to be investigated.