Carlos M. De Castro, MD, highlights the phase III Apply-PNH study presented at ASH 2022.
Carlos M. De Castro, MD: In PNH [paroxysmal nocturnal hemoglobinuria], the needs are 2-fold. Over the past 20 years, we’ve developed complement inhibitors that have changed PNH in terms of treatment, quality of life, and overall survival. We started with eculizumab going back to 2002. Then ravulizumab came along, and pegcetacoplan, a C3 inhibitor, came along. We have some very good treatments that are very effective. There are still some people who experience some hemolysis, and that’s 1 of the key things we’re still having problems with: patients who have hemolysis and feel lousy when they get that and may even occasionally need a transfusion. That’s 1 of the biggest needs.
The second biggest need is in understanding the bone marrow failure that accompanies PNH. Some people are cytopenic in terms of white blood cells and platelets. Is there a way to correct that and even potentially cure the disease as normal stem cells take over from these PNH stem cells? Those are probably the 2 biggest needs: finding better therapies for hemolysis that are more convenient—we’re going to talk about some of the oral drugs coming out—and finding something for patients with bone marrow failure.
There were a lot of exciting data presented at the recent ASH [American Society of Hematology Annual Meeting] on all fronts involving PNH. The APPLY-PNH study used iptacopan in patients who’ve had a suboptimal response to either eculizumab or ravulizumab with a low hemoglobin count. The purpose of that study was to take 1 of these new oral factor B inhibitors, which is a new target for us. Factor B is involved in the alternative pathway activation. If we target that, we can block that alternative pathway, which is where a lot of the amplification of complement occurs. By blocking the pathway, we not only prohibit the intravascular hemolysis that’s so prominent in PNH, and that’s what the C5 inhibitors block, but we also can get the extravascular hemolysis that occurs probably from C3 fragment coding on the red cells. Those cells will then get taken up in the spleen and liver and be destroyed outside the blood system.
The study was designed and randomized in a 2-to-1 fashion. Twice as many patients got iptacopan as those who were randomized to continue on eculizumab or ravulizumab. The primary end points of the study were a rise in hemoglobin of 2 g/dL or the maintenance of hemoglobin above 12 g/dL. As I recall, over 80% of the patients on iptacopan hit these co-primary end points, which was wonderful to see. Typically, patients on eculizumab and ravulizumab don’t have normal hemoglobin levels; they have maintenance. They’re no longer anemic and need transfusions or feeling bad, but they don’t ever get to that higher level. Here we have something that’s proving that we’re blocking both intravascular and extravascular hemolysis and getting benefit.
There were a lot of secondary end points, including avoiding transfusion, FACIT [Functional Assessment of Chronic Illness Therapy]–Fatigue score. All of these looked very beneficial and in favor of the iptacopan. Iptacopan is a wonderful new drug. It’s taken twice a day orally, so it’s a new mode of administration. Eculizumab, ravulizumab, and pegcetacoplan have to be given intravenously or subcutaneously. This really is a nice, new avenue that’s going to be much more convenient for patients. But what do you do with compliance issues? What if somebody misses a dose accidentally? What if they go on a trip and forget their medications, are they going to get into trouble with breakthrough hemolysis? Those are questions we have to see.
These data were in patients who’ve already been treated and had a suboptimal response to a C5 inhibitor. We would love to see this in the up-front setting, and that study is being done. Not in the United States or Europe, because we already have drugs that are available. But in countries where there are no treatment alternatives, you can do an up-front naïve study. That’s being done now to see how well this works, but there’s no reason to think it’s going to work as well as we see in this study.
Lastly, we need some long-term data about the adverse effects and risks with this. We’ve always worried that blocking at the proximal points in complement might lead to more infections. We haven’t seen that so far with any of the proximal inhibitors coming out, including this 1. We want to know more data about thrombotic risks and a little more about breakthrough hemolysis.
Transcript edited for clarity.