Novel complement-blocking therapies for paroxysmal nocturnal hemoglobinuria (PNH) are under development, and some have been recently approved by the US Food and Drug Administration (FDA) to provide patients with more treatment options. Researchers at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition presented data discussing the safety and efficacy of some of these agents.

Following these proceedings, featured expert Jaroslaw P. Maciejewski, MD, PhD, FACP, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Maciejewski’s clinical perspectives on these findings are presented here. 

Data on emerging complement inhibitors for PNH were presented at ASH 2023. One such drug, crovalimab, is a novel C5 inhibitor that is administered as a loading dose intravenously with subsequent monthly subcutaneous injections (abstract 575). Of the emerging complement inhibitors for PNH, it is the one that is the closest to being approved by the FDA. Other agents include the C5 inhibitor pozelimab, which is being evaluated in combination with the RNA interference drug cemdisiran (abstract 2716); OMS906, an alternative complement pathway MASP-3 inhibitor (abstract 4082); and KP104, a bifunctional C5 antibody/factor H fusion protein (abstract 572).

There are 4 FDA-approved drugs for the treatment of PNH: eculizumab, ravulizumab, pegcetacoplan, and, most recently, the factor B inhibitor iptacopan, which is the first oral drug for PNH. While C5 inhibitors are very effective, there are some shortfalls, including incomplete responses and rare refractory patients. Primary or secondary failure of C5 inhibitors due to extravascular hemolysis is addressed by more proximal-acting inhibitors targeting factor B, factor D, and C3, among many others. Proximal complement inhibitors will change the treatment landscape and expand the spectrum of treatment options, which may improve extravascular hemolysis and/or the prevention of residual steady-state hemolysis on C5 inhibitors or acute breakthroughs.

Pegcetacoplan and iptacopan have been tested in nonresponders and in lesser-than-optimal responders to C5 inhibitors. However, any superiority in efficacy when these 2 drugs are compared with each other or with the existing C5 inhibitors will be decided by future observations. So, when choosing between medications, some patients who prefer an oral medication might choose iptacopan over pegcetacoplan, while others may prefer the more familiar drug in particular when they are already on pegcetacoplan. Being averse to change is common, particularly if they have good response and they have gotten used to a certain routine.

Some patients with PNH truly do feel that their lives would be improved if they only had to take a pill to treat their disease. For patients receiving an injection or an infusion, there can be psychologic barriers, time-related issues, issues with traveling to the center, co-pays, and parking-related issues, depending on where they live. Patients may also perceive their disease as more severe if they are dependent on a hospital for their treatment. The freedom of taking a pill and moving on means a lot to many people, even if their perception of their disease severity might not be correct. So, many patients with PNH might prefer to start on an oral agent.

Regarding safety, whether more proximal complement inhibition is associated with more infectious complications is unclear. Long-term, if we equalize patient-year exposure to the drugs, there could be some difference with the newer agents, but there was not a greater risk of infectious complications in patients who were treated with pegcetacoplan or iptacopan in clinical trials. Nevertheless, in accordance with the Advisory Committee on Immunization Practices (ACIP) guidelines, patients with PNH treated with complement-blocking therapy should receive vaccines against encapsulated bacteria, including Neisseria meningitidis, Haemophilus influenzae type B, and Streptococcus pneumoniae.

Although breakthrough hemolysis has not been a significant clinical problem for me, if there are signs of breakthrough hemolysis in patients receiving an oral agent, it can be easily mitigated by a brief increase of the dose, facilitated over a telephone call. However, this is very difficult to do in somebody who just received an infusion. Infusions are not instant, and you have to schedule them. So, in the case of breakthrough hemolysis, these patients require emergency care.

Currently, investigations are focusing on the elimination of hemolysis and associated thrombotic complications, which is more of a maintenance or supportive care type of treatment. Very little is being pursued in terms of curing PNH. We have transplants, but the other issue is therapies that are directed toward the elimination of the PNH clone.