Several new therapies, including agents with novel mechanisms of action (MOAs) against the complement system, have been developed for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). Researchers at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition discussed data from several studies addressing the efficacy and safety of some of these novel agents when used alone or in combination for the treatment of patients with PNH.

Following these proceedings, featured expert Ronald S. Go, MD, was interviewed by Conference Reporter Medical Director Lauren Weinand, MD. Dr Go’s clinical perspectives on these findings are presented here.

For a disease as rare as PNH, it is remarkable to have so many US Food and Drug Administration (FDA)–approved therapies. There are several agents that are currently available, and several others with novel MOAs targeting different parts of the complement system that are in development. Currently, distal anti-C5 inhibitors are considered the backbone of PNH therapy. The use of distal inhibitors and agents with other MOAs is currently being evaluated both alone and in combination. Again, we are fortunate to have so many drugs available for this rare disease, and we are certainly looking forward to seeing mature data for these available agents and data for newer agents with novel MOAs.

There were several abstracts presented at ASH 2024 that provided data on new and emerging agents for the treatment of patients with PNH. For example, Christopher Patriquin and colleagues presented an abstract on the efficacy and safety of the combination of pozelimab plus cemdisiran vs ravulizumab monotherapy in patients with treatment-naive PNH (abstract 306). Pozelimab is an anti-C5 monoclonal antibody, while cemdisiran is a silencing RNA that reduces levels of circulating C5. The rationale for using this combination is that, by both inactivating and reducing levels of C5, there may be increased efficacy. The downsides of using such a combination are the increased inconvenience of having to take 2 drugs and the potential for increased costs. This study showed that the 2-drug combination resulted in good control of PNH by various parameters, such as hemoglobin and lactate dehydrogenase (LDH), and a slightly higher proportion of patients with near-normal LDH levels. Overall, there was generally similar safety between the 2 regimens, with the exception of headaches tending to be higher with the use of pozelimab plus cemdisiran (28%) compared with ravulizumab (17%). However, the sample size was small, and, hopefully, we will see more data and perhaps get FDA approval in the future.

An open-label, phase 2 study of 13 patients with PNH who had suboptimal response to ravulizumab presented at the recent ASH meeting evaluated the alternative pathway MASP-3 inhibitor zaltenibart (OMS906), which is a different target compared with all other FDA-approved complement inhibitors (abstract 4072). These preliminary results from the patients who received zaltenibart monotherapy showed that there were no new safety signals of concern and that patients with extravascular and intravascular hemolysis had improvements in hemoglobin levels and reticulocyte counts. The study is ongoing, so there will be additional efficacy data coming out in the future.

Another abstract presented at ASH 2024 provided long-term follow-up of the COMMODORE-2 trial, which was a phase 3 trial evaluating the efficacy and safety of crovalimab in treatment-naive patients with PNH (abstract 2687). In this study, Alexander Röth, MD, et al included more than 200 patients, and the data showed that efficacy was maintained over a median of 2 years of follow-up and that there were no new safety signals. In particular, researchers reported mostly mild or moderate and manageable immune complex reactions when patients were switched between eculizumab and crovalimab. This suggests that crovalimab is going to be a strong candidate for another anti-C5 therapy in the first-line treatment of PNH.

Finally, long-term patient-reported outcomes from a study reporting on the use of danicopan as an add-on therapy to ravulizumab or eculizumab were also presented at the recent ASH meeting (abstract 2692). Over 72 weeks of follow-up, patients experienced improvements in patient-reported fatigue, quality of life (QOL), and physical function. Notably, the QOL scores were very close to those that were seen in the general population. Improved QOL is important in real-world practice because we often see patients with near-normal or normal hemoglobin levels but who still do not feel well. This may be due to some residual hemolysis that is still occurring that can result in the release of chemicals, many of which cannot be measured but may potentially impact how a patient feels.

Overall, the advances in drug development for the treatment of PNH seem to parallel the advances in drug development for the treatment of cancer. The first step in treating diseases such as PNH is to reduce the hemolysis, and we have been successful in achieving this with anti-C5 inhibitors. Once patients are not transfusion dependent, we turn to addressing QOL, perhaps by investigating therapies with different MOAs, and such measures are being incorporated into clinical studies. At that point, safety, tolerability, and cost also become important considerations.