Hematologic outcomes are the primary measure of therapeutic efficacy in clinical trials that are evaluating treatments for paroxysmal nocturnal hemoglobinuria (PNH). Ronald S. Go, MD, discusses various hematologic outcomes and their importance, reporting on recent data from several phase 3 trials presented at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition.

Following these presentations, featured expert Ronald S. Go, MD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Dr Go’s clinical perspectives on these findings are presented here.

The good thing about PNH is that some of the hematologic laboratory values correlate with patient symptoms and even quality of life. Most trials measure hemoglobin levels and the resolution of anemia by the avoidance of transfusions, which are very important outcomes. Secondary hematologic outcomes are surrogate markers such as lactate dehydrogenase (LDH), haptoglobin, and reticulocyte count. Patients with PNH may continue to have low levels of haptoglobin, meaning that low-grade hemolysis is going on in the background, and LDH may be mildly elevated; however, such patients can live almost near-normal lives if their hemoglobin levels are back to normal.

Other hematologic outcomes besides laboratory measures include complications such as thrombosis, aplastic anemia, and transformation to malignancy, but it is difficult to show differences in outcomes without long-term follow-up. We do not know if complement inhibitors will prevent or minimize these complications. These drugs stop the hemolysis but not the underlying problem in PNH (ie, the PNH clone is still there). Finally, many clinical trials have quality-of-life fatigue scores built in, and these are certainly a very important end point.

Several studies presented at ASH 2023 reported the long-term safety and efficacy of complement inhibitors. For example, a long-term follow-up of patients from the phase 3 study 301 evaluating ravulizumab showed that the agent is effective over time, meaning that its effects are long-lasting and that people rarely develop breakthrough hemolysis or become resistant to therapy (abstract 2714). These findings confirm that patients achieve durable hematologic remission with ravulizumab, and they confirm its safety because it works long-term.

Long-term efficacy and safety data were also reported with pegcetacoplan from the phase 3 PEGASUS and PRINCE trials and the open-label extension study 307, with follow-up of up to 3 years (abstract 574). Efficacy and safety were similar to that described in previous reports, and a discontinuation rate of approximately 13% was also reported. People were able to tolerate the pegcetacoplan.

In addition, final 48-week data from the phase 3 APPLY-PNH trial with oral iptacopan were also presented at ASH 2023 (abstract 571). The benefits with iptacopan therapy started quickly, so it is a fast-acting agent; remissions were durable; and thrombotic complications were uncommon.

The risk of thrombosis is low with both C5 and C3 inhibitor therapy, and trials have not shown that one class is better than the other in terms of reducing thrombosis. Since PNH is rare, trials may not be powered because they have so few patients participating. Proximal complement inhibition with a factor B or C3 inhibitor could have an advantage because these agents can block extravascular hemolysis in the spleen, whereas C5 inhibitors cannot. Whether that translates into better thrombosis prevention is still unclear.