A novel, composite endpoint for patients with paroxysmal nocturnal hemoglobinuria (PNH) appears to effectively evaluate treatment effectiveness, according to research published in the European Journal of Haematology.

PNH, a rare hematologic disorder linked with aplastic anemia, is caused by the terminal complement pathway’s activation. The disorder may cause intravascular hemolysis, thrombosis, organ damage, and possibly death, with up to 23% of patients presenting with PNH requiring hospitalization.

Thrombosis is, in particular, linked with up to 67% of PNH-related deaths, and as many as 43% of patients with PNH experience multiple thrombotic events. The disorder may also lead to symptoms including severe fatigue, abdominal pain, and headache, which may reduce patient quality of life (QoL).

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Although several complement inhibitors have, over the past several decades, been approved for the treatment of PNH, some, including the monoclonal antibody eculizumab, may cause adverse events necessitating treatment reduction or discontinuation.

Because of the many potential clinical variables involved with PNH presentation and treatment, a single clinical endpoint may be insufficient for evaluating therapy effectiveness. For this study, researchers evaluated the benefits of a composite endpoint in determining therapy effectiveness among patients with PNH.

Overall, data from 246 patients, all of whom were complement inhibitor-naïve, were included. Patients received either ravulizumab (125 patients) or eculizumab (121 patients); at baseline, lactate dehydrogenase (LDH) ratios were greater than 3 x ULN in 85.6% and 86.8% of patients, respectively, and the mean serum-free C5 levels were 104.1 and 144.4 μg/mL.

A group of experts selected candidate endpoint variables for the composite; these included LDH levels, which measure intravascular hemolysis, complete terminal complement inhibition, major adverse vascular events or events leading to treatment discontinuation or death, transfusion avoidance, and QoL improvements. The researchers developed a composite variable using these recommendations, and defined thresholds for each candidate endpoint. Only the QoL improvement recommendation was not included in the composite endpoint.

In the ravulizumab and eculizumab arms, 51.2% and 41.3% of patients, respectively, met all thresholds of the composite endpoint. On analysis, the treatment difference was 9.4% (95% CI, -3%-21.5%).

In the ravulizumab group, all patients had complete terminal complement inhibition and reduced lactate dehydrogenase levels.

“This composite endpoint is recommended for use in future PNH research to explore clinical benefit,” the authors wrote. “Furthermore, its use in health technology assessments should be evaluated.”

Disclosure: The study author(s) declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Kulasekararaj A, Glasmacher A, Liu P, et al. Composite endpoint to evaluate complement inhibition therapy in patients with paroxysmal nocturnal hemoglobinuria. Eur J Haematol. Published online January 31, 2022. doi:10.1111/ejh.13746