• Alexander Röth, NishimuraJun-IchiJIGraduate School of Medicine, Osaka University, Osaka, Japan., Zsolt Nagy, Julia Gaàl-Weisinger, Jens Panse, Sung-Soo Yoon, Miklos Egyed, Satoshi Ichikawa, Yoshikazu Ito, Jin Seok Kim, Haruhiko Ninomiya, Hubert Schrezenmeier, Simona Sica, Kensuke Usuki, Flore Sicre de Fontbrune, Juliette Soret, Alexandre Sostelly, James Higginson, Andreas Dieckmann, Brittany Gentile, Judith Anzures-Cabrera, Kenji Shinomiya, Gregor Jordan, Marta Biedzka-Sarek, Barbara Klughammer, Angelika Jahreis, Christoph Bucher, and Régis Peffault de Latour.
• Department of Hematology, West German Cancer Center, University Hospital Essen, Essen, Germany.
• Blood. 2020 Mar 19; 135 (12): 912-920.

AbstractComplement C5 inhibition is the standard of care (SoC) for patients with paroxysmal nocturnal hemoglobinuria (PNH) with significant clinical symptoms. Constant and complete suppression of the terminal complement pathway and the high serum concentration of C5 pose challenges to drug development that result in IV-only treatment options. Crovalimab, a sequential monoclonal antibody recycling technology antibody was engineered for extended self-administered subcutaneous dosing of small volumes in diseases amenable for C5 inhibition. A 3-part open-label adaptive phase 1/2 trial was conducted to assess safety, pharmacokinetics, pharmacodynamics, and exploratory efficacy in healthy volunteers (part 1), as well as in complement blockade-naive (part 2) and C5 inhibitor-treated (part 3) PNH patients. Twenty-nine patients were included in part 2 (n = 10) and part 3 (n = 19). Crovalimab concentrations exceeded the prespecified 100-µg/mL level and resulted in complete and sustained terminal complement pathway inhibition in treatment-naive and C5 inhibitor-pretreated PNH patients. Hemolytic activity and free C5 levels were suppressed below clinically relevant thresholds (liposome assay <10 U/mL and <50 ng/mL, respectively). Safety was consistent with the known profile of C5 inhibition. As expected, formation of drug-target-drug complexes was observed in all 19 patients switching to crovalimab, manifesting as transient mild or moderate vasculitic skin reactions in 2 of 19 participants. Both events resolved under continued treatment with crovalimab. Subcutaneous crovalimab (680 mg; 4 mL), administered once every 4 weeks, provides complete and sustained terminal complement pathway inhibition in patients with PNH, warranting further clinical development (ClinicalTrials.gov identifier, NCT03157635).© 2020 by The American Society of Hematology.

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