• Alexander Röth, Wilma Barcellini, Shirley D'Sa, Yoshitaka Miyakawa, Catherine M Broome, Marc Michel, David J Kuter, Bernd Jilma, Tor H A Tvedt, Joachim Fruebis, Xiaoyu Jiang, Stella Lin, Caroline Reuter, Jaime Morales-Arias, William Hobbs, and Sigbjørn Berentsen.
• From the Department of Hematology and Stem Cell Transplantation, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany (A.R.); Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Cà Granda Ospedale Maggiore Policlinico, Milan, Italy (W.B.); the Centre for Waldenström's Macroglobulinaemia and Related Conditions, University College London Hospitals National Health Service Foundation Trust, London (S.D.); the Thrombosis and Hemostasis Center, Saitama Medical University Hospital, Saitama, Japan (Y.M.); the Division of Hematology, MedStar Georgetown University Hospital, Washington, DC (C.M.B.); the Department of Internal Medicine, Henri-Mondor University Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris-Est Créteil, Créteil, France (M.M.); the Division of Hematology, Massachusetts General Hospital, Harvard Medical School, Boston (D.J.K.), Bioverativ, Cambridge (J.F.), and Sanofi, Waltham (X.J., S.L., C.R., J.M.-A., W.H.) - all in Massachusetts; the Department of Clinical Pharmacology, Medical University of Vienna, Vienna (B.J.); and the Section for Hematology, Department of Medicine, Haukeland University Hospital, Bergen (T.H.A.T.), and the Department of Research and Innovation, Haugesund Hospital, Haugesund (S.B.) - both in Norway.
• N. Engl. J. Med. 2021 Apr 8; 384 (14): 1323-1334.

BackgroundCold agglutinin disease is a rare autoimmune hemolytic anemia characterized by hemolysis that is caused by activation of the classic complement pathway. Sutimlimab, a humanized monoclonal antibody, selectively targets the C1s protein, a C1 complex serine protease responsible for activating this pathway.MethodsWe conducted a 26-week multicenter, open-label, single-group study to assess the efficacy and safety of intravenous sutimlimab in patients with cold agglutinin disease and a recent history of transfusion. The composite primary end point was a normalization of the hemoglobin level to 12 g or more per deciliter or an increase in the hemoglobin level of 2 g or more per deciliter from baseline, without red-cell transfusion or medications prohibited by the protocol.ResultsA total of 24 patients were enrolled and received at least one dose of sutimlimab; 13 patients (54%) met the criteria for the composite primary end point. The least-squares mean increase in hemoglobin level was 2.6 g per deciliter at the time of treatment assessment (weeks 23, 25, and 26). A mean hemoglobin level of more than 11 g per deciliter was maintained in patients from week 3 through the end of the study period. The mean bilirubin levels normalized by week 3. A total of 17 patients (71%) did not receive a transfusion from week 5 through week 26. Clinically meaningful reductions in fatigue were observed by week 1 and were maintained throughout the study. Activity in the classic complement pathway was rapidly inhibited, as assessed by a functional assay. Increased hemoglobin levels, reduced bilirubin levels, and reduced fatigue coincided with inhibition of the classic complement pathway. At least one adverse event occurred during the treatment period in 22 patients (92%). Seven patients (29%) had at least one serious adverse event, none of which were determined by the investigators to be related to sutimlimab. No meningococcal infections occurred.ConclusionsIn patients with cold agglutinin disease who received sutimlimab, selective upstream inhibition of activity in the classic complement pathway rapidly halted hemolysis, increased hemoglobin levels, and reduced fatigue. (Funded by Sanofi; CARDINAL ClinicalTrials.gov number, NCT03347396.).Copyright © 2021 Massachusetts Medical Society.

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