Sutimlimab in Patients with Cold Agglutinin Disease: Results of the Randomized Placebo-controlled Phase 3 CADENZA Trial

Author(s): Alexander Röth1,Sigbjørn Berentsen2,Wilma Barcellini3,Shirley D’Sa4,Bernd Jilma5,Marc Michel6,Ilene C. Weitz7,Masaki Yamaguchi8,Jun-ichi Nishimura9,Josephine M. I. Vos10,Michael Storek11,Nancy Wong11,Parija Patel11,Xiaoyu Jiang11,Deepthi S. Vagge12,Marek Wardęcki13,Frank Shafer11,Michelle Lee11,Catherine M. Broome14
Lucio Gordan MD

Very well-tolerated therapy with impressive clinical and laboratorial improvement of this uncommon disease process.


Sutimlimab, a first-in-class humanized immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits the classical complement pathway at C1s, rapidly halted hemolysis in the single-arm CARDINAL study in recently transfused patients with cold agglutinin disease (CAD). CADENZA was a 26-week randomized, placebo-controlled phase 3 study to assess safety and efficacy of sutimlimab in patients with CAD without recent (within 6 months prior to enrollment) transfusion history. Forty-two patients with screening hemoglobin ≤10 g/dL, elevated bilirubin, and ≥1 CAD symptom received sutimlimab (n = 22) or placebo (n = 20) on days 0 and 7 and then biweekly. Composite primary endpoint criteria (hemoglobin increase ≥1.5 g/dL at treatment assessment timepoint [mean of weeks 23, 25, 26], avoidance of transfusion, and study-prohibited CAD therapy [weeks 5-26]) were met by 16 patients (73%) on sutimlimab, and 3 patients (15%) on placebo (odds ratio, 15.9 [95% confidence interval, 2.9, 88.0; P < .001]). Sutimlimab, but not placebo, significantly increased mean hemoglobin and FACIT-Fatigue scores at treatment assessment timepoint. Sutimlimab normalized mean bilirubin by week 1. Improvements correlated with near-complete inhibition of the classical complement pathway (2.3% mean activity at week 1) and C4 normalization. Twenty-one (96%) sutimlimab patients and 20 (100%) placebo patients experienced ≥1 treatment-emergent adverse event. Headache, hypertension, rhinitis, Raynaud phenomenon, and acrocyanosis were more frequent with sutimlimab vs placebo, with a difference of ≥3 patients between groups. Three sutimlimab patients discontinued owing to adverse events; no placebo patients discontinued. These data demonstrate that sutimlimab has potential to be an important advancement in the treatment of CAD. This trial was registered at as #NCT03347422.

Author Affiliations

1Department of Hematology and Stem Cell Transplantation, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany;2Department of Research and Innovation, Haugesund Hospital, Haugesund, Norway;3Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy;4UCLH Centre for Waldenström’s Macroglobulinemia and Related Conditions, University College London Hospitals National Health Service (NHS) Foundation Trust, London, United Kingdom;5Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria;6Henri-Mondor University Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Est Créteil (UPEC), Créteil, France;7Jane Anne Nohl Division of Hematology Keck-University of Southern California (USC) School of Medicine, Los Angeles, CA;8Department of Hematology, Ishikawa Prefectural Central Hospital, Kanazawa, Japan;9Department of Hematology and Oncology, Osaka University Graduate School of Medicine, Osaka, Japan;10Department of Hematology, Amsterdam University Medical Centers (UMC) & Sanquin, Amsterdam, The Netherlands;11Sanofi, Cambridge, MA;12IQVIA, Bangalore, Karnataka, India;13Sanofi, Warsaw, Poland; and14Division of Hematology, MedStarGeorgetown University Hospital, Washington, DC

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