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Sustained clinical benefit with sutimlimab in cold agglutinin disease patients with a history of red blood cell transfusion

Sutimlimab is a first-in-class selective anti-C1s classical complement pathway inhibitor. Final 2-year data of the pivotal, phase III CARDINAL study demonstrate that this agent induces a rapid and sustained inhibition of hemolysis, with durable improvements in anaemia and fatigue scores. Furthermore, the treatment was generally well tolerated.


CAD is a rare chronic autoimmune hemolytic anemia characterized by classical complement pathway (CP)-mediated hemolysis. In addition to the red blood cell agglutination-mediated circulatory symptoms, CAD leads to chronic anemia, profound fatigue, chronic hemolysis, and chronic hemolytic crisis. Furthermore, CAD significantly increases the risk for thromboembolic events. Sutimlimab is a first-in-class humanized monoclonal antibody that selectively inhibits C1s of the C1 complex, preventing CP activation, while leaving the alternative and lectin pathways intact. Previously, interim results of the CARDINAL study with a follow-up of 1 year, demonstrated that sutimlimab induces sustained improvements in hemolytic markers and a better quality of life for patients with CAD who received at least 1 blood transfusion in the last 6 months. These findings formed the basis for the FDA to approve this agent for the treatment of patients with CAD, making it the first approved pharmacotherapeutic option in this setting. During the 2022 annual EHA meeting, updated 2-year results of this trial were presented.

Study design

CARDINAL was a phase III, open-label, single-arm study with a 26-week treatment period (Part A) and a 2- year extension (Part B). In this trial, sutimlimab was administered through intravenous infusions on days 0 and 7, followed by bi-weekly dosing. The main efficacy endpoints of CARDINAL included the change from baseline in hemolytic markers, pharmacodynamic (PD) markers and blood transfusions. In addition to this, quality of life (QoL) was assessed using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale. Safety endpoints included the incidence of treatment-emergent adverse event (TEAE) and serious TEAE (TESAE). Patients were eligible for the study if they were 18 years or older, had a confirmed CAD diagnosis and received at least 1 blood cell transfusion in the 6 months preceding study enrollment. Furthermore, they had to have a hemoglobin level of ≤ 10g/dl and have a bilirubin level above the normal reference range.


In total, 24 patients were enrolled in Part A of the study of whom 22 completed Part A and entered Part B. The median age of these patients was 72 years, their mean hemoglobin level was 8.6 g/dl with a mean bilirubin level of 52 mmol/L. The mean fatigue score for patients in the study was 32.4. Sutimlimab induced a rapid and sustained HB increase, with a mean hemoglobin increase of 1.35 g/dl from baseline to week 1. Furthermore, a stable and durable hemoglobin level ≥ 11 g/dl was achieved from week 5 to 131. In addition to this, also the bilirubin levels were durably normalized following treatment with sutimlimab. Importantly, the mean FACIT-Fatigue scores were improved within 1 week and this improvement remained clinically relevant (change ≥ 5) from Week 1–123. Improvements in hemoglobin, bilirubin, and FACIT-Fatigue correlated with normalization of C4 and near-complete inhibition of CP activity. Normalization of mean absolute reticulocyte count was observed alongside normalized haptoglobin levels and reductions in the lactate dehydrogenase level. From week 26–131, two thirds of patients (68.2%) remained transfusion-independent.

All 22 patients in the presented analysis experienced at least one TEAE; with at least 1 TESAE in 54.5% of patients. Serious infections were reported in 7, including one patient developing sepsis due to streptococcus pneumoniae. Three patients discontinued the study due to AEs (cyanosis and klebsiella pneumoniae, vitreous hemorrhage, cyanosis and gastrointestinal symptoms including erosive gastritis). There were no cases of systemic lupus erythematosus, serious hypersensitivity, or anaphylaxis.


Final two-year results from the CARDINAL study show that sutimlimab maintains mean hemoglobin levels > 11g/dL, and achieves sustained normalization of the mean bilirubin, haptoglobin and reticulocyte count. Sutimlimab continued to improve FACIT-Fatigue scores, with no newly identified safety concerns at 2 years of treatment. In conclusion, this study demonstrates that sutimlimab is an effective and well-tolerated long-term therapy for the management of chronic CAD.


A. Röth, et al. Inhinition of complement C1S with sutimlimab in patients with cold agglutinin disease (CAD): 2 year follow-up from the CARDINAL study. Presented at EHA 2022; Abstract S285.

Speaker Alexander Röth

Alexander Röth

Alexander Röth, MD, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany


See: Keyslides


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