Sutimlimab, a Complement C1s Inhibitor, Improves Quality of Life in Patients with Cold Agglutinin Disease: Patient-Reported Outcomes Results of the Phase 3 Cardinal Study

Introduction

Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia characterized by activation of the classical complement pathway (CP) and extravascular hemolysis, resulting in a variety of symptoms, including profound fatigue, that may lead to a reduced quality of life (QoL). However, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and other QoL measures have not been previously evaluated in CAD. Sutimlimab (formerly BIVV009) is a first-in-class humanized monoclonal anti-C1s antibody that selectively inhibits the C1 complex of complement, preventing CP activation. It has recently been shown to stop hemolysis and significantly improve anemia in CAD. We describe the effect of sutimlimab on patient-reported outcomes (PRO) as a measure of QoL, as assessed in Part A of the Phase 3 Cardinal study (NCT03347396).

Methods

Cardinal is an open-label, single-arm study in patients with CAD. Part A evaluated the efficacy and safety of sutimlimab over 26 weeks. Patients with primary CAD and ≥1 blood transfusion in the prior 6 months were enrolled. Informed consent was provided. Sutimlimab was administered intravenously on Days 0 and 7, and biweekly thereafter. Patients weighing <75 kg or ≥75 kg received a 6.5 g or 7.5 g dose, respectively. Mean change from baseline in fatigue was assessed as a secondary endpoint using the FACIT-F scale at the treatment assessment time point (TAT; defined as the average of the values from Weeks 23, 25, and 26). Mean change from baseline for exploratory endpoints of QoL was assessed using the EuroQol 5-dimension 5-level (EQ-5D-5L) questionnaire and the 12-Item Short Form Health Survey (SF-12). Results were reported using descriptive statistics.

Results

Patients with CAD in this study were characterized by abnormal baseline QoL measures, consistent with conditions such as cancer and autoimmune disorders, and demonstrated clinically meaningful improvements across all PROs measured after treatment with sutimlimab. Of 24 patients enrolled, 17 had evaluable FACIT-F values at the TAT. Improvements in FACIT-F score were observed by Week 1 and were maintained through Week 26. Mean (standard deviation [SD]) FACIT-F scores increased from 32.5 (10.6) at baseline (a score indicative of severe fatigue) to 44.3 (6.5) at the TAT, with an estimated mean (standard error) FACIT-F score increase of 10.9 (1.4). Clinically meaningful FACIT-F improvements (≥3-point increases) were achieved in ≥75% of patients (interquartile range: 5.0–15.5 points). Among the 16 patients evaluable for EQ-5D-5L, the mean (SD) increases in index and visual analog scale scores from baseline to Week 26 were 0.074 (0.185) and 16.8 (16.9), respectively. Mobility and usual activities domains had the greatest improvements. The mean (SD) increases in SF-12 physical and mental component scores from baseline to Week 26 were 5.37 (7.60) and 4.37 (10.02) points (n=16), respectively. Improvements in all these QoL measures correlated with resolution of hemolysis, near-complete inhibition of CP activity, and rapid normalization of complement C4 (Figures 1A and 1B).

Conclusions

The Phase 3 Cardinal study demonstrated that, in addition to the degree of anemia, CP activation with subsequent hemolysis plays a critical role as a driver of fatigue symptoms and poor QoL in patients with CAD. Treatment with sutimlimab, an inhibitor of complement C1s, resulted in rapid, clinically meaningful improvements in all PRO measures evaluated, further supporting the effectiveness of targeting the CP in the management of patients with this condition.