Sustained improvements in patient-reported outcomes with sutimlimab in patients with cold agglutinin disease

Sutimlimab, is a first-in-class humanised monoclonal anti-C1s antibody that prevents the complement pathway activation. Previously, results of the phase III CARDINAL trial demonstrated significant improvements in anaemia and a blockage of haemolysis in patients with cold agglutinin disease (CAD) treated with sutimlimab. One-year interim follow-up data of this trial demonstrate that continuous classical complement pathway inhibition with sutimlimab results in rapid, sustained and clinically meaningful improvements in all evaluated patient-reported outcome measures.

Cold agglutinin disease (CAD) is a rare, chronic autoimmune haemolytic anaemia mediated entirely by the classical complement pathway (CP) activation. Clinical manifestations of CAD include anaemia, profound fatigue and weakness. In addition, complement-mediated inflammation contributes to the fatigue experienced by patients.  CAD negatively affects the daily activities and the overall physical health of patients with a significant impact on their social life and relations, concentration, memory, and mood. Sutimlimab is a first-in-class humanised monoclonal anti-C1s antibody that selectively inhibits the C1 complex of complement, preventing complement pathway activation. Sutimlimab previously demonstrated to impair haemolysis, improve haemoglobin levels and normalise bilirubin levels in patients with CAD. In CARDINAL (part A), sutimlimab treatment of patients with CAD resulted in rapid, clinically meaningful improvements in patient-reported outcome (PRO) measures up to 26 weeks. At EHA 2021, Prof. Röth presented the effect of sutimlimab on PROs at one year from the ongoing CARDINAL part B extension study.

CARDINAL study design

CARDINAL is a phase III open-label, single-arm study in patients with primary CAD who received at least one blood transfusion within six months prior to the study. In order to be eligible for the study, patients had to have a baseline haemoglobin level of ≤10 g/dL and active haemolysis. In addition, they were not allowed to have received rituximab within three months or combination therapies within six months prior to study initiation. Patients received sutimlimab intravenously on days 0 and 7 and biweekly thereafter. Patients weighing less than 75 kg received doses of 6.5 g while patients with a body weight of at least 75 kg received 7.5 g per dose. Part A of the study evaluated the efficacy and safety of sutimlimab over a timeframe of 26 weeks, while part B is an ongoing two-year safety extension study. Of 24 enrolled patients, 22 patients completed Part A, and all entered Part B.

Improvements in patient-reported outcomes

At baseline, the mean FACIT-fatigue score was 32.5 already improving by 7 points after one week of sutimlimab. Scores reached 40.7 at week 3 and the mean score remained above 40 from week 3 to week 51 onwards. Improvements in FACIT-fatigue scores coincided with positive changes in clinical parameters (haemoglobin and bilirubin) an in markers of classical CP activity. Overall, from baseline to week 51, FACIT-Fatigue score (N=18/22) improved by a  mean (SD) of 11.4 (11.9) points. The mean increase in the 12-item Short Form Health Survey (SF-12) physical component scores from baseline to week 51 was 6.6, while the mean increase in SF-12 mental component score from baseline to week 51 was 3.6 points, with clinically meaningful changes already occurring at week five. Increases in the SF-12 score appear to coincide with reduction in classical CP activity and normalised total C4 level. The mean change from baseline in EQ-5D-5L index and EQ-5D VAS scores improved from baseline to week 51 during sutimlimab treatment (increase of 0.078 for EQ-5D-5L and of 14.5 for EQ-5D VAS) and were considered clinically meaningful. In addition, improvements were seen in each of the five EQ-5D-5L domains and by week 51, no patients reported anxiety or depression. Considerable improvements were also seen in mobility, self-care and usual activities. While one-third of patients reported severe fatigue at baseline, no patients reported severe fatigue at week 51. Furthermore, in the Patient Global Impression of Change, at week 51, 90.5% of patients responded as ‘very much’ or ‘much’ improved relative to baseline, with no patients reporting a response of ‘worse’.

Conclusion

One-year interim follow-up CARDINAL study data demonstrate that continuous classical complement pathway inhibition with sutimlimab results in rapid, sustained and clinically meaningful improvements in all evaluated PRO measures. Classical complement pathway activation with subsequent haemolysis plays a critical role as a driver of fatigue and a poor QoL in patients with CAD. These findings provide further support for continued inhibition of the classical complement pathway at C1s in the management of patients with CAD.

Reference

Röth A, et al. Sustained improvements in patient-reported outcomes with sutimlimab in patients with cold agglutinin disease: 1-year follow-up interim results from the CARDINAL study. Presented at EHA 2021; Abstract S312.