Sutimlimab improves the quality of life of patients with cold agglutinin disease

Sutimlimab, is a first-in-class humanised monoclonal anti-C1s antibody that selectively inhibits the C1 complex. In doing so, sutimlimab prevents the complement pathway activation. Previously, results of the phase III CARDINAL trial demonstrated a significantly improved anaemia and a blockage of haemolysis in patients with cold agglutinin disease (CAD). Quality of life results of this trial, demonstrated during EHA 2020, indicate that sutimlimab also provides a rapid and clinically meaningful improvement in all patient-reported outcome measures. As such, these data further support the effectiveness of targeting the classical pathway in the management of patients with CAD.

Background

CAD is a rare autoimmune haemolytic anaemia characterised by the activation of the classical complement pathway (CP) and by extravascular haemolysis. This results in a variety of symptoms, including profound fatigue, anaemia and weakness that may lead to a reduced quality of life (QoL). Sutimlimab is a first-in-class humanised monoclonal anti-C1s antibody that selectively inhibits the C1 complex of complement, preventing CP activation. Recently, results of the pivotal CARDINAL trial demonstrated that sutimlimab stops haemolysis and significantly improves the anaemia in patients with CAD. As a secondary endpoint, the CARDINAL study also looked into the effect of sutimlimab on patient-reported outcomes as a measure of QoL.

Cardinal is an open-label, single-arm study in patients with primary CAD who received at least one blood transfusion within six months prior to the study enrolment. 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 safety extension study.

Results

All patients in the CARDINAL study (N=24) were characterised by abnormal baseline QoL measures consistent with conditions such as cancer and autoimmune disorders. All of them experienced clinically meaningful improvements across all patient-reported outcomes (PROs) after treatment with sutimlimab. At the treatment assessment time point (TAT), 17 out of 24 patients had evaluable FACIT-F values and improvements in this score were observed as of week one and were maintained throughout week 26. The mean FACIT-F score increase was 10.9 (from 32.5 at baseline to 44.3 at the TAT). In total, 88.2% of the patients achieved a clinically meaningful FACIT-F improvement of at least 3-points increase.

In total, 16 patients were evaluable for the 5-level EuroQol 5 dimensions questionnaire (EQ-5D-5L). Among these patients the mean (SD) increases in index and visual analogue scale scores from baseline to week 26 were 0.074 (0.185) and 16.8 (16.9), respectively. Finally, patients showed the greatest improvements in mobility (from 69.5% of patients with no or slight problems at baseline to 82.4% at week 26) and usual activities (52.1% of patients with no or slight problems at baseline to 82.4% at week 26).

The mean increase in the 12-item Short Form Health Survey (SF-12) physical component scores from baseline to week 26 was 5.9 (from 38.7 to 44.6) while the mean increase in SF-12 mental component score from baseline to week 26 was 3.3 points (from 49.8 to 53.1) with clinically meaningful changes already occurring at week 5. Improvements in all these QoL measures were correlated with resolution of haemolysis, with a near-complete inhibition of CP activity, and with a rapid normalization of complement C4. By week 26, the vast majority (93.8%) of patients responded as ‘improved’ on the Patient Global Impression of Change relative to baseline with no patients reporting a worsening. Most patients (88.2%) who completed the Patient Global Impression of Fatigue Severity had mild or moderate fatigue, with no patients reporting severe fatigue. This is a clear improvement from baseline at which point 83.3% of the patients suffered from fatigue, with approximately one third reporting severe fatigue.

Conclusions

The phase III CARDINAL study demonstrated that, in addition to the degree of anaemia, complement cascade activation with subsequent haemolysis 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.

Reference

Röth A, Barcellini W, Anderson Tvedt TH, et al. 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. Presented at EHA 2020; Abstract S333.