Sutimlimab improves outcomes in patients with cold agglutinin disease

Cold agglutinin disease (CAD) is a rare autoimmune disorder characterized by the premature destruction of red blood cells (hemolysis). Given the central role of the complement system in the CAD pathogenesis, C1s complement inhibitors have been evaluated in the treatment of CAD. In this respect, results of the first part of the CADENZA trial showed that sutimlimab is effective in the treatment of CAD, but long-term data with this agent were lacking. During ASH 2022, data were presented for phase II of this trial, demonstrating a significant improvement in fatigue and quality of life (QoL) in CAD up to one year after the start of sutimlimab.

Background

CAD is a rare chronic autoimmune hemolytic anemia that is mediated by classical complement pathway activation, leading to fatigue and a poor QoL. In part A of the randomized, double-blind, placebo-controlled, Phase 3 CADENZA trial (NCT03347422), the C1s complement inhibitor sutimlimab rapidly halted hemolysis and increased hemoglobin levels in CAD patients without a recent history of transfusion. This resulted in improvements in the fatigue of patients and led to rapid improvements in patient-reported outcomes (PROs) up to 26 weeks. During ASH 2022, data were presented on the long-term effect of sutimlimab on PROs in patients with CAD treated in the open-label Part B extension of CADENZA.

Study design

In the open-label extension Part B of CADENZA, all patients who had completed Part A were eligible to receive biweekly doses of sutimlimab at 6.5 g (if <75 kg) or 7.5 g (if ≥75 kg), until 1 year after the last patient completed Part A. PRO endpoints included Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), 12-Item Short Form Health Survey (SF-12), EuroQol visual analogue scale (EQ-VAS), Patient Global Impression of Change from baseline (PGIC), and Patient Global Impression of fatigue Severity (PGIS).

Results

In total, 42 patients were enrolled in Part A of the study of whom 39 entered Part B. Of these 39 patients, 32 (82.1%) completed Part B. Patients randomized to sutimlimab in Part A showed a clinically meaningful improvement in FACIT-Fatigue mean score over baseline that exceeded the clinically important change (CIC) of 5 points by Week 1, a benefit that was sustained throughout Week 87 (N=13). Patients who were randomized to placebo in Part A (ex-placebo) and switched to sutimlimab demonstrated rapid improvements in their FACIT-Fatigue scores. In this group, the mean change from baseline in FACIT-Fatigue score was 7.96 points 13 weeks after sutimlimab initiation. Importantly, mean improvements were sustained above CIC for over one year from completion of Part A. Improvements in the physical (PCS) and mental (MCS) component scores of the SF-12 in patients receiving sutimlimab in Part A were also considered to be above the CICs, determined as changes above 3.9 and 2.8 points respectively. Importantly, the improvements from baseline above CIC were sustained in the PCS throughout 87 weeks in all patients in Part B. In Part B of the study, the MCS remained above CIC for all patients treated with sutimlimab in Part A. Improvements in MCS among patients from the ex-placebo group proved to be consistently improved from baseline and exceeded CIC at Week 75. The mean changes in PCS and MCS from baseline for all patients at 87 weeks were 7.2 and 3.93, respectively. Furthermore, EQ VAS showed a consistent increase from baseline in all patients with a mean change from baseline at Week 87 of 15.57 points. Finally, the PGIC remained positive throughout the treatment period, with 93.3% of patients still reporting improvements from baseline by week 87. Overall, 46.7% of patients reported no or mild fatigue at baseline, while this increased to 78.6% at Week 87.

Conclusions

Results of part B of the CADENZA study underscore that sutimlimab induces a durable long-term improvement in the QoL of patients with CAD. These findings demonstrate that continued inhibition of the classical complement pathway with sutimlimab results in meaningful long-term improvement in fatigue and patient-reported QoL, in addition to improving hematologic parameters in patients with CAD.

Reference

Roeth A, et al. Sutimlimab provides sustained improvements in patient-reported outcomes and quality of life in patients with cold agglutinin disease: Open-label extension of the randomized, phase 3 Cadenza study. Gepresenteerd tijdens ASH 2022; abstract 31.