P1469: inhibition of complement c1s with sutimlimab in patients with cold agglutinin disease (cad): results following 9-week off-treatment period (washout) in the phase 3 cadenza study

Topic: 28. Enzymopathies, membranopathies and other anemias Background: CAD is a rare, chronic autoimmune hemolytic anemia characterized by classical complement pathway (CP)-mediated hemolysis. Sutimlimab (SUT) is a first-in-class, humanized, monoclonal antibody that selectively inhibits C1s, preventing CP activation. Throughout the CADENZA study (NCT03347422), treatment with SUT resulted in sustained improvements in anemia, hemolytic markers, and quality of life (QoL) in patients (pts) with CAD and no recent history of transfusion (≤1 during the previous 12 months; 0 during the last 6 months). Aims: To report results from the follow-up visit 9 weeks after last SUT dose in the Phase 3 CADENZA study. Methods: In CADENZA Part A, eligible pts (n=42) were randomized 1:1 to receive intravenous SUT or placebo on Days 0 and 7, followed by biweekly dosing through Week 25. All pts completing Part A were eligible to enter the Part B open-label extension study and receive biweekly SUT, continuing until 1 year after the last pt had completed Part A. Following the last SUT dose, all pts were assessed at a 9-week follow-up visit (early termination/safety follow-up [ET/SFU]). Efficacy measures included hemoglobin (Hb) levels, hemolytic/pharmacodynamic markers, transfusion requirements and the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale. Safety endpoints included incidence of adverse events (AEs) and serious AEs occurring during the 9-week follow up period. Descriptive statistics, frequency, or percentage were used to analyze outcomes. Results: Of 39 pts enrolled in Part B, 32 (82%) completed the treatment period and 37 (95%) were assessed during the 9-week follow-up period (6 pts with ET data). Mean (standard error [SE]) Hb was 11.58 (0.33) g/dL (n=39) at the last-available visit on SUT treatment (LV; last non-missing value in Part B) compared with 9.26 (0.15) g/dL (n=39) at baseline (BL); mean Hb at ET/SFU was 9.46 (0.33) g/dL (n=35). Mean (SE) total bilirubin was 17.31 (2.77) µmol/L (n=36) at LV vs 35.04 (1.95) µmol/L (n=35) at BL, and 36.78 (3.09) µmol/L at ET/SFU (n=34). Mean (SE) FACIT-Fatigue score was 41.71 (1.66, n=39) at LV vs 32.96 (1.79, n=39) at BL, and 31.29 (2.28, n=37) at ET/SFU. Absolute reticulocyte count saw sustained reductions during the treatment period; at ET/SFU, values approached BL levels. Decreases in mean lactate dehydrogenase were modest and observed inconsistently during the Part B treatment period. Upon starting SUT treatment, total C4 was consistently increased until cessation of treatment, returning towards BL at ET/SFU. The near-complete inhibition of Wieslab-CP activity observed with SUT treatment was reversed at ET/SFU. Six of nine pts receiving transfusions in Part B received them after the last dose of SUT. During the 9-week post-treatment follow-up period, 16 (41.0%) pts experienced a total of 55 AEs. One event was assessed as related to SUT by the investigator (Grade 2 upper respiratory tract infection). There were no thromboembolic events. Most AEs in the off-treatment period could be attributed to worsening of underlying CAD; fatigue (10 [25.6%]) pts), anemia (7 [17.9%] pts), dyspnea (4 [10.3%] pts), asthenia and hemoglobinuria (3 [7.7%] pts, each) and Raynaud’s phenomenon (1 [2.6%] pts). Summary/Conclusion: After 9 weeks of post-treatment follow-up in the CADENZA trial, mean levels of hemolytic markers, Hb and QoL scores approached pre-SUT values. These results highlight the importance of continuous therapy in pts treated with SUT for CAD. Figure:Keywords: Hemolysis, Complement, Hemoglobin, Autoimmune hemolytic anemia (AIHA)