P1486: serum biomarkers as predictors of response to sutimlimab in cold agglutinin disease (cad): a post-hoc analysis of phase 3 cardinal and cadenza study data

Topic: 28. Enzymopathies, membranopathies and other anemias Background: Cold agglutinin disease (CAD) is a rare, chronic autoimmune hemolytic anemia characterized by hemolysis from immunoglobulin M (IgM)-induced classical complement pathway activation. Sutimlimab, a first-in-class, humanized, monoclonal antibody selectively inhibits C1s of the C1 complex, thereby preventing classical complement pathway activation; sutimlimab is currently approved for use in the EU, Japan, and USA. The Phase 3 CARDINAL (NCT03347396) and CADENZA (NCT03347422) studies demonstrated that sutimlimab results in sustained improvements in anemia, hemolytic markers, and quality of life in patients with CAD; CARDINAL assessed patients with a recent history of transfusion (≥1 in the last 6 months), while CADENZA investigated patients with no recent history of transfusion (≤1 during the last 12 months, 0 during the last 6 months). Aims: This study assesses if baseline serum markers are associated with response as defined by the primary endpoints of the CARDINAL and CADENZA studies. Methods: All patients who received sutimlimab during Part A (26 weeks) of the CARDINAL (n=22) and CADENZA (n=19) trials were included in this combined analysis. Serum markers collected at baseline were evaluated for predicting responder status. Patients were classified as either responders or non-responders based on whether they met the primary endpoint criteria defined by the clinical trial. For a patient to be a responder in the CARDINAL trial, a hemoglobin (Hb) increase ≥2.0 g/dL from baseline at the treatment assessment timepoint (TAT; defined as the mean value from Weeks 23, 25, and 26) or Hb level ≥12.0 g/dL at TAT was required. For the CADENZA trial, a Hb increase ≥1.5 g/dL from baseline at TAT was required. Other mandatory conditions for both clinical trials for responder status were: no blood transfusion from Week 5 through Week 26, and no treatment for CAD beyond what was permitted per protocol. Descriptive statistics, frequency, or percentage were used to analyze outcomes. Results: Of the 41 patients included in the analysis, 29 (70.7%) were classified as responders (n=13 CARDINAL; n=16 CADENZA). The mean age (standard deviation [SD]) of responders (67.0 [9.9] years) was significantly lower than non-responders (74.3 [7.3] years; p-value=0.0262). No significant differences were noted for ethnicity, race, sex, geographic location, or body mass index. The median (range) reticulocyte count in responders (164.9 [28–301] 109/L) was significantly higher at baseline than in non-responders (102.0 [4–185] 109/L; p-value=0.0055). Significant differences in the median (range) reticulocyte index (semi-quantitative index of the adequacy of bone marrow response to anemia) between responders (4.7 [1–9]) and non-responders (2.6 [1–5]; p-value=0.0091) were also observed. Lower levels of median (range) IgM antibodies were noted in responders (2.37 [0.5–22.4 g/L]) compared with non-responders (6.22 [1.2–12.4] g/L; p-value=0.0080); upper limit of normal for IgM was 3.0 g/L. No significant differences in bilirubin, C4, CAD titer, erythropoietin, ferritin, Functional Assessment of Chronic Illness Therapy – Fatigue, haptoglobin, hemoglobin, lactate dehydrogenase, or total iron-binding capacity were noted at baseline between responders and non-responders. Summary/Conclusion: Post hoc analysis of Phase 3 trial data suggests that predictive serum biomarkers for sutimlimab response in patients with CAD may exist (such as reticulocyte count, reticulocyte index and IgM levels) and should be explored further. Figure:Keywords: Hemoglobin, Complement, Autoimmune hemolytic anemia (AIHA), Hemolysis