P1675: SUTIMLIMAB PROVIDES SUSTAINED IMPROVEMENTS IN PATIENT-REPORTED OUTCOMES AND QUALITY OF LIFE IN PATIENTS WITH COLD AGGLUTININ DISEASE: OPEN-LABEL EXTENSION OF THE PHASE 3 CADENZA STUDY
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SUBMITTER: Roth A
PROVIDER: S-EPMC10430149 | biostudies-literature | 2023 Aug
REPOSITORIES: biostudies-literature
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Project description:BackgroundCold agglutinin disease (CAD) is a rare subtype of autoimmune haemolytic anaemia characterised by classical complement pathway-mediated haemolysis, fatigue, and poor quality of life (QoL). Sutimlimab, a C1s inhibitor, rapidly halted haemolysis, and improved patient-reported outcomes (PROs) in patients with CAD in two phase 3 trials (CARDINAL and CADENZA). Here we report PROs from the CADENZA open-label extension (Part B).MethodsThe first patient was enrolled in CADENZA (NCT03347422) in March 2018 (Part A) and the last patient completed the study in December 2021 (Part B). All patients who completed the 26-week Part A were eligible to receive biweekly doses of sutimlimab in Part B for up to 1 year after the last patient completed Part A. PROs were assessed throughout Part B, until the last on-treatment visit with available assessment (LV), and after a 9-week washout.FindingsIn total, 32/39 patients completed Part B; median Part B treatment duration: 99 weeks. Patients switching from placebo to sutimlimab in Part B experienced rapid improvement in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score and other PROs. Sustained, clinically important improvements in FACIT-Fatigue were observed throughout Part B in patients who switched to sutimlimab and those continuing sutimlimab treatment (combined-group mean [SE] change from baseline at LV: 8.8 [2.1]). Similarly, the combined-group mean [SE] change for 12-Item Short Form Health Survey physical (4.9 [1.7]) and mental (4.0 [1.8]) component scores exceeded clinically important changes from baseline at LV. EuroQol visual analogue scale showed consistent and sustained increases from baseline with sutimlimab treatment. Following a 9-week washout, all PROs approached baseline values.InterpretationContinued inhibition of the classical complement pathway with sutimlimab results in meaningful long-term improvements in PROs (fatigue and QoL) in patients with CAD.FundingSanofi.
| S-EPMC11304688 | biostudies-literature
Project description:Sutimlimab, a first-in-class humanized immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits the classical complement pathway at C1s, rapidly halted hemolysis in the single-arm CARDINAL study in recently transfused patients with cold agglutinin disease (CAD). CADENZA was a 26-week randomized, placebo-controlled phase 3 study to assess safety and efficacy of sutimlimab in patients with CAD without recent (within 6 months prior to enrollment) transfusion history. Forty-two patients with screening hemoglobin ≤10 g/dL, elevated bilirubin, and ≥1 CAD symptom received sutimlimab (n = 22) or placebo (n = 20) on days 0 and 7 and then biweekly. Composite primary endpoint criteria (hemoglobin increase ≥1.5 g/dL at treatment assessment timepoint [mean of weeks 23, 25, 26], avoidance of transfusion, and study-prohibited CAD therapy [weeks 5-26]) were met by 16 patients (73%) on sutimlimab, and 3 patients (15%) on placebo (odds ratio, 15.9 [95% confidence interval, 2.9, 88.0; P < .001]). Sutimlimab, but not placebo, significantly increased mean hemoglobin and FACIT-Fatigue scores at treatment assessment timepoint. Sutimlimab normalized mean bilirubin by week 1. Improvements correlated with near-complete inhibition of the classical complement pathway (2.3% mean activity at week 1) and C4 normalization. Twenty-one (96%) sutimlimab patients and 20 (100%) placebo patients experienced ≥1 treatment-emergent adverse event. Headache, hypertension, rhinitis, Raynaud phenomenon, and acrocyanosis were more frequent with sutimlimab vs placebo, with a difference of ≥3 patients between groups. Three sutimlimab patients discontinued owing to adverse events; no placebo patients discontinued. These data demonstrate that sutimlimab has potential to be an important advancement in the treatment of CAD. This trial was registered at www.clinicaltrials.gov as #NCT03347422.
| S-EPMC9437710 | biostudies-literature
Project description:Cold agglutinin disease (CAD) is a rare autoimmune haemolytic anaemia mediated by the classical complement pathway (CP). Sutimlimab selectively targets complement C1s inhibiting classical CP activation. In CADENZA Part A (26-weeks), a placebo-controlled study in patients without recent transfusion history, sutimlimab reduced haemolysis, anaemia, and fatigue, and was generally well tolerated. The CADENZA study (NCT03347422) started in March 2018 (Part A) and completed in December 2021 (Part B). All patients in Part B were eligible to receive sutimlimab for up to 1 year after the last patient completed Part A. Efficacy and safety was assessed throughout Part B, until the last on-treatment visit with available assessment (LV), and after a 9-week washout. In total, 32/39 patients completed Part B; median treatment duration: 99 weeks. Similar sustained improvements in haemolysis, anaemia, and quality of life were observed in patients switching to sutimlimab and those continuing sutimlimab. Mean LV values for the combined group (ie, placebo-to-sutimlimab group and sutimlimab-to-sutimlimab group) improved from baseline for haemoglobin (≥11.0 g/dL on-treatment vs 9.3 g/dL at baseline), bilirubin (≤20.0 μmol/L on-treatment vs 35.0 μmol/L at baseline), and FACIT-Fatigue scores. Following a 9-week washout, inhibition of CP activity was reversed, and haemolytic markers approached baseline levels. Overall, sutimlimab was generally well tolerated throughout the study. No patients developed systemic lupus erythematosus or meningococcal infections. During the 9-week washout, most adverse events could be attributed to recurrence of underlying CAD. The CADENZA Part B results support the sustained efficacy and safety of sutimlimab for treatment of CAD; however, upon discontinuation disease activity reoccurs. Sanofi.
| S-EPMC11293518 | biostudies-literature
Project description: Not available
| S-EPMC10189382 | biostudies-literature
Project description:Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia and a bone marrow clonal lymphoproliferative disorder. Hemolysis in CAD is complement-dependent and mediated by the classical activation pathway. Patients also frequently suffer from fatigue and cold-induced circulatory symptoms. Although not all patients need treatment, the symptom burden has previously been underestimated. Effective therapies target the clonal lymphoproliferation or the complement activation. Sutimlimab, a humanized monoclonal IgG4 antibody that binds and inactivates complement protein C1s, is the most extensively investigated complement inhibitor for the treatment of CAD. This review addresses the preclinical studies of sutimlimab and the studies of pharmacokinetics and pharmacodynamics. We then describe and discuss the prospective clinical trials that established sutimlimab as a rapidly acting, highly efficacious, and low-toxic therapeutic agent. This complement inhibitor does not improve the cold-induced circulatory symptoms, which are not complement-mediated. Sutimlimab is approved for the treatment of CAD in the US, Japan, and the European Union. A tentative therapeutic algorithm is presented. The choice of therapy for CAD should be based on an individual assessment, and patients requiring therapy should be considered for inclusion in clinical trials.
| S-EPMC10155901 | biostudies-literature
Project description:Patients with cold agglutinin disease (CAD) experience fatigue and poor quality of life. However, previous CAD-related studies have not explored patient-reported outcomes such as the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue. Sutimlimab, a C1s complement inhibitor, has been shown to halt haemolysis in CAD. Here, we present 26-weeks' patient-reported data from CARDINAL Part A (ClinicalTrials.gov, NCT03347396), which assessed efficacy and safety of sutimlimab in patients with CAD and recent history of transfusion. Aside from measuring changes in haemolytic markers, FACIT-Fatigue was measured at the treatment assessment timepoint (TAT; average of weeks 23, 25, and 26). Exploratory endpoints included the change in EuroQol 5-dimension 5-level questionnaire (EQ-5D-5L) and the 12-Item Short Form Health Survey (SF-12) at TAT, and Patient Global Impression of Change (PGIC), and Patient Global Impression of (fatigue) Severity (PGIS) at week 26. Mean (range) FACIT-Fatigue scores increased from 32.5 (14.0-47.0) at baseline (a score indicative of severe fatigue) to 44.3 (28.0-51.0) at TAT. Considerable improvements were reported for EQ-5D-5L at TAT, SF-12 scores at TAT, and PGIC and PGIS scores at week 26. Sutimlimab treatment resulted in sustained improvements in symptoms of fatigue and overall quality of life in patients with CAD. NCT03347396. Registered 20 November, 2017.
| S-EPMC9463238 | biostudies-literature
Project description:Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia with a substantial burden on patient's quality of life. CARDINAL was a 2-part, open-label, single-arm, multicenter phase 3 study evaluating the C1s inhibitor, sutimlimab, for treatment of CAD. Part A consisted of the pivotal study phase, with the part B extension phase assessing long-term safety and durability of response including patient-reported outcomes, which is the focus of this report. Altogether, 22 patients continued from part A to part B, majority female (68.2%) with a median age of 71.5 years (range, 55-85). Throughout treatment, score improvement on the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale exceeded a predefined, group-level clinically important change of ≥5 points vs baseline, with a mean (standard error [SE]) change of 11.7 (3.7) points at week 135. The 12-Item Short Form Health Survey physical and mental component scores remained above baseline, with week 123 mean change (SE) exceeding clinically important changes of 3.9 for physical and 2.8 for mental component scores at 4.7 (2.8) and 3.8 (5.7) points, respectively. EuroQol Visual Analogue Scale, scoring patients' self-rated health, also remained above baseline with a change of 17.1 (5.6) points at week 135. Patient Global Impression of (fatigue) Severity improved vs baseline, corroborating FACIT-Fatigue scores. Patient Global Impression of Change indicated a reduction in perceived disease burden. Data from CARDINAL part B support sustained alleviation of CAD disease burden after long-term treatment with sutimlimab over 2 years, returning toward baseline upon treatment cessation. This trial was registered at www.clinicaltrials.gov as #NCT03347396.
| S-EPMC10558612 | biostudies-literature
Project description:Cold agglutinin disease (CAD) is a complement-dependent disorder, with extravascular and intravascular hemolysis resulting from initial or terminal complement activation, respectively. We tested the efficacy and safety of eculizumab, an inhibitor of the terminal complement pathway. Treatment-requiring patients received 600 mg eculizumab weekly for 4 weeks, followed 1 week later by 900 mg every other week through week 26. The primary end point was the difference in the lactate dehydrogenase level between the first and the last day of therapy. Twelve patients with chronic CAD and 1 patient with an acute cold agglutinin syndrome were included. The median lactate dehydrogenase level decreased from 572 U/L (interquartile range [IQR], 534-685) to 334 U/L (IQR, 243-567; P = .0215), paralleled by an increase in hemoglobin from 9.35 g/dL (IQR, 8.80-10.80) to 10.15 g/dL (IQR, 9.00-11.35; P = .0391; Wilcoxon signed-rank test). Three patients maintained and 8 patients acquired transfusion independence, and 1 patient each showed a reduced or increased transfusion requirement, respectively (P = .0215; exact McNemar's test). Patients with cold agglutinins with a thermal amplitude of 37°C tended to have less pronounced lactate dehydrogenase responses than patients with cold agglutinins with narrower thermal amplitudes. In the latter, responses were observed at lower serum levels of eculizumab than they were in the former. In contrast to hemolysis, cold-induced circulatory symptoms remained unaffected. In conclusion, eculizumab significantly reduced hemolysis and transfusion requirement in patients with CAD. Suppression of hemolysis caused by cold agglutinins with a wide thermal amplitude may require higher eculizumab doses than used here. The trial is registered with EudraCT (#2009-016966-97) and www.clinicaltrials.gov (#NCT01303952).
| S-EPMC6177646 | biostudies-literature
Project description: Not available
| S-EPMC9001000 | biostudies-literature
Project description:Primary chronic cold agglutinin disease (CAD) is a well-defined clinicopathologic entity in which a specific, clonal lymphoproliferative B-cell bone marrow disorder results in autoimmune hemolytic anemia. The immune hemolysis is entirely complement-dependent, predominantly mediated by activation of the classical pathway and phagocytosis of erythrocytes opsonized with complement protein C3b. Typical clinical features in CAD have diagnostic and therapeutic implications. Pharmacologic treatment should be offered to patients with symptom-producing anemia or disabling circulatory symptoms. CAD should not be treated with corticosteroids. Based on an individualized approach, rituximab monotherapy or rituximab-fludarabine in combination is recommended as first-line therapy. Rituximab-bendamustine is still an investigational therapy. Although complement-modulating agents are still to be considered experimental in CAD, therapy with the anti-C1s monoclonal antibody TNT009 seems promising.
| S-EPMC6142439 | biostudies-other