Sustained inhibition of complement C1s with sutimlimab over 2 years in patients with cold agglutinin disease

Röth, Alexander; Barcellini, Wilma; D’Sa, Shirley; Miyakawa, Yoshitaka; Broome, Catherine; Michel, Marc; Kuter, David J.; Jilma, Bernd; Tvedt, Tor Henrik Anderson; Weitz, Ilene C.; Yoo, Ronnie; Jayawardene, Deepthi; Vagge, Deepthi S; Kralova, Katarina; Shafer, Frank; Wardęcki, Marek; Lee, Michelle; Berentsen, Sigbjørn

doi:10.1002/ajh.26965

Cited by 12 publications

(17 citation statements)

References 25 publications

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“…After completion of the 26-week pivotal phase of the study (part A) in 2019, the 1-year interim in 2020 and the 2-year, long-term extension phase (part B) in 2021, sutimlimab was found to be an effective and well-tolerated therapy. 9 , 13 , 14 …”

Section: Introductionmentioning

confidence: 99%

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Long-term sutimlimab improves quality of life for patients with cold agglutinin disease: CARDINAL 2-year follow-up

et al. 2023

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Cold agglutinin disease (CAD) is a rare form of autoimmune hemolytic anemia with a substantial burden on patient quality of life. CARDINAL (NCT03347396) was a two-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, the focus of this report. Altogether, 22 patients continued from Part A to Part B, majority female (68.2%) with a median (range) age of 71.5 (55-85) years. Throughout treatment, score improvement on the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale exceeded a pre-defined, group-level clinically important change of ≥5 points versus 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 (SE) change 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 versus 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 following long-term treatment with sutimlimab over 2 years, returning towards baseline upon treatment cessation.

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Section: Introductionmentioning

confidence: 99%

“… 9 Sutimlimab treatment had a rapid and sustained effect on Hb levels and hemolytic markers, as well as yielded a clinically meaningful reduction in fatigue (secondary end point), with only mild-to-moderate adverse events assessed as treatment-related. 9 , 13 , 14 …”

Section: Introductionmentioning

confidence: 99%

Long-term sutimlimab improves quality of life for patients with cold agglutinin disease: CARDINAL 2-year follow-up

et al. 2023

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“…Maneuvers include blanketing or maintaining higher ambient room temperatures at 37 • C-40 • C, and if transfusion is required, using a blood warmer. In severe cases of CAS, one may use sutimlimab (anti-C1s) [79][80][81][82][83][84][85][86].…”

Section: Treatmentmentioning

confidence: 99%

Section: Treatmentmentioning

confidence: 99%

“…CAD is a more difficult-to-treat AIHA, as the antibody is usually associated with a chronic disease and the monoclonal antibody produced can cause more severe anemia than in CAS [79][80][81][82][83][84][85][86]. Therefore, treatment can consist of rituximab or anti-complement therapies such as sutimlimab to block the classical complement activation pathway [58,65,[79][80][81][82] or eculizumab to block the membrane attack complex of complement activation pathway [58,78,83,84]. To limit the production of the causal antibody and to diminish the cellular biomass of the driving condition, rituximab with or without strong immunosuppressive drugs such as fludarabine or bendamustine may be prescribed [58,78,83,84].…”

Section: Treatmentmentioning

confidence: 99%

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Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses and Management

Loriamini,

Cserti-Gazdewich,

Branch

2024

IJMS

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: Autoimmune hemolytic anemias (AIHAs) are conditions involving the production of antibodies against one’s own red blood cells (RBCs). These can be primary with unknown cause or secondary (by association with diseases or infections). There are several different categories of AIHAs recognized according to their features in the direct antiglobulin test (DAT). (1) Warm-antibody AIHA (wAIHA) exhibits a pan-reactive IgG autoantibody recognizing a portion of band 3 (wherein the DAT may be positive with IgG, C3d or both). Treatment involves glucocorticoids and steroid-sparing agents and may consider IVIG or monoclonal antibodies to CD20, CD38 or C1q. (2) Cold-antibody AIHA due to IgMs range from cold agglutinin syndrome (CAS) to cold agglutin disease (CAD). These are typically specific to the Ii blood group system, with the former (CAS) being polyclonal and the latter (CAD) being a more severe and monoclonal entity. The DAT in either case is positive only with C3d. Foundationally, the patient is kept warm, though treatment for significant complement-related outcomes may, therefore, capitalize on monoclonal options against C1q or C5. (3) Mixed AIHA, also called combined cold and warm AIHA, has a DAT positive for both IgG and C3d, with treatment approaches inclusive of those appropriate for wAIHA and cold AIHA. (4) Paroxysmal cold hemoglobinuria (PCH), also termed Donath–Landsteiner test-positive AIHA, has a DAT positive only for C3d, driven upstream by a biphasic cold-reactive IgG antibody recruiting complement. Although usually self-remitting, management may consider monoclonal antibodies to C1q or C5. (5) Direct antiglobulin test-negative AIHA (DAT-neg AIHA), due to IgG antibody below detection thresholds in the DAT, or by non-detected IgM or IgA antibodies, is managed as wAIHA. (6) Drug-induced immune hemolytic anemia (DIIHA) appears as wAIHA with DAT IgG and/or C3d. Some cases may resolve after ceasing the instigating drug. (7) Passenger lymphocyte syndrome, found after transplantation, is caused by B-cells transferred from an antigen-negative donor whose antibodies react with a recipient who produces antigen-positive RBCs. This comprehensive review will discuss in detail each of these AIHAs and provide information on diagnosis, pathophysiology and treatment modalities.

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Cost‐effectiveness of sutimlimab in cold agglutinin disease

Ito,

Wang,

Purcell

et al. 2024

American J Hematol

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Primary cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia caused by cold‐reactive antibodies that bind to red blood cells and lead to complement‐mediated hemolysis. Patients with primary CAD experience the burden of increased health resource utilization and reduced quality of life. The standard‐of‐care (SOC) in patients with primary CAD has included cold avoidance, transfusion support, and chemoimmunotherapy. The use of sutimlimab, a humanized monoclonal antibody that selectively inhibits C1‐mediated hemolysis, was shown to reduce transfusion‐dependence and improve quality of life across two pivotal phase 3 studies, further supported by 2‐year extension data. Using data from the transfusion‐dependent patient population that led to sutimlimab's initial FDA approval, we performed the first‐ever cost‐effectiveness analysis in primary CAD. The projected incremental cost‐effectiveness ratio (ICER) in our Markov model was $2 340 000/QALY, significantly above an upper‐end conventional US willingness‐to‐pay threshold of $150 000/QALY. These results are consistent across scenarios of higher body weight and a pan‐refractory SOC patient phenotype (i.e., treated sequentially with bendamustine‐rituximab, bortezomib, ibrutinib, and eculizumab). No parameter variations in deterministic sensitivity analyses changed our conclusion. In probabilistic sensitivity analysis, SOC was favored over sutimlimab in 100% of 10 000 iterations. Exploratory threshold analyses showed that significant price reduction (>80%) or time‐limited treatment (<18 months) followed by lifelong clinical remission off sutimlimab would allow sutimlimab to become cost‐effective. The impact of sutimlimab on health system costs with longer term follow‐up data merits future study and consideration through a distributional cost‐effectiveness framework.

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Sustained inhibition of complement C1s with sutimlimab over 2 years in patients with cold agglutinin disease

Cited by 12 publications

References 25 publications

Long-term sutimlimab improves quality of life for patients with cold agglutinin disease: CARDINAL 2-year follow-up

Long-term sutimlimab improves quality of life for patients with cold agglutinin disease: CARDINAL 2-year follow-up

Autoimmune Hemolytic Anemias: Classifications, Pathophysiology, Diagnoses and Management

Cost‐effectiveness of sutimlimab in cold agglutinin disease

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