Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial

Abstract

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 CAD patients 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, 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 three patients (15%) on placebo (odds ratio, 15.9 [95% confidence interval 2.9, 88.0; P<0.001]). 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's phenomenon, and acrocyanosis were more frequent with sutimlimab versus placebo, with a difference of ≥3 patients between groups. Three sutimlimab patients discontinued due to adverse events; no placebo patients discontinued. These data demonstrate that sutimlimab has potential to be an important advancement in the treatment of CAD. (ClinicalTrials.gov: NCT03347422)

The contribution of the alternative pathway in complement activation on cell surfaces depends on the strength of classical pathway initiation

“…Therefore, intervention in the amplification loop may not be an effective therapy for human CP‐mediated diseases such as AIHA, in which complement activation via antibodies is the sole activation route. Treatment of CP‐initiated autoimmune diseases may be most effective when using complement inhibitory drugs targeting the very initiation of the CP, for example by C1‐esterase inhibitor or sutimlimab, 24 both inhibiting the CP protease C1s. 64 , 65 , 66 , 67 Targeting the AP remains relevant in AP‐mediated disease.…”

“… 6 The two complement therapeutics currently available in the clinic block C3 and C5 22 , 23 and thus do not target a specific activation pathway. However, complement therapeutics targeting specific complement activation pathways are emerging, such as the recently approved anti‐C1s sutimlimab, 24 for which a better understanding of the role of the AP in different diseases and contexts will be important. 6 , 11 , 25 , 26 …”

Rise of the planet of rare anemias: An update on emerging treatment strategies

“…Complement modulation is the most promising drug under study for CAD: sutimlimab, a monoclonal antibody against complement protein C1s, demonstrated a short time to response, rapid normalization of hemolysis, and good safety profile in two phase 3 trials ( 41 , 42 ). Results were further updated, demonstrating long-lasting responses while on treatment ( 43 ) and reappearance of hemolysis in most patients discontinuing the drug in an 8 weeks washout periodv ( 44 ).…”

The Importance of C5aR2 in Neutrophil Function and Its Impact on Neutrophil-mediated Diseases

“…The recent FDA approval of several compounds that target the complement system either at the level of the classical pathway (CP) [51,52], the alternative pathway (AP) C3 [53,54], or the terminal pathway C5aR1 [55] and the successful treatment of paroxysmal nocturnal hemoglubinuria (PNH) patients with the terminal pathway inhibiting anti-C5 mAb eculizumab and derivatives [56][57][58] paved the way for an extensive pipeline of new therapeutic inhibitors targeting the complement system at several levels [59][60][61].…”