Sustained Complement C1s Inhibition with Sutimlimab in Patients with Cold Agglutinin Disease Results in Continued Efficacy during Part B of the Randomized Placebo-Controlled Phase 3 Cadenza Study (NCT03347422)

Background: Cold agglutinin disease (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 prevents CP activation by selectively inhibiting C1s; both the alternative and lectin pathways remain intact. In the randomized, double-blind, placebo-controlled Part A (26 weeks) of Phase 3 CADENZA, SUT treatment resulted in rapid and sustained improvements in hemoglobin (Hb), hemolytic markers and quality of life (QoL).

Aims: To report the long-term safety and efficacy of SUT treatment in patients with CAD from the open-label Part B extension of CADENZA.

Methods: In Part A, eligible patients with CAD without a history of recent blood transfusion (≤1 during previous 12 months; 0 during last 6 months), received SUT or placebo (PBO) through intravenous infusions on Days 0 and 7, then biweekly. All patients completing Part A were eligible to enter Part B and receive biweekly SUT for ≥1 year after the last patient completed Part A. Efficacy data up to Week 79 as well as the last available patients' values are reported. Efficacy endpoints included change from baseline (BL) in Hb, hemolytic and pharmacodynamic markers, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue, and blood transfusions. Safety data was recorded throughout the study; treatment emergent adverse event (TEAE) and serious TEAE (TESAE).

Results: Of the 42 patients enrolled in Part A, 39 completed Part A and entered Part B, with 32 (82.1%) completing Part B; 7 (17.9%) patients discontinued the study prematurely, due to TESAE (n=1), lack of efficacy (n=3), withdrawal of consent (n=2) and withdrawal by sponsor (n=1). SUT treatment rapidly improved Hb levels; mean (SE) Hb at the end of Part A was 11.51 (0.40) g/dL and 9.43 (0.40) g/dL for SUT and PBO groups, respectively. In Part B, improvements in Hb were sustained in the SUT group and the ex-PBO group saw rapid and comparable increases in Hb upon initiation of SUT; at Week 79 mean (SE) Hb levels were 11.86 (0.54) g/dL and 11.76 (0.58) g/dL in the SUT only and ex-PBO groups, respectively (Panel A). Mean total bilirubin was normalized with SUT treatment in Part A and sustained in Part B; similar decreases were observed for patients in the ex-PBO group when they started receiving SUT in Part B (Panel B). Improvements in mean [SE] FACIT-Fatigue scores (BL: 32.96 [1.79]) observed in Part A were sustained in Part B in the SUT only group (44.31 [2.19] at Week 87); the mean FACIT-Fatigue score increased to comparable levels in the ex-PBO group (41.40 [2.71] at Week 87). Improvements in Hb, bilirubin, and FACIT-Fatigue correlated with normalization of C4 and near-complete inhibition of CP activity, that was maintained through the end of treatment. Reductions in mean absolute reticulocyte count and increases in haptoglobin levels observed with SUT treatment in Part A were maintained in Part B, and upon initiation of SUT in Part B, the ex-PBO group reached comparable levels. In Part B, 9 (23.1%) patients received a ≥1 transfusion. Thirty-six (92.3%) patients experienced ≥1 TEAE in Part B. Seven (17.9%) patients experienced a total of 11 TESAEs; one TESAE of hypertension was assessed as related to SUT by the investigator. Thromboembolic events (transient ischemic attack [n=1]; deep vein thrombosis [n=1]) were observed in 2 (5.1%) patients with underlying risk factors for thromboembolism. Both events were assessed as non-serious and unrelated to SUT by the Investigator. One TESAE of infection (urinary tract infection Grade ≥3) was reported. No meningococcal infections, serious events of hypersensitivity, anaphylaxis or systemic lupus erythematosus were reported. One patient with a history of tobacco use (received PBO in Part A) experienced a TESAE of squamous cell carcinoma of the lung with fatal outcome. SUT was withdrawn due to this TESAE prior to the patient's death.

Conclusion: Long-term treatment with SUT, an anti-C1s CP inhibitor, maintained mean Hb levels >11 g/dL, achieved sustained normalization of bilirubin and led to clinically meaningful improvements of FACIT-Fatigue scores, while maintaining a favourable safety profile. Improvements in anemia, inhibition of hemolysis and favourable effects on QoL were rapidly achieved and sustained to a similar extent in those patients administered SUT throughout the study and those who switched to SUT treatment in Part B.

Roeth:Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Biocryst: Consultancy, Honoraria; Apellis Pharmaceuticals: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Alexion Pharmaceuticals: Consultancy, Honoraria, Research Funding. Berentsen:Mundipharma: Research Funding; Sobi: Consultancy; True North Therapeutics: Consultancy; Sanofi: Consultancy, Honoraria; Apellis Pharmaceuticals: Consultancy, Honoraria; Alexion Pharmaceuticals, Inc.: Honoraria; Bioverativ: Consultancy, Honoraria; Janssen-Cilag: Honoraria. Barcellini:Momenta: Honoraria; Agios: Honoraria, Research Funding; Alexion: Honoraria; Apellis: Honoraria; Biocryst: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Novartis: Honoraria; SOBI: Honoraria; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Speakers Bureau. D'Sa:Sanofi: Honoraria, Other: conference expenses. Jilma:Sanofi: Consultancy, Honoraria, Other: travel costs and lectures. Michel:Novartis: Other: Boards, speaker at educational sessions; argenx: Other: Boards, speaker at educational sessions; Sobi: Other: Boards, speaker at educational sessions; UCB: Other: Boards, speaker at educational sessions; Amgen: Other: Boards, speaker at educational sessions. Nishimura:Sanofi: Consultancy; Alexion: Consultancy; Roche: Consultancy, Patents & Royalties; Chugai: Consultancy, Patents & Royalties; Novartis: Consultancy; Sobi: Consultancy; Biocryst: Consultancy. Vos:Sanofi: Consultancy; Beigene: Research Funding; Celgene: Other: Travel support. Cid:Pharm-Olam: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MacoPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Grifols: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Fresenius Kabi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kawasumi Laboratories: Research Funding; Cerus: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; TerumoBCT: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Storek:Sanofi: Current Employment, Current holder of stock options in a privately-held company. Wong:Sanofi: Current Employment. Yoo:Sanofi: Current Employment, Current holder of stock options in a privately-held company. Wang:Sanofi: Current Employment. Vagge:IQVIA: Other: employee of IQVIA, provided support under contract to Sanofi. Wardecki:Sanofi: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: Planned filing of patent application concerning sutimlimab. Shafer:Sanofi: Current Employment. Lee:Sanofi: Current Employment. Broome:Sanofi: Honoraria, Other: Participation on a Data Safety Monitoring Board or Advisory Board , Research Funding; Alexion: Other: Participation on a Data Safety Monitoring Board or Advisory Board, Speakers Bureau; Argenx: Other: Participation on a Data Safety Monitoring Board or Advisory Board, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Rigel: Research Funding.