Inhibition of Complement C1s with Sutimlimab in Patients with Cold Agglutinin Disease (CAD): Interim Results of the Phase 3 Cardinal Study Long-Term Follow-up
Authors: Röth Alexander , Barcellini Wilma , D'Sa Shirley , Miyakawa Yoshitaka , Broome Catherine M , Michel Marc , Kuter David J. , Jilma Bernd , Anderson Tvedt Tor Henrik , Weitz Ilene C. , Patel Parija , Jiang Xiaoyu , Reuter Caroline , Su Jun , Shafer Frank , Lee Michelle , Hobbs William , Berentsen Sigbjørn 
Published: February 2021

Introduction
CAD is a rare chronic autoimmune hemolytic anemia characterized by classical complement pathway (CP)-mediated hemolysis, resulting in predominant extravascular red blood cell destruction in the liver, anemia, and fatigue. Patients with CAD have an increased risk of thromboembolism and early mortality. There are no approved pharmacologic treatments for CAD.
Sutimlimab (formerly BIVV009) is a first-in-class humanized monoclonal anti-C1s antibody that selectively inhibits the C1 complex of complement, preventing CP activation, while leaving the lectin and alternative pathways intact. The aim of the Cardinal study (NCT03347396) is to assess efficacy and safety of sutimlimab in adults with CAD and a recent history of transfusion. The primary efficacy endpoint for the 26-week treatment period was met (Röth et al. Blood. 2019); interim results of the 1-year long-term follow-up (Week 53 study visit) are presented.
Methods
Cardinal is a Phase 3, open-label, single-arm, multicenter study with a 26-week treatment period (Part A) and an ongoing extension (Part B) for 2 years after the last patient completes Part A; interim data are available for Part B (minimum 1-year follow-up; data cut: January 16, 2020). Patients with confirmed CAD diagnosis were enrolled. Eligibility criteria included baseline hemoglobin (Hb) ≤10 g/dL and ≥1 blood transfusion in the prior 6 months. Sutimlimab was administered intravenously on Days 0 and 7, followed by biweekly infusions. Patients &lt;75 kg or ≥75 kg received a 6.5 g or 7.5 g dose, respectively. The primary objectives of the interim Part B analysis are to evaluate long-term safety and tolerability of sutimlimab for ≥53 weeks; secondary objectives are to investigate the durability of response over time. Efficacy endpoints included change from baseline in hemolytic markers and the patient-reported outcome: Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale. Outcomes were analyzed using descriptive statistics, frequency, or percentage.
Results
Twenty-four patients enrolled and 22 completed Part A (2 patients withdrew for reasons unrelated to the study drug). All patients who completed Part A entered Part B. The mean (standard deviation [SD]) age was 71.3 (8.2) years and 62.5% were female. In Part A, the mean (range) baseline Hb was 8.6 (4.9-11.1) g/dL. The median (range) number of transfusions &lt;6 months prior to enrollment was 2 (1-19); 62.5% of patients had failed prior therapies. Hb improved rapidly after first sutimlimab dose and mean Hb was &gt;11 g/dL from Week 5 (Part A) to Week 53 (Part B; Figure 1). Mean total bilirubin was normalized by Week 3 and remained &lt;20 µmol/L to Week 53. Normalization of mean (SD) absolute reticulocyte count (baseline: 138 [68] ×109/L; Week 3: 65 [40] ×109/L) was observed alongside normalized haptoglobin levels and reductions in lactate dehydrogenase. Seventeen (70.8%) and 19 (86.4%) patients remained transfusion-free from Week 5 to Week 26 and Week 26 to Week 53, respectively. FACIT-F scores improved within 1 week and remained &gt;40 from Week 3 to Week 51 at last data recording, consistent with a clinically meaningful improvement. Hb, bilirubin, and FACIT-F improvements correlated with the normalization of complement C4 (mean [SD] total C4 at baseline: 0.04 [0.07] g/L; Week 25: 0.29 [0.07] g/L) and near-complete inhibition of CP activity (mean [SD] CP at baseline: 20.0% [16.7]; Week 25: 3.0% [3.1]). From baseline to Week 53, all 24 patients experienced ≥1 treatment-emergent adverse event (TEAE); 12 (50.0%) patients experienced a serious TEAE. One serious TEAE (viral infection) was associated with sutimlimab. Serious (including bacterial) infections were reported, but no meningococcal infections were identified. There was 1 TEAE of device-related thrombosis (assessed as unrelated to study drug) in Part B; there were no other vascular thromboembolic TEAEs. One patient died due to a progressive carcinoma (unrelated to study drug).
Conclusions
The 1-year interim follow-up results of the Phase 3 Cardinal study show that sutimlimab, a first-in-class selective CP inhibitor, has a sustained treatment effect in CAD; via long-term complement inhibition, sutimlimab maintains both Hb levels &gt;11 g/dL and improved FACIT-F, with no new safety concerns identified. These positive results support sutimlimab use as an effective and well-tolerated long-term therapy for the management of chronic primary CAD.

Disclosures
Röth: Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Biocryst: Consultancy, Honoraria; Apellis: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Barcellini:Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Other: invited speaker , Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: invited speaker , Research Funding. D'Sa:Sanofi: Honoraria; BeiGene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Miyakawa:Bioverativ and Sanofi: Consultancy. Broome:Alexion: Honoraria; apellis: Honoraria; argenx: Honoraria; sanofi: Honoraria. Michel:Alexion Pharmaceuticals: Consultancy; Bioverativ: Consultancy; Rigel: Consultancy. Kuter:Kezar Life Sciences, Inc: Other, Research Funding; CRICO: Consultancy, Honoraria; Caremark: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Immunovant: Consultancy, Honoraria; Shionogi: Consultancy; Protalex: Consultancy, Honoraria, Research Funding; Immunovant: Other: Travel Expenses, Research Funding; Kyowa-Kirin: Consultancy, Honoraria; Merck Sharp Dohme: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Actelion (Syntimmune): Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Up-To-Date: Consultancy, Honoraria, Patents & Royalties; Zafgen: Consultancy, Honoraria; Sanofi (Genzyme): Consultancy, Honoraria; UCB: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Momenta: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Dova: Consultancy, Honoraria; Shionogi: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Principia: Consultancy, Research Funding; Protalix Biotherapeutics: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Argenx: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Alnylam: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Agios: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Principia Biopharma: Consultancy, Honoraria, Other, Research Funding; Protalex: Consultancy, Honoraria, Other, Research Funding; Rigel: Consultancy, Honoraria, Other, Research Funding; Takeda (Bioverativ): Consultancy, Honoraria, Other, Research Funding. Jilma:Bioverativ: Consultancy, Other: reimbursement for travel costs for scientific presentations; True North Therapeutics: Consultancy, Other: reimbursement for travel costs for scientific presentations. Anderson Tvedt:Alexion Pharmaceuticals, Inc, Novartis, and Ablynx: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Ablynx: Membership on an entity's Board of Directors or advisory committees. Weitz:Apellis: Consultancy, Honoraria; Alexion: Consultancy, Honoraria, Speakers Bureau. Patel:Sanofi: Current Employment. Jiang:Sanofi: Current Employment. Reuter:Sanofi: Current Employment. Su:Sanofi: Current Employment. Shafer:Sanofi: Current Employment. Lee:Sanofi: Current Employment. Hobbs:Sanofi: Ended employment in the past 24 months. Berentsen:Mundipharma: Research Funding; Apellis Pharmaceuticals: Consultancy, Other: lecture honoraria; Bioverativ: Consultancy, Other: lecture honoraria; Janssen-Cilag: Other: lecture honoraria; Alexion Pharmaceuticals, Inc,: Other: lecture honoraria; Momenta Pharmaceuticals: Consultancy; True North Therapeutics: Other: lecture honoraria.