Inhibition of complement C1s in patients with cold agglutinin disease: lessons learned from a named patient program

Abstract

Cold agglutinin disease (CAD) causes predominantly extravascular hemolysis and anemia via complement activation. Sutimlimab is a novel humanized monoclonal antibody directed against classical pathway complement factor C1s. We aimed to evaluate the safety and efficacy of long-term maintenance treatment with sutimlimab in patients with CAD. Seven CAD patients treated with sutimlimab as part of a phase 1B study were transitioned to a named patient program. After a loading dose, patients received biweekly (once every 2 weeks) infusions of sutimlimab at various doses. When a patient’s laboratory data showed signs of breakthrough hemolysis, the dose of sutimlimab was increased. Three patients started with a dose of 45 mg/kg, another 3 with 60 mg/kg, and 1 with a fixed dose of 5.5 g every other week. All CAD patients responded to re-treatment, and sutimlimab increased hemoglobin from a median initial level of 7.7 g/dL to a median peak of 12.5 g/dL (P = .016). Patients maintained near normal hemoglobin levels except for a few breakthrough events that were related to underdosing and which resolved after the appropriate dose increase. Four of the patients included were eventually treated with a biweekly 5.5 g fixed-dose regimen of sutimlimab. None of them had any breakthrough hemolysis. All patients remained transfusion free while receiving sutimlimab. There were no treatment-related serious adverse events. Overlapping treatment with erythropoietin, rituximab, or ibrutinib in individual patients was safe and did not cause untoward drug interactions. Long-term maintenance treatment with sutimlimab was safe, effectively inhibited hemolysis, and significantly increased hemoglobin levels in re-exposed, previously transfusion-dependent CAD patients.

Autoimmune hemolytic anemia: current knowledge and perspectives

“…TNT003 is a murine monoclonal antibody which targets the specific serine protease C1s, and its effectiveness has been investigated in vitro and in vivo [120,121]. Sutimlimab -a humanized anti-C1 monoclonal antibody (formerly called BIVV009 or TNT009) rapidly inhibits hemolysis in patients with CAD, increases Hb and resolves anemia, furthermore the patients remain transfusion-free [122,123].…”

Halting targeted and collateral damage to red blood cells by the complement system

“…Theoretically, the risk of such infections in patients treated with a more upstream inhibitor specific for C3, thereby both blocking bacterial opsonization and bacterial killing via MAC, may be even higher. Substantial clinical data are currently lacking, although small ongoing trials so far supported a favorable safety profile [ 86 , 87 ].…”

“…First results of the phase III trial show rapid and sustained effects in preventing hemolysis, increasing hemoglobin levels, and improving quality of life. Sanofi [ 79 , 86 , 87 ] TNT003 Monoclonal antibody n.s. AIHA (CAD) Preclinical Effective in inhibiting C3 deposition in plasma of CAD patients in vitro Sanofi (Bioverativ, True North Therapeutics) [ 95 ] C1q ANX005 Monoclonal antibody IV Huntington disease, amythrophic lateral sclerosis, Guillan–Barre syndrome II Annexon [ 96 ] C2 ARGX-117 Monoclonal antibody IV n.s.…”

“… Preclinical Argenx [ 97 ] PRO-02 Monoclonal antibody n.s. Ischemia-reperfusion injury or antibody-mediated disease Preclinical Prothix [ 98 ] C3 APL-9 Peptide IV Severe COVID-19 I/II Apellis, NCT04402060 Compstatin (AMY101, Cp40) Peptide SC or IV Gingivitis; COVID-19 II Amyndas, [ 83 , 85 , 86 ] Pegcetacoplan (APL-2) Peptide SC AIHA; PNH; age-related macular degeneration II (AIHA) and III Apellis [ 99 ] SLN500 RNAi n.s. n.s.…”

Rituximab Use in Warm and Cold Autoimmune Hemolytic Anemia

“…All previously transfused patients achieved transfusion independence [ 109 ]. These responses were recapped in a named patient program in responders with every 2 weeks maintenance resulting in sustained increase in hemoglobin to near normal levels and transfusion independence in all patients upon re-exposure [ 110 ]. Sutimlimab was granted breakthrough therapy designation by the US Food and Drug Administration for the treatment of CAD based on these data and a Phase 3 trial recently completed the accrual.…”