S905 LONG TERM INHIBITION OF COMPLEMENT C1S IN PATIENTS WITH COLD AGGLUTININ DISEASE: RESULTS FROM A NAMED PATIENT PROGRAM
Authors: G. Gelbenegger, C. Schoergenhofer, C. Sillaber, S. D'Sa, M. Fillitz, T. Schenk, J.C. Gilbert, R. Cartwright, B. Jilma, U. Jaeger
Journal: HemaSphere (2019)

Background: Cold agglutinin disease (CAD) is a subtype of autoimmune hemolytic anemia in which cold‐induced binding of antibodies directed against antigens on the erythrocyte surface cause hemolysis and anemia via complement activation. Sutimlimab is a novel, humanized monoclonal antibody directed against classical pathway complement factor C1 s. Aims: To evaluate the safety and efficacy of continuous long‐term maintenance treatment with sutimlimab in patients with CAD. Methods: CAD patients treated with sutimlimab as part of a phase 1b study (Jaeger U et al; Blood 2019) were transitioned to a named patient program (NPP). After a loading dose, patients received bi‐weekly infusions of sutimlimab at various doses. When a patient showed laboratory signs of breakthrough hemolysis, the dose of sutimlimab was increased. The data are censored by the inclusion of those patients into an open label extension of the original sutimlimab trial. Results: Seven patients with CAD participated in this NPP. Most of the patients had a prior history of multiple treatment failures and increased transfusion needs. Treatment duration with sutimlimab ranged from 2–21 months and doses were tailored to the specific individual patient's clinical and laboratory responses. Three patients started with a dose of 45 mg/kg, another three with 60 mg/kg and two patients with a fixed‐dose of 5.5 g every other week. Sutimlimab infusions were well tolerated without need for premedication. All 7 patients responded to the drug. Effective complement inhibition was mirrored by a decrease in total complement activity CH50, increase in C4 levels and normalization of bilirubin. Sutimlimab infusions increased hemoglobin (Hb) from a mean initial level of 7.8 g/dL to a mean peak of 12.3 g/dL (p &lt; 0.001). Patients maintained near normal Hb levels and inhibition of hemolysis for the duration of the study, except for few breakthrough events that were related to under‐dosing and which were resolved after the appropriate dose increase. Five of the patients were eventually treated with 5.5 g of sutimlimab every 2 weeks. Of these, one had breakthrough hemolysis. This was consistent with PK/PD modeling showing a low but existent risk of decreased drug effect with this dose in certain individuals, thereby leading to the use of a higher dosing regimen for the pivotal trials. Two patients were removed from the NPP due to unrelated severe health conditions precluding use of a concurrent investigational drug (uterine cancer with active radiation, hydrocephalus with shunt implantation). One patient that was being treated with ibrutininb for lymphoplasmocytic lymphoma developed an infection‐associated hemolytic crisis and was temporarily re‐treated with sutimlimab. Initiation of sutimlimab treatment was associated with a rapid recovery to near normal Hb levels. All patients remained transfusion‐free while on sutimlimab. There have been no serious adverse events related to this investigational drug. Summary/Conclusion: Long‐term maintenance treatment with sutimlimab was safe, effectively inhibited hemolysis and significantly increased Hb levels in previously transfusion‐dependent CAD patients. Classical complement blockade through C1 s inhibition may be an effective therapeutic target for continuous treatment of CAD patients over time. Doses higher than 5.5 g may be needed in some cases. Two phase 3 trials (NCT03347396, NCT03347422) evaluating the use of sutimlimab in primary CAD are currently underway.