LONG TERM INHIBITION OF COMPLEMENT C1S IN PATIENTS WITH COLD AGGLUTININ DISEASE: RESULTS FROM A NAMED PATIENT PROGRAM
Author(s): ,
Georg Gelbenegger
Affiliations:
Department of Clinical Pharmacology,Medical University of Vienna,Vienna,Austria
,
Christian Schoergenhofer
Affiliations:
Department of Clinical Pharmacology,Medical University of Vienna,Vienna,Austria
,
Christian Sillaber
Affiliations:
Department of Internal Medicine I, Division of Hematology,Medical University of Vienna,Vienna,Austria
,
Shirley D'Sa
Affiliations:
UCLH Centre for Waldenströms Macroglobulinaemia and Related Conditions,University College London Hospitals NHS Foundation Trust,London,United Kingdom
,
Michael Fillitz
Affiliations:
Department of Internal Medicine,Hanusch Krankenhaus,Vienna,Austria
,
Thomas Schenk
Affiliations:
Department of Internal Medicine,Universitätsklinikum St. Pölten,St. Pölten,Austria
,
James C. Gilbert
Affiliations:
Band Therapeutics, LLC,Lexington, MA,United States
,
Ronwyn Cartwright
Affiliations:
Worthing Hospital, Western Sussex Hospitals NHS Foundation Trust,Worthing,United Kingdom
,
Bernd Jilma
Affiliations:
Department of Clinical Pharmacology,Medical University of Vienna,Vienna,Austria
Ulrich Jaeger
Affiliations:
Department of Internal Medicine I, Division of Hematology,Medical University of Vienna,Vienna,Austria
EHA Library. Gelbenegger G. Jun 15, 2019; 267488; S905
Georg Gelbenegger
Georg Gelbenegger
Contributions
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Abstract

Abstract: S905

Type: Oral Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 16:15 - 16:30

Location: Hall G104

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 C1s.

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<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.

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 C1s 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.

Session topic: 31. Transfusion medicine

Keyword(s): Antibody, Autoimmune hemolytic anemia (AIHA), Complement

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