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INHIBITION OF COMPLEMENT C1S WITH SUTIMLIMAB IN PATIENTS WITH COLD AGGLUTININ DISEASE (CAD): RESULTS FOLLOWING 9-WEEK WASHOUT PERIOD IN PHASE 3 CARDINAL STUDY (NCT03347396)
Author(s): ,
Alexander Röth
Affiliations:
Department of Hematology and Stem Cell Transplantation,West German Cancer Center, University Hospital Essen, University of Duisburg-Essen,Essen,Allemagne;Department of Hematology and Stem Cell Transplantation,West German Cancer Center, University Hospital Essen, University of Duisburg-Essen,Essen,Deutschland;Department of Hematology and Stem Cell Transplantation,West German Cancer Center, Universi
,
Wilma Barcellini
Affiliations:
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico,Milan,Italie;Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico,Milan,Italien;Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico,Milan,Italia;Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico,Milan,Italy;Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico,Milan,Italia;Fondazione IRCCS Ca' Granda Ospedale Maggiore
,
Shirley D'Sa
Affiliations:
UCLH Centre for Waldenström's Macroglobulinemia and Related Conditions, University College London Hospitals NHS Foundation Trust,London,Royaume-uni;UCLH Centre for Waldenström's Macroglobulinemia and Related Conditions, University College London Hospitals NHS Foundation Trust,London,Vereinigtes Königreich;UCLH Centre for Waldenström's Macroglobulinemia and Related Conditions, University College Lo
,
Yoshitaka Miyakawa
Affiliations:
Thrombosis and Hemostasis Center, Saitama Medical University Hospital,Saitama,Japon;Thrombosis and Hemostasis Center, Saitama Medical University Hospital,Saitama,Japan;Thrombosis and Hemostasis Center, Saitama Medical University Hospital,Saitama,Giappone;Thrombosis and Hemostasis Center, Saitama Medical University Hospital,Saitama,Japan;Thrombosis and Hemostasis Center, Saitama Medical University
,
Catherine M. Broome
Affiliations:
Division of Hematology,MedStar Georgetown University Hospital,Washington DC,États-unis;Division of Hematology,MedStar Georgetown University Hospital,Washington DC,Vereinigte Staaten;Division of Hematology,MedStar Georgetown University Hospital,Washington DC,Stati Uniti;Division of Hematology,MedStar Georgetown University Hospital,Washington DC,United States;Division of Hematology,MedStar Georgetow
,
Marc Michel
Affiliations:
Henri-Mondor University Hospital, Assistance Publique-Hôpitaux de Paris, UPEC,Créteil,France;Henri-Mondor University Hospital, Assistance Publique-Hôpitaux de Paris, UPEC,Créteil,Frankreich;Henri-Mondor University Hospital, Assistance Publique-Hôpitaux de Paris, UPEC,Créteil,Francia;Henri-Mondor University Hospital, Assistance Publique-Hôpitaux de Paris, UPEC,Créteil,France;Henri-Mondor University
,
David J. Kuter
Affiliations:
Division of Hematology,Massachusetts General Hospital, Harvard Medical School, Boston,Boston, MA,États-unis;Division of Hematology,Massachusetts General Hospital, Harvard Medical School, Boston,Boston, MA,Vereinigte Staaten;Division of Hematology,Massachusetts General Hospital, Harvard Medical School, Boston,Boston, MA,Stati Uniti;Division of Hematology,Massachusetts General Hospital, Harvard Medi
,
Bernd Jilma
Affiliations:
Department of Clinical Pharmacology,Medical University of Vienna,Vienna,Autriche;Department of Clinical Pharmacology,Medical University of Vienna,Vienna,Österreich;Department of Clinical Pharmacology,Medical University of Vienna,Vienna,Austria;Department of Clinical Pharmacology,Medical University of Vienna,Vienna,Austria;Department of Clinical Pharmacology,Medical University of Vienna,Vienna,Aust
,
Tor Henrik Anderson Tvedt
Affiliations:
Section for Hematology, Department of Medicine,Haukeland University Hospital,Bergen,Norvège;Section for Hematology, Department of Medicine,Haukeland University Hospital,Bergen,Norwegen;Section for Hematology, Department of Medicine,Haukeland University Hospital,Bergen,Norvegia;Section for Hematology, Department of Medicine,Haukeland University Hospital,Bergen,Norway;Section for Hematology, Departm
,
Ilene C. Weitz
Affiliations:
Keck School of Medicine of USC,Los Angeles, CA,États-unis;Keck School of Medicine of USC,Los Angeles, CA,Vereinigte Staaten;Keck School of Medicine of USC,Los Angeles, CA,Stati Uniti;Keck School of Medicine of USC,Los Angeles, CA,United States;Keck School of Medicine of USC,Los Angeles, CA,Estados Unidos;Keck School of Medicine of USC,Los Angeles, CA,Verenigde Staten;Keck School of Medicine of USC
,
Timothee Sourdille
Affiliations:
Sanofi,Cambridge, MA,États-unis;Sanofi,Cambridge, MA,Vereinigte Staaten;Sanofi,Cambridge, MA,Stati Uniti;Sanofi,Cambridge, MA,United States;Sanofi,Cambridge, MA,Estados Unidos;Sanofi,Cambridge, MA,Verenigde Staten;Sanofi,Cambridge, MA,Estados Unidos;Sanofi,Cambridge, MA,United States;Sanofi,Cambridge, MA,USA
,
Jennifer Wang
Affiliations:
Sanofi,Cambridge, MA,États-unis;Sanofi,Cambridge, MA,Vereinigte Staaten;Sanofi,Cambridge, MA,Stati Uniti;Sanofi,Cambridge, MA,United States;Sanofi,Cambridge, MA,Estados Unidos;Sanofi,Cambridge, MA,Verenigde Staten;Sanofi,Cambridge, MA,Estados Unidos;Sanofi,Cambridge, MA,United States;Sanofi,Cambridge, MA,USA
,
Deepthi S. Vagge
Affiliations:
IQVIA,Bangalore,Inde;IQVIA,Bangalore,Indien;IQVIA,Bangalore,India;IQVIA,Bangalore,印度;IQVIA,Bangalore,India;IQVIA,Bangalore,India;IQVIA,Bangalore,Índia;IQVIA,Bangalore,Индия;IQVIA,Bangalore,Indien
,
Katarina Kralova
Affiliations:
Sanofi,Paris,France;Sanofi,Paris,Frankreich;Sanofi,Paris,Francia;Sanofi,Paris,France;Sanofi,Paris,Francia;Sanofi,Paris,Frankrijk;Sanofi,Paris,França;Sanofi,Paris,Франция ;Sanofi,Paris,Frankrike
,
Frank Shafer
Affiliations:
Sanofi,Bridgewater, NJ,États-unis;Sanofi,Bridgewater, NJ,Vereinigte Staaten;Sanofi,Bridgewater, NJ,Stati Uniti;Sanofi,Bridgewater, NJ,United States;Sanofi,Bridgewater, NJ,Estados Unidos;Sanofi,Bridgewater, NJ,Verenigde Staten;Sanofi,Bridgewater, NJ,Estados Unidos;Sanofi,Bridgewater, NJ,United States;Sanofi,Bridgewater, NJ,USA
,
Marek Wardecki
Affiliations:
Sanofi,Warsaw,Pologne;Sanofi,Warsaw,Polen;Sanofi,Warsaw,Polonia;Sanofi,Warsaw,Poland;Sanofi,Warsaw,Polonia;Sanofi,Warsaw,Polen;Sanofi,Warsaw,Polonia;Sanofi,Warsaw,Польша;Sanofi,Warsaw,Polen
,
Michelle Lee
Affiliations:
Sanofi,Cambridge, MA,États-unis;Sanofi,Cambridge, MA,Vereinigte Staaten;Sanofi,Cambridge, MA,Stati Uniti;Sanofi,Cambridge, MA,United States;Sanofi,Cambridge, MA,Estados Unidos;Sanofi,Cambridge, MA,Verenigde Staten;Sanofi,Cambridge, MA,Estados Unidos;Sanofi,Cambridge, MA,United States;Sanofi,Cambridge, MA,USA
Sigbjørn Berentsen
Affiliations:
Department of Research and Innovation,Haugesund Hospital,Haugesund,Norvège;Department of Research and Innovation,Haugesund Hospital,Haugesund,Norwegen;Department of Research and Innovation,Haugesund Hospital,Haugesund,Norvegia;Department of Research and Innovation,Haugesund Hospital,Haugesund,Norway;Department of Research and Innovation,Haugesund Hospital,Haugesund,Noruega;Department of Research a
(Abstract release date: 05/12/22) EHA Library. Röth A. 06/10/22; 358395; P1538
Alexander Röth
Alexander Röth
Contributions
Abstract
Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P1538

Type: Poster presentation

Session title: Enzymopathies, membranopathies and other anemias

Background
CAD is a rare, chronic autoimmune hemolytic anemia characterized by classical complement pathway (CP)-mediated hemolysis. Sutimlimab is a first-in-class humanized monoclonal antibody and C1s inhibitor that selectively targets the classical CP while leaving lectin and alternative pathways intact. 

Aims
To report results from the 9-week follow-up visit after the last sutimlimab dose in the CARDINAL study.

Methods
CARDINAL is a two-part, open-label, single-arm study. In Part A, sutimlimab was administered on Days 0 and 7, then biweekly through Week 25. Patients then entered a Part B open-label extension and received biweekly sutimlimab for up to 3 years (N=22). Upon completion of dosing, or if a patient terminated the study early, a follow-up visit was completed 9 weeks after administration of the last dose of sutimlimab. Efficacy measures included hemoglobin (Hb) levels, hemolytic markers (total bilirubin, lactate dehydrogenase [LDH] and reticulocyte count); quality of life was assessed using the FACIT-Fatigue Score; PK/PD markers included Wieslab CP and total C4; adverse event data were collected. Descriptive statistics, frequency, or percentage were used to analyze outcomes.

Results
Of 22 patients who entered study Part B, 20 were assessed at the 9-week follow-up visit; 2 patients were not assessed due to death during the 9-week follow-up period. From baseline to last available on-treatment value, mean Hb improved to >12 g/dL, a mean (SD) change from baseline of 3.6 (2.19) g/dL (n=22); the mean (SD) Hb level at 9-week follow-up was 10.1 (1.6) g/dL (n=20), a decrease of 2.28 (1.8) g/dL from the last available on-treatment value (Figure 1). The mean levels of selected hemolytic markers (including bilirubin, LDH, reticulocytes), were decreased compared to baseline at the last available on-treatment time point, returning towards baseline 9 weeks after the last sutimlimab dose (Figure 1). The mean (SD) FACIT-Fatigue score increased from 32.4 (10.9) at baseline to 40.5 (9.3) at the last available on-treatment time point and returned to 34.1 (14.3) points at the 9-week follow-up (Figure 1). From Week 1, total C4 was consistently increased from baseline during treatment and returned towards baseline at the 9-week follow-up. The near-complete inhibition of CP activity observed throughout the treatment period was reversed at follow-up after discontinuation of sutimlimab. 45 treatment-emergent adverse events (TEAE) occurred after the last dose of sutimlimab in 11 patients. 10 of the 11 patients experienced TEAEs that were attributed to exacerbation of underlying CAD and included worsening of CAD in 3 patients, hemolysis in 1 patient, acrocyanosis in 2 patients, and anemia in 4 patients. 5 events were reported as serious TEAE (TESAE) in 3 patients, including 2 fatal events. TESAEs included: non-cardiac chest pain in 1 patient; acrocyanosis and fatal event of klebsiella pneumonia in 1 patient; and a femoral neck fracture and death due to CAD exacerbation (approximately 1.5 months after the last dose of sutimlimab) in 1 patient with complex medical history including myelodysplastic syndrome.

Conclusion
In the 9-week washout period following the final dose of sutimlimab, classical complement pathway inhibition was reversed, and hemolytic markers and fatigue scores approached pre-sutimlimab values. Most of the TEAEs were due to exacerbation of underlying CAD.

Keyword(s): Autoimmune hemolytic anemia (AIHA), Complement, Hemoglobin, Hemolysis

Presentation during EHA2022: All (e)Poster presentations will be made available as of Friday, June 10, 2022 (09:00 CEST) and will be accessible for on-demand viewing until Monday, August 15, 2022 on the Congress platform.

Abstract: P1538

Type: Poster presentation

Session title: Enzymopathies, membranopathies and other anemias

Background
CAD is a rare, chronic autoimmune hemolytic anemia characterized by classical complement pathway (CP)-mediated hemolysis. Sutimlimab is a first-in-class humanized monoclonal antibody and C1s inhibitor that selectively targets the classical CP while leaving lectin and alternative pathways intact. 

Aims
To report results from the 9-week follow-up visit after the last sutimlimab dose in the CARDINAL study.

Methods
CARDINAL is a two-part, open-label, single-arm study. In Part A, sutimlimab was administered on Days 0 and 7, then biweekly through Week 25. Patients then entered a Part B open-label extension and received biweekly sutimlimab for up to 3 years (N=22). Upon completion of dosing, or if a patient terminated the study early, a follow-up visit was completed 9 weeks after administration of the last dose of sutimlimab. Efficacy measures included hemoglobin (Hb) levels, hemolytic markers (total bilirubin, lactate dehydrogenase [LDH] and reticulocyte count); quality of life was assessed using the FACIT-Fatigue Score; PK/PD markers included Wieslab CP and total C4; adverse event data were collected. Descriptive statistics, frequency, or percentage were used to analyze outcomes.

Results
Of 22 patients who entered study Part B, 20 were assessed at the 9-week follow-up visit; 2 patients were not assessed due to death during the 9-week follow-up period. From baseline to last available on-treatment value, mean Hb improved to >12 g/dL, a mean (SD) change from baseline of 3.6 (2.19) g/dL (n=22); the mean (SD) Hb level at 9-week follow-up was 10.1 (1.6) g/dL (n=20), a decrease of 2.28 (1.8) g/dL from the last available on-treatment value (Figure 1). The mean levels of selected hemolytic markers (including bilirubin, LDH, reticulocytes), were decreased compared to baseline at the last available on-treatment time point, returning towards baseline 9 weeks after the last sutimlimab dose (Figure 1). The mean (SD) FACIT-Fatigue score increased from 32.4 (10.9) at baseline to 40.5 (9.3) at the last available on-treatment time point and returned to 34.1 (14.3) points at the 9-week follow-up (Figure 1). From Week 1, total C4 was consistently increased from baseline during treatment and returned towards baseline at the 9-week follow-up. The near-complete inhibition of CP activity observed throughout the treatment period was reversed at follow-up after discontinuation of sutimlimab. 45 treatment-emergent adverse events (TEAE) occurred after the last dose of sutimlimab in 11 patients. 10 of the 11 patients experienced TEAEs that were attributed to exacerbation of underlying CAD and included worsening of CAD in 3 patients, hemolysis in 1 patient, acrocyanosis in 2 patients, and anemia in 4 patients. 5 events were reported as serious TEAE (TESAE) in 3 patients, including 2 fatal events. TESAEs included: non-cardiac chest pain in 1 patient; acrocyanosis and fatal event of klebsiella pneumonia in 1 patient; and a femoral neck fracture and death due to CAD exacerbation (approximately 1.5 months after the last dose of sutimlimab) in 1 patient with complex medical history including myelodysplastic syndrome.

Conclusion
In the 9-week washout period following the final dose of sutimlimab, classical complement pathway inhibition was reversed, and hemolytic markers and fatigue scores approached pre-sutimlimab values. Most of the TEAEs were due to exacerbation of underlying CAD.

Keyword(s): Autoimmune hemolytic anemia (AIHA), Complement, Hemoglobin, Hemolysis

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