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INHIBITION OF COMPLEMENT C1S WITH SUTIMLIMAB IN PATIENTS WITH COLD AGGLUTININ DISEASE (CAD): 2-YEAR FOLLOW-UP FROM THE CARDINAL STUDY
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 Geor
,
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, MA,États-unis;Division of Hematology,Massachusetts General Hospital, Harvard Medical School,Boston, MA,Vereinigte Staaten;Division of Hematology,Massachusetts General Hospital, Harvard Medical School,Boston, MA,Stati Uniti;Division of Hematology,Massachusetts General Hospital, Harvard Medical School,Boston, MA,Un
,
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,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
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; 357149; S285
Alexander Röth
Alexander Röth
Contributions
Abstract
Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S285

Type: Oral Presentation

Session title: Transfusion and autoimmune hemolytic anemia

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 that selectively inhibits C1s of the C1 complex, preventing CP activation, while leaving the alternative and lectin pathways intact. One-year interim follow-up from the CARDINAL study (NCT03347396) have previously demonstrated that sutimlimab resulted in sustained improvements in hemolytic markers and quality of life.

Aims
To report 2-year sutimlimab efficacy and safety from the CARDINAL Part B extension. 

Methods
CARDINAL was a Phase 3, open-label, single-arm study with a 26-week treatment period (Part A) and a 2-year extension (Part B) after the last patient (pt) finishes Part A. Sutimlimab was administered through intravenous infusions on Days 0 and 7, followed by biweekly dosing. Efficacy data through Week 131, the last data recording within the 2-year Part B period, are reported here. Efficacy endpoints included change from baseline in hemolytic markers, pharmacodynamic (PD) markers and blood transfusions. Quality of life (QOL) was assessed using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale. Safety was recorded until end-of-study visit 9 weeks after their last dose; endpoints included incidence of treatment-emergent adverse event (TEAE) and serious TEAE (TESAE). Descriptive statistics, frequency, and percentage were used to analyze outcomes.

Results
Of the 24 pts enrolled in Part A, 22 completed Part A and entered Part B, with 19 (86.4%) pts completing Part B. Sutimlimab treatment improved mean (SD) hemoglobin (Hb) levels within one week; mean Hb remained >11 g/dL from Week 5–131 (baseline: 8.64 (1.67) (Figure). Mean total bilirubin was normalized from Week 3–131 (Figure). Mean FACIT-Fatigue scores improved within 1 week and remained ≥5 from Week 1–123 (Figure), consistent with a clinically meaningful change. Improvements in Hb, bilirubin, and FACIT-Fatigue correlated with normalization of C4 and near-complete inhibition of CP activity. Normalization of mean absolute reticulocyte count was observed alongside normalized haptoglobin levels and reductions in LDH. From Week 26–131, 15 (68.2%) pts remained transfusion-independent. All 22 pts experienced ≥1 TEAE; 12 (54.5%) pts experienced ≥1 TESAE. Serious infections were reported in 7 (31.8%) pts, including one pt with sepsis due to streptococcus pneumoniae. No meningococcal infections were reported. Three pts discontinued the study due to AEs (cyanosis and klebsiella pneumoniae (n=1); vitreous hemorrhage (n=1); cyanosis and gastrointestinal symptoms including erosive gastritis (n=1)). No pts developed systemic lupus erythematosus, serious hypersensitivity or anaphylaxis. Two pts died during the study (klebsiella pneumoniae (n=1); exacerbation of CAD (n=1) in a patient with a femoral neck fracture and complex medical history including myelodysplastic syndrome, approximately 1.5 months after receiving the last dose of sutimlimab).

Conclusion
Sutimlimab, a first-in-class selective anti-C1s classical complement pathway inhibitor, maintained mean Hb levels >11g/dL, achieved sustained normalization of mean bilirubin, haptoglobin and reticulocyte count. Sutimlimab continued to improve FACIT-Fatigue scores, with no newly identified safety concerns at 2 years of treatment. This study has demonstrated that sutimlimab is an effective and well-tolerated long-term therapy for the management of chronic CAD through continued upstream inhibition of the classical CP.

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

Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S285

Type: Oral Presentation

Session title: Transfusion and autoimmune hemolytic anemia

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 that selectively inhibits C1s of the C1 complex, preventing CP activation, while leaving the alternative and lectin pathways intact. One-year interim follow-up from the CARDINAL study (NCT03347396) have previously demonstrated that sutimlimab resulted in sustained improvements in hemolytic markers and quality of life.

Aims
To report 2-year sutimlimab efficacy and safety from the CARDINAL Part B extension. 

Methods
CARDINAL was a Phase 3, open-label, single-arm study with a 26-week treatment period (Part A) and a 2-year extension (Part B) after the last patient (pt) finishes Part A. Sutimlimab was administered through intravenous infusions on Days 0 and 7, followed by biweekly dosing. Efficacy data through Week 131, the last data recording within the 2-year Part B period, are reported here. Efficacy endpoints included change from baseline in hemolytic markers, pharmacodynamic (PD) markers and blood transfusions. Quality of life (QOL) was assessed using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale. Safety was recorded until end-of-study visit 9 weeks after their last dose; endpoints included incidence of treatment-emergent adverse event (TEAE) and serious TEAE (TESAE). Descriptive statistics, frequency, and percentage were used to analyze outcomes.

Results
Of the 24 pts enrolled in Part A, 22 completed Part A and entered Part B, with 19 (86.4%) pts completing Part B. Sutimlimab treatment improved mean (SD) hemoglobin (Hb) levels within one week; mean Hb remained >11 g/dL from Week 5–131 (baseline: 8.64 (1.67) (Figure). Mean total bilirubin was normalized from Week 3–131 (Figure). Mean FACIT-Fatigue scores improved within 1 week and remained ≥5 from Week 1–123 (Figure), consistent with a clinically meaningful change. Improvements in Hb, bilirubin, and FACIT-Fatigue correlated with normalization of C4 and near-complete inhibition of CP activity. Normalization of mean absolute reticulocyte count was observed alongside normalized haptoglobin levels and reductions in LDH. From Week 26–131, 15 (68.2%) pts remained transfusion-independent. All 22 pts experienced ≥1 TEAE; 12 (54.5%) pts experienced ≥1 TESAE. Serious infections were reported in 7 (31.8%) pts, including one pt with sepsis due to streptococcus pneumoniae. No meningococcal infections were reported. Three pts discontinued the study due to AEs (cyanosis and klebsiella pneumoniae (n=1); vitreous hemorrhage (n=1); cyanosis and gastrointestinal symptoms including erosive gastritis (n=1)). No pts developed systemic lupus erythematosus, serious hypersensitivity or anaphylaxis. Two pts died during the study (klebsiella pneumoniae (n=1); exacerbation of CAD (n=1) in a patient with a femoral neck fracture and complex medical history including myelodysplastic syndrome, approximately 1.5 months after receiving the last dose of sutimlimab).

Conclusion
Sutimlimab, a first-in-class selective anti-C1s classical complement pathway inhibitor, maintained mean Hb levels >11g/dL, achieved sustained normalization of mean bilirubin, haptoglobin and reticulocyte count. Sutimlimab continued to improve FACIT-Fatigue scores, with no newly identified safety concerns at 2 years of treatment. This study has demonstrated that sutimlimab is an effective and well-tolerated long-term therapy for the management of chronic CAD through continued upstream inhibition of the classical CP.

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

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