New pivotal data at EHA 2021 reinforces sutimlimab as a first-in-class investigational C1s inhibitor with the potential to be...
June 11 2021 - 3:00AM
New
pivotal data at EHA 2021 reinforces
sutimlimab as a first-in-class
investigational C1s inhibitor with the potential to be the first
approved treatment for hemolysis in
people with cold
agglutinin disease, a serious and chronic
autoimmune hemolytic
anemia
- Phase 3 data from the CADENZA study met the primary composite
endpoint with statistical significance; secondary endpoint data
were clinically meaningful
- Findings provide further evidence that sutimlimab results in
rapid inhibition of C1-activated hemolysis within one week of
treatment and had a sustained treatment effect throughout the
study
PARIS – June
11, 2021 – Results from Part A of
CADENZA, a pivotal Phase 3 double-blind, placebo-controlled study
evaluating the safety and efficacy of sutimlimab in people with
cold agglutinin disease (CAD) without a recent history of blood
transfusion (within the prior six months), will be presented in an
oral session at the European Hematology Association 2021 Congress.
The data demonstrated treatment with sutimlimab resulted in rapid
and sustained inhibition of C1-activated hemolysis in people with
CAD, noted within one week of treatment, and clinically significant
improvements in hemoglobin and fatigue when compared to placebo
during the course of the study.
“Cold agglutinin disease causes the body’s
immune system to mistakenly destroy its healthy red blood cells.
People living with cold agglutinin disease experience the crippling
impact of chronic hemolysis that can cause severe anemia, profound
fatigue and can have acute hemolytic crisis,” said principal
investigator and presenting author Professor Alexander Röth, M.D.,
Department of Hematology and Stem Cell Transplantation, University
Hospital, University of Duisburg-Essen, Germany. “The positive
evidence from the CADENZA trial demonstrate significant
improvements in hemolysis and meaningful impact on key measures of
anemia and fatigue.”
CADENZA is a second pivotal Phase 3 study
investigating sutimlimab in the treatment of CAD. The primary
efficacy outcome was the proportion of patients who met all three
of the following components: improvement in hemoglobin ≥1.5 g/dL
from baseline at treatment assessment timepoint, (average of Weeks
23, 25, and 26); avoidance of transfusions from Week 5 through Week
26; and avoidance of other CAD-related therapies beyond what was
permitted from Week 5 through Week 26. The secondary efficacy
measures assessed improvement from baseline in key indicators of
the disease process including hemoglobin, bilirubin, lactate
dehydrogenase (LDH) levels, and quality of life as measured by
Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue
Score.
“The results from CADENZA and data from the
Phase 3 CARDINAL study, presented as a late-breaker at the American
Society of Hematology congress in 2019, will be the basis of our
filing with the European Medicines Agency. Together, the studies
highlight the promising potential of sutimlimab to have a
meaningful impact for people living with CAD,” said Karin
Knobe, M.D., Ph.D., Head of Development, Rare and Rare Blood
Disorders, Sanofi. “Based on the robust clinical evidence we have
to-date, sutimlimab significantly inhibits hemolysis and has the
potential to be an important new treatment for CAD.”
CADENZA Phase 3 study data (final Part A) presented at
EHA 2021
The CADENZA trial is a Phase 3, randomized,
double-blind, placebo-controlled study to assess the efficacy and
safety of sutimlimab in patients with CAD without a recent history
of blood transfusion (within the past 6 months). Eligible patients
were randomized 1:1 to receive a fixed weight-based dose (6.5g or
7.5g) of sutimlimab or placebo via intravenous infusion on Day 0,
Day 7 and then once every other week up to Week 26. The open-label
Part B of the study is ongoing and will evaluate long-term safety
as well as durability of response to sutimlimab in all participants
with CAD.
Forty-two patients (mean age of 66.7 years) were
enrolled and randomized to either sutimlimab (N=22) or placebo
(N=20). Overall, 19 (86%) and 20 (100%) patients in the sutimlimab
and placebo groups, respectively, completed Part A and continued
into Part B. Three (14%) patients from the sutimlimab group
discontinued Part A early due to adverse events.
Efficacy and safety
data:
- Seventy-three
percent (n=16) of patients treated with sutimlimab met the primary
composite endpoint, demonstrating improvement in hemoglobin ≥1.5
g/dL from baseline at treatment assessment timepoint (Weeks 23, 25,
and 26); avoidance of transfusions from Week 5 through Week 26; and
avoidance of other CAD-related therapies beyond what was permitted
from Week 5 through Week 26 compared to 15% (n=3) in the placebo
group (Odds Ratio=15.9, 95% CI: 2.9 to 88.0, p<0.001).
- Data showed
sutimlimab increased and sustained mean hemoglobin levels from
baseline to treatment assessment timepoint (Week 26) representing a
statistically significant least squares (LS) mean difference of 2.6
g/dL (p<0.001; 95% CI:1.8 to 3.4) when compared with placebo.
Hemoglobin improved rapidly, with a LS mean increase from baseline
of ≥1 g/dL by Week 1 and ≥2 g/dL by Week 3. Overall mean hemoglobin
levels were maintained >11 g/dL from Week 3 through treatment
assessment timepoint, demonstrating a sustained effect throughout
the remainder of the treatment period.
- A
statistically significant improvement in fatigue as measured by
FACIT-Fatigue assessment was achieved in patients treated with
sutimlimab when compared to the placebo group, 10.8 points versus
1.9, respectively, with a LS mean difference of 8.9 points
(p<0.001; 95% CI:4.0 to 13.9). A 5 or greater point increase in
FACIT-Fatigue score suggests a clinically important change. 1
- Patients
treated with sutimlimab had greater mean reductions in bilirubin, a
key marker of hemolysis, from baseline to treatment assessment
timepoint as compared with the placebo group (-22.1 μmol/L versus
-1.8 μmol/L, respectively). Mean bilirubin levels were normalized
below the upper limit of normal within 1 to 3 weeks in the
sutimlimab group (upper limit of reference range 20.5 µmol/L) and
maintained levels below the upper limit of normal to week 26.
- Treatment with
sutimlimab led to meaningful improvements in LDH, an additional
hemolysis marker, from baseline to treatment assessment timepoint
compared to placebo ( -150.8 U/L versus +7.6 U/L).
- Twenty-one
patients (95.5%) in the sutimlimab group and 20 patients (100%) in
the placebo group experienced at least one treatment emergent
adverse event (TEAE).
- Three patients
(13.6%) in the sutimlimab group experienced at least one
treatment-emergent serious adverse event (TESAE) (n=4), including
one TESAE assessed by the investigator as related to sutimlimab
(cerebral venous thrombosis in a patient with a history of
diabetes). One patient (5%) in the placebo group had three
TESAEs.
- Treatment
emergent adverse events reported more often in the sutimlimab group
vs. placebo (difference of ≥ 3 patients between groups) were:
headache (23% versus 10%), hypertension (23% versus 0%), rhinitis
(18% versus 0%), Raynaud’s phenomenon (18% versus 0%), and
acrocyanosis (14% versus 0%). No deaths or meningococcal infections
were reported.
Cold agglutinin
disease, a rare and chronic
condition
Cold agglutinin disease (CAD) is a rare, chronic
autoimmune hemolytic anemia that causes the body’s immune system to
mistakenly attack healthy red blood cells and cause their
destruction (hemolysis) via activation of the classical complement
pathway. CAD patients may experience chronic anemia, profound
fatigue, acute hemolytic crisis, and other potential complications,
including an increased risk of thromboembolic events and early
death.2,3,4 CAD impacts the lives of an estimated 12,000
people in the U.S., Europe, and Japan.5 Currently there are no
approved therapies for CAD.
About CARDINAL Phase 3
Study
CARDINAL was the first of two pivotal Phase 3
studies investigating sutimlimab as a potential treatment for CAD.
CARDINAL is an open-label, single-arm study to assess the efficacy
and safety of sutimlimab in adult patients with CAD who received a
recent blood transfusion. The CARDINAL data were presented in
the Late-Breaking Abstracts Session at the 61st Annual
Meeting of the American Society of Hematology in December 2019 and
are the basis of the Biologics License Application submission with
the U.S Food and Drug Administration (FDA).
About Sutimlimab
Sutimlimab is an investigational, humanized
monoclonal antibody that is designed to selectively target and
inhibit C1s in the classical complement pathway, which is part of
the innate immune system. By blocking C1s, sutimlimab inhibits the
activation of the classical complement pathway with the goal of
halting C1-activated hemolysis in CAD to prevent the abnormal
destruction of healthy red blood cells. By selectively inhibiting
the classical pathway upstream at C1s, sutimlimab does not inhibit
the lectin and alternative complement pathways.
Sutimlimab has been granted Breakthrough Therapy
by the U.S. Food and Drug Administration (FDA) and Orphan Drug
status by the FDA, European Medicines Agency (EMA) and the
Pharmaceuticals and Medical Devices Agency in Japan. Sutimlimab is
currently under clinical investigation and has not been approved by
any regulatory authority. Sanofi plans to resubmit its Biologics
License Application with the U.S FDA in the second half of
2021.
________________________
- Hill Q, et al.
Important Change in FACIT-Fatigue Score for Patients with Cold
Agglutinin Disease: An Analysis Using the Phase 3 CARDINAL and
CADENZA Studies. Poster presentation European Hematology
Association Congress July 2021
- Broome C, et al. Increased risk of
thrombotic events in cold agglutinin disease: A 10-year
retrospective analysis. Res Pract Thromb Haemost.
2020;00:1–8.
- Quentin A. Hill, Rajeshwari
Punekar, Jaime Morales Arias, Catherine M Broome, Jun Su; Mortality
Among Patients with Cold Agglutinin Disease in the United States:
An Electronic Health Record (EHR)-Based
Analysis. Blood 2019; 134 (Supplement_1): 4790.
- Lauren C. Bylsma, Anne Gulbech
Ording, Adam Rosenthal, Buket Öztürk, Jon P. Fryzek, Jaime Morales
Arias, Alexander Röth, Sigbjørn Berentsen; Occurrence,
thromboembolic risk, and mortality in Danish patients with cold
agglutinin disease. Blood Adv 2019; 3 (20):
2980–2985.
- Berentsen S,
et al. Haematologica. 2006;91(4):460-466
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