Asundexian

Factor XI inhibition – the new paradigm
for atrial fibrillation and stroke

GREGORY Y H LIP MD FRCP (Lond Edin Glasg) FACC FESC FEHRA
Price-Evans Chair of Cardiovascular Medicine, University of Liverpool, UK

National Institute for Health and Care Research (NIHR) Senior Investigator
Distinguished Professor, Aalborg University, Denmark
Professor of Cardiovascular Medicine, Liverpool John Moores University, United Kingdom;

Adjunct Professor, Yonsei University, Seoul; Adjunct Professor, Seoul National University, South Korea
………………………………………………………………………………..
©Prof GYH Lip

Declaration of Interests
• Guideline membership/reviewing: ESC Guidelines on Atrial Fibrillation 2010 and Focused Update 2012, 2020;
ESC Guidelines on Heart Failure, 2012; American College of Chest Physicians Antithrombotic Therapy Guidelines
for Atrial Fibrillation, 2012; NICE Guidelines on Atrial Fibrillation, 2006 and 2014; NICE Quality Standards on
Atrial Fibrillation 2015; ESC Cardio-oncology Task Force, 2015; ESC Working Group on Thrombosis position
documents (2011-). Chairman, Scientific Documents Committee, European Heart Rhythm Association (EHRA).
Chairman, 2018 CHEST guidelines from American College of Chest Physicians. Writing Group, 2021 Asia Pacific
Heart Rhythm Society Guidelines on Stroke Prevention.
• Steering Committees/trials: Includes steering committees for various Phase II and III studies, Health Economics
& Outcomes Research, etc. Investigator in various clinical trials in cardiovascular disease, including those on
antithrombotic therapies in atrial fibrillation, acute coronary syndrome, lipids, etc.
• Editorial Roles: Editor-in-Chief (clinical), Thrombosis & Haemostasis; Associate Editor, Europace; Guest Editor,
Circulation, American Heart Journal.
• Consultant/Advisor/Speaker:
– Consultant and Speaker for BMS/Pfizer, Boehringer Ingelheim, Bayer, Anthos and Daiichi-Sankyo. No direct
personal fees.
Factor XI
inhibitors:
cardiovascular
perspectives
De Caterina et al
European Heart
Journal (2023) 44,
280–292
Greco et
al
Circulation.
2023;147:
897–913.
Factor XI Inhibitors in
Early Clinical Trials: A
Meta-analysis
Galli et al Thromb Haemostat
2023 Mar 24. doi: 10.1055/a-2043-
0346.
Phase 2 Studies of
FXI Inhibitors in
Patients With ESRD,
Atrial Fibrillation,
Stroke, and
Myocardial
Infarction
Greco et al Circulation.
2023;147:897–913.
Piccini et al Lancet. 2022 Apr 9;399(10333):1383-1390.
Near complete
inhibition of
Factor XI
activity with 20
and 50 mg dose
asundexian

Piccini et al
Lancet. 2022 Apr
9;399(10333):1383-
1390.
PACIFIC-AF
• Near complete inhibition of Factor XI activity with 20 and 50 mg dose
asundexian
• Only few bleeding outcome events were observed
• 48 participants with a bleeding event in total
• Point estimators of risk ratios in favor of asundexian
• For the pooled 20 and 50 mg doses as well as for 50 mg alone the confidence intervals could
exclude 1 for CRNM bleeding as well as for minor bleeding and all bleeding
• Overall bleeding rates lower than expected
(for Apixaban: 4% assumed vs. 2.4% observed)
• No information on efficacy events: limited events with fewer than 10 events
total

Non-Cardioembolic Ischemic Stroke 1Kleindorfer,
2Wang,
et al. Stroke 2021; 52: e364–467;
et al. NEJM 2013; 369:11-9;
3Johnston, et al. NEJM 2018; 379:215-25;
4Johnston, et al. NEJM 2020;383:207-17;
5Dawson, et al. Eur Stroke J 2022
Ischemic Stroke
Small vessel Large artery

Cardioembolic Other Cryptogenic
disease atherosclerosis
27% 2% 35%
23% 13%
Non-cardioembolic: ~75% of all ischemic stroke1
Substantial recurrence rate (>6%/yr) despite

current guideline recommended treatment2-5
Shoamanesh et al Lancet 2022
PACIFIC-Stroke: Schema https://doi.org/10.1016/S0140-6736(22)01588-4
Prospective, randomized, double-blind, placebo-controlled, phase 2, dose-ranging
study
Asundexian 50 mg QD n = 447
Asundexian 20 mg QD n = 450 2 weeks

Patients with
Non-Cardioembolic
post study drug
Ischemic stroke ≤48 hrs
R
Asundexian 10 mg QD n = 455 observation
from symptom onset period
Placebo QD n = 456
Background APT
Day 1 6-12 Months EOS
Randomization EOT
MRI prior to or up to 72 hours post MRI
randomization
Enrollment: 1808 patients between June 15, 2020 and

July 22, 2021 at 196 sites in 23 countries
Factor XIa inhibition with asundexian after acute non-
cardioembolic ischaemic stroke (PACIFIC-Stroke): an international,
randomised, double-blind, placebo- controlled, phase 2b trial
Shoamanesh et al Lancet 2022 https://doi.org/10.1016/S0140-6736(22)01588-4
Asundexian did not reduce the composite of covert brain infarction or ischaemic stroke and did not
increase the composite of major or clinically relevant non-major bleeding compared with placebo in
patients with acute, non-cardioembolic ischaemic stroke.
Shoamanesh et al Lancet 2022
Bleeding Outcomes https://doi.org/10.1016/S0140-6736(22)01588-4
A. Major or Clinically-Relevant Non-Major Bleeding (ISTH) B. All Bleeding
HR 1.57, 90% CI 0.91 – 2.71
5 12 10.8% 10.8%
4.3% 4.3% 10.0% 10.0%
3.9% 10
4 8.3%
% of patients
3.1%
% of patients
8
3 2.4%
6
2
4
1 2
0 0
ASU 10 ASU 20 ASU 50 ASU pooled Placebo ASU 10 ASU 20 ASU 50 ASU pooled Placebo
C. Hemorrhagic transformation in patients with baseline MRI after randomization

Asundexian 10 Asundexian 20 Asundexian, 50
Placebo (N=296) ASU = Asundexian, HI =
(N=277) (N=265) (N=277)
HI1 and 2 29.6% 29.4% 30.3% 32.8% hemorrhagic infarct, PH =
parenchymal hematoma
PH1 and 2 1.1% 0.4% 0% 1.4%
On top of antiplatelet therapy, no relevant increase in bleeding and hemorrhagic

transformation of index stroke with any dose of asundexian compared with placebo
Sharma M. AXIOMATIC-SSP: Antithrombotic treatment with factor XIa inhibition to optimize
management of acute thromboembolic events for secondary stroke prevention.
Presented at: European Society of Cardiology 2022 Conference; August 28, 2022.
• No dose response
for the primary
composite endpoint
(symptomatic
ischemic stroke +
covert brain
infarction)
• Milvexian was
associated with
fewer symptomatic
ischemic strokes at
all doses except 200
mg BID
Doses from 25 mg to 100 mg BID showed similar relative risk reduction for symptomatic
ischemic stroke at approximately 30% versus placebo
• Numerical increases
in major bleeding
(BARC Type 3) at
milvexian doses of 50
mg BID and above;
the majority were GI
bleeds
• No increase in
symptomatic ICH
bleeding (BARC Type
3c) versus placebo
• No fatal bleeding
(BARC Type 5)
Major bleeding: The incidence of major bleeding was low (0.6%-1.6%)

Ongoing Randomized Trials of FXI
Inhibitors Enrolling ≥100 Patients
Greco et al Circulation.
2023;147:897–913.
Reversal agents
for current and
forthcoming direct
oral
anticoagulants
Van Es et al Eur Heart J

2023;
https://doi.org/10.1093/eur
heartj/ehad123
Factor XI inhibition – the new paradigm for
atrial fibrillation and stroke
Where are we with the evidence … from Phase 2 RCTs at present
Atrial fibrillation
• Asundexian had less bleeding compared to apixaban
Stroke
• Asundexian did not reduce the composite of covert brain infarction or ischemic stroke
and no dose response could be shown in patients with acute, non-cardioembolic
ischemic stroke.
• Treatment with asundexian 50mg reduced recurrent symptomatic ischemic strokes and TIAs, particularly
among those with atherosclerosis
• No significant increase in the risk of major or intracranial bleeding with asundexian
• Milvexian was associated with fewer symptomatic ischemic strokes at doses from 25
mg to 100 mg BID, approximately 30% versus placebo
• The incidence of major bleeding was low (0.6%-1.6%)
Data from ongoing Phase 3 RCTs are awaited

Asundexian

Uploaded by

Copyright:

Available Formats

Asundexian

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Asundexian

Uploaded by

Copyright:

Available Formats

Factor XI inhibition – the new paradigm

for atrial fibrillation and stroke

Price-Evans Chair of Cardiovascular Medicine, University of Liverpool, UK

Professor of Cardiovascular Medicine, Liverpool John Moores University, United Kingdom;

©Prof GYH Lip

Piccini et al Lancet. 2022 Apr 9;399(10333):1383-1390.

Piccini et al Lancet. 2022 Apr 9;399(10333):1383-1390.

Small vessel Large artery

Non-cardioembolic: ~75% of all ischemic stroke1

Substantial recurrence rate (>6%/yr) despite

Asundexian 20 mg QD n = 450 2 weeks

Enrollment: 1808 patients between June 15, 2020 and

C. Hemorrhagic transformation in patients with baseline MRI after randomization

On top of antiplatelet therapy, no relevant increase in bleeding and hemorrhagic

Major bleeding: The incidence of major bleeding was low (0.6%-1.6%)

Van Es et al Eur Heart J

Data from ongoing Phase 3 RCTs are awaited

You might also like