AstraZeneca to proceed with regulatory
filings to convert from conditional to full approval in the
US and EU
ANNEXA-I, a post-marketing Phase IV trial to assess the efficacy
and safety of ANDEXXA (andexanet alfa) in patients on oral FXa
inhibitor treatment including apixaban and rivaroxaban experiencing
an intracranial hemorrhage, will be stopped early.1 The decision is
based on achieving pre-specified stopping criteria of superior
hemostatic efficacy, the ability to limit the expansion of a
potentially life-threatening bleed in the brain, versus usual
care.1,2
The recommendation to stop the trial was made by the independent
Data and Safety Monitoring Board (DSMB) following a planned interim
assessment of efficacy after 450 patients had been randomized and
followed for one month, which showed ANDEXXA’s reversal benefits
earlier in the study enrolment than originally anticipated.
Stuart J. Connolly, MD, FRCPC, Senior Scientist at Population
Health Research Institute and professor emeritus at McMaster
University in Hamilton, Ontario, said: “We are pleased that the
study has met its efficacy endpoint at the planned interim
analysis, showing improved control of bleeding with targeted
anticoagulation reversal, compared to usual care. We look forward
to sharing the full efficacy and safety results after further
analysis, with the hope that the data will pave the way for further
guidance on the treatment of potentially life-threatening
bleeds.”
Mene Pangalos, Executive Vice President, BioPharmaceuticals
R&D, AstraZeneca, said:
“Millions of people worldwide depend on FXa inhibitors to
prevent harmful blood clots from forming, but these agents also
carry a small but significant risk of increasing the likelihood
that an acute major bleed could occur. We are proud to offer the
first and only approved treatment to specifically reverse FXa
inhibitor activity and help achieve hemostasis, providing an
effective and reliable treatment when immediate care is
required.”
ANDEXXA is specifically designed to rapidly reverse the
anticoagulation effects of direct oral FXa inhibitors due to
life-threatening or uncontrolled bleeding.3 The treatment has been
granted accelerated approval in the US and is conditionally
approved in the EU, Switzerland and UK as Ondexxya for adults
treated with FXa inhibitors apixaban and rivaroxaban. It is also
approved in Japan as Ondexxya for FXa inhibitors apixaban,
rivaroxaban, or edoxaban. Use of ANDEXXA is supported by over 15
national and international guidelines across multiple
disciplines.4-19
AstraZeneca will now initiate closure of ANNEXA-I and proceed
with regulatory filings in the US and EU to convert to full label
approval. The full efficacy and safety results will be submitted
for presentation at a forthcoming medical meeting and
publication.
IMPORTANT SAFETY INFORMATION FOR ANDEXXA® (coagulation factor
Xa [recombinant], inactivated-zhzo)
WARNING: THROMBOEMBOLIC RISKS, ISCHEMIC RISKS, CARDIAC
ARREST, AND SUDDEN DEATHS
Treatment with ANDEXXA has been associated with serious and
life-threatening adverse events, including:
- Arterial and venous thromboembolic events
- Ischemic events, including myocardial infarction and
ischemic stroke
- Cardiac arrest
- Sudden deaths
Monitor for thromboembolic events and initiate
anticoagulation when medically appropriate. Monitor for
symptoms and signs that precede cardiac arrest and provide
treatment as needed.
WARNINGS AND PRECAUTIONS
- Arterial and venous thromboembolic events, ischemic events, and
cardiac events, including sudden death, have occurred during
treatment with ANDEXXA. To reduce thromboembolic risk, resume
anticoagulant therapy as soon as medically appropriate following
treatment with ANDEXXA. The safety of ANDEXXA has not been
evaluated in subjects who experienced thromboembolic events or
disseminated intravascular coagulation within two weeks prior to
the life-threatening bleeding event requiring treatment with
ANDEXXA. Safety of ANDEXXA also has not been evaluated in subjects
who received prothrombin complex concentrates, recombinant factor
VIIa, or whole blood products within seven days prior to the
bleeding event.
- Re-elevation or incomplete reversal of anticoagulant activity
can occur.
- ANDEXXA may interfere with the anticoagulant effect of heparin.
If anticoagulation is needed, use an alternative anticoagulant to
heparin.
ADVERSE REACTIONS
The most common adverse reactions (≥ 5%) in bleeding subjects
receiving ANDEXXA were urinary tract infections and pneumonia. The
most common adverse reactions (≥ 3%) in healthy volunteers treated
with ANDEXXA were infusion-related reactions.
Please see full Prescribing Information, including Boxed
WARNING.
INDICATION
ANDEXXA® (coagulation factor Xa [recombinant], inactivated-zhzo)
is a recombinant modified human factor Xa (FXa) protein indicated
for patients treated with rivaroxaban or apixaban, when reversal of
anticoagulation is needed due to life-threatening or uncontrolled
bleeding.
This indication is approved under accelerated approval based on
the change from baseline in anti-FXa activity in healthy
volunteers. An improvement in hemostasis has not been established.
Continued approval for this indication may be contingent upon the
results of studies that demonstrate an improvement in hemostasis in
patients.
Limitations of Use
ANDEXXA has not been shown to be effective for, and is not
indicated for, the treatment of bleeding related to any FXa
inhibitors other than apixaban or rivaroxaban.
Notes
Life-threatening bleeding
Millions of people worldwide depend on Factor Xa (FXa)
inhibitors to manage their risk of blood clots developing.20 These
medicines are important to maintaining health and wellbeing,
however, carry a small but significant risk of an acute major
bleed.21-26 There are different forms of uncontrolled bleeding that
may occur. One that has high risk of being life threatening, if
left untreated, is an intracranial hemorrhage (ICH).27-29 There is
an urgent need for access to specific reversal agents for patients
treated with FXa inhibitors as major bleeding can be life
threatening and can happen inside the body, so may not be visible.
As prescriptions for FXa inhibitors increase, the need for
efficacious and reliable care for uncontrolled bleeds
grows.30,31
ANNEXA-I
ANNEXA-I is a randomized, multi-center clinical trial designed
to determine the efficacy and safety of andexanet alfa versus usual
care in adult patients (≥18 years) with an intracranial hemorrhage
who have received oral FXa inhibitors, including apixaban and
rivaroxaban, and is part of the post-marketing study commitment
required to support full US and EU approvals.1 ANNEXA-I enrolled
over 450 adult patients with an intracranial hemorrhage who were
also being treated with FXa inhibitors (apixaban and rivaroxaban),
a type of direct oral anticoagulant (DOAC), commonly referred to as
blood-thinners. The primary endpoint was the rate of effective
hemostasis, or stopping the flow of blood, following treatment with
ANDEXXA compared with usual care, including four-factor prothrombin
complex concentrate (4F-PCC).1,2 ANNEXA-I was conducted in patients
with acute ICH, which are typically assessed by hematoma bleed size
and location.1 There is an established method for measurement of
hematoma size and expansion, allowing for definitive assessment of
hemostatic efficacy.32,33
ANDEXXA
ANDEXXA (andexanet alfa) is a recombinant protein specifically
designed to bind to FXa inhibitors and rapidly reverse their
anticoagulant effect.34 ANDEXXA is a modified form of the human FXa
molecule, an enzyme that helps blood clot. ANDEXXA works by acting
as a decoy for oral and injectable FXa inhibitors, which target and
bind to FXa, allowing them to exert their anticoagulant effect.
When ANDEXXA is given through an intravenous infusion to a patient
with FXa inhibitor-related bleeding, it binds with high affinity to
the FXa inhibitor, prevents it from inhibiting the activity of FXa
and reverses the anticoagulant effects of the inhibitor.
AstraZeneca in CVRM
Cardiovascular, Renal and Metabolism (CVRM), part of
BioPharmaceuticals, forms one of AstraZeneca’s three disease areas
and is a key growth driver for the Company. By following the
science to understand more clearly the underlying links between the
heart, kidneys and pancreas, AstraZeneca is investing in a
portfolio of medicines for organ protection and improving outcomes
by slowing disease progression, reducing risks and tackling
co-morbidities. The Company’s ambition is to modify or halt the
natural course of CVRM diseases and potentially regenerate organs
and restore function, by continuing to deliver transformative
science that improves treatment practices and CV health for
millions of patients worldwide.
AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company
that focuses on the discovery, development, and commercialization
of prescription medicines in Oncology, Rare Diseases, and
BioPharmaceuticals, including Cardiovascular, Renal &
Metabolism, and Respiratory & Immunology. Based in Cambridge,
UK, AstraZeneca operates in over 100 countries and its innovative
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@AstraZenecaUS.
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