– Breakthrough Product is a Major Advance in the
Treatment of Patients Hospitalized with Life-Threatening
Bleeding –
Portola Pharmaceuticals, Inc.® (Nasdaq:PTLA) today announced that
the U.S. Food and Drug Administration (FDA) has approved Andexxa®
[coagulation factor Xa (recombinant), inactivated-zhzo], the first
and only antidote indicated for patients treated with rivaroxaban
and apixaban, when reversal of anticoagulation is needed due to
life-threatening or uncontrolled bleeding.
Andexxa received both U.S. Orphan Drug and FDA
Breakthrough Therapy designations and was approved under the FDA’s
Accelerated Approval pathway based on the change from baseline in
anti-Factor Xa activity in healthy volunteers. Continued approval
for this indication may be contingent upon post-marketing study
results to demonstrate an improvement in hemostasis in
patients.
“Today’s approval represents a significant step
forward in patient care and one that the medical community has been
eagerly anticipating,” said Stuart J. Connolly, M.D., ANNEXA-4
Executive Committee chairman and professor in the Department of
Medicine of the Faculty of Health Sciences at McMaster University
in Hamilton, Ontario. “Andexxa’s rapid reversal of the
anticoagulating effects of rivaroxaban and apixaban will help
clinicians treat life-threatening bleeds, where every minute
counts.”
The use of Factor Xa inhibitors is rapidly
growing because of their efficacy and safety profile compared to
enoxaparin and warfarin in preventing and treating
thromboembolic conditions such as stroke, pulmonary embolism
and venous thromboembolism (VTE). This growth has come with a
related increase in the incidence of hospital admissions and deaths
related to bleeding, the major complication of anticoagulation. In
the U.S. alone in 2016, there were approximately 117,000 hospital
admissions attributable to Factor Xa inhibitor-related bleeding and
nearly 2,000 bleeding-related deaths per month.
“We are grateful to the patients who
participated in our trials, our clinical trial collaborators, our
employees and the FDA for their help in bringing this new drug to
market for the benefit of patients with Factor Xa inhibitor-related
bleeding,” said Bill Lis, chief executive officer of Portola. “We
are proud that Andexxa is a first-in-class medicine discovered in
our labs. In addition to Bevyxxa, the first and only anticoagulant
approved for extended VTE prevention in acute hospitalized medical
patients, Andexxa is our second FDA-approved product with the
potential to save lives and have a major impact on global public
health. We remain committed to our scientific leadership in the
fields of thrombosis and hematologic cancers.”
The approval of Andexxa is supported by data
from two Phase 3 ANNEXA studies (ANNEXA-R and ANNEXA-A) published
in The New England Journal of Medicine, which evaluated the safety
and efficacy of Andexxa in reversing the anticoagulant activity of
the Factor Xa inhibitors rivaroxaban and apixaban in healthy
volunteers (Figure 1 and Figure 2, respectively). As described in
the label, results demonstrated that Andexxa rapidly and
significantly reversed anti-Factor Xa activity (the anticoagulant
mechanism of these medicines). The median decrease in anti-Factor
Xa activity from baseline was 97 percent for rivaroxaban and 92
percent for apixaban.
Figure
1: http://resource.globenewswire.com/Resource/Download/4095503f-3499-484d-b338-8bfafc30b9a2
Figure 2:
http://resource.globenewswire.com/Resource/Download/31eec65f-c059-43e3-aab2-f249be97a217
Interim data from the ongoing ANNEXA-4
single-arm, open-label study in patients with
major bleeding also were assessed by the FDA as part of its
review and approval. Data from 185 evaluable patients showed that
Andexxa rapidly and significantly reversed anti-Factor Xa activity
when administered as a bolus and sustained this reversal when
followed by a 120-minute infusion. The median decrease from
baseline was 90 percent for rivaroxaban and 93 percent for
apixaban.
For additional Important Safety Information and
Andexxa’s full Prescribing Information, please visit
http://www.Andexxa.com.
The post-marketing requirement is a clinical
trial that randomizes patients to receive either Andexxa or usual
care (the type of care the enrolling institution would provide in
the absence of Andexxa). This study is scheduled to be initiated in
2019 and be reported in 2023.
“The expansion of available reversal agents for
people prescribed newer oral anticoagulant therapies is crucial,”
said Randy Fenninger, chief executive officer of the National Blood
Clot Alliance, a patient-led, voluntary health advocacy
organization. “The availability now of a reversal agent specific to
rivaroxaban and apixaban expands choice and enables patients and
providers to consider these treatment options with greater
confidence.”
Consistent with the Company’s prior plan,
Portola expects to launch Andexxa under an Early Supply Program
with Generation 1 product in early June. Broader commercial launch
is anticipated in early 2019 upon FDA approval of its Generation 2
manufacturing process.
The Marketing Authorization Application (MAA)
for andexanet alfa is also under review by the European Medicines
Agency. The Committee for Medicinal Products for Human Use (CHMP)
communicated a positive trend vote on the MAA in February 2018. A
formal opinion from the CHMP is expected by the end of 2018, and
the European Commission is expected to issue a decision in early
2019.
Conference Call DetailsThe live
conference call, scheduled for Friday, May 4, 2018 at 8:30
a.m. ET, can be accessed by phone by calling (844) 452-6828
from the U.S. and Canada, or 1 (765) 507-2588
internationally, and using the passcode 1357748. The webcast can be
accessed live on the Investor Relations section of the Company's
website at http://investors.portola.com. It will be archived
for 30 days following the call.
About Andexxa Andexxa is a
recombinant protein specifically designed to bind to Factor Xa
inhibitors and rapidly reverse their anticoagulant effect. Andexxa
is a modified form of the human Factor Xa molecule, an enzyme that
helps blood clot. Andexxa works by acting as a decoy for oral and
injectable Factor Xa inhibitors, which target and bind to Factor
Xa, which allows them to exert their anticoagulant effect. When
Andexxa is given to a patient with Factor Xa inhibitor-related
bleeding, it binds to the Factor Xa inhibitor and prevents it from
inhibiting the activity of Factor Xa and reverses the anticoagulant
effects of the inhibitor.
IMPORTANT INFORMATION FOR ANDEXXA
[coagulation factor Xa (recombinant),
inactivated-zhzo]
BOXED WARNING: THROMBOEMBOLIC RISKS,
ISCHEMIC RISKS, CARDIAC ARREST AND SUDDEN DEATHS
See full prescribing information for
complete boxed warning
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.
IndicationAndexxa [coagulation
factor Xa (recombinant), inactivated-zhzo] is indicated for
patients treated with rivaroxaban and 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-Factor Xa (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 to demonstrate an
improvement in hemostasis in patients.
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 and rivaroxaban.
SELECT IMPORTANT SAFETY
INFORMATION
Thromboembolic Risk
Arterial and venous thromboembolic events,
ischemic events, sudden deaths, or events where a thrombotic event
could not be ruled out were observed within 30 days post- Andexxa
administration in 33 of the 185 patients (17.8%) evaluable for
safety in the ongoing ANNEXA-4 study. The median time to these
events was six days. Of the 86 patients who were re-anticoagulated
prior to a thrombotic event, 11 (12.7%) patients experienced a
thromboembolic event, ischemic event, cardiac event or death.
Monitor patients treated with Andexxa for signs
and symptoms of arterial and venous thromboembolic events, ischemic
events, and cardiac arrest. To reduce thromboembolic risk, resume
anticoagulant therapy as soon as medically appropriate following
treatment with Andexxa.
No thromboembolic events were observed in 223
healthy volunteers who received Factor Xa inhibitors and were
treated with Andexxa.
The safety of Andexxa has not been evaluated in
patients 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 patients 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
Anti-FXa ActivityThe time course of anti-FXa activity
following Andexxa administration was consistent among the healthy
volunteer studies and the ANNEXA-4 study in bleeding patients.
Compared to baseline, there was a rapid and substantial decrease in
anti-FXa activity corresponding to the Andexxa bolus. This decrease
was sustained through the end of the Andexxa continuous infusion.
Following the infusion, there was an increase in anti-FXa activity,
which peaked four hours after infusion in ANNEXA-4 subjects. After
this peak, the anti-FXa activity decreased at a rate similar to the
clearance of the FXa inhibitors.
Thirty-eight patients who were anticoagulated
with apixaban had baseline levels of anti-FXa activity > 150
ng/mL. Nineteen of these 38 (50%) patients experienced a > 93%
decrease from baseline anti-FXa activity after administration of
Andexxa. Eleven patients who were anticoagulated with rivaroxaban
had baseline anti-FXa activity levels > 300 ng/mL. Five of the
11 patients experienced a > 90% decrease from baseline anti-FXa
activity after administration of Andexxa.
Adverse ReactionsThe most
common adverse reactions (≥ 5%) in patients receiving Andexxa were
urinary tract infections and pneumonia.
The most common adverse reactions (≥ 3%) in
healthy volunteers treated with Andexxa were infusion-related
reactions.
ImmunogenicityAs with all
therapeutic proteins, there is potential for immunogenicity. Low
titers of anti-Andexxa antibodies were observed in
26/145 healthy subjects (17%); 6% (9/145) were first observed
at Day 30 with 20 subjects (14%) still having titers at the last
time point (days 44 to 48). To date, the pattern of antibody
response in patients in the ANNEXA-4 study has been similar to that
observed in healthy volunteers with 6% of the patients having
antibodies against Andexxa (6/98 patients). None of these
anti-Andexxa antibodies were neutralizing. No antibodies
cross-reacting with FX or FXa were detected in healthy subjects
(0/145) or in bleeding patients to date (0/98).
Portola Pharmaceuticals, Inc. Portola
Pharmaceuticals is a commercial-stage biopharmaceutical company
focused on the discovery, development and commercialization of
novel therapeutics that could significantly advance the fields of
thrombosis and other hematologic diseases. The Company’s two
FDA-approved medicines are Bevyxxa® (betrixaban), the first and
only oral, once-daily Factor Xa inhibitor, and Andexxa®
[coagulation factor Xa (recombinant), inactivated-zhzo], the first
and only antidote for the Factor Xa inhibitors rivaroxaban and
apixaban. The company also is advancing cerdulatinib, a SYK/JAK
inhibitor for the treatment of hematologic cancers.
Forward-Looking StatementsThis
announcement contains forward-looking statements, including
statements relating to Portola Pharmaceuticals’ expectations
regarding post-marketing commitments required for Andexxa, the
potential of Andexxa to save lives in the U.S. and other countries
and the timing of commercial availability of Andexxa and regulatory
milestones in Europe. These statements are subject to significant
risks and uncertainties, and actual results could differ materially
from those projected. Portola Pharmaceuticals cautions investors
not to place undue reliance on the forward-looking statements
contained in this release. These risks and uncertainties include,
without limitation, risks and uncertainties that physicians may not
see the benefits of utilizing Andexxa for the indications which it
is approved; the ability of Portola to continue to manufacture
Andexxa and to expand approved manufacturing facilities; the
possibility of unfavorable results from additional clinical trials
involving Andexxa; the risk that the EMA, may not approve Andexxa
in the currently anticipated timelines or at all, and that any
marketing approvals may have significant limitations on its use;
the risk that Portola may not obtain additional regulatory
approvals necessary to expand approved indications for Andexxa; and
other general business risks which could have a material adverse
impact on Portola’s business, including risks associated with the
launch of Portola’s first product Bevyxxa®; regulatory actions or
delays or government regulation generally; Portola’s ability to
obtain or maintain proprietary intellectual property protection;
the particular prescribing preferences of physicians and patients;
global trends toward health care cost containment, including
government, payor and general public pricing and reimbursement
pressures; general economic and industry conditions, including the
effects of the persistently weak economic and financial environment
in many countries; safety, quality or manufacturing issues. Risks
and uncertainties relating to Portola Pharmaceuticals and
its business can be found in the “Risk Factors” section of Portola
Pharmaceuticals’ Annual Report on Form 10-K for 2017, which was
filed with the SEC on March 1, 2018, as updated by
subsequent periodic reports filed by Portola with the SEC,
including Quarterly Reports on Form 10-Q and Current Reports on
Form 8-K which are deemed “filed” with the SEC. Portola
Pharmaceuticals undertakes no duty or obligation to update any
forward-looking statements contained in this release as a result of
new information, future events or changes in Portola
Pharmaceuticals’ expectations.
|
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Investor Contact: Cara Miller Portola
Pharmaceuticals IR@portola.com
|
Media Contact: Christie Teller Pure
Communications cteller@purecommunications.com |
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