--AndexXa Rapidly Reversed Anticoagulant Effect
of Factor Xa Inhibitors; Excellent or Good Hemostasis Was Achieved
in 79 Percent of Patients Over 12 Hours--
Portola Pharmaceuticals Inc.® (Nasdaq:PTLA) today announced interim
results from the ongoing Phase 3b/4 ANNEXA™-4 study of AndexXa™
(andexanet alfa), a Factor Xa inhibitor antidote. In this study of
patients with Factor Xa inhibitor-associated acute major bleeding,
a preliminary analysis of interim data from 67 patients (of whom 47
were evaluated for efficacy) showed that AndexXa rapidly and
substantially reversed anti-Factor Xa activity (the anticoagulant
mechanism of these drugs) when administered as a bolus, and
sustained this reversal when followed by a 120-minute infusion.
Additionally, 79 percent of these patients achieved excellent or
good hemostasis (stoppage of bleeding) over a 12-hour period
following infusion. These interim results were presented orally
today in a Late-Breaking Science Hot Line session at the European
Society of Cardiology (ESC) 2016 Congress in Rome. The interim
results were published simultaneously online by The New England
Journal of Medicine (NEJM) and are accessible at
http://investors.portola.com.
“In this preliminary analysis, AndexXa was effective in rapidly
reversing anti-Factor Xa inhibitor activity and restoring normal
blood clotting in real-world patients with Factor Xa
inhibitor-related bleeding. Based on these interim results, we
believe that ANNEXA-4 is on track to achieve its co-primary
efficacy endpoints upon study completion,” 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. “The hemostatic efficacy
results are especially important because no FDA or EMA-approved
antidote is available for these patients and no existing therapies,
including plasma-derived products for warfarin reversal, have
demonstrated reversal of Factor Xa inhibitor activity or clinical
efficacy and safety.”
Factor Xa inhibitors are associated with a decreased risk of
intracranial hemorrhage compared to warfarin, however the
consequences are similar and can be fatal. In large randomized
trials, the 30-day mortality rate in Factor Xa inhibitor patients
with intracranial hemorrhage (ICH) exceeds 40 percent.
The interim results from all 67 patients who received AndexXa
showed that the antidote was not associated with any infusion
reactions, and no patients developed antibodies to Factor Xa or
Factor X or neutralizing antibodies to AndexXa. During the 30-day
follow-up period, thrombotic events occurred in 12 patients (18
percent), and death occurred in 10 patients (15 percent). These
events occurred within the range expected in this population given
the severity of the bleeding, their underlying thrombotic risk, and
the low percentage who restarted anticoagulant therapy following
their bleeding episode.
“The ANNEXA-4 interim results are preliminary yet encouraging
because the percentage of patients who have achieved excellent or
good hemostasis is higher than the co-primary endpoint threshold of
above 50 percent defined in the study protocol,” said John
Curnutte, M.D. Ph.D., executive vice president, research and
development at Portola. “This threshold was determined based on
historical benchmarks of hemostatic control achieved with agents in
studies of warfarin reversal and on expert opinion. What is also
encouraging is that following two reviews that included the
patients described in this report, the Data and Safety Monitoring
Board recommended that the study proceed as planned.”
ANNEXA-4 Study Design ANNEXA-4 is a global,
single-arm, open-label clinical trial designed to evaluate AndexXa,
a U.S. Food and Drug Administration (FDA)-designated Breakthrough
Therapy, in patients who present with an acute major bleed while
receiving apixaban, rivaroxaban, edoxaban or enoxaparin. For
ethical reasons, this multi-center, prospective cohort study is not
randomized and all participants receive AndexXa given as a bolus
dose over 30 minutes followed by a two-hour infusion. Patients
receive a low or high dose depending on which Factor Xa inhibitor
they have received and the time they received it. Patients are
evaluated for 30 days following AndexXa administration. The
co-primary efficacy endpoints are the percent change in anti-Factor
Xa activity at two hours and assessment of hemostasis over 12 hours
following the infusion. Hemostatic efficacy is assessed by an
independent endpoint adjudication committee as either excellent,
good or poor/none. To date, ANNEXA-4 has enrolled more than 130
patients of the approximately 270 patients targeted for
inclusion.
ANNEXA-4 Interim ResultsThe interim results
included safety data from 67 patients who experienced
life-threatening gastrointestinal bleeding (49 percent),
intracranial bleeding (42 percent) or bleeding at another site (9
percent) within 18 hours of administration of apixaban (31
patients), rivaroxaban (32 patients) or enoxaparin (4
patients).
The efficacy population included only those 47 patients whose
bleed severity met the specific inclusion criteria, as determined
by an independent adjudication committee, and whose baseline
anti-Factor Xa activity was substantially elevated. The interim
efficacy results showed the following:
- AndexXa rapidly and substantially reversed anti-Factor Xa
activity, and these levels were sustained for the duration of
administration. Following the bolus dose, median anti-Factor Xa
activity decreased by 89 percent from baseline for patients on
rivaroxaban and by 93 percent for patients on apixaban, and was
sustained at similar levels for the duration of the two-hour
infusion.
- AndexXa was associated with normalization of blood clotting and
cessation of bleeding. The independent adjudication committee
determined that 37 of 47 patients (79 percent) achieved excellent
or good hemostasis. Among patients with gastrointestinal bleeding,
84 percent had excellent or good hemostasis as did 80 percent of
patients with intracranial bleeding. Hemostatic efficacy was
similar for patients on apixaban (75 percent) and rivaroxaban (81
percent).
Investor Event Webcast Information
Members of Portola’s senior management team, together with Dr.
Stuart J. Connolly, ANNEXA-4 Executive Committee chairman, and Dr.
C. Michael Gibson, ANNEXA-4 Executive Committee member, will
present and discuss the data during an investor event today,
Tuesday, August 30, following the ANNEXA-4 interim results data
presentation at the ESC Congress. The investor event will be
simultaneously webcast and will take place from 5:00-6:00 p.m.
CEST/11 a.m. - 12 p.m. EDT. To access the live and subsequently
archived webcast, go to the Investor Relations section of the
company's website at http://investors.portola.com. A replay will be
available for 30 days following the live event.
About the Need for a Factor Xa Inhibitor
AntidoteAnnually, 1 to 4 percent of patients treated with
Factor Xa inhibitors may experience major bleeding, and an
additional 1 percent may require emergency surgery. Commensurate
with the increase in the use of Factor Xa inhibitors -- for stroke
prevention in atrial fibrillation; treatment and prevention of deep
vein thrombosis (DVT) and pulmonary embolism; and prevention of DVT
following knee or hip replacement surgery -- the number of hospital
admissions due to bleeding associated with these agents continues
to grow. In the United States, more than 80,000 patients treated
with oral Factor Xa inhibitors were admitted to the hospital due to
bleeding during 2015. Including patients taking the injectable
Factor Xa inhibitor enoxaparin, it is estimated that more than
100,000 U.S. patients could benefit from an antidote annually.
Currently, there is no FDA-approved antidote for Factor Xa
inhibitors for these patients.
About AndexXa AndexXa, an investigational drug,
is a modified human Factor Xa molecule that acts as a decoy to
target and sequester with high specificity both oral and injectable
Factor Xa inhibitors in the blood. Once bound, the Factor Xa
inhibitors are unable to bind to and inhibit native Factor Xa, thus
potentially allowing for the restoration of normal hemostatic
processes. AndexXa is the first compound being studied as an
antidote for Factor Xa inhibitors that directly and specifically
reverses anti-Factor Xa activity – the anticoagulant mechanism of
these agents.
On August 17, 2016, Portola received a Complete Response Letter
(CRL) from the FDA regarding its Biologics License Application
(BLA) for AndexXa. The Company plans to meet with the FDA as soon
as possible in order to resolve the outstanding questions in the
CRL and determine appropriate next steps. In the EU, Portola
submitted a Marketing Authorization Application (MAA), which has
been validated and is under review by the European Medicines Agency
(EMA).
About Portola Pharmaceuticals,
Inc.
Portola Pharmaceuticals is a biopharmaceutical company
developing product candidates that could significantly advance the
fields of thrombosis and other hematologic diseases. The Company is
advancing three programs, including betrixaban, an oral, once-daily
Factor Xa inhibitor; AndexXa™ (andexanet alfa), a recombinant
protein designed to reverse the anticoagulant effect in patients
treated with an oral or injectable Factor Xa inhibitor; and
cerdulatinib, a Syk/JAK inhibitor in development to treat
hematologic cancers. Portola's partnered program is focused on
developing selective Syk inhibitors for inflammatory conditions.
For more information, visit www.portola.com and follow the
Company on Twitter @Portola_Pharma.
Forward-looking Statements
Statements contained in this press release regarding matters
that are not historical facts are "forward-looking statements"
within the meaning of the Private Securities Litigation Reform Act
of 1995. Because such statements are subject to risks and
uncertainties, actual results may differ materially from those
expressed or implied by such forward-looking statements. Such
statements include, but are not limited to, statements regarding
the potential future regulatory approval of andexanet alfa and
patient populations that could benefit from a Factor Xa inhibitor
reversal agent. Risks that contribute to the uncertain nature of
the forward-looking statements include the risk that we may be
unable to satisfy regulatory requirements for such approval, we may
be unable to manufacture andexanet alfa on a commercial scale, and
we will need additional capital to fund our operations. These and
other risks and uncertainties are described more fully in our most
recent filings with the Securities and Exchange Commission,
including our Current Report on 8-K filed on August 19, 2016, and
our most recent quarterly report on Form 10-Q, which was filed on
August 9, 2016. All forward-looking statements contained in this
press release speak only as of the date on which they were made. We
undertake no obligation to update such statements to reflect events
that occur or circumstances that exist after the date on which they
were made.
Investor Contact:
Ana Kapor
Portola Pharmaceuticals
ir@portola.com
Media Contact:
Julie Normart
W2O Group
jnormart@w2ogroup.com
415.946.1087
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