Portola Pharmaceuticals, Inc. (Nasdaq:PTLA) today announced new
interim findings from a Phase 2 proof-of-concept study of its
investigational Factor Xa inhibitor antidote, Andexanet alfa, in
healthy volunteers who received the Factor Xa inhibitor Eliquis®
(apixaban). Andexanet alfa was administered intravenously as a
bolus followed by a continuous infusion for up to two hours. Data
from this study showed a rapid and nearly complete reversal of the
anticoagulation effect of Eliquis measured at two minutes following
completion of the bolus, which was sustained during infusion for up
to two hours.
"Currently, there are no approved agents for reversing or
stopping the anticoagulant effect of novel Factor Xa inhibitors. We
believe that as the use of Factor Xa inhibitors extends to millions
of patients, a reversal agent for the estimated hundreds of
thousands of patients who will experience a significant acute bleed
or who will require urgent surgery will be important," said John T.
Curnutte, M.D., Ph.D., executive vice president of research and
development for Portola. "This study shows that the safety and
activity seen with Andexanet alfa in previous clinical studies can
be extended in duration, demonstrating that the nearly complete
anticoagulation reversal can be sustained for the duration of the
infusion. This may allow physicians to treat a broader range of
patients, such as those with bleeding due to a traumatic injury or
those requiring surgery. We plan to initiate pivotal studies in
2014 as part of our pursuit of an expedited approval process to
address this unmet need."
These new interim findings demonstrated that two minutes after
completion of a 420 mg bolus dose of Andexanet alfa (n=6), the
anticoagulant activity of Eliquis was reversed by approximately 92%
(p < 0.0001) as measured by anti-Factor Xa activity compared
with placebo (n=3). At the end of the two-hour infusion, the
anticoagulation activity of Eliquis remained reversed by
approximately 91% (p < 0.0001). The safety follow-up for this
study is ongoing with no serious adverse events or premature
discontinuations of Andexanet alfa reported to date. Safety data
for over 65 healthy volunteers dosed with Andexanet alfa across
Phase 1 and Phase 2 clinical studies showed no thrombotic events or
antibodies against Andexanet alfa, endogenous Factor Xa, or Factor
X. One serious adverse event, a case of pneumonia, was seen in the
Phase 1 study.
Need for Reversal Agent for Factor Xa
Inhibitors
Currently, millions of patients are treated with Factor Xa
inhibitors for short-term use or chronic conditions, and the
anticoagulant market is expected to continue to grow with the
adoption of novel oral anticoagulants. Clinical trial results
suggest that, depending on their underlying medical condition,
annually between 1% and 4% of these patients will experience
uncontrolled bleeding and an additional 1% will require emergency
surgery i. Currently, there is no antidote or reversal agent
approved for use against Factor Xa inhibitors. Leading clinicians
have identified, and the United States Food and Drug Administration
(FDA) has recognized, the lack of an effective reversal agent for
Factor Xa inhibitors as a significant unmet medical need.
Phase 2 Study Design and Results
This randomized, placebo-controlled, double-blind, cohort
dose-escalation Phase 2 proof-of-concept study treated 54 healthy
volunteers with 5 mg of Eliquis twice a day on days 1 through 6 and
then randomized them in a 6:3 ratio to intravenous (IV) Andexanet
alfa in six different cohorts. The first three cohorts were a
single IV bolus at 90 mg, 210 mg and 420 mg. The last three cohorts
were 420 mg IV bolus plus either a 45-minute infusion, a two-hour
infusion or a repeat bolus at 45 minutes.
Portola previously announced positive pharmacodynamic and safety
data from the three bolus-only dose cohorts. Those data
demonstrated a dose-related reversal of the anticoagulant activity
of Eliquis. Two minutes after administration of 420 mg Andexanet
alfa (n=6), the anticoagulant activity of Eliquis decreased by
greater than 95% as measured by anti-Factor Xa activity compared
with placebo (n=3). The reversal of anti-Factor Xa activity
correlated with a reduction in the level of free, unbound Eliquis
in the plasma consistent with the mechanism of action of Andexanet
alfa. The data were previously presented in an oral session at the
XXIV Congress of the International Society on Thrombosis and
Haemostasis in Amsterdam in July 2013.
About Andexanet Alfa (PRT4445*)
Andexanet alfa is a novel recombinant, modified Factor Xa
molecule that has the potential to be the first universal antidote
to reverse the effects of Factor Xa inhibitors in patients who
suffer an uncontrolled bleeding episode, trauma, or require
emergency surgery. Andexanet alfa is similar to native Factor Xa,
but has been modified to restrict its biological activity, such as
its ability to cleave thrombin, an enzyme involved in the clotting
cascade. Andexanet alfa acts as a Factor Xa decoy that binds and
sequesters direct Factor Xa inhibitors in the blood. Once bound to
Andexanet alfa, the Factor Xa inhibitors are unable to bind to and
inhibit native Factor Xa. The native Factor Xa should then be
available to participate in the coagulation process and restore
hemostasis.
Portola has entered into collaboration agreements with each of
the pharmaceutical companies that have Factor Xa inhibitors on the
market or in clinical development, including Bristol-Myers Squibb
and Pfizer, Bayer HealthCare and Janssen Pharmaceuticals, and
Daiichi Sankyo, while retaining all rights to the program. The
company is conducting a series of Phase 2 proof-of-concept studies
to evaluate the safety, tolerability, pharmacokinetics and
pharmacodynamics of Andexanet alfa after dosing of a direct or
indirect Factor Xa inhibitor in healthy volunteers. The direct and
indirect Factor Xa inhibitors include Eliquis® (apixaban), XARELTO®
(rivaroxaban), Lovenox® (enoxaparin), Lixiana® (edoxaban) and
Portola's investigational oral Factor Xa inhibitor, Betrixaban.
About Portola Pharmaceuticals, Inc.
Portola Pharmaceuticals is a biopharmaceutical company focused
on the development and commercialization of novel therapeutics in
the areas of thrombosis, other hematologic disorders and
inflammation. Portola's wholly-owned lead compound, Betrixaban, is
a novel, oral, once-daily Factor Xa inhibitor in Phase 3
development for extended-duration prophylaxis of a form of
thrombosis known as venous thromboembolism (VTE) in acute medically
ill patients. Currently, there is no anticoagulant approved for
extended-duration VTE prophylaxis in this population. Portola's
second lead development candidate, Andexanet alfa (PRT4445*), has
the potential to be the first universal antidote to reverse the
effects of Factor Xa inhibitors in patients who suffer an
uncontrolled bleeding episode or trauma, or who require emergency
surgery. Portola retains full, worldwide commercial rights to
Andexanet alfa. Portola's third product candidate, PRT2070, is an
orally available kinase inhibitor that uniquely inhibits two
validated tumor proliferation pathways -- spleen tyrosine kinase
(Syk) and janus kinase (JAK). It is currently being studied in
patients with genetically-defined hematologic cancers, as well as
for patients who have failed therapy due to relapse or acquired
mutations. Portola's fourth program is partnered with Biogen Idec
and is focused on the development of PRT2607, a selective Syk
inhibitor. For more information, visit www.portola.com.
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
Andexanet alfa's potential efficacy, safety, duration of activity
and potential to reverse the effects of all Factor Xa inhibitors,
the potential for physicians to treat a broader range of patients,
our plans for future clinical studies and pursuit of an expedited
approval process for Andexanet alfa and anticipated growth in the
market for anticoagulants. Risks that contribute to the uncertain
nature of the forward-looking statements include: the accuracy of
Portola's estimates regarding its ability to initiate and/or
complete its clinical studies; the success of Portola's clinical
studies and the demonstrated efficacy of Portola's product
candidates thereunder; regulatory developments in the United States
and foreign countries; and Portola's ability to attract and retain
key scientific or management personnel. These and other risks and
uncertainties are described more fully in Portola's most recent
filings with the Securities and Exchange Commission. All
forward-looking statements contained in this press release speak
only as of the date on which they were made. Portola undertakes no
obligation to update such statements to reflect events that occur
or circumstances that exist after the date on which they were
made.
*PRT4445 has a proposed International Nonproprietary Name (pINN)
of Andexanet alfa.
___________________________
i Rivaroxaban ROCKET (3.6% TIMI Major); Apixaban ARISTOTLE (2.1%
ISTH Major, 0.96 TIMI Major); Levi, Blood. 2008;111:4471-4476;
Circulation. 2012;126:343-348.
CONTACT: Investor Contact:
Alexandra Santos
Portola Pharmaceuticals
ir@portola.com
650.246.7239
Media Contact:
Joey Fleury
BrewLife
jfleury@brewlife.com
415.946.1090
Portola Pharmaceuticals (NASDAQ:PTLA)
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