Portola Pharmaceuticals, Inc. (NASDAQ: PTLA) today announced
positive pharmacodynamic and safety data from a Phase 2
proof-of-concept study of its investigational Factor Xa inhibitor
antidote PRT4445 in healthy volunteers who were administered the
Factor Xa inhibitor Eliquis® (apixaban). Results showed greater
than a 95 percent reversal of the anticoagulant activity of Eliquis
was achieved within two minutes of intravenously administered
high-dose PRT4445, which has a tentatively approved International
Nonproprietary Name (INN) of andexanet alfa. In the study,
andexanet alfa was well tolerated, with no serious adverse events
or immunologic effects observed. The data were presented in an oral
session at the XXIV Congress of the International Society on
Thrombosis and Haemostasis (ISTH) in Amsterdam by Mark Crowther,
M.D., M.Sc., FRCPC, professor of medicine, Department of Medicine,
Hematology and Thromboembolism, McMaster University, Hamilton,
Ontario.
"Clinicians are gaining expertise with the use of Factor Xa
inhibitors, but there is no effective way to reverse or stop the
anticoagulation effect of these agents when a patient requires it,"
said Dr. Crowther. "These are the first Phase 2 data to indicate
that a product can reverse the anticoagulation effect of a Factor
Xa inhibitor."
Major bleeding events occur infrequently in patients taking
Factor Xa inhibitors (1-4 percent per year in several clinical
studies involving patients taking a Factor Xa inhibitor on a
chronic basis), and standard measures are currently employed to
manage these events. However, there is presently no approved
antidote or reversal agent that is specifically intended for use
against Factor Xa inhibitors. Development of andexanet alfa,
specifically designed to reverse the activity of Factor Xa
inhibitors, may provide an antidote for patients who experience an
uncontrolled major bleeding event or require emergency surgery.
Portola entered into a collaboration agreement with
Bristol-Myers Squibb Company and Pfizer Inc. to study andexanet
alfa with Eliquis in the Phase 2 study. This is the first in a
series of Phase 2 studies that are evaluating the safety and
pharmacodynamic activity of andexanet alfa in healthy volunteers
who have been administered one of several Factor Xa inhibitors.
Portola is currently evaluating andexanet alfa and XARELTO®
(rivaroxaban) in a separate Phase 2 study and expects to complete
that evaluation in 2013.
"The lack of an effective antidote is restricting the use of
Factor Xa inhibitors to patients at low risk for bleeding or
requiring surgery. Leading clinicians have identified an antidote
as a significant unmet clinical need," said John T. Curnutte, M.D.
Ph.D., executive vice president of research and development for
Portola. "Based on this need and our data, we believe that
andexanet alfa may be granted an accelerated development pathway
and we are working closely with the FDA to advance this program as
quickly as possible."
Phase 2 Study Design and Results In the
randomized, placebo-controlled, double-blind, cohort
dose-escalation Phase 2 study, 27 healthy volunteers were treated
on days 1-6 with Eliquis 5 mg twice a day (to steady state) and
then randomized in a 6:3 ratio to intravenous andexanet alfa (in
three different dose cohorts -- 90 mg, 210 mg or 420 mg) or saline
on day 6, three hours after receiving the last Eliquis dose.
Pharmacodynamic and safety data were collected through day 48 and
pharmacokinetic data through day 10.
Results demonstrated a dose-dependent 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 percent as measured by
anti-Factor Xa activity. Similarly, the 210 mg dose reduced
anti-Factor Xa activity by 80 percent compared with saline (n=9).
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.
Safety data for all 27 healthy volunteers after 48 days of
follow-up showed no thrombotic events, serious adverse events or
premature discontinuations of andexanet alfa. The incidence of
adverse events with andexanet alfa was similar to that with the
control. No antibodies were generated against andexanet alfa,
endogenous Factor Xa or Factor X.
About Andexanet Alfa Andexanet alfa is a
novel recombinant protein designed to reverse the anticoagulant
activity in patients treated with a Factor Xa inhibitor who suffer
an uncontrolled bleeding episode or need to undergo emergency
surgery. Andexanet alfa is similar to native Factor Xa, but has
been modified to restrict its biological activity to the reversal
of the anticoagulant effects of Factor Xa inhibitors. Andexanet
alfa acts as a Factor Xa decoy that binds and sequestors 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 is then available to participate in
the coagulation process and restore hemostasis. Results from a
Phase 1 single ascending dose safety and tolerability study of
andexanet alfa conducted by Portola in 32 healthy volunteers showed
no apparent safety signals, including no thrombotic adverse events
and no antibodies against andexanet alfa, endogenous Factor Xa or
Factor X.
About Portola Pharmaceuticals, Inc.
Portola is a biopharmaceutical company focused on the development
and commercialization of novel therapeutics in the areas of
thrombosis (blood clots), other hematologic disorders and
inflammation for patients who currently have limited or no approved
treatment options. Portola's current development-stage portfolio
consists of three compounds discovered through its internal
research efforts and one discovered by Portola scientists during
their time at a prior company.
Portola's two lead programs address significant unmet medical
needs in the area of thrombosis.
Portola's lead compound, betrixaban, is an investigational,
novel, oral, once-daily inhibitor of Factor Xa in Phase 3
development for extended duration prophylaxis (preventive
treatment) 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, is
a recombinant protein designed to reverse the anticoagulant
activity in patients treated with a Factor Xa inhibitor who suffer
an uncontrolled bleeding episode or require emergency surgery.
Portola has entered into collaboration agreements with
Bristol-Myers Squibb Company and Pfizer Inc., with Bayer Pharma AG
and Janssen Pharmaceuticals, Inc., and with Daiichi Sankyo to study
andexanet alfa with Eliquis® (apixaban), XARELTO® (rivaroxaban) and
edoxaban, respectively, in Portola's Phase 2 studies. Portola
retains full, worldwide commercial rights with respect to andexanet
alfa.
Portola's third product candidate, PRT2070, is an orally
available kinase inhibitor being developed for hematologic (blood)
cancers and inflammatory disorders. PRT2070 inhibits spleen
tyrosine kinase (Syk) and janus kinases (JAK), enzymes that
regulate important signaling pathways. Portola plans to file an
Investigational New Drug (IND) application in the third quarter of
2013and initiate a Phase 1/2 clinical study of PRT2070 in 2013 in
patients with B-cell hematologic cancers who have failed or
relapsed on existing marketed therapies or products in development,
including patients with identified mutations. Portola's fourth
program, PRT2607 and other highly selective Syk inhibitors, is
partnered with Biogen Idec Inc.
Forward-looking statement 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 use of
betrixaban as a Factor Xa inhibitor, the use of PRT4445, which has
a tentatively approved International Nonproprietary Name (INN) of
andexanet alfa, to reverse the anticoagulant activity in patients
treated with a Factor Xa inhibitor, the use of PRT2070 or PRT2607
as kinase inhibitors and any of Portola's clinical trials,
including Portola's Phase 3 APEX study for betrixaban, Phase 2
proof-of-concept studies for PRT4445 and Phase1/2 study for
PRT2070. 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 trials; the success of Portola's clinical trials and the
demonstrated efficacy of Portola's product candidates thereunder;
the accuracy of Portola's estimates regarding its expenses and
capital requirements; regulatory developments in the United States
and foreign countries; Portola's ability to obtain and maintain
intellectual property protection for its product candidates; and
the loss of key scientific or management personnel. These and other
risks and uncertainties are described more fully in Portola's
filings with the Securities and Exchange Commission, including
without limitation its Registration Statement on Form S-1 that was
originally filed with the Securities and Exchange Commission on
April 12, 2013, and the amendments thereto. 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.
Eliquis is a registered trademark of Bristol-Myers Squibb
Company.
Contacts: Mardi Dier CFO Portola Pharmaceuticals Email Contact
Paul Laland BrewLife Email Contact +1.415.519.6610
Portola Pharmaceuticals (NASDAQ:PTLA)
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