Portola Pharmaceuticals (Nasdaq:PTLA) today announced additional
results of a Phase 2 proof-of-concept study that showed andexanet
alfa's ability to immediately reverse the anticoagulation activity
of XARELTO® (rivaroxaban) through the administration of a short
intravenous bolus. The data also showed that this reversal can be
prolonged if needed by a continuous infusion. Andexanet alfa was
well tolerated, with no serious adverse events reported. The data
were presented at the 55th American Society of Hematology (ASH)
Annual Meeting in New Orleans by lead investigator Mark Crowther,
M.D., M.Sc., associate chair, Department of Medicine, McMaster
University, Hamilton, Ontario.
Andexanet alfa has the potential to be a first-in-class
universal antidote designed to reverse the anticoagulant activity
of Factor Xa inhibitors in patients who experience an uncontrolled
bleeding episode or who require emergency surgery. By the year
2020, Portola estimates that the number of patients presenting to
the hospital who could benefit from an antidote may approach
500,000 in the United States, Japan and the five largest European
Union countries alone. In November 2013, andexanet alfa was
designated as a breakthrough therapy by the U.S. Food and Drug
Administration.
"We have now shown that andexanet alfa produces immediate,
dose-dependent and well-tolerated reversal of multiple Factor Xa
inhibitors. Andexanet alfa's unique flexibility to provide
short-term reversal through the administration of an intravenous
bolus or sustained reversal by the addition of an extended infusion
is critical in covering the multiple clinical scenarios where a
reversal agent is needed," said John T. Curnutte, M.D., Ph.D.,
executive vice president of research and development for Portola.
"Importantly, we believe andexanet alfa's highly specific mechanism
of action may minimize complications that can be associated with
agents that have off-target activity."
Phase 2 Study Design and Results
The randomized, double-blind, placebo-controlled, cohort
dose-escalation Phase 2 proof-of-concept study treated healthy
volunteers with an oral dose of XARELTO® at 20 mg once daily for
six days and then randomized 36 volunteers in a 6:3 ratio to
andexanet alfa in four different dosing cohorts. The first three
cohorts received a single IV bolus of andexanet alfa at 210 mg, 420
mg or 600 mg, respectively. A fourth cohort received a single IV
bolus of andexanet alfa at 720 mg followed by a 4 mg/minute
infusion for one hour.
Immediately following completion of the 210 mg, 420 mg, 600 mg
and 720 mg bolus doses of andexanet alfa, anti-Factor Xa activity
decreased dose-dependently by 20 percent, 53 percent, 70 percent
and 81 percent, respectively, from the pre-andexanet alfa level and
returned to placebo levels approximately two hours after treatment.
In parallel, the plasma concentrations of unbound XARELTO® were
decreased by 32 percent, 51 percent, 75 percent and 70 percent
respectively, relative to pre-andexanet alfa values.
XARELTO®-induced inhibition of thrombin generation and prolongation
of both prothrombin time and activated clotting time approached
normal levels with andexanet alfa in a dose-dependent manner.
Safety data showed that andexanet alfa was well tolerated, with
no thrombotic events or serious adverse events reported. No
antibodies to Factor Xa or Factor X were observed in this or other
Phase 2 studies, which have included a total of more than 80
volunteers.
Investor Briefing Webcast Details
Portola will host an investor briefing today, Monday, December
9, at 2:05 p.m. Central Time (3:05 p.m. Eastern Time) during the
ASH Annual Meeting in New Orleans. During the event, Portola's
senior management team will provide an update on the Company's
recent business progress. A live webcast of the event will be
available via the Investor Relations section of the Company's
website at www.portola.com. A replay will be available on the
Company's website for 30 days following the live event.
About Andexanet Alfa (PRT4445*) Andexanet alfa
is a first-in-class recombinant, modified Factor Xa molecule being
developed as a direct reversal agent (antidote) for patients
receiving a Factor Xa inhibitor who suffer an uncontrolled bleeding
episode or who require emergency surgery. Andexanet alfa acts as a
Factor Xa decoy that targets and sequesters with high specificity
both direct and indirect Factor Xa inhibitors in the
blood. Once bound, the Factor Xa inhibitors are unable to bind
to and inhibit native Factor Xa, thus allowing for the restoration
of normal hemostatic processes. Through its mechanism of action,
andexanet alfa has the potential to act as a universal antidote and
address the direct cause of the patient's inhibited clotting
activity without being prothrombotic.
Andexanet alfa has been designated as a breakthrough therapy by
the U.S. Food and Drug Administration (FDA). The FDA's
breakthrough therapy designation is intended to expedite the
development and review of drugs for serious or life-threatening
conditions.i Portola is pursuing an Accelerated Approval
pathway for andexanet alfa and plans to initiate
registration-enabling studies in 2014 to potentially bring this
therapy to patients in need.
The Company has reported data from its ongoing Phase 2
proof-of-concept studies of andexanet alfa and the Factor Xa
inhibitors Eliquis® and XARELTO®. Additional studies are
ongoing with Lovenox® (enoxaparin), Lixiana® and Portola's
investigational oral Factor Xa inhibitor, betrixaban, which is
being studied in a Phase 3 clinical trial and has the potential to
be the first oral Factor Xa inhibitor approved for venous
thromboembolism (VTE) prevention in acute medically ill patients.
Portola has entered into clinical collaboration agreements with all
of the manufacturers of direct Factor Xa inhibitors, including
Bristol-Myers Squibb and Pfizer (Eliquis® [apixaban]), Bayer
HealthCare and Janssen Pharmaceuticals (XARELTO® [rivaroxaban]),
and Daiichi Sankyo (Lixiana® [edoxaban]), while retaining all
rights to the program.
About Portola Pharmaceuticals, Inc. Portola
Pharmaceuticals is a biopharmaceutical company focused on the
development and commercialization of novel therapeutics in the
areas of thrombosis and hematology.
Betrixaban 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 venous
thromboembolism (VTE) in acute medically ill patients. Betrixaban's
properties may be uniquely suited to potentially demonstrate
efficacy without significantly increasing bleeding in this patient
population. Currently, there is no anticoagulant approved for
extended-duration VTE prophylaxis in acute medically ill patients.
Andexanet Alfa* (PRT4445) Portola's second lead development
candidate, andexanet alfa (PRT4445), has the potential to be a
first-in-class universal antidote to directly reverse the effects
of Factor Xa inhibitors in patients who suffer an uncontrolled
bleeding episode or who require emergency surgery. Portola retains
full, worldwide commercial rights to andexanet alfa, which has been
designated as a breakthrough therapy by the U.S. Food and Drug
Administration.
Cerdulatinib* (PRT2070) and PRT2607 Portola's third product
candidate, cerdulatinib (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 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: Portola's plans for future clinical studies and
pursuit of an Accelerated Approval process for andexanet alfa,
anticipated growth in the market for anticoagulants, and the
potential efficacy, safety, and activity of andexanet alfa,
betrixaban, and cerdulatinib. 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 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.
*Andexanet alfa and cerdulatinib are proposed International
Nonproprietary Names (pINN).
i New England Journal of Medicine 369:20; November 14, 2013.
http://www.nejm.org/doi/pdf/10.1056/NEJMp1311439. Accessed November
23, 2013.
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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