Portola Pharmaceuticals (Nasdaq:PTLA) today announced full results
from the first part of the Phase 3 ANNEXA™-R (Andexanet Alfa a
Novel Antidote to the Anticoagulant Effects of fXa Inhibitors –
Rivaroxaban) study, which is evaluating the safety and efficacy of
andexanet alfa with the Factor Xa inhibitor XARELTO® (rivaroxaban)
in healthy volunteers. Results showed the first part of this
registration-enabling study met all primary and secondary endpoints
with high statistical significance (p<0.0001 compared with
placebo). Andexanet alfa administered as an intravenous (IV) bolus
produced rapid and significant reversal of the anticoagulant effect
of XARELTO® as measured by anti-Factor Xa activity (>90 percent
reduction of mean anti-Factor Xa activity within five minutes of
the end of administration). Additionally, there was a significant
reduction in the level of free (unbound) XARELTO® in the plasma,
and thrombin generation was rapidly restored to within the normal
baseline range following administration of andexanet alfa. In the
study, andexanet alfa was well tolerated. There were no serious or
severe adverse events, no thrombotic events, and no antibodies to
Factor X or Xa observed.
Andexanet alfa, a U.S. Food and Drug Administration
(FDA)-designated breakthrough therapy, is a recombinant protein
specifically designed to reverse the anticoagulant activity in
patients treated with an oral or injectable Factor Xa inhibitor.
Andexanet alfa has the potential to be a first-in-class antidote
for anticoagulated patients who suffer a major bleeding episode or
require emergency surgery.
"Given the rapid and near-complete reversal of the anticoagulant
effect of XARELTO® demonstrated in the Phase 3 ANNEXA-R study and
of apixaban in the Phase 3 ANNEXA-A study, we believe that
andexanet alfa has the potential to become the first approved
universal antidote for Factor Xa inhibitors and the standard of
care to manage bleeding associated with these novel
anticoagulants," said John T. Curnutte, M.D., Ph.D., executive vice
president, research and development for Portola. "Andexanet alfa is
the only Factor Xa inhibitor antidote in development shown to
directly and significantly impact definitive markers of
coagulation, such as anti-Factor Xa levels, in clinical studies. We
plan to submit these data as part of our Biologics License
Application to the FDA by the end of this year. With andexanet alfa
and betrixaban, our investigational Factor Xa inhibitor, we are
building a robust thrombosis franchise of potentially life-saving
medicines that could benefit millions of patients worldwide."
ANNEXA-R Study Design and Results
The randomized, double-blind, placebo-controlled Phase 3
ANNEXA-R study is evaluating the safety and efficacy of andexanet
alfa in reversing XARELTO®-induced anticoagulation in healthy
volunteers ages 50-75 years. Efficacy is being evaluated using
biomarker endpoints, with anti-Factor Xa levels as the primary
endpoint. Secondary endpoints include plasma levels of free unbound
XARELTO® and endogenous thrombin potential (ETP), a measure of
thrombin generation.
In the first part of the ANNEXA-R study, 41 healthy volunteers
were given XARELTO® 20 mg once daily for four days to steady state.
They were then randomized in a 2:1 ratio to receive at Cmax either
andexanet alfa administered as an 800 mg IV bolus (n=27) or placebo
(n=14).
Results showed that, for the primary endpoint, andexanet alfa
reduced the anti-Factor Xa activity of rivaroxaban from baseline to
nadir by >90 percent, a highly significant difference
(p<0.0001). For the secondary endpoints:
- Significantly more andexanet alfa subjects (26 of 27) than
placebo subjects (0) had a 90 percent or greater reduction in
anti-Factor Xa activity from baseline to nadir (p<0.0001).
- The free (unbound) XARELTO® concentration from baseline to
nadir was reduced significantly by andexanet alfa compared with
placebo (p<0.0001).
- ETP significantly increased from baseline to peak in andexanet
alfa subjects compared with placebo subjects (p<0.0001).
- 26 of 27 andexanet alfa subjects returned to the normal range
of thrombin generation within 10 minutes of the end of the bolus
administration.
In the study, andexanet alfa was well tolerated. There were no
serious or severe adverse events, no thrombotic events, and no
antibodies to Factor X or Xa were observed.
In the second part of the ANNEXA-R study, approximately 40
healthy volunteers will be given XARELTO® 20 mg once daily for four
days and will then be randomized in a 2:1 ratio to receive either
andexanet alfa administered as an 800 mg IV bolus followed by a
continuous infusion of 8 mg/min for 120 minutes or to placebo. Data
from this part of the study are expected in mid-2015.
Data Presentation
The abstract of the study results was posted today and can be
accessed at http://www.abstractsonline.com/pp8/#!/3658. The data
will be presented at the American College of Cardiology's (ACC)
64th Annual Scientific Session in San Diego on Monday, March 16, at
11:30 a.m. PT in an oral session titled "Highlighted Original
Research: Acute Coronary Syndromes and the Year in Review."
About the Need for a Factor Xa Inhibitor
Antidote
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. Recent
patient datai confirm earlier clinical trial results showing that,
annually, between 1-4 percent of patients treated with Factor Xa
inhibitors may experience major bleeding and an additional 1
percent may require emergency surgery. Development of a specific
antidote designed to reverse the anticoagulant activity of Factor
Xa inhibitors may provide an important treatment option for
patients who experience a major bleeding event or require emergency
surgery.
About Andexanet Alfa
Andexanet alfa 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 allowing for the restoration of normal hemostatic
processes. Andexanet alfa has the potential to address numerous
clinical scenarios where an antidote is needed by allowing for
flexible and controlled reversal. This can be short-acting through
the administration of an IV bolus or longer-acting with the
addition of an extended infusion.
Andexanet alfa is the only compound being studied as a reversal
agent for Factor Xa inhibitors that directly and specifically
corrects anti-Factor Xa activity -- the anticoagulant mechanism of
these agents.
Andexanet alfa has been granted orphan drug designation by the
FDA for reversing the anticoagulant effect of direct or indirect
Factor Xa inhibitors in patients experiencing a serious
uncontrolled bleeding event or who require urgent or emergent
surgery.
About the Andexanet Alfa Clinical Development
Program
Portola is evaluating andexanet alfa in two randomized,
placebo-controlled Phase 3 ANNEXA™ (Andexanet Alfa a Novel Antidote
to the Anticoagulant Effects of fXA Inhibitors) registration
studies using pharmacodynamic endpoints agreed to with the FDA,
including anti-Factor Xa inhibitor units, to demonstrate efficacy.
The Company reported statistically significant results from the
first part of the Phase 3 ANNEXA-A study, which evaluated andexanet
alfa administered as a single IV bolus dose with Bristol-Myers
Squibb Company and Pfizer Inc.'s direct Factor Xa inhibitor
apixaban, and from the first part of the Phase 3 ANNEXA-R study
with Bayer HealthCare and Janssen's direct Factor Xa inhibitor
rivaroxaban. The second parts of the ANNEXA-A and ANNEXA-R studies
are ongoing and are evaluating a bolus plus a continuous infusion
of andexanet alfa to sustain the reversal of anticoagulation
activity.
ANNEXA-4, a Phase 4 single-arm confirmatory study in patients
receiving apixaban, rivaroxaban, edoxaban or enoxaparin (a low
molecular weight heparin and indirect Factor Xa inhibitor) who
present with an acute major bleed, is also ongoing. Data from the
ANNEXA-A and ANNEXA-R studies, as well as data from a small number
of patients from ANNEXA-4, will serve as the clinical basis of a
Biologics License Application (BLA), which Portola plans to submit
under an Accelerated Approval pathway.
Results from four separate Phase 2 proof-of concept studies with
apixaban, rivaroxaban, edoxaban and enoxaparin in healthy
volunteers demonstrated that andexanet alfa immediately reversed
the anticoagulation activity of each Factor Xa inhibitor and that
the reversal could be sustained. Andexanet alfa has been shown to
be well tolerated in clinical studies, which have included more
than 140 healthy volunteers. No thrombotic events or antibodies to
Factor Xa or Factor X have been observed.
A Phase 2 proof-of-concept study with Portola's investigational
Factor Xa inhibitor betrixaban is planned.
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 its three wholly-owned programs using novel biomarker and
genetic approaches that may increase the likelihood of clinical,
regulatory and commercial success of its potentially life-saving
therapies. Portola's partnered program is focused on developing
selective Syk inhibitors for inflammatory conditions.
Betrixaban Portola's wholly-owned, oral, once-daily Factor Xa
inhibitor betrixaban is being evaluated in the only biomarker-based
Phase 3 study for hospital-to-home prophylaxis of venous
thromboembolism (VTE) in acute medically ill patients. Betrixaban's
distinct properties may have the potential to allow the agent to
demonstrate efficacy without the significant increase in the rate
of major bleeding that was seen in this patient population with
other Factor Xa inhibitors. If approved, betrixaban could be the
first anticoagulant for both hospital and post-discharge VTE
prophylaxis and the standard of care in this large market of more
than 20 million patients in the G7 countries alone.
Andexanet Alfa
Andexanet alfa, a U.S. Food and Drug Administration
(FDA)-designated breakthrough therapy, is a recombinant protein
designed to reverse the anticoagulant activity in patients treated
with an oral or injectable Factor Xa inhibitor. Andexanet alfa has
the potential to be a first-in-class antidote for anticoagulated
patients who suffer a major bleeding episode or require emergency
surgery. Portola has entered into Phase 3 clinical collaboration
agreements with all of the manufacturers of direct Factor Xa
inhibitors – Bristol-Myers Squibb and Pfizer (Eliquis [apixaban]),
Bayer HealthCare and Janssen Pharmaceuticals (XARELTO®
[rivaroxaban]), and Daiichi Sankyo (edoxaban) – while retaining all
commercial rights to andexanet alfa. The Company is currently
evaluating andexanet alfa in the Phase 3 and Phase 4 ANNEXA™
(Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of
fXA Inhibitors) registration studies.
Cerdulatinib
Portola's product candidate in the area of hematologic cancer,
cerdulatinib, is an orally available molecule that uniquely
inhibits two validated tumor proliferation pathways – spleen
tyrosine kinase (Syk) and janus kinase (JAK). It is currently being
evaluated in a Phase 1/2a proof-of-concept study in patients with B
cell leukemias or lymphomas with a focus on genetically-defined
subtypes, as well as in patients who have failed therapy due to
relapse or acquired mutations.
For more information, visit www.portola.com and follow the
Company on Twitter @Portola_Pharma.
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, clinical trial cost, design and
timing, the potential indications, efficacy, safety and activity of
andexanet alfa, and the potential market and indications for our
other product candidates. 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; Portola's ability
to manufacture andexanet alfa; 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, including its Annual Report on Form 10-K, which was
filed on March 2, 2015. 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.
i Source: Truven MARKETSCAN® Commercial, Medicare Supplemental
and Medicaid Database (12 months ending March 2014).
CONTACT: Media: Joey Fleury, BrewLife, jfleury@brewlife.com, 415.946.1090
Investors: Alexandra Santos, Portola Pharmaceuticals, ir@portola.com, 650.246.7239
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