Portola Pharmaceuticals (Nasdaq:PTLA) announced that the results of
its Phase 3 ANNEXA™ (Andexanet Alfa a Novel Antidote to the
Anticoagulant Effects of FXa Inhibitors) studies were published
online today by The New England Journal of Medicine. ANNEXA-R and
ANNEXA-A evaluated the safety and efficacy of andexanet alfa, an
investigational reversal agent, which was designated a breakthrough
therapy by the U.S. Food and Drug Administration (FDA), for
reversing the anticoagulant activity of the Factor Xa inhibitors
rivaroxaban and apixaban, respectively, in healthy volunteers.
Results showed that both ANNEXA Part 1 (bolus only) and Part 2
(bolus plus continuous infusion) met all primary and secondary
efficacy endpoints, including the measurement of reversal Anti-Xa
activity (p<0.0001) for both rivaroxaban and apixaban.
In Part 1, andexanet alfa given as an IV bolus reversed the
anticoagulant effect of the Factor Xa inhibitors to no-effect
levels, as measured by anti-Factor Xa activity, within two to five
minutes of administration (p<0.0001). In Part 2, andexanet alfa
administered as an IV bolus followed by a continuous two-hour
infusion sustained that reversal for the duration of the infusion,
reducing anticoagulant activity (p<0.0001). Andexanet alfa was
well tolerated, with no serious or severe adverse events, no
thrombotic events, and no antibodies to Factor X or Xa
observed.
Full results of Part 2 of ANNEXA-R also were presented today
during a Late Breaking Clinical Trial session at the American Heart
Association’s (AHA) Scientific Sessions 2015 in Orlando, Florida,
in an abstract entitled: ANNEXA™-R Part 2: A Phase 3 Randomized,
Double-Blind, Placebo-Controlled Trial Demonstrating Sustained
Reversal of Rivaroxaban-Induced Anticoagulation in Older Subjects
by Andexanet Alfa (PRT064445), a Universal Antidote for Factor Xa
(FXa) Inhibitors.
Commensurate with the increase in use of Factor Xa inhibitors,
the number of hospital admissions due to bleeding associated with
these agents continues to grow. Annually, 1 to 4 percent of
patients treated with Factor Xa inhibitors may experience major
bleeding, and an additional 1 percent may require emergency
surgery. In the United States alone, during the 12 months ended
April 2015, there were over 50,000 rivaroxaban or apixaban treated
patients admitted to the hospital due to bleeding1. This number
does not account for patients taking the injectable Factor Xa
inhibitor enoxaparin or those on a Factor Xa inhibitor undergoing
emergency surgery. In the United States, more than 100,000 patients
annually may benefit from a reversal agent. Currently, there is no
FDA-approved reversal agent for Factor Xa inhibitors for these
patients. Portola is developing andexanet alfa, a recombinant
protein specifically designed to reverse the anticoagulant activity
of Factor Xa inhibitors, as a universal reversal agent for patients
anticoagulated with an oral or injectable Factor Xa inhibitor who
experience a serious uncontrolled bleeding event or who require
urgent or emergency surgery.
Four-factor PCCs, are not approved to reverse the anticoagulant
effects of Factor Xa inhibitors, and no known label-enabling
studies are ongoing. Additionally, the FDA and the European
Medicines Agency do not view four-factor PCCs, which are only
approved to reverse the effects of vitamin K and include a black
box warning for blood clots, as a standard of care therapy for this
patient population.
“The ANNEXA studies demonstrated that andexanet alfa can rapidly
reverse the anticoagulant effect of Factor Xa inhibitors for both
short and sustained periods with a good safety profile. This is
important because it means that andexanet alfa, by allowing for
flexible and controlled reversal, could address different clinical
scenarios in which a reversal agent is needed,” said John T.
Curnutte, M.D., Ph.D., executive vice president, research and
development, for Portola. “These positive ANNEXA study results
suggest that andexanet alfa, if approved, could become the first
universal reversal agent for Factor Xa inhibitors and could also
become the new standard of care for managing serious uncontrolled
bleeding in patients treated with these novel anticoagulants.”
Design of ANNEXA StudiesThe randomized,
double-blind, placebo-controlled Phase 3 ANNEXA-R and ANNEXA-A
studies evaluated the safety and efficacy of andexanet alfa in
reversing the anticoagulant effect of rivaroxaban and apixaban,
respectively, in healthy volunteers aged 50-68 years. Efficacy was
evaluated using widely accepted coagulation biomarkers. The primary
endpoint was reduction in anti-Factor Xa levels; secondary
endpoints included reduction in plasma levels of free unbound
rivaroxaban or apixaban and restoration of the endogenous thrombin
potential (ETP), a measure of thrombin generation.
ANNEXA-R Efficacy Results In Part 1, 41 healthy
volunteers were given rivaroxaban 20 mg once daily for four days
and then randomized in a 2:1 ratio to receive either andexanet alfa
administered as an 800 mg IV bolus (n=27) or placebo (n=14). Within
two to five minutes of completion of the bolus dose, andexanet alfa
significantly reversed the anticoagulant activity of rivaroxaban
(by 92 percent) compared with placebo (p<0.0001), as measured by
anti-Factor Xa activity; significantly reduced the level of free
(unbound) rivaroxaban in the plasma compared with placebo
(p<0.0001); and fully restored thrombin generation in 96 percent
of subjects (p<0.0001 vs. placebo).
In Part 2, 39 healthy volunteers were given rivaroxaban 20 mg
once daily for four days and then 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
(n=26) or placebo (n=13). Andexanet alfa significantly reduced
anti-Factor Xa activity by 97 percent compared with placebo
(p<0.0001), with reversal persisting for 1 to 2 hours after
completion of the infusion. The reduction in free unbound
rivaroxaban was sustained with the bolus plus infusion, which
significantly reduced the mean plasma concentration of free unbound
rivaroxaban compared with placebo (p<0.0001). Andexanet alfa
also restored thrombin generation to normal in all subjects who
received the compound (p<0.0001 vs. placebo).
ANNEXA-A Efficacy ResultsIn Part 1, 33 subjects
were given apixaban 5 mg twice daily for 3.5 days and then
randomized in a 3:1 ratio to receive either andexanet alfa
administered as a 400 mg IV bolus (n=24) or placebo (n=9). Within
two to five minutes of completion of the bolus dose, andexanet alfa
significantly reversed the anticoagulant activity of apixaban (by
94 percent) compared with placebo (p<0.0001), as measured by
anti-Factor Xa activity; significantly reduced the level of free
(unbound) apixaban in the plasma compared with placebo
(p<0.0001); and fully restored thrombin generation in 100
percent of subjects (p<0.0001 vs. placebo).
In Part 2, 31 healthy volunteers were given apixaban 5 mg twice
daily for four days and then randomized in a 3:1 ratio to receive
either andexanet alfa administered as a 400 mg IV bolus followed by
a continuous infusion of 4 mg/min for 120 minutes (n=24) or placebo
(n=8). Andexanet alfa significantly reduced anti-Factor Xa activity
by 92 percent compared with placebo (p<0.0001), with reversal
persisting for 1 to 2 hours after completion of the infusion. The
reduction in free unbound apixaban was sustained with the bolus
plus infusion, which significantly reduced the mean plasma
concentration of free unbound apixaban compared with placebo
(p=0.0002). Andexanet alfa also restored thrombin generation to
normal in all subjects who received the compound (p<0.0001 vs.
placebo).
ANNEXA Safety ResultsAndexanet alfa was well
tolerated in both studies. No serious or severe adverse events, no
thrombotic events, and no antibodies to Factor X or Xa were
reported. All adverse events related to andexanet administration
were non-serious and mild.
About Andexanet AlfaAndexanet 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
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.
Portola is currently evaluating andexanet alfa in ANNEXA-4, a
Phase 4 single-arm, open label 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. Data from a small number of
patients from ANNEXA-4, as well as data from ANNEXA-A and ANNEXA-R,
will serve as the clinical basis for the Biologics License
Application (BLA). A rolling submission of the BLA has been
initiated under Accelerated Approval and the submission package is
expected to be complete by the end of this year.
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.
These programs include betrixaban, an oral, once-daily Factor Xa
inhibitor being evaluated in the APEX Phase 3 study for prophylaxis
of venous thromboembolism; 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 StatementsStatements 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 to
treat patients needing reversal of Factor Xa anticoagulation
effects, the projected number of patients that could benefit from
andexanet alfa, the potential for andexanet alfa to become the
first universal reversal agent for Factor Xa inhibitors and the
standard of care for managing major bleeding among patients on
Factor Xa inhibitors, our plans for pursuit of regulatory approval
of andexanet alfa, including the anticipated timing of completion
of the submission of our BLA submission package, and the likelihood
of clinical, regulatory and commercial success for andexanet alfa
and our other product candidates. Risks that contribute to the
uncertain nature of the forward-looking statements include: our
expectation that we will incur losses for the foreseeable future
and will need additional funds to finance our operations; the
accuracy of our estimates regarding our ability to initiate and/or
complete our clinical trials and the timing and expense of these
trials; the pace of enrollment in our clinical trials; the results
of our clinical trials related to the efficacy and safety of our
product candidates; the risk that regulatory approval of our
product candidates may not be received in a timely manner, or at
all; our potential inability to manufacture andexanet alfa and our
other product candidates on a commercial scale in a timely or
cost-efficient manner; the accuracy of estimates regarding our
expenses and capital requirements; our ability to successfully
build a hospital-based sales force and commercial infrastructure;
regulatory developments in the United States and foreign countries;
our ability to obtain and maintain intellectual property protection
for our product candidates; and our ability to retain key
scientific or management personnel. These and other risks and
uncertainties are described more fully in our most recent filings
with the Securities and Exchange Commission, including our Annual
Report on Form 10-K, which was filed on March 2, 2015, and
Quarterly Report on Form 10-Q for the third quarter of 2015, which
was filed on November 9, 2015. 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.
1 Truven, MarketScan Commercial, Medicare Supplemental,
last 12 months ending April 30, 2015. Medicaid accounts for ~5% of
the total bleed related admissions.
Investor Contact:
Ana Kapor
Portola Pharmaceuticals
ir@portola.com
Media Contact:
Julie Normart
W2O Group
jnormart@w2ogroup.com
Portola Pharmaceuticals (NASDAQ:PTLA)
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