SOUTH SAN FRANCISCO, Calif.,
July 8, 2019 /PRNewswire/ -- Portola
Pharmaceuticals, Inc.® (Nasdaq: PTLA) today announced
new in vitro data establishing the relationship
between concentrations of the direct oral anticoagulants (DOACs)
apixaban and rivaroxaban and the ability of four-factor prothrombin
complex concentrate (4F-PCC) to correct inhibition of thrombin
generation, compared with warfarin anticoagulation reversal by
4F-PCC. Data were presented on July 8,
2019 during a poster session at the Annual Congress of the
International Society on Thrombosis and Haemostasis (ISTH 2019) in
Melbourne, Australia.
Results showed that, while effective in reversing inhibition of
thrombin generation in plasma from patients treated with warfarin,
4F-PCCs did not appear to have an effect on the inhibition of
thrombin generation by apixaban or rivaroxaban unless the Factor Xa
inhibitor concentration was less than 75 ng/mL. In contrast, data
from the same thrombin generation assay demonstrated that
Andexxa® [coagulation factor Xa (recombinant),
inactivated-zhzo] fully corrected the inhibition of thrombin
generation by apixaban and rivaroxaban across a broad range of
inhibitor concentrations.
"The results of this new in vitro study provide further
evidence as to why 4F-PCCs are not currently indicated or approved
for the reversal of Factor Xa activity in patients treated with
apixaban and rivaroxaban," said Pamela
Conley, Ph.D., senior vice president of research at Portola
Pharmaceuticals. "While our study results further support the
efficacy of 4F-PCCs in reversing the anticoagulant effects of
warfarin, they appear to have minimal impact on the inhibition of
thrombin generation by direct Factor Xa inhibitors over the range
of exposures typically seen in bleeding patients. For example, in
the ANNEXA-4 trial of Andexxa in Factor Xa inhibitor-treated
patients with acute major bleeding, approximately 75% of the
patients had anticoagulant concentrations above 75 ng/mL at the
time of Andexxa reversal therapy."
In this study, tissue factor (TF)-initiated thrombin generation
was assessed using plasma from healthy donors or patients treated
with warfarin. Reversal of warfarin anticoagulation by 4F-PCC
(using commercially available
Kcentra®/Beriplex®) was performed using
individual plasma samples from warfarin-treated patients to which
the equivalent of either the low or high therapeutic 4F-PCC dose
was added. Reversal of apixaban or rivaroxaban anticoagulation by
4F-PCC and Andexxa was similarly measured using normal human plasma
containing different concentrations of Factor Xa inhibitor (0-250
ng/mL for rivaroxaban and 0-125 ng/mL for apixaban). Finally, the
effect of individual purified plasma components of 4F-PCC on
thrombin generation in normal plasma was measured.
"These data demonstrate that 4F-PCCs are likely not to be
effective in reversing DOAC concentrations over 75 ng/mL and
underscore the need for Andexxa, a unique reversal agent designed
specifically to reverse Factor Xa inhibitor activity in apixaban-
or rivaroxaban-treated patients experiencing a life-threatening
bleed," said Scott Garland,
president and chief executive officer of Portola. "Andexxa is now recognized by 16 U.S.
and European medical society guidelines and we look forward to
continuing to generate additional data that further characterizes
the efficacy and safety profile of Andexxa. Our hope is that this
ongoing research will assist in ensuring that physicians have the
information they need to appropriately treat life-threatening
bleeds associated with Factor Xa inhibitor use."
The use of Factor Xa inhibitors is rapidly growing because of
their efficacy and safety profile compared to warfarin and
enoxaparin in preventing and treating thromboembolic conditions
such as stroke, pulmonary embolism and venous thromboembolism
(VTE). This growth has come with a related increase in the
incidence of hospital admissions and deaths related to bleeding,
the major complication of anticoagulation. In the U.S. alone in
2017, there were approximately 140,000 hospital admissions
attributable to Factor Xa inhibitor-related bleeding.
Andexxa is the first and only reversal agent approved for adult
patients treated with the Factor Xa inhibitors apixaban or
rivaroxaban when reversal of anticoagulation is needed due to
life-threatening or uncontrolled bleeding. It received both Orphan
Drug and Breakthrough Therapy designations from the U.S. Food and
Drug Administration (FDA), and it was approved on May 3, 2018, under the FDA's Accelerated Approval
pathway. It is marketed in Europe
as Ondexxya® (andexanet alfa).
IMPORTANT SAFETY INFORMATION FOR ANDEXXA [coagulation factor
Xa (recombinant), inactivated-zhzo]
BOXED WARNING: THROMBOEMBOLIC RISKS, ISCHEMIC RISKS, CARDIAC
ARREST AND SUDDEN DEATHS
See full prescribing information for complete boxed
warning
Treatment with Andexxa has been associated with serious and
life‑threatening adverse events, including:
- Arterial and venous thromboembolic events
- Ischemic events, including myocardial infarction and
ischemic stroke
- Cardiac arrest
- Sudden deaths
Monitor for thromboembolic events and initiate
anticoagulation when medically appropriate. Monitor for symptoms
and signs that precede cardiac arrest and provide treatment as
needed.
Indication
Andexxa [coagulation factor Xa
(recombinant), inactivated-zhzo] is a recombinant modified human
Factor Xa (FXa) protein indicated for patients treated with
rivaroxaban or apixaban, when reversal of anticoagulation is needed
due to life-threatening or uncontrolled bleeding.
This indication is approved under accelerated approval based on
the change from baseline in anti-FXa activity in healthy
volunteers. An improvement in hemostasis has not been established.
Continued approval for this indication may be contingent upon the
results of studies to demonstrate an improvement in hemostasis in
patients.
Limitation of Use
Andexxa has not been shown to be effective for, and is not
indicated for, the treatment of bleeding related to any FXa
inhibitors other than apixaban or rivaroxaban.
SELECT IMPORTANT SAFETY INFORMATION
Thromboembolic and Ischemic Risk
The thromboembolic and ischemic risks were assessed in 185
patients who received the Generation 1 product and in 124 patients
who received the Generation 2 product. The median time to first
event was six days, and patients were observed for these events for
30 days following Andexxa infusion. Of the 86 patients who received
Generation 1 product and were re-anticoagulated prior to a
thrombotic event, 11 (12.7%) patients experienced a thromboembolic
event, ischemic event, cardiac event or death.
Monitor patients treated with Andexxa for signs and symptoms of
arterial and venous thromboembolic events, ischemic events, and
cardiac arrest. To reduce thromboembolic risk, resume anticoagulant
therapy as soon as medically appropriate following treatment with
Andexxa.
The safety of Andexxa has not been evaluated in patients who
experienced thromboembolic events or disseminated intravascular
coagulation within two weeks prior to the life-threatening bleeding
event requiring treatment with Andexxa. Safety of Andexxa also has
not been evaluated in patients who received prothrombin complex
concentrates, recombinant Factor VIIa, or whole blood products
within seven days prior to the bleeding event.
Re-elevation or Incomplete Reversal of Anti-FXa
Activity
The time course of anti-FXa activity following
Andexxa administration was consistent among the healthy volunteer
studies and the ANNEXA-4 study in bleeding patients. Compared to
baseline, there was a rapid and substantial decrease in anti-FXa
activity corresponding to the Andexxa bolus. This decrease was
sustained through the end of the Andexxa continuous infusion. The
anti-FXa activity returned to the placebo levels approximately two
hours after completion of a bolus or continuous infusion.
Subsequently, the anti-FXa activity decreased at a rate similar to
the clearance of the FXa inhibitors.
Thirty-eight patients who received the Generation 1 product were
anticoagulated with apixaban and had baseline levels of anti-FXa
activity > 150 ng/mL. Nineteen of these 38 (50%) patients
experienced a > 93% decrease from baseline anti-FXa activity
after administration of Andexxa. Eleven patients who were
anticoagulated with rivaroxaban had baseline anti-FXa activity
levels > 300 ng/mL. Five of the 11 patients experienced a >
90% decrease from baseline anti-FXa activity after administration
of Andexxa. Anti-FXa activity levels for patients who received the
Generation 2 product were not available.
Adverse Reactions
The most common adverse reactions (≥
5%) in patients receiving Andexxa were urinary tract infections and
pneumonia.
The most common adverse reactions (≥ 3%) in healthy volunteers
treated with Andexxa were infusion-related reactions.
Immunogenicity
As with all therapeutic proteins, there
is potential for immunogenicity. Using an electrochemiluminescence
(ECL)-based assay, 145 Generation 1 Andexxa-treated healthy
subjects were tested for antibodies to Andexxa as well as
antibodies cross-reacting with Factor X (FX) and FXa. Low titers of
anti-Andexxa antibodies were observed in 26/145 healthy subjects
(17%); 6% (9/145) were first observed at Day 30 with 20 subjects
(14%) still having titers at the last time point (days 44 to 48).
To date, the pattern of antibody response in patients in the
ANNEXA-4 study has been similar to that observed in healthy
volunteers with 6% (6/98) of the patients having antibodies against
Andexxa. None of these anti-Andexxa antibodies were neutralizing.
No antibodies cross-reacting with FX or FXa were detected in
healthy subjects (0/145) or in bleeding patients (0/98) to date.
There is insufficient data to assess for the presence of
anti-Andexxa antibodies for subjects received the Generation 2
product.
About Portola Pharmaceuticals, Inc.
Portola
Pharmaceuticals is a global, commercial-stage biopharmaceutical
company focused on the discovery, development and commercialization
of novel therapeutics that could significantly advance the fields
of thrombosis and other hematologic conditions. The Company's first
two commercialized products are Andexxa® [coagulation
factor Xa (recombinant), inactivated-zhzo], marketed in
Europe as Ondexxya®
(andexanet alfa), and Bevyxxa® (betrixaban). The company
also is advancing cerdulatinib, a SYK/JAK inhibitor being developed
for the treatment of hematologic cancers. Founded in 2003 in
South San Francisco, California,
Portola has operations in
the United States and Europe.
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: the
potential of Andexxa to address life-threatening bleeding
associated with the use of the Factor Xa inhibitors apixaban or
rivaroxaban, clinical treatment of patients and the need for a
specific Factor Xa inhibitor reversal agent. These statements are
subject to significant risks and uncertainties, and actual results
could differ materially from those projected. These risks and
uncertainties include, without limitation, the risk that
physicians, patients and payers may not see the benefits of
utilizing Andexxa; the possibility of unfavorable results from
additional clinical trials involving Andexxa; the risk that
reimbursement limitations may have significant limitations on its
use; the risk that we may not obtain additional regulatory
approvals necessary to expand approved indications for Andexxa; our
ability to establish commercial operations in Europe and generate product revenue within
projected timelines and budget; 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
expenses and capital requirements; our ability to successfully
build a hospital-based sales force and commercial infrastructure;
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 most
recent annual report on Form 10-Q. 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.
Kcentra® and Beriplex® are registered
trademarks of CSL Behring GmbH and CSL Behring Canada,
respectively.
Investor
Contact:
|
Media
Contact:
|
Cara
Miller
|
Julie
Normart
|
Portola
Pharmaceuticals
|
Pure
Communications
|
IR@portola.com
|
jnormart@purecommunications.com
|
View original content to download
multimedia:http://www.prnewswire.com/news-releases/portola-pharmaceuticals-presents-new-in-vitro-data-demonstrating-that-four-factor-prothrombin-complex-concentrates-4f-pccs-had-no-direct-effect-on-inhibition-of-thrombin-generation-by-factor-xa-inhibitors-300880682.html
SOURCE Portola Pharmaceuticals, Inc.®