Portola Pharmaceuticals, Inc.® (Nasdaq: PTLA) today announced the
presentation of a new analysis of data from an important subgroup
of ANNEXA-4, the Company’s Phase 3b/4 trial of its Factor Xa
inhibitor antidote Andexxa® [coagulation factor Xa (recombinant),
inactivated-zhzo] in patients with acute major bleeding while
taking a Factor Xa inhibitor. Data on a key subset of patients with
spontaneous (non-traumatic) intracranial hemorrhage are being
featured in an oral presentation today at the 5th European Stroke
Organisation Conference (ESOC 2019) in Milan, Italy.
Spontaneous intracranial hemorrhage is a
bleeding event in the brain not caused by trauma, and it is
associated with high rates of mortality and morbidity. Among the
352 patients in the ANNEXA-4 study, 227 (64%) experienced an
intracranial hemorrhage. Of these,128 (56%) were treated for a
spontaneous intracranial hemorrhage, 98 of which were evaluable for
hemostatic efficacy. Among this subset, 79% (n=77/98) achieved
excellent or good hemostasis (stoppage of bleeding) over the
12-hour period following treatment with Andexxa, as determined by
an independent adjudication committee. This is consistent with the
82% (n=204/249) reported in the full ANNEXA-4 study across patients
with all types of bleeds (e.g., intracranial hemorrhage bleeds,
gastrointestinal and other compartmental bleeds).
Among the 98 efficacy evaluable patients in this
subset, the median increase in hematoma volume from baseline to 12
hours was 0.06 milliliters, a volume increase of 1% over
baseline. Further, 71 patients in this subset experienced a
spontaneous, single-compartment, intracerebral hemorrhage, a bleed
type that allows for the most precise measurement of hematoma
volume. Of the patients that achieved excellent or good hemostatic
efficacy within one hour post Andexxa, 98% (n=55/56) maintained
excellent or good hemostatic control 12 hours following Andexxa
administration.
Within 30 days of enrollment, thrombotic events
occurred in 14 patients with spontaneous intracranial hemorrhage
(10.9%) and death occurred in 24 patients (18.8%), consistent with
the full ANNEXA-4 study results and the high background thrombotic
risk of the enrolled patient population. Among the 18 patients who
re-started oral anticoagulation therapy within 30 days, no
thrombotic events were observed. The majority of thrombotic events
occurred in patients who delayed or did not re-start
anticoagulation therapy with a Factor Xa inhibitor during the
follow-up period.
“A spontaneous intracranial hemorrhage while on
a Factor Xa inhibitor is a significant challenge that can result in
death, and for which there traditionally have been no direct
pharmacologic treatment options,” said Andrew M. Demchuk, M.D.,
FRCPC, director of the Calgary Stroke Program at the University of
Calgary. “These data demonstrate that, even in this
difficult-to-treat subset of patients, the hemostatic efficacy and
safety of Andexxa is compelling and consistent. Additionally, there
were no observed thrombotic events after resumption of oral
anticoagulation when it was possible.”
The worldwide use of Factor Xa inhibitors is
rapidly growing because of their efficacy and safety profile
compared to warfarin in preventing and treating
thromboembolic conditions such as stroke, pulmonary embolism
and venous thromboembolism (VTE). This growth has come with a
parallel increase in the incidence of hospital admissions and
deaths related to major bleeding, the most significant complication
of anticoagulation. In the U.S. alone in 2017, there were
approximately 140,000 hospital admissions attributable to Factor Xa
inhibitor-related bleeding. “These data help to further
characterize the durable hemostatic efficacy of Andexxa regardless
of age, dose, type of Factor Xa inhibitor and type of bleed, and we
look forward to continuing to generate additional data that
highlight Andexxa’s safety and efficacy profile,” said Scott
Garland, Portola’s president and chief executive officer. “We have
a significant opportunity to impact patient lives, and we are
working as fast as we can to ensure patients in the U.S. and Europe
have access to this potentially life-saving medicine.”
Andexxa received both U.S. Orphan Drug and U.S.
Food and Drug Administration (FDA) Breakthrough Therapy
designations and was approved on May 3, 2018 under the FDA's
Accelerated Approval pathway. It received conditional marketing
authorization from the European Commission on April 26, 2019, and
will be marketed in Europe as Ondexxya® (andexanet alfa). It is the
first and only antidote indicated for patients treated with
rivaroxaban or apixaban, when reversal of anticoagulation is needed
due to life-threatening or uncontrolled bleeding.
ANNEXA-4 Study Design
ANNEXA-4 is a global, prospective, single-arm,
open-label clinical trial designed to evaluate andexanet alfa in
patients who present with an acute major bleed while receiving
apixaban, rivaroxaban, edoxaban or enoxaparin. This multi-center
cohort study was not randomized and all participants received
andexanet alfa given as a bolus dose over 20-30 minutes followed by
a two-hour (120 minute) infusion. Patients received a low or high
dose infusion depending on which Factor Xa inhibitor they received
and the time since they received the last dose. Patients were
evaluated for 30 days following andexanet alfa administration. The
co-primary efficacy endpoints are the maximum percent reduction in
anti-Factor Xa activity and assessment of hemostasis over 12 hours
following the infusion. Hemostatic efficacy was assessed by an
independent endpoint adjudication committee using predetermined
criteria as either excellent, good or poor/none. The primary safety
endpoints were mortality and thrombotic events at 30 days, and the
development of antibodies to Andexxa or to native Factor X and
Factor Xa.
Among the 227 patients in the ANNEXA-4 trial who
experienced an intracranial hemorrhage, 99 (44%) experienced a
traumatic intracranial bleed and 128 (56%) experienced a
spontaneous (non-traumatic) intracranial bleed. There are four
basic anatomic types of intracranial bleeds: 1) intracerebral
(within the brain tissue itself); 2) intraventricular (in the
hollow cavities in the center of the brain that contain spinal
fluid); 3) subdural (under the outer lining of the brain); and 4)
subarachnoid (under the inner lining of the brain). The bleeding
can be confined to any one of these four types or, occasionally,
occurs in combination.
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.
IndicationAndexxa [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 ActivityThe 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 ReactionsThe 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.
ImmunogenicityAs 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 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: 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, the need
for a specific Factor Xa inhibitor reversal agent, the number of
patients who could potentially benefit from Andexxa and our plans
to launch Ondexxya in Europe. 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.
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Investor Contact: |
Media Contact: |
Cara Miller |
Julie Normart |
Portola Pharmaceuticals |
Pure Communications |
IR@portola.com |
jnormart@purecommunications.com |
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