– Excellent or Good Hemostasis Achieved in 82
Percent of Evaluable Patients –
Portola Pharmaceuticals, Inc.® (Nasdaq: PTLA) today announced full
results from ANNEXA-4, the Company’s Phase 3b/4 trial of its Factor
Xa inhibitor antidote Andexxa® [coagulation factor Xa
(recombinant), inactivated-zhzo] in patients experiencing
acute major bleeding while taking a Factor Xa inhibitor. Data are
being presented as a late-breaking oral presentation today at the
International Stroke Conference 2019 and published simultaneously
online by The New England Journal of Medicine (NEJM).
Full data from 352 patients (249 of which were
evaluable for hemostatic efficacy; all 352 were evaluable for
safety) showed that Andexxa rapidly and significantly reversed
anti-Factor Xa activity when administered as a bolus, and sustained
this reversal when followed by a 120-minute infusion. Anti-Factor
Xa activity is a measure of the anticoagulant activity of apixaban,
rivaroxaban, edoxaban and enoxaparin, the anticoagulants studied in
ANNEXA-4. Among all 352 patients, 64 percent (n=227) were treated
for intracranial hemorrhage (ICH) and 26 percent (n=90) were
treated for a gastrointestinal bleed. Of those evaluated for
efficacy 82 percent (n=204) achieved excellent or good hemostasis
(stoppage of bleeding) over the 12-hour period following treatment
with Andexxa, as determined by an independent adjudication
committee.
Within 30 days of enrollment, thrombotic events occurred in 34
patients (9.7 percent) and death occurred in 49 patients (13.9
percent), consistent with previous ANNEXA-4 trial results and with
the high background thrombotic risk of the enrolled patient
population. 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. Among the 100
patients who re-started oral anticoagulation therapy, no thrombotic
events were observed. Two patients experienced an infusion reaction
and none developed antibodies to Factor Xa or Factor X or
neutralizing antibodies to Andexxa.
“The consistency of the hemostatic efficacy and
safety – regardless of age, dose, type of Factor Xa inhibitor and
type of bleed – confirms the potential of Andexxa to address
life-threatening bleeding associated with the use of the Factor Xa
inhibitors apixaban or rivaroxaban,” said Truman J. Milling
Jr., M.D., FACEP, Seton Dell Medical School Stroke Institute and
ANNEXA-4 Executive Committee member. “We now also have new data
demonstrating no observed thrombotic events after resumption of
oral anticoagulation. This is a particularly significant finding
given the clinical importance of re-initiating therapy as soon as
possible, even in the wake of a major bleeding event.”
The worldwide 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
proportional 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.
“The need for a specific Factor Xa inhibitor
reversal agent is clear. As Factor Xa inhibitor use continues to
grow, so does the prevalence of life-threatening bleeds such as an
ICH, which carries a mortality rate of nearly 50 percent,” said
John Curnutte, M.D., Ph.D., head of research and development at
Portola. “The consistency of the ANNEXA-4 data, the strong response
from the international medical societies that have already added
Andexxa to their guidelines and the initial demand following the
approval of Andexxa in May 2018 highlight its potential to
benefit thousands of patients facing life-threatening bleeding
associated with the use of rivaroxaban or apixaban.”
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. Andexxa 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, and it was recently
added to the 2019 AHA/ACC/HRS guidelines.
ANNEXA-4 Study DesignANNEXA-4
is a global, 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, prospective 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 death, thrombotic events and development of antibodies to
Andexxa or to native Factor X and Factor Xa.
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 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 diseases.
The Company’s two FDA-approved medicines are Andexxa® [coagulation
factor Xa (recombinant), inactivated-zhzo], the first and only
antidote for patients treated with rivaroxaban and apixaban when
reversal of anticoagulation is needed due to life-threatening or
uncontrolled bleeding, and Bevyxxa® (betrixaban), the first and
only oral, once-daily Factor Xa inhibitor for the prevention of VTE
in adult patients hospitalized for an acute medical illness. The
company also is advancing cerdulatinib, a Syk/JAK inhibitor for the
treatment of hematologic cancers.
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. These include statements relating to Portola
Pharmaceuticals’ expectations regarding 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 and the number of patients who could potentially benefit from
Andexxa. 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 the EMA may not approve Andexxa in the
currently anticipated timelines or at all, and that any marketing
approvals or 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 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 quarterly 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.
Investor
Contact:Cara MillerPortola
PharmaceuticalsIR@portola.com |
Media
Contact:Julie NormartPure
Communicationsjnormart@purecommunications.com |
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