SOUTH SAN FRANCISCO, Calif.,
Oct. 28, 2019 /PRNewswire/ -- Portola
Pharmaceuticals, Inc.® (Nasdaq: PTLA) today announced
the presentation of a new exploratory analysis of data from
ANNEXA-4, the Company's Phase 3b/4
trial of its Factor Xa inhibitor antidote Andexxa®
[coagulation factor Xa (recombinant), inactivated-zhzo], in a key
subgroup of patients with acute gastrointestinal (GI) bleeding
while taking a Factor Xa inhibitor.
The data will be featured at the American College of
Gastroenterology (ACG) 2019 Annual Scientific Meeting in
San Antonio, Texas, during a
plenary session on Tuesday, October 29,
2019, from 3:25 p.m. CDT to 3:35 p.m.
CDT (Location: Stars at Night Ballroom – B4; Plenary Session
3B, Abstract 53).
GI bleeding is a common type of anticoagulant-related bleeding
that occurs in the upper or lower GI tract. Among the 352 patients
in the ANNEXA-4 study, 90 (26%) were treated for acute GI
bleeding and 62 (18%) were evaluable for hemostatic efficacy.
Among this subset, 82% (n=51/62) 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., GI, intracranial hemorrhages and other sites of
bleeding). Both the exploratory analysis and full study results
showed that Andexxa rapidly and potently reversed anti-factor Xa
activity.
Patients with GI bleeding were considered efficacy evaluable if
they were determined to have major bleeding, as defined by
hemodynamic compromise or bleeding associated with a hemoglobin
(Hb) drop ≥ 2 g/dL or a baseline Hb ≤ 8 g/dL, and a baseline
anti-factor Xa activity ≥ 75 ng/mL (≥ 0.25 IU/mL for enoxaparin
patients).
Among the 90 safety evaluable patients with acute GI bleeding,
and within 30 days of enrollment, thrombotic events occurred in six
patients (7%) and death occurred in 10 patients (11%), consistent
with the full ANNEXA-4 study results and the high background
thrombotic risk of the enrolled patient population. No thrombotic
events were observed among the 40 (44%) patients who re-started
oral anticoagulation therapy. By comparison, among the 352
safety evaluable patients in ANNEXA-4 and within 30 days of
enrollment, thrombotic events occurred in 34 patients (9.7%) and
death occurred in 49 patients (13.9%). All of the thrombotic events
occurred in patients who delayed or did not re-start
anticoagulation therapy with a Factor Xa inhibitor during the
follow-up period.
"Major bleeding associated with use of Factor Xa inhibitors is a
serious and life-threatening complication," said Deborah Siegal, M.D., ACG presenter and
assistant professor in the Department of Medicine of the Faculty of
Health Sciences at McMaster University
in Hamilton, Ontario. "This
ANNEXA-4 sub-analysis of patients with bleeding in the GI tract –
the most common site of anticoagulant-related bleeding – continues
to demonstrate the consistency of the hemostatic efficacy and
safety of Andexxa."
The use of Factor Xa inhibitors is growing rapidly because of
their efficacy and safety profile compared to enoxaparin and
warfarin 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 2017, there were approximately
150,000 hospital admissions attributable to Factor Xa
inhibitor-related bleeding and approximately 2,100 bleeding-related
deaths per month in the U.S.
"We are pleased that these data continue to highlight the
durability of the hemostatic efficacy of Andexxa across patient
populations, including those who experience Factor Xa
inhibitor-related bleeding in more common sites such as the GI
tract," said Scott Garland,
Portola's president and chief
executive officer. "The presentation of this analysis is part of
our long-term strategy to build awareness of the clinical data
supporting Andexxa, and become the standard of care for the
hundreds of thousands of patients taking Factor Xa inhibitors who
may require access to this potentially life-saving medicine."
Andexxa is a recombinant protein specifically designed to bind
to Factor Xa inhibitors and rapidly reverse their anticoagulant
effect. Andexxa was approved by the FDA in May 2018 as 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. Andexxa received both U.S. Orphan Drug and FDA
Breakthrough Therapy designations and was approved under the FDA's
Accelerated Approval pathway based on the change from baseline in
anti-factor Xa activity in healthy volunteers. It is marketed in
Europe as
Ondexxya® (andexanet alfa).
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. Among the 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.
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,
statements regarding Portola's long-term strategy to
build awareness of the clinical data supporting Andexxa, and become
the standard of care for the patients taking Factor Xa inhibitors
who may require a reversal agent and the potential benefit of
Andexxa. Risks that contribute to the uncertain nature of the
forward-looking statements include: the risk that physicians,
patients and payers may not see the benefits of utilizing Andexxa
for the indications for which it is approved; our ability to
continue to manufacture our products and to expand approved
manufacturing facilities; the possibility of unfavorable results
from additional clinical trials involving Andexxa; our ability to
grow our commercial operations in the EU and generate product
revenue within projected timelines and budget; the risk that we may
not obtain additional regulatory approvals necessary to expand or
maintain 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; our ability to
retain key scientific or management personnel and general market
conditions. 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.
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SOURCE Portola Pharmaceuticals, Inc.®