Bristol-Myers
Squibb Company (NYSE:BMY) and Pfizer
Inc. (NYSE:PFE) today announced that the European Commission has
approved Eliquis for the treatment of DVT and PE, and the
prevention of recurrent DVT and PE in adults. The European Commission
approval applies to all European Union (EU) member states as well as
Iceland and Norway. Eliquis is also approved in the EU for the
prevention of venous thromboembolism (VTE) in adults who have undergone
elective total hip or knee replacement surgery, and for the prevention
of stroke and systemic embolism in adult patients with nonvalvular
atrial fibrillation (NVAF) with one or more risk factors.
“Every year, approximately one million patients in the EU are diagnosed
with VTE,” said Dr. Elliott Levy, senior vice president, head of
Specialty Development, Bristol-Myers Squibb. “Once a VTE has occurred,
approximately 33 percent of patients may experience a recurrence within
10 years.”
The marketing authorization for Eliquis follows the positive
opinion issued by the Committee for Medicinal Products for Human Use
(CHMP) of the European Medicines Agency, and is supported by two pivotal
Phase 3 clinical trials, AMPLIFY and AMPLIFY-EXT. AMPLIFY (Apixaban
for the initial Management of PuLmonary embolIsm
and deep vein thrombosis as First-line therapY) was
designed to demonstrate the efficacy and safety of Eliquis for
the treatment of DVT and PE versus enoxaparin 1 mg/kg twice daily
subcutaneously for at least 5 days (until INR≥ 2) and warfarin (target
INR range 2.0-3.0) orally for six months. AMPLIFY-EXT (Apixaban
after the initial Management of PuLmonary embolIsm
and deep vein thrombosis with First-line therapY-EXTended
treatment) was designed to demonstrate the efficacy and safety of Eliquis
compared to placebo for the prevention of recurrent DVT and PE
following six to 12 months of anticoagulant treatment for DVT and/or PE.
“The European Commission’s approval of Eliquis for the treatment
of DVT and PE and the prevention of recurrence is an important milestone
and demonstrates Bristol-Myers Squibb and Pfizer’s ongoing commitment to
bringing innovative medicines to patients who need them,” said Steve
Romano, senior vice president, head of Medicines Development Group for
Global Innovative Pharmaceuticals, Pfizer Inc.
About the Clinical Trial Program
AMPLIFY
As described in the SmPC, in the AMPLIFY study a total of 5,395 patients
were randomized to treatment with Eliquis 10 mg twice daily
orally for seven days followed by Eliquis 5 mg twice daily orally
for six months, or enoxaparin 1 mg/kg twice daily subcutaneously for at
least five days (until INR≥ 2) and warfarin (target INR range 2.0-3.0)
orally for six months.
The mean age was 56.9 years and 89.8 percent of randomized patients had
unprovoked VTE events.
In the study, Eliquis was shown to be non-inferior to
enoxaparin/warfarin in the combined primary endpoint of adjudicated
recurrent symptomatic VTE (nonfatal DVT or nonfatal PE) or VTE-related
death.
Eliquis efficacy in initial treatment of VTE was consistent
between patients who were treated for a PE [Relative Risk 0.9; 95
percent CI (0.5, 1.6)] or DVT [Relative Risk 0.8; 95 percent CI (0.5,
1.3)]. Efficacy across subgroups, including age, gender, body mass index
(BMI), renal function, extent of index PE, location of DVT thrombus, and
prior parenteral heparin use was generally consistent.
For patients randomized to warfarin, the mean percentage of time in
therapeutic range (TTR) (INR 2.0-3.0) was 60.9. The effect of Eliquis
on recurrent symptomatic VTE or VTE- related death was consistent across
the different levels of center TTR; within the highest quartile of TTR
according to center, the relative risk for Eliquis vs
enoxaparin/warfarin was 0.79 (95 percent CI, 0.39, 1.61).
The primary safety endpoint was major bleeding. In the study, Eliquis
was statistically superior to enoxaparin/warfarin in the primary safety
endpoint [Relative Risk 0.31, 95 percent confidence interval (0.17,
0.55), P-value <0.0001].
The adjudicated major bleeding and clinically relevant non-major (CRNM)
bleeding at any anatomical site were generally lower in the Eliquis
group as compared to the enoxaparin/warfarin group. Adjudicated
International Society on Thrombosis and Haemostasis (ISTH) major
gastrointestinal bleeding occurred in 6 (0.2 percent) Eliquis-treated
patients and 17 (0.6 percent) enoxaparin/warfarin-treated patients.
AMPLIFY- EXT
As described in the SmPC, in the AMPLIFY-EXT study a total of 2,482
patients were randomized to treatment with Eliquis 2.5 mg twice
daily orally, Eliquis 5 mg twice daily orally, or placebo for 12
months after completing six to 12 months of initial anticoagulant
treatment. Of these, 836 patients (33.7 percent) participated in the
AMPLIFY study prior to enrollment in the AMPLIFY-EXT study.
The mean age was 56.7 years and 91.7 percent of randomized patients had
unprovoked VTE events.
In the study, both doses of Eliquis were statistically superior
to placebo in the primary endpoint of symptomatic, recurrent VTE
(nonfatal DVT or nonfatal PE) or all-cause death.
Eliquis efficacy for prevention of a recurrence of a VTE was
maintained across subgroups, including age, gender, BMI, and renal
function.
The primary safety endpoint was major bleeding during the treatment
period. In the study, the incidence in major bleeding for both Eliquis
doses was not statistically different from placebo. There was no
statistically significant difference in the incidence of major,
clinically relevant non-major, minor, and all bleeding between the Eliquis
2.5 mg twice daily and placebo treatment groups. The recommended dose of Eliquis
for the prevention of recurrent DVT and PE is 2.5 mg taken orally twice
daily.
Adjudicated ISTH major gastrointestinal bleeding occurred in 1 (0.1
percent) Eliquis-treated patient at the 5 mg twice daily dose, no
patients at the 2.5 mg twice daily dose, and 1 (0.1 percent)
placebo-treated patient.
About Eliquis
Eliquis (apixaban) is an oral selective Factor Xa inhibitor. By
inhibiting Factor Xa, a key blood clotting protein, Eliquis
decreases thrombin generation and blood clot formation. Eliquis
is approved to reduce the risk of stroke and systemic embolism in adult
patients with NVAF in the United States, European Union, Japan and a
number of other countries around the world. Eliquis is approved
for the prophylaxis of VTE in adult patients who have undergone elective
hip or knee replacement surgery in the United States, European Union and
a number of other countries around the world. Eliquis is not
approved for this indication in Japan. Eliquis is approved for
the treatment of DVT and PE, and prevention of recurrent DVT and PE in
the European Union. Eliquis is not approved for this indication
in the United States.
IMPORTANT SAFETY INFORMATION FROM U.S.
PRESCRIBING INFORMATION
WARNINGS: (A) DISCONTINUING ELIQUIS IN PATIENTS WITH
NONVALVULAR ATRIAL FIBRILLATION WITHOUT ADEQUATE CONTINUOUS
ANTICOAGULATION INCREASES RISK OF STROKE, (B) SPINAL/EPIDURAL HEMATOMA
(A) Discontinuing ELIQUIS places patients at an increased risk of
thrombotic events. An increased rate of stroke was observed following
discontinuation of ELIQUIS in clinical trials in patients with
nonvalvular atrial fibrillation. If anticoagulation with ELIQUIS must be
discontinued for a reason other than pathological bleeding, coverage
with another anticoagulant should be strongly considered.
(B) When neuraxial anesthesia (epidural/spinal anesthesia) or spinal
puncture is employed, patients anticoagulated or scheduled to be
anticoagulated with low molecular weight heparins, heparinoids, or
Factor Xa inhibitors for prevention of thromboembolic complications are
at risk of developing an epidural or spinal hematoma which can result in
long-term or permanent paralysis.
The risk of these events may be increased by the use of indwelling
epidural catheters for administration of analgesia or by the concomitant
use of drugs affecting hemostasis such as nonsteroidal anti-inflammatory
drugs (NSAIDs), platelet aggregation inhibitors, or other
anticoagulants. The risk also appears to be increased by traumatic or
repeated epidural or spinal puncture.
Monitor patients for signs and symptoms of neurologic impairment. If
neurologic compromise is noted, urgent treatment is necessary. Consider
the potential benefit versus risk before neuraxial intervention in
patients anticoagulated or to be anticoagulated for thromboprophylaxis
CONTRAINDICATIONS
-
Active pathological bleeding
-
Severe hypersensitivity reaction to ELIQUIS (apixaban) (e.g.,
anaphylactic reactions)
WARNINGS AND PRECAUTIONS
-
Increased Risk of Stroke with Discontinuation of ELIQUIS in
Patients with Nonvalvular Atrial Fibrillation: Discontinuing
ELIQUIS in the absence of adequate alternative anticoagulation
increases the risk of thrombotic events. An increased rate of stroke
was observed during the transition from ELIQUIS to warfarin in
clinical trials in patients with nonvalvular atrial fibrillation. If
ELIQUIS must be discontinued for a reason other than pathological
bleeding, consider coverage with another anticoagulant.
-
Bleeding Risk: ELIQUIS increases the risk of bleeding and can
cause serious, potentially fatal bleeding. Concomitant use of drugs
affecting hemostasis increases the risk of bleeding including aspirin
and other anti-platelet agents, other anticoagulants, heparin,
thrombolytic agents, SSRIs, SNRIs, and NSAIDs. Patients should be made
aware of signs or symptoms of blood loss and instructed to immediately
report to an emergency room. Discontinue ELIQUIS in patients with
active pathological hemorrhage.
-
There is no established way to reverse the anticoagulant effect of
apixaban, which can be expected to persist for at least 24 hours after
the last dose (i.e., about two half-lives). A specific antidote for
ELIQUIS is not available. Hemodialysis does not appear to have a
substantial impact on apixaban exposure. Protamine sulfate and vitamin
K would not be expected to affect the anticoagulant activity of
apixaban. There is no experience with antifibrinolytic agents
(tranexamic acid, aminocaproic acid) in individuals receiving
apixaban. There is neither scientific rationale for reversal nor
experience with systemic hemostatics (desmopressin and aprotinin) in
individuals receiving apixaban. Use of procoagulant reversal agents
such as prothrombin complex concentrate, activated prothrombin complex
concentrate, or recombinant factor VIIa may be considered but has not
been evaluated in clinical studies. Activated charcoal reduces
absorption of apixaban thereby lowering apixaban plasma concentrations.
-
Prosthetic Heart Valves: The safety and efficacy of ELIQUIS
have not been studied in patients with prosthetic heart valves and is
not recommended in these patients.
ADVERSE REACTIONS
The most common and most serious adverse reactions reported with ELIQUIS
(apixaban) were related to bleeding.
TEMPORARY INTERRUPTION FOR SURGERY AND OTHER INTERVENTIONS
ELIQUIS should be discontinued at least 48 hours prior to elective
surgery or invasive procedures with a moderate or high risk of
unacceptable or clinically significant bleeding. ELIQUIS should be
discontinued at least 24 hours prior to elective surgery or invasive
procedures with a low risk of bleeding or where the bleeding would be
noncritical in location and easily controlled. Bridging anticoagulation
during the 24 to 48 hours after stopping ELIQUIS and prior to the
intervention is not generally required. ELIQUIS should be restarted
after the surgical or other procedures as soon as adequate hemostasis
has been established.
DRUG INTERACTIONS
-
Strong Dual Inhibitors of CYP3A4 and P-gp: Inhibitors of CYP3A4
and P-gp increase exposure to apixaban and increase the risk of
bleeding. For patients receiving 5 mg twice daily, the dose of ELIQUIS
should be decreased when it is coadministered with drugs that are
strong dual inhibitors of CYP3A4 and P-gp (e.g., ketoconazole,
itraconazole, ritonavir, or clarithromycin). In patients already
taking ELIQUIS at a dose of 2.5 mg twice daily, avoid coadministration
with strong dual inhibitors of CYP3A4 and P-gp.
-
Strong Dual Inducers of CYP3A4 and P-gp: Avoid concomitant use
of ELIQUIS with strong dual inducers of CYP3A4 and P-gp (e.g.,
rifampin, carbamazepine, phenytoin, St. John’s wort) because such
drugs will decrease exposure to apixaban and increase the risk of
stroke.
-
Anticoagulants and Antiplatelet Agents: Coadministration of
antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic
NSAID use increases the risk of bleeding. APPRAISE-2, a
placebo-controlled clinical trial of apixaban in high-risk post-acute
coronary syndrome patients treated with aspirin or the combination of
aspirin and clopidogrel, was terminated early due to a higher rate of
bleeding with apixaban compared to placebo.
PREGNANCY CATEGORY B
There are no adequate and well-controlled studies of ELIQUIS in pregnant
women. Treatment is likely to increase the risk of hemorrhage during
pregnancy and delivery. ELIQUIS should be used during pregnancy only if
the potential benefit outweighs the potential risk to the mother and
fetus.
Please see full Prescribing Information, including BOXED WARNINGS and
Medication Guide, available at www.bms.com.
About DVT and PE
Venous thromboembolism, or VTE, encompasses two serious conditions: deep
vein thrombosis (DVT) and pulmonary embolism (PE). DVT is a blood clot
in a vein, usually in the lower leg, thigh, or pelvis, which partially
or totally blocks the flow of blood. PE is a blood clot blocking one or
more vessels in the lungs. DVT causes multiple symptoms including pain,
swelling, and redness, and more importantly, can progress to PE, which
carries the risk of sudden death. Approximately one million patients in
the EU are diagnosed every year with VTE.
About the Bristol-Myers Squibb/Pfizer Collaboration
In 2007, Pfizer and Bristol-Myers Squibb entered into a worldwide
collaboration to develop and commercialize apixaban, an oral
anticoagulant discovered by Bristol-Myers Squibb. This global alliance
combines Bristol-Myers Squibb's long-standing strengths in
cardiovascular drug development and commercialization with Pfizer’s
global scale and expertise in this field.
About Bristol-Myers Squibb
Bristol-Myers Squibb is a global biopharmaceutical company whose mission
is to discover, develop and deliver innovative medicines that help
patients prevail over serious diseases. For more information, please
visit www.bms.com.
About Pfizer Inc.: Working together for a healthier world™
At Pfizer, we apply science and our global resources to bring therapies
to people that extend and significantly improve their lives. We strive
to set the standard for quality, safety and value in the discovery,
development and manufacture of health care products. Our global
portfolio includes medicines and vaccines as well as many of the world's
best-known consumer health care products. Every day, Pfizer colleagues
work across developed and emerging markets to advance wellness,
prevention, treatments and cures that challenge the most feared diseases
of our time. Consistent with our responsibility as one of the world's
premier innovative biopharmaceutical companies, we collaborate with
health care providers, governments and local communities to support and
expand access to reliable, affordable health care around the world. For
more than 150 years, Pfizer has worked to make a difference for all who
rely on us. To learn more, please visit us at www.pfizer.com.
Bristol-Myers Squibb Forward-Looking Statement
This press release contains "forward-looking statements" as that term
is defined in the Private Securities Litigation Reform Act of 1995
regarding product development. Such forward-looking
statements are based on current expectations and involve inherent risks
and uncertainties, including factors that could delay, divert or change
any of them, and could cause actual outcomes and results to differ
materially from current expectations. No forward-looking
statement can be guaranteed. Among other risks, there can be
no guarantee that the approval of these additional indications in Europe
will lead to increased commercial success or that Eliquis will be
approved for these additional indications in the U.S. or in other
countries. Forward-looking statements in this press release should be
evaluated together with the many uncertainties that affect Bristol-Myers
Squibb's business, particularly those identified in the cautionary
factors discussion in Bristol-Myers Squibb's Annual Report on Form 10-K
for the year ended December 31, 2013, in our Quarterly Reports on Form
10-Q and our Current Reports on Form 8-K. Bristol-Myers
Squibb undertakes no obligation to publicly update any forward-looking
statement, whether as a result of new information, future events or
otherwise.
PFIZER DISCLOSURE NOTICE:
The information contained in this release is as of July 29, 2014.
Pfizer assumes no obligation to update forward-looking statements
contained in this release as the result of new information or future
events or developments.
This release contains forward-looking information about Eliquis’s
(apixaban’s) potential benefits and about additional indications for
Eliquis in the EU for the treatment of deep vein thrombosis (DVT) and
pulmonary embolism (PE) and the prevention of recurrent DVT and PE in
adults that involves substantial risks and uncertainties that could
cause actual results to differ materially from those expressed or
implied by such statements. Risks and uncertainties include, among other
things, the uncertainties regarding the commercial success of the
additional indications in the EU; whether and when the FDA or regulatory
authorities in other jurisdictions will approve applications for these
potential additional indications, as well as their decisions regarding
labeling and other matters that could affect the availability or
commercial potential of such potential additional indications;and
competitive developments.
A further description of risks and uncertainties can be found in
Pfizer’s Annual Report on Form 10-K for the fiscal year ended December
31, 2013 and in our subsequent reports on Form 10-Q, including in the
sections thereof captioned “Risk Factors” and “Forward-Looking
Information That May Affect Future Results”, as well as in its
subsequent reports on Form 8-K, all of which are filed with the SEC and
available at www.sec.gov
and www.pfizer.com.
Copyright Business Wire 2014