Portola, Bristol-Myers Squibb and Pfizer Announce Full Results of Second Part of Phase 3 ANNEXA-A(TM) Study Demonstrating That Investigational Andexanet Alfa Sustained Reversal of Anticoagulant Effect of Factor Xa Inhibitor Eliquis (apixaban)
Data Presented Today in Late-Breaking Clinical Trial Oral Session at International Society on Thrombosis and Haemostasis (ISTH) 2015 Congress
SOUTH SAN FRANCISCO, Calif., PRINCETON, N.J. and NEW YORK, June 22, 2015 (GLOBE NEWSWIRE) -- Portola Pharmaceuticals (PTLA), Bristol-Myers Squibb Company (BMY) and Pfizer Inc. (PFE) today announced full results from the second part of the Phase 3 ANNEXA(TM)-A (Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of FXa Inhibitors -- Apixaban) study. This registration-enabling study evaluated the safety and efficacy of andexanet alfa, an investigational antidote and U.S. Food and Drug Administration (FDA)-designated breakthrough therapy, administered as an intravenous (IV) bolus followed by a continuous two-hour infusion to sustain the reversal of anticoagulation activity of the Factor Xa inhibitor Eliquis (apixaban) in healthy volunteers ages 50-75 years.
This second part of the study achieved all primary and pre-specified secondary endpoints with high statistical significance. Andexanet alfa produced rapid reversal of the anticoagulant effect of Eliquis, as measured by anti-Factor Xa activity, which was sustained for the duration of the infusion. Andexanet alfa significantly reduced the level of free unbound Eliquis in the plasma and restored thrombin generation to normal. Andexanet alfa was well tolerated, with no serious adverse events, thrombotic events, or antibodies to Factor X or Xa reported. Mild infusion reactions were reported in six subjects: four in the andexanet arm and two in the placebo arm. No subjects discontinued the study due to an adverse event. The full data set was presented today in a Late-Breaking Clinical Trial oral session at the International Society on Thrombosis and Haemostasis (ISTH) 2015 Congress in Toronto.
"These Phase 3 findings demonstrate that andexanet alfa can rapidly reverse anticoagulant activity for a short or sustained period of time and that anticoagulant activity can be reinitiated following discontinuation of the infusion. This is significant given different clinical needs for shorter-duration or longer-duration reversal," said John T. Curnutte, M.D., Ph.D., executive vice president, research and development, for Portola. "Importantly, our trial endpoints are based on the accepted pharmacodynamic measurements of anticoagulant activity agreed to with regulatory authorities and serve as the basis for our accelerated approval pathway. The results to date across our Phase 2 and Phase 3 andexanet alfa studies with both oral and injectable Factor Xa inhibitors suggest that andexanet alfa is the only investigational reversal agent to clinically show meaningful reversal of Factor Xa anticoagulant activity. There is an increasing number of patients on Factor Xa inhibitors who may need their anticoagulant reversed because they are bleeding or require surgery."
"Bristol-Myers Squibb and Pfizer are committed to continuing to deliver innovative therapies to patients and are pleased with the positive results of both parts of the ANNEXA-A study," said Rory O'Connor, M.D., senior vice president and head of Global Medical Affairs, Global Innovative Pharmaceuticals Business, Pfizer Inc. "Patients often take anticoagulants to treat or reduce the risk of life-threatening blood clots from forming. In patients who experience a major bleeding event or require emergency surgery, there is a need to stop the blood thinning effects of an anticoagulant. In this study, andexanet alfa was shown to rapidly reverse the anticoagulant effects of Eliquis."
"We are proud to share in the presentation of this ANNEXA-A Part 2 study data," said Douglas Manion, M.D., head of specialty development, Bristol-Myers Squibb. "As we saw in Part 1, these results demonstrate that andexanet alfa could prove to be an effective reversal agent for Eliquis."
Portola plans to submit data from the ANNEXA-A (apixaban) and ANNEXA-R (rivaroxaban) studies, and initial data from a Phase 4 study, as part of its Biologics License Application (BLA) to the FDA under an Accelerated Approval pathway by the end of 2015.
ANNEXA-A Study Design
The randomized, double-blind, placebo-controlled Phase 3 ANNEXA-A study evaluated the safety and efficacy of andexanet alfa in reversing apixaban-induced anticoagulation in older healthy volunteers ages 50-75 years. Efficacy was evaluated using biomarker endpoints, with anti-Factor Xa levels as the primary endpoint. Secondary endpoints included plasma levels of free unbound apixaban and endogenous thrombin potential (ETP), a measure of thrombin generation.
In ANNEXA-A Part 1, 33 healthy volunteers were given apixaban 5 mg twice daily for four days and then randomized in a 3:1 ratio to andexanet alfa administered as a 400 mg IV bolus (n=24) or to placebo (n=9). In the second part of the study, 31 healthy volunteers were given apixaban 5 mg twice daily for four days and then randomized in a 3:1 ratio to andexanet alfa administered as a 400 mg IV bolus followed by a continuous infusion of 4 mg/min for 120 minutes (n=23) or to placebo (n=8).
ANNEXA-A Study Part 2 Results
Results showed that, following the administration of a bolus of andexanet alfa, the anticoagulant activity of apixaban, as measured by anti-Factor Xa activity, was reversed by 93.5 percent (p<0.0001). Following completion of the two-hour continuous infusion of andexanet alfa, the anticoagulant activity of apixaban remained significantly reversed, by 92.7 percent (p<0.0001). These two endpoints demonstrate that andexanet alfa infusion was able to keep anti-Factor Xa levels flat from the end of the bolus (93.5 percent) to the end of the two-hour infusion (92.7 percent).
Additional secondary endpoints showed:
- Reversal of at least 80 percent of anti-Factor Xa activity occurred in all 23 subjects who received andexanet alfa (p<0.0001).
- Plasma levels of free unbound apixaban were significantly reduced with andexanet alfa (p=0.0002).
- Thrombin generation at peak (end of infusion) was restored to the normal range in 23 out of 23 (100 percent) andexanet alfa recipients.
- Thrombin generation above the lower limit of normal occurred in all 23 subjects who received andexanet alfa (p<0.0001).
No serious adverse events, thrombotic events, or antibodies to Factor X or Xa were reported following andexanet alfa administration. Mild infusion reactions were reported in six subjects.
No subjects discontinued the study due to an adverse event.
Addressing the Absence of a Factor Xa Inhibitor Antidote
Currently, millions of patients are treated with Factor Xa inhibitors for short-term use or chronic conditions, and the anticoagulant market is expected to continue to grow. Recent patient data confirm earlier clinical trial results showing that, annually, between 1 to 4 percent of patients treated with Factor Xa inhibitors may experience major bleeding and an additional 1 percent may require emergency surgery. Development of a specific antidote designed to reverse the anticoagulant activity of Factor Xa inhibitors may provide an important treatment option for patients who experience a major bleeding event or require emergency surgery.
About Andexanet Alfa
Andexanet alfa is a modified human Factor Xa molecule that acts as a decoy to target and sequester with high specificity both oral and injectable Factor Xa inhibitors in the blood. Once bound, the Factor Xa inhibitors are unable to bind to and inhibit native Factor Xa, thus allowing for the restoration of normal hemostatic processes. Andexanet alfa has the potential to address numerous clinical scenarios where an antidote is needed by allowing for flexible and controlled reversal. This can be short-acting through the administration of an IV bolus or longer-acting with the addition of an extended infusion.
Andexanet alfa is the only compound being studied as a reversal agent for Factor Xa inhibitors that directly and specifically corrects anti-Factor Xa activity, the anticoagulant mechanism of these agents.
Andexanet alfa has been granted orphan drug designation by the FDA for reversing the anticoagulant effect of direct or indirect Factor Xa inhibitors in patients experiencing a serious uncontrolled bleeding event or who require urgent or emergent surgery.
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 for multiple indications in the U.S. based on efficacy and safety data, including results from seven Phase 3 clinical trials. Eliquis is a prescription medicine indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation; for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery; for the treatment of DVT and PE; and to reduce the risk of recurrent DVT and PE following initial therapy.
ELIQUIS Indications and Important Safety Information
ELIQUIS is indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.
ELIQUIS is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have undergone hip or knee replacement surgery.
ELIQUIS is indicated for the treatment of DVT and PE, and to reduce the risk of recurrent DVT and PE following initial therapy.
ELIQUIS Important Safety Information
WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA
(A) Premature discontinuation of any oral anticoagulant, including ELIQUIS, increases the risk of thrombotic events. If anticoagulation with ELIQUIS is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.
(B) Epidural or spinal hematomas may occur in patients treated with ELIQUIS who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:
- use of indwelling epidural catheters
- concomitant use of other drugs that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants
- a history of traumatic or repeated epidural or spinal punctures
- a history of spinal deformity or spinal surgery
- optimal timing between the administration of ELIQUIS and neuraxial procedures is not known
Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.
Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated.
- Active pathological bleeding
- Severe hypersensitivity reaction to ELIQUIS (e.g., anaphylactic reactions)
WARNINGS AND PRECAUTIONS
- Increased Risk of Thrombotic Events after Premature Discontinuation: Premature discontinuation of any oral anticoagulant, including 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 atrial fibrillation patients. If ELIQUIS is discontinued for a reason other than pathological bleeding or completion of a course of therapy, 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.
- Advise patients of signs and symptoms of blood loss and to report them immediately or go 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.
Spinal/Epidural Anesthesia or Puncture: Patients treated with Eliquis undergoing spinal/epidural anesthesia or puncture may develop an epidural or spinal hematoma which can result in long-term or permanent paralysis.
The risk of these events may be increased by the postoperative use of indwelling epidural catheters or the concomitant use of medicinal products affecting hemostasis. Indwelling epidural or intrathecal catheters should not be removed earlier than 24 hours after the last administration of ELIQUIS. The next dose of ELIQUIS should not be administered earlier than 5 hours after the removal of the catheter. The risk may also be increased by traumatic or repeated epidural or spinal puncture. If traumatic puncture occurs, delay the administration of ELIQUIS for 48 hours.
Monitor patients frequently and if neurological compromise is noted, urgent diagnosis and treatment is necessary. Physicians should consider the potential benefit versus the risk of neuraxial intervention in Eliquis patients.
- 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.
- Acute PE in Hemodynamically Unstable Patients or Patients who Require Thrombolysis or Pulmonary Embolectomy: Initiation of ELIQUIS is not recommended as an alternative to unfractionated heparin for the initial treatment of patients with PE who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.
- The most common and most serious adverse reactions reported with ELIQUIS 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.
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 ELIQUIS doses greater than 2.5 mg twice daily, the dose of ELIQUIS should be decreased by 50% when it is coadministered with drugs that are strong dual inhibitors of CYP3A4 and P-gp (e.g., ketoconazole, itraconazole, ritonavir, or clarithromycin). For patients receiving 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 and other thromboembolic events.
- 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 Portola Pharmaceuticals, Inc.
Portola Pharmaceuticals is a biopharmaceutical company developing product candidates that could significantly advance the fields of thrombosis and other hematologic diseases. The Company is advancing its three wholly-owned programs using novel biomarker and genetic approaches that may increase the likelihood of clinical, regulatory and commercial success of its potentially life-saving therapies. Portola's partnered programs are focused on developing selective Syk inhibitors for inflammatory conditions.
Portola's wholly-owned, oral, once-daily Factor Xa inhibitor betrixaban is being evaluated in the only biomarker-based Phase 3 study for hospital-to-home prophylaxis of venous thromboembolism (VTE) in acute medically ill patients. Betrixaban's distinct properties may have the potential to allow the agent to demonstrate efficacy without the significant increase in the rate of major bleeding that was seen in this patient population with other Factor Xa inhibitors. If approved, betrixaban could be the first anticoagulant for both hospital and post-discharge VTE prophylaxis and the standard of care in this large market of more than 20 million patients in the G7 countries alone.
Andexanet alfa, an FDA-designated breakthrough therapy, is a recombinant protein designed to reverse the anticoagulant effect in patients treated with an oral or injectable Factor Xa inhibitor. Andexanet alfa has the potential to be a first-in-class antidote for anticoagulated patients who suffer a major bleeding episode or require emergency surgery. Portola has entered into Phase 3 clinical collaboration agreements with all of the manufacturers of direct Factor Xa inhibitors while retaining all commercial rights to andexanet alfa. The Company is currently evaluating andexanet alfa in the Phase 3 and Phase 4 ANNEXA(TM) (Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of FXa Inhibitors) registration studies.
Portola's product candidate in the area of hematologic cancer, cerdulatinib, is an orally available molecule that uniquely inhibits two validated tumor proliferation pathways -- spleen tyrosine kinase (Syk) and janus kinase (JAK). It is currently being evaluated in a Phase 1/2a proof-of-concept study in patients with B cell leukemias or lymphomas with a focus on genetically-defined subtypes, as well as in patients who have failed therapy due to relapse or acquired mutations.
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 http://www.bms.com or follow us on Twitter at http://twitter.com/bmsnews.
About Pfizer Inc.: Working together for a healthier world(TM)
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.
Portola Forward-Looking Statement
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 plans for future clinical studies and pursuit of an Accelerated Approval process for andexanet alfa, anticipated growth in the market for anticoagulants, the potential indications, efficacy, safety and activity of andexanet alfa, and the potential market and indications for its other product candidates. Risks that contribute to the uncertain nature of the forward-looking statements include: the accuracy of Portola's estimates regarding its ability to initiate and/or complete its clinical trials; the success of Portola's clinical trials and the demonstrated efficacy of Portola's product candidates thereunder; the accuracy of Portola's estimates regarding its expenses and capital requirements; Portola's ability to manufacture andexanet alfa; regulatory developments in the United States and foreign countries; Portola's ability to obtain and maintain intellectual property protection for its product candidates; and the loss of key scientific or management personnel. These and other risks and uncertainties are described more fully in Portola's most recent filings with the Securities and Exchange Commission, including its Annual Report on Form 10-K, which was filed on March 2, 2015, and Quarterly Report on Form 10-Q, which was filed on May 7, 2015. All forward-looking statements contained in this press release speak only as of the date on which they were made. Portola undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.
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. 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, 2014, 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 June 22, 2015. 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 and andexanet alfa, including their potential benefits, 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 inherent in research and development, including the possibility of unfavorable clinical trial results, including unfavorable new clinical data and additional analyses of existing clinical data; whether and when any BLA may be filed for andexanet alfa; whether and when regulatory authorities will approve any such BLA; 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, 2014 and in its subsequent reports on Form 10-Q, including in the sections thereof captioned "Risk Factors" and "Forward-Looking Information and Factors 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.
Portola Media: Julie Normart, W2OGroup, [email protected] Investors: Michele Mantynen, [email protected] Bristol-Myers Squibb Media: Kirby Hosea, 609-419-5071, [email protected] Investors: Ranya Dajani, 609-252-5330, [email protected]; Bill Szablewski, 609-252-5894, [email protected] Pfizer Inc. Media: Steven Danehy, 212-733-1538, [email protected] Investors: Ryan Crowe, 212-733-8160, [email protected]