Portola Pharmaceuticals Announces Three Phase 3 APEX Substudy Results Showing Further Benefits of Treating Acute Medically Ill Patients with Extended-Duration Betrixaban
NEW ORLEANS and SOUTH SAN FRANCISCO, Calif., Nov. 14, 2016 (GLOBE NEWSWIRE) -- Portola Pharmaceuticals, Inc.® (Nasdaq:PTLA) today announced results from three substudies of the pivotal Phase 3 APEX Study of betrixaban, an oral, once-daily Factor Xa inhibitor anticoagulant in development for the prevention of venous thromboembolism (VTE) in acute medically ill patients. Findings from the analyses were presented by the PERFUSE Study Group at the American Heart Association (AHA) Scientific Sessions 2016.
In a retrospective APEX substudy on stroke, researchers assessed the potential of extended-duration thromboprophylaxis with betrixaban compared with standard-dose enoxaparin to reduce the risk of stroke in hospitalized acute medically ill patients. The substudy found that extended-duration betrixaban significantly reduced all-cause stroke (0.54 percent for betrixaban vs. 0.97 percent for enoxaparin; RRR=44 percent, p=0.032) and ischemic stroke (0.48 percent for betrixaban vs. 0.91 percent for enoxaparin; RRR=47 percent, p=0.026) through 77 days of follow up. The results were presented today by C. Michael Gibson, M.S., M.D., in the Sol Sherry Distinguished Lecture in Thrombosis at AHA and simultaneously published in the peer-reviewed journal Circulation.
“Stroke is a potentially fatal complication, but little is known about the effectiveness of novel oral anticoagulants in preventing stroke among the acute medically ill patient population. We were encouraged to find that betrixaban was associated with a reduction in the risk of all-cause stroke within 30 to 60 days, which was driven predominantly by a reduction in ischemic stroke, without an increased risk of major bleeding,” said Dr. Gibson, APEX Executive Committee Member and Steering Committee Chairman; professor, Harvard Medical School; and chairman of the PERFUSE Study Group. “The unique properties of betrixaban may, in part, explain the observed reduction in stroke without an increase in major bleeding in this study population. These findings are especially important because they demonstrate the potential for betrixaban to improve stroke outcomes in these patients.”
A second retrospective APEX substudy, presented today at AHA by Purva Jain, M.P.H., biostatistician for the PERFUSE Study Group, found that both the first symptomatic VTE event and the total number of symptomatic VTE events were reduced in patients treated with extended-duration oral betrixaban compared with standard-duration enoxaparin through the end of the study (abstract #640). The results suggest that this reduction in the total burden of symptomatic VTE events among patients taking betrixaban may reduce the use of healthcare resources and alleviate costs related to inpatient and outpatient care, and pharmacy use.
Lastly, in a poster session tomorrow, November 15, Gerald Chi, M.D., of the PERFUSE Study Group, will present results from a third retrospective APEX substudy. The findings showed that the addition of a patient’s D-dimer level to the IMPROVE score (used to stratify hospitalized medical patients by their risk for VTE) to derive the IMPROVEDD score may further optimize VTE risk stratification.
Stroke Substudy (Abstract #277)
In this substudy, the mean age of study participants was 76 years, 45 percent were male, 13 percent had had a stroke, and 45 percent had congestive heart failure. Stroke events were adjudicated by an independent blinded-event adjudication committee and assessed through last patient contact. The findings showed that, among the 3,716 patients treated with extended-duration betrixaban and the 3,716 patients treated with standard-of-care enoxaparin:
- There were fewer all-cause strokes among those treated with betrixaban than enoxaparin through 77 days of follow-up (0.54 percent vs. 0.97 percent; p=0.032).
- There were fewer ischemic strokes among those treated with betrixaban than enoxaparin through 77 days of follow-up (0.48 percent vs. 0.91 percent; p=0.026).
- The composite endpoint of all-cause stroke and transient ischemic attack (TIA) was also reduced among study subjects treated with extended-duration betrixaban versus enoxaparin (0.65 percent vs. 1.10 percent; p=0.034).
- Among patients at highest risk for stroke – i.e., those who had a prior ischemic stroke or a history of congestive heart failure -- the risk of all-cause stroke was reduced with betrixaban compared with enoxaparin (0.72 percent vs. 1.48 percent; p=0.019), as was ischemic stroke (0.63 percent vs. 1.38 percent; p=0.014).
About the APEX Study
The pivotal Phase 3 APEX Study enrolled 7,513 patients at more than 450 clinical sites worldwide and assessed the superiority of extended-duration anticoagulation with oral betrixaban for 35-42 days compared with standard-duration injectable enoxaparin for 10+4 days in preventing VTE in high-risk acute medically ill patients. The primary efficacy endpoint was a composite of asymptomatic proximal DVT (deep vein thrombosis) (detected on ultrasound), symptomatic DVT (proximal or distal), non-fatal pulmonary embolism (PE) and VTE-related death. The primary safety endpoint was major bleeding through seven days after drug discontinuation.
Results showed that betrixaban reduced the incidence of VTE compared with enoxaparin at a p value approaching statistical significance (p=0.054) in the primary efficacy analysis subgroup of 3,870 patients with elevated D-dimer levels. It also significantly reduced VTE in several pre-specified analyses of the primary efficacy analysis subgroup as well as in the overall study population (p=0.006) of 7,513 patients. No statistical difference in major bleeding was observed between the betrixaban and enoxaparin arms in either of the primary analysis patient subgroup or in the overall study population.
Full results from the multicenter, randomized, active-controlled APEX Study were presented at the 62nd Annual International Society on Thrombosis and Haemostasis (ISTH) Scientific and Standardization Committee (SSC) Meeting in May 2016 and published online in The New England Journal of Medicine in May 2016.i
Betrixaban, an investigational drug, directly inhibits the activity of Factor Xa, an important validated target in the blood coagulation pathway, to prevent life-threatening thrombosis. Betrixaban has distinct properties that may allow it to demonstrate clinical benefit without the significant imbalance in the risk of major bleeding seen with other agents in the class. These include a 19-25-hour half-life for once-daily dosing; a low peak-to-trough drug concentration ratio that minimizes anticoagulant variability; low renal clearance; and no significant CYP3A4 metabolism, which may reduce the risk of drug-drug interactions.
Betrixaban has been given Fast Track designation by the U.S. Food and Drug Administration (FDA). Portola submitted a New Drug Application to the FDA in October 2016 seeking approval to market betrixaban for extended-duration prophylaxis of VTE in acute medically ill patients with risk factors for VTE. Portola expects a response from the FDA within 60 days as to whether the NDA is complete and acceptable for filing.
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 three programs, including betrixaban, an oral, once-daily Factor Xa inhibitor; AndexXa™ (andexanet alfa), a recombinant protein designed to reverse the anticoagulant effect in patients treated with an oral or injectable Factor Xa inhibitor; and cerdulatinib, a Syk/JAK inhibitor in development to treat hematologic cancers. Portola's partnered program is focused on developing selective Syk inhibitors for inflammatory conditions. For more information, visit www.portola.com and follow the Company on Twitter @Portola_Pharma.
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 development of our product candidates, our regulatory applications and estimated timelines associated therewith. Risks that contribute to the uncertain nature of the forward-looking statements include: failure to obtain regulatory approval for one or more of our product candidates, our expectation that we will incur losses for the foreseeable future and will need additional funds to finance our operations; the results of our clinical trials related to the efficacy and safety of our product candidates; our potential inability to manufacture our product candidates on a commercial scale in a timely or cost-efficient manner; the accuracy of our estimates regarding expenses and capital requirements; regulatory developments in the United States and foreign countries; 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, which was filed on November 7, 2016. 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.
i Cohen AT, Harrington RA, Goldhaber SZ, Hull RD, Wiens BL, et al. Extended thromboprophylaxis with betrixaban in acutely ill medical patients. N Engl J Med. 2016;375:534-544.
Ana KaporPortola Pharmaceuticalsir@portola.com
Julie NormartW2O Groupjnormart@w2ogroup.com
Portola Pharmaceuticals, Inc.