After presenting full results from the phase III trial with Portola Pharmaceuticals Inc.’s oral betrixaban for prophylaxis of venous thromboembolism (VTE) in France, study steering committee leader Michael Gibson told BioWorld Today that the company is “beginning to chip away at the chip of the iceberg with respect to the data and will continue to work closely with [the FDA] to explore all their questions.” South San Francisco-based Portola plans to submit a new drug application to the FDA in the second half of this year, and pursue approval in Europe as well.
The once-daily factor Xa inhibitor narrowly missed its primary endpoint in top-line data reported in March from the study called APEX (Acute Medically Ill VTE Prevention with Extended Duration Betrixaban). Betrixaban, fast-tracked by the FDA, reduced VTE risk by 20 percent to 25 percent in the overall study population with no increase in the risk of major bleeds, but such benefit did not reach a pre-specified level of statistical significance. For patients in group one of the study, those with elevated concentrations of a protein fragment that can indicate blood clots called D-dimer, betrixaban produced a relative risk of 0.806, with a “p” value of 0.054, just short of the goal. Because a sequential testing procedure was part of the statistical analysis plan OK’d by U.S. regulators, the outcomes in group one had to meet that threshold. (See BioWorld Today, March 25, 2016.)
Complete data from APEX rolled out at the 62nd International Society on Thrombosis and Hemostasis Scientific and Standardization Committee meeting in Montpellier, France. Gibson is the senior author of a simultaneously published article detailing the results in the New England Journal of Medicine, as well as steering committee chairman for APEX and a member of the trial’s executive committee. APEX enrolled 7,513 patients at more than 450 sites worldwide, testing the superiority of betrixaban as a VTE prophylactic of extended-duration for 35 days compared to standard-duration Lovenox (enoxaparin, Sanofi SA) for 10±4 days. The trial was designed in cooperation with the FDA and the EMA to incorporate a patient enrichment and statistical analysis plan derived from guidance issued by the FDA in 2012. As noted in March, a pre-specified subgroup of D-dimer-positive patients showed promise.
“The first look at the data was in the smallest sample size in the study,” Gibson said, and the full results are “much more robust,” showing symptomatic event reduction of 44 percent “when you go all the way out the entire duration of the study in all the patients, [with] no increase in major bleeding, which is a first in this class.” Specifically, Portola zeroed in on fatal or irreversible bleeds. “These are some of the most objective, rigorous endpoints” of the sort with which “no one can argue,” he said, and the experiment turned up “highly significant reductions in those hard, hard endpoints.” In the 0.054 “p” value miss, the argued-over classification of one patient could have meant an important difference, he noted.
Another Trial ‘likely’?
“We used the local [D-dimer] tests to facilitate enrollment, but when you use the more accurate, precise and reproducible central D-dimer value, it turns out that cohort one [had] the most significant reduction,” Gibson said. “If you’re using the enrichment strategy, you’ve got to use something that’s highly specific. When you use the central D-dimer value, a lot of those people we thought were D-dimer positive – 136 of them – turned out to be D-dimer negative. We had polluted the D-dimer results with some false positives. When you drill down and use a much more specific test, the D-dimer cohort really shines. It’s that kind of biological plausibility to the data that adds credibility.” The dose response variance among some patients given 40 mg vs. those getting 80 mg proved telling as well, he said.
Gibson also pointed to the “consistency of the results across all cohorts, and between MAGELLAN and this study.” The experiment called MAGELLAN (Multicenter, Randomized, Parallel-group Efficacy and Safety Study for the Prevention of Venous Thromboembolism in Hospitalized Medically Ill Patients Comparing Rivaroxaban With Enoxaparin) was carried out to test the anticoagulant Xarelto (rivaroxaban, Bayer AG/Johnson & Johnson) once daily for 35 days compared to Lovenox therapy. “The numbers are nearly identical if you look at central D-dimer as a way to stratify and event reductions,” he said. “The numbers are super-imposable. The difference is that we had no excess bleeding [because of] much lower renal clearance of betrixaban and the much lower peak-to-trough ratios.”
Cowen and Co. analyst Phil Nadeau said in March that he found it “likely” that U.S. regulators will want another phase III trial to bolster APEX. Gibson declined to speculate. “The FDA doesn’t ever give you guidance and say you must hit this or that endpoint,” he said. “It’s a conversation with a review of all the data.” But so far, the agency has not insisted on further experiments. About 400,000 VTEs with 150,000 deaths happen annually in the U.S. “That’s a big public health impact. I’m hopeful and optimistic that they’ll look favorably upon” the data because of the major need, he said.
Acute medically ill patients (the segment that Portola targets with its therapy) are hospitalized for serious common medical conditions such as heart failure, stroke, infection and pulmonary disease. Despite the use of standard-of-care clot busters, a significant number of patients end up suffering a VTE event, and more than half of VTEs occur after Lovenox is discontinued and the patient is discharged from the hospital. No anticoagulant, including any of the marketed oral factor Xa inhibitors, is yet approved or guideline-recommended for extended-duration VTE prophylaxis in that patient group.
Portola’s stock (NASDAQ:PTLA) closed Friday at $27.50, up $1.21 cents.