Shares of Portola Pharmaceuticals Inc. (NASDAQ:PTLA) fell by $8.35, or 29.2 percent, on Thursday to close at $20.27 on news that, during a pivotal phase III trial, its once-daily factor Xa inhibitor candidate, betrixaban, fell short of proving statistically better than a standard-of-care anticoagulant for the primary group of patients that it had expected to help, heightening risk that it could fail to gain regulatory approvals.
While betrixaban reduced the risk of venous thrombosis (VTE) by 20 percent to 25 percent in the overall study population with no increase in the risk of major bleeds, that benefit did not reach a pre-specified level of statistical significance. The shortfall for the FDA fast-tracked drug will be a topic of discussion between the company and the FDA, it said.
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 (RR) of 0.806, with a "p" value of 0.054, just shy of the mark. Because a sequential testing procedure was agreed to in the company's FDA-approved statistical analysis plan for the study to be technically positive, the results in group one would have had to meet that threshold.
However, because the significance level was so close, Portola said it decided to move ahead with analysis of patients in a second group, those who had elevated D-dimer or were 75 years of age or older. For those patients, 91 percent of the overall study population, betrixaban produced a statistically significant relative risk of 0.8 (p=0.029). In the overall study population, betrixaban produced a relative risk of 0.76 (p=0.006).
Portola CEO Bill Lis told BioWorld Today that "despite the borderline results in group one, we believe the robustness and efficacy in group two and the overall population along with group can support an FDA submission."
Set against a backdrop of no statistical difference in major bleeding between the betrixaban and Lovenox (enoxaparin, Sanofi SA) arms in any of those three patient groups, Lis said that "the story for the net clinical benefit is pretty strong."
Analyst reaction to the top-line data was mixed, with most embracing the efficacy seen in the larger dataset while hedging their bets by removing potential economic contributions from betrixaban from their models, as William Blair analyst John Sonnier did.
"This result is surprising to us, and many others who shared our thoughts, as we expected a lower RR ratio than the 0.806 in the elevated D-Dimer population paired with a higher, potentially statistically significant, bleeding risk," wrote Credit Suisse analyst Vamil Divan. "Ultimately, the question now becomes whether the FDA will accept the additional analyses done in the second and third cohorts despite the previous trial protocol of only moving beyond cohort one if it was successful."
The trial, called APEX, evaluated extended-duration anticoagulation with betrixaban compared with anticoagulation with Lovenox for the prevention of VTE in acute, medically ill patients. It was designed to assess the relative risk in the composite endpoint of asymptomatic proximal deep venous thrombosis (DVT), symptomatic DVT, nonfatal pulmonary embolism or VTE-related death in high-risk acute medically ill patients treated with oral betrixaban for 35 to 47 days vs. standard-of-care preventive anticoagulation with injectable Lovenox dosed for between six and 14 days. It included 7,513 patients worldwide.
The full results of APEX will be presented at the International Society on Thrombosis and Haemostasis Congress on May 27. Full data will also be submitted for publication.
Outside the focus of Thursday's sell-off, Portola is nearing what most expect to be an August approval for andexanet alfa, an antidote designed to reverse the anticoagulant activity of both direct and indirect factor Xa inhibitors. The company filed a biologics license application with the FDA in the first quarter. The antidote is being reviewed under an accelerated approval pathway with a PDUFA date of Aug. 17.