Portola Pharmaceuticals' (PTLA) 7,513 person head to head study evaluating its next-generation anticoagulant betrixaban against standard of care Lovenox in the prevention of blood clots missed its endpoint in one trial cohort.

By study design, efficacy in cohort 1 had to have a p-value -- a measure of significance -- of less than 0.05 to evaluate cohort two and cohort 2 had to have a p-value of less than 0.05 to evaluate the entire population. The p-value in cohort 1 was 0.054, which was slightly above the 0.05 gold standard.

However, because the p-value was so close to the mark, management still evaluated cohort 2 and the overall population and found that efficacy in those groups were backed up by p-values of 0.029 and 0.006, respectively. The company's management plans to discuss the overall study results with the FDA soon and they remain undaunted in their plans to file a new drug application later this year.

First, a bit of background
Betrixaban is a factor Xa inhibitor that attempts to keep blood from clotting by interrupting a key clotting enzyme. Factor Xa drugs Xarelto and Eliquis, made by Johnson & Johnson (JNJ 1.49%) and partners Bristol-Myers Squibb (BMY 0.17%) and Pfizer (PFE 3.64%), respectively, are already on the market for use in various indications, and the use of those drugs has grown steadily as doctors increasingly view them as superior to warfarin, a decades-old drug that can interact with common foods and cause brain hemorrhage.

Because the market for anticoagulant drugs tops $10 billion and factor Xa drugs can cost tens of thousands of dollars per year, Xarelto and Eliquis have become billion dollar blockbusters. Last year, Xarelto sales were $1.9 billion for J&J and Eliquis sales were $1.9 billion for Bristol-Myers Squibb and Pfizer.

Although Xarelto and Eliquis have become widely embraced, they are not approved for use to prevent clots in acute medically ill patients, or patients who have been hospitalized for serious medical conditions, such as heart failure or stroke.

Instead, the standard of care is Sanofi's (SNY 2.88%) Lovenox. Prior to losing patent protection in 2007, Lovenox sales totaled $3 billion per year. Currently, generic Lovenox is most widely used in this at-risk patient population.

Improving upon care
Lovenox has been used in this indications since 1993, and Portola Pharmaceuticals hoped to demonstrate that betrixaban could outperform it similarly to how Xarelto and Eliquis outperformed warfarin.

The need for a new alternative therapy for the prevention of blood clots is massive. In the G7 countries, Portola Pharmaceuticals reports that there are 20 million acute medically ill patients who are at risk of developing venous thromboembolism either while they're hospitalized or after they're discharged. Despite Lovenox's widespread use, more than 1 million cases of VTE are reported annually -- and sadly, 150,000 patients pass away because of it.

Unlike Lovenox, which is dosed via injection, betrixaban is taken orally. In this study, patients were given either betrixaban once-daily for 35 to 47 days or Lovenox once-daily for 6 to 14 days.

In the first cohort, the relative risk of a VTE was reduced by about 19%, however, as stated earlier, the p-value was 0.054. In cohort 2 and the overall study population, risk of VTE in the betrixaban group was reduced by 20% and 24%, respectively.


Looking ahead
There's a multibillion market opportunity in this indication, and with cohort 1 missing by so little and cohort 2 and the overall study delivering positive efficacy, Portola Pharmaceuticals management remains committed to a commercial launch.

Investors hoping for a slam-dunk trial victory are undoubtedly disappointed, but this trial may still allow for betrixaban to win approval under the FDA's accelerated pathway in 2017.

Additionally, Portola Pharmaceuticals remains on track for a FDA decision in August for its factor Xa reversal agent, andexanet alfa. That antidote was developed with support from Johnson & Johnson, Bristol-Myers Squibb, and Pfizer, but Portola retains full rights to the drug in most markets worldwide. If approved, andexanet alfa could generate sales in the hundreds of millions of dollars per year.

Nevertheless, betrixaban is the much larger market opportunity for the company, and the absence of definitive trial data casts enough doubt to warrant a reduction in Portola Pharmaceuticals valuation until more clarity is offered up regarding how the FDA views betrixaban relative to Lovenox in light of this trial.