Image source: Portola Pharmaceuticals.

After a mixed-bag of trial results for its clinical-stage anticoagulant caused shares to tumble back in March, Portola Pharmaceuticals (PTLA) has offered up additional data that supports an FDA filing for approval. Although an eventual FDA green light is far from guaranteed, I think this additional data improves the company's odds for a regulatory go-ahead. 

Revolutionizing care

Patients at risk of life-threatening blood clots have been prescribed the anticoagulant warfarin for decades. Warfarin blocks the clotting ability of vitamin K, but it's far from a perfect solution. Warfarin patients often have to have their doses adjusted, they can suffer dangerous hemorrhages, and they have to watch their diets closely to avoid foods rich in vitamin K.

Recently, an entirely new class of anticoagulants, known as factor Xa inhibitors, have won FDA approval. Because they're easier to dose, potentially safer, and don't require a special diet, these drugs are quickly becoming the new standard.

The two best-selling factor Xa drugs currently on the market are Johnson & Johnson's (JNJ -0.29%) Xarelto, and Bristol-Myers Squibb's(BMY 0.07%) and Pfizer, Inc.'s (PFE -1.24%) Eliquis. Those drugs generated total sales approaching $4 billion last year, and first-quarter results put these two drugs on pace to deliver combined sales of more than $5 billion in 2016. Specifically, Xarelto's sales grew 29%, to $567 million in Q1, while Eliquis sales (as reported by Bristol-Myers Squibb), more than doubled, to $734 million.

Although factor Xa therapies like Xarelto and Eliquis are quickly displacing warfarin, neither of these drugs is specifically approved for use in the prevention of blood clots in post-acute-care hospital patients. Instead, the standard of care for preventing venous thromboembolism, or VTE, in these patients is Sanofi's Lovenox, an injection-dosed therapy that's administered to patients when they are in the hospital.

Because Lovenox can prevent VTE in many elderly and acutely ill patients, it became a top seller, with $3 billion in annual sales, before losing patent protection. However, Lovenox doesn't prevent VTE in patients after they're discharged from the hospital, and sadly, hundreds of thousands of these patients suffered a VTE event after they'd returned home.

For that reason, Portola Pharmaceuticals developed betrixaban, a factor Xa inhibitor that's specifically designed to displace Lovenox use in these patients. Betrixaban is a once-daily pill that can be taken at home for weeks after hospital discharge, and it's formulated to have a class-leading half life that provides patients with more-consistent protection from blood clots.

Stumbling across the finish line

Portola Pharmaceuticals investors were dealt a big blow when management reported what appeared to be less-than-stellar Phase 3 results for betrixaban in March. In a 7,500 patient trial evaluating betrixaban head to head against Lovenox, betrixaban failed to reduce VTE by a statistically significant amount in a key group of patients. Usually, the failure to hit the primary endpoint in a trial is a deal-breaker, so investors bailed out of Portola Pharmaceuticals stock. However, selling shares might have been premature because, as the saying goes, "there's more to the story."

Betrixaban's Phase 3 trial -- developed in concert with the FDA -- involved three study groups, or cohorts. The first cohort included patients with clinical evidence of blood clots as determined by elevated D-dimer levels. The next cohort included patients who either had elevated D-dimer levels, or were over age 75. The final cohort included all patients in the study.

Source: Portola Pharmaceuticals.

In theory, people who are showing evidence of clots, or the first cohort, should benefit most from betrixaban. However, betrixaban failed to achieve statistical significance, or a p-value of 0.05, in this patient group. Instead, its p-value was 0.054. 

Failure in the first cohort, however, didn't translate into failure in the larger two remaining cohorts. Both cohort 2 and cohort 3 showed that betrixaban was significantly better than Lovenox at reducing VTE. Importantly, betrixaban reduced VTE without increasing the risk of bleeding. Overall, there was a 24% relative risk reduction for betrixaban versus Lovenox across the entire study, with a compelling p-value of 0.006.

New data on the scene

When Portola's management held its conference call in March to discuss its Phase 3 results, they said they'd provide additional insight into the drug's efficacy and safety at an upcoming industry conference. The tone struck by management at the time suggested that this additional information could support betrixaban's chances for commercialization.

This week, management presented the updated data, and the information appears to boost the likelihood of an eventual betrixaban approval. Specifically, the company shared a slide showing that the relative risk reduction for cohort 1 patients who had their D-dimer evaluated by a central laboratory instead of a local lab was statistically better than Lovenox -- by a lot. In fact, central laboratory D-dimer patients had the best risk reduction of VTE of any group evaluated, and the lowest p-value.

Source: Portola Pharmaceuticals.

Looking ahead

Portola's management has shared its trial data with the FDA, and confirmed its fast-track status for betrixaban. Because fast-track status gives Portola Pharmaceuticals pre-filing access, the company should be able to put together the most-compelling argument possible for the drug's approval. 

If the company files betrixaban for approval soon -- it plans to do so in the coming months -- then an approval could open up a multibillion-dollar market to the company. Globally, 20 million acutely ill patients are at risk of VTE. 

However, an FDA approval isn't a lock for betrixaban. The FDA could still frown upon the cohort 1 data. If that happens, there's a risk that this drug doesn't make it onto the market. If it doesn't get approved, then investors will need to hope that Portola Pharmaceuticals' andexanet alfa is a hit.

Andexanet alfa is a factor Xa reversal agent that could get the FDA's nod in August. Fortunately, the unmet need for an antidote for fast-growing factor Xa therapies like Xarelto and Eliquis means that Portola Pharmaceuticals could still be shareholder friendly, regardless of betrixaban's fate.

Betrixaban's peak sales potential is bigger than andexanet alfa's, and that means that investors should watch the company's progress with the FDA closely. If Portola Pharmaceuticals gets its filing to the agency by the end of 2016, then a decision could come on betrixaban next summer.