The attributes of Merck/Portola's Factor Xa inhibitor betrixaban, and where it fits in the crowded development space of novel anticoagulants, came into sharper focus with the release of new Phase II data at the American College of Cardiology annual meeting.

Factor Xa inhibitors and direct thrombin inhibitors are among the many novel oral anticoagulants competing to make warfarin a thing of the past (¹ [A#0072010024]). Among the drawbacks of the widely-used warfarin, a vitamin K-dependent coagulation factor inhibitor, are the need for close monitoring, food-drug interactions and problems with tolerability, such as in patients with severe kidney disease.

Of the up-and-coming anticoagulants, those furthest along in development are Boehringer Ingelheim's direct thrombin inhibitor Pradaxa (dabigatran) and two Factor Xa inhibitors - Bayer/Johnson & Johnson's Xarelto (rivaroxaban) and Pfizer/Bristol-Myers Squibb's apixaban.

Differentiation between these agents will be based on a range of intrinsic qualities, including bioavailability, level of renal excretion and half life (see chart: " ² How Novel Anticoagulants Stack Up Against Each Other ").The efficacy and safety results from clinical trials, as presented at ACC and other medical meetings, also is being scrutinized closely for signs of where the novel agents can find entry points on the market.

Some of the data have been so positive as to fuel high hopes for the entire field of novel anticoagulants, as well as setting a high competitive bar for rivals. Results for dabigatran, which is already on the market for some indications in Europe, have generated much enthusiasm in recent months. In August, Boehringer Ingelheim released positive results from the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) study of two doses of dabigatran in 18,000 patients with atrial fibrillation. A dose of 150 mg given twice daily reduced the risk of stroke and systemic embolism by 34 percent, a superior result compared to warfarin (³ Also see "Boehringer-Ingelheim Now RE-LYing On Pradaxa Approval In Stroke Prevention" - Pink Sheet, 7 September, 2009.). A lower dose of 110 mg proved non-inferior to warfarin in reducing these risks.

A new sub-analysis of the RE-LY data assessed effects on patients based on their risk for these events: low, moderate and high. The higher dose was effective at reducing stroke and systemic embolism rates, regardless of risk level, according to results presented March 17 at the ACC meeting. The 110 mg dose was as effective as warfarin for risk reduction. And both doses were associated with lower rates of major bleeding compared to well-controlled warfarin in low-risk patients, the company reported. The results suggest that dabigatran could find wider use in patients at lower risk, for whom warfarin is now deemed too risky.

Merck's entry into the novel anticoagulant race came last summer, when it signed on with the privately-held Portola Pharmaceuticals to develop and commercialize betrixaban for $50 million, plus another $420 million in milestone payments and double-digit royalties (⁴ Also see "Portola Marries Factor Xa Clot Buster Off To Merck" - Pink Sheet, 9 July, 2009.).

Results from a dose-finding study of the once-daily betrixaban were aired on March 15 at the ACC meeting, giving the first glimpse of the betrixaban profile and shedding further light on the drug's potential. The Phase IIb EXPLORE Xa study tested three doses of betrixaban in a blinded fashion - 40 mg, 60 mg and 80 mg - against open-label warfarin in about 500 patients with non-valvular atrial fibrillation or atrial flutter and at least one risk factor for stroke.

Patients were followed for from three to twelve months. The primary endpoint was the time to occurrence of major or clinically relevant non-major bleeding. Bleeding rates were 0.8 percent, 3.9 percent and 3.9 percent for the betrixaban 40 mg, 60 mg, and 80 mg doses, respectively, compared to 5.5 percent in the warfarin group.

In the 40 mg betrixaban dose group, the difference was statistically significant, while in the other two dosing groups, the results were not significant, reported lead investigator Michael Ezekowitz, Lankenau Institute for Medical Research in Wynnewood, Penn. D-dimer tests showed drug activity at all three doses.

Betrixaban Readies For Phase III

The results provide an indication of the drug's potency, though efficacy still must be validated in Phase III.

"It remains to be seen how effective betrixaban is," commented Nikhil Mehta, an analyst with U.K. research firm Decision Resources. "The Phase II study showed that betrixaban does work but warfarin is a tough comparator in clinical trials for stroke prevention."

Timing for the launch of a Phase III trial of betrixaban is yet to be decided, but it seems likely that at least two doses will be tested, said Ezekowitz.

However, some aspects of Phase II trial design could complicate further analysis, observed Barclays Capital analyst Charles Butler in a March 17 note. The patient population in the trial had an unusually high body weight (about half weighed more than 90 kg, or 198 pounds). Also, about 40 percent of those in the warfarin arm were also taking aspirin, which could have resulted in higher bleeding rates for the control group.

"Both body weight and aspirin co-administration may have clouded the bleeding safety data," Butler said.

GI Side Effects Also Cause Concern

There were also an unexpectedly higher rate of GI side effects, such as diarrhea, nausea, vomiting and constipation among those taking betrixaban.

"There did seem to be a higher incidence of GI complaints, but I need to emphasize only one patient discontinued therapy because of GI symptoms," Ezekowitz said. "But obviously this will be monitored very carefully in any future trials."

Because of the small sample size, it's hard to judge the importance of the GI side effects, Mehta said. Non-compliance due to tolerability problems is a worry for physicians about all of the new anticoagulants, given that the outcome of non-compliance could be a stroke, he added.

Ezekowitz said the cause of the GI side effects is unclear, but could be due to the fact that the warfarin arm was open-label and that could have biased the reporting of side effects. Or the problem may lay in the large size of the pill. It's possible that the drug will be reformulated in a smaller size for Phase III.

However, Butler commented that the large pill size is insufficient to explain the nausea, vomiting, and diarrhea. He also suggested that the GI profile may be more of an issue in a real-world setting than in a clinical trial. "While these side effects were not severe enough to lead to discontinuation, we question how they would translate to outside the clinical trial setting, where patients tend to be less compliant."

Overall though, Butler concluded, betrixaban has a number of advantages in the race to develop an alternative to warfarin. "It remains too early to project betrixaban's future without Phase III outcomes data," he said, but allowed that "its differentiated features could allow betrixaban to carve out a niche in this competitive space."

Possible Niche In Renal Impairment

Compared to other drugs in development, renal excretion with betrixaban is extremely low, at less than 5 percent. That compares to 80 percent for dabigatran. Such an attribute could translate into a market opportunity for betrixaban to be used in patients with renal impairment.

The Explore Xa study included many older people (median age of the population was 74) and also admitted those with renal dysfunction. The findings support use in patients with severe renal dysfunction who would be at a higher bleeding risk on drugs that accumulated due to renal excretion. About 40 percent of atrial fibrillation patients have modest or severe renal impairment, representing a fairly sizeable proportion of the eligible target population for an anticoagulant like betrixaban, Mehta noted.

Similarly, experts in a March 16 ACC session on novel anticoagulants highlighted the effect on kidneys as an important competitive factor. Robert Guigliano, Brigham and Women's Hospital, said that the lack of renal excretion is a "very desirable characteristic."

"Betrixaban looks very promising in patients with renal insufficiency," he said.

Factor Xa Antidote In Early Development

Unlike warfarin, betrixaban is not metabolized by the cytochrome P450 pathway, which could help avoid drug-drug interactions, according to Merck and Portola. And its long half life of 20 hours makes once-daily dosing possible and minimizes risks associated with missed doses.

However, longer half life is not always an advantage. One downside of taking anticoagulants is that it becomes a problem in patients who have a severe bleed and/or who need surgical procedures (⁵ Also see "Oral Factor Xa Inhibitors Come Closer To Offering An Alternative To Warfarin" - Pink Sheet, 17 August, 2009.). An antidote is available for warfarin to reverse the drug's action in these situations, though it is cumbersome to administer. Absent an antidote, blood transfusions may be required in emergency medical situations. Drugs with shorter half lives are in the patient's body for less time and therefore arguably more reversible.

In tandem with development of betrixaban, Portola is developing an antidote - an asset that would be welcomed on the market. The antidote is only in preclinical stages, but the company expects it will get fast track status from FDA based on unmet need. The product will be made available for use with all Factor Xa inhibitors, Portola executives said.

- Emily Hayes ( ⁶ e.hayes@elsevier.com )

Momentum Grows For Novel Oral Anticoagulants Out To Replace Warfarin

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