Janssen Plans New U.S. Filing For Xarelto, Based On Positive EINSTEIN-PE Results
By Emily Hayes

With the results from the EINSTEIN-PE non-inferiority trial, which showed a 50% reduction in major bleeding compared to the standard of care, Johnson & Johnson subsidiary Janssen Inc.is planning a second-quarter filing with FDA for its anti-coagulant Xarelto (rivaroxaban) in treatment and secondary prevention of symptomatic pulmonary embolism.

In the randomized, open-label trial of 4,833 PE patients with or without deep vein thrombosis, the oral Factor Xa inhibitor had similar efficacy to standard of care treatment with Sanofi’s now generic low molecular weight heparin Lovenox (enoxaparin) followed by a vitamin K antagonist (warfarin or acenocoumarol). Rivaroxaban was also on par with the standard of care for the primary safety endpoint of major and non-major bleeding overall, but was significantly better when it came to major bleeding, which is most concerning for doctors. Results were presented at the American College of Cardiology meeting March 26 and published the same day in the New England Journal of Medicine.

“We have the same benefit for efficacy, with a really nice reduction in major and critical organ bleeding,” said Paul Burton, vice president and cardiovascular franchise medical leader at Janssen, during an interview at the ACC meeting.

Commenting on the bleeding rates after the trial data were presented, discussant C. Michael Gibson of Beth Israel Deaconess described the results as “impressive,” especially as major bleeding can cost from $5,000 to $10,000 per episode.

If successful, Xarelto, which is partnered ex-US with Bayer AG, could become the first novel oral anticoagulant to get this indication in the U.S., according to the company. Burton noted that when it comes to PE, rivaroxaban is farthest along in development compared to rivals and that EINSTEIN-PE is the largest study done of a novel anticoagulant in this indication. Janssen/Bayer’s program for rivaroxaban in PE includes 9,000 patients and the total program includes 75,000.

Xarelto is one of a new breed of novel anti-coagulants seeking to replace the decades-old generic vitamin K antagonist warfarin, which is difficult to administer and requires regular blood monitoring. Most have targeted the most profitable indication of prevention of stroke in atrial fibrillation first, with Boehringer Ingelheim GMBH’s Pradaxa (dabigatran) FDA-approved for stroke prevention in AF and Bristol-Myers Squibb Co./Pfizer Inc.’s Eliquis (apixaban) under FDA review in that indication. But prevention of venous thromboembolism (VTE), which includes deep vein thrombosis and PE, is also a promising market.

Xarelto was initially approved by FDA for prevention of deep vein thrombosis and then received a new indication for preventing stroke in patients with AF ("Xarelto Approval For Stroke Prevention Sets Up Marketing Battle With Pradaxa" — "The Pink Sheet," Nov. 7, 2011). An indication in acute coronary syndromes has priority review with FDA following a filing in late-December; it could go before FDA’s Cardiovascular Drugs Advisory Committee in May.

And now Janssen believes it can add PE to the list of new indications, based on the EINSTEIN-PE data.

“If all four come to fruition, we will certainly have the broadest range of indications in the U.S. for any of the new anticoagulants on the market or coming to market,” said Burton.

Offering Mostly A One-Drug Approach

Typically, when a patient has suspected PE, they are given an injection of heparin right away. Then when the diagnosis is confirmed, they are given warfarin and are weaned off the heparin as warfarin starts to take effect. Heparin treatment is typically given for up to seven days, while warfarin treatment lasts from three to 12 months. Unlike other novel anticoagulants, which were tested after five to 10 days of initial therapy with heparin in VTE indications, rivaroxaban has the possibility to be used with a much shorter course of treatment with heparin.

The EINSTEIN-PE trial allowed all patients to have up to 48 hours of heparin treatment prior to study entry, and almost all patients in the rivaroxaban arm had actually received enoxaparin prior to randomization, though in the vast majority, treatment was limited to two days or less.

Initial administration of heparin is “unavoidable” in VTE trials and “consistent with current practice, pending confirmation of a diagnosis,” Harry Buller of the Academic Medical Center in the Netherlands and colleagues wrote in the NEJM paper.

Rivaroxaban is normally given once daily. But in this indication, researchers thought a higher dose was needed in the initial treatment period. A 15 mg dose of rivaroxaban was given twice a day for the first three weeks, and from then on the dose was reduced to 20 mg once a day.

Treatment in the comparator arm consisted of injectable enoxaparin, with a median treatment duration of eight days, followed by a vitamin K antagonist. Quality of warfarin treatment, as measured by the time the INR was in the therapeutic target range was “well within clinical acceptability,” the NEJM authors noted. In this study, the INR on average was in the therapeutic range 62.7% of the time and exceeded 3.0 only 15.5% of the time. Total treatment typically lasted from six to 12 months in both groups.

The primary efficacy measure was the rate of symptomatic recurrent venous thromboembolism, a composite of fatal or nonfatal PE or DVT, and the principal safety measure was the rate of major or clinically relevant bleeding. Rivaroxaban demonstrated non-inferiority, with a 2.1% VTE rate (50 events) compared to 1.8% (44 events) for the comparator. The two arms were similar when it came to the primary safety endpoint of the first episode of major and clinically relevant non-major bleeding episodes, with 10.3% (249 episodes) in the rivaroxaban group vs. 11.4% (274) for standard therapy. Major bleeding was significantly lower in those taking rivaroxaban: 26 episodes (1.1%), half of the rate for the comparator arm at 52 cases.

Presenting results at the ACC meeting, Buller stressed that there also was no signal for myocardial infarction or damage to liver function in the study. And results were similar in subgroups, with little variation depending on age, renal function or presence of obesity. Safety was “very consistent in these various groups,” Buller said. As to the major bleeds, he noted that there were zero fatal cases of intracranial hemorrhage in the rivaroxaban arm, compared to one in patients on standard therapy. There was one non-fatal case of intracranial hemorrhage for those taking rivaroxaban, compared to 10 in the comparator group.

Challenging Standard Of Care

Xarelto is the only new oral anticoagulant to have separate DVT and PE trials, a factor that could strengthen its value proposition in the clinic, Decision Resources analyst Matthew Killeen said in an e-mailed comment to “The Pink Sheet” DAILY.

Additionally, thought leaders perceive Xarelto’s one-drug approach to acute DVT and PE treatment to be a “major advantage that could significantly streamline care,” the analyst said.

The two-step standard of care with heparin overlapped with warfarin has been around for “half a century,” and is “effective but complex,” the NEJM article states. Janssen’s release about the results noted that rivaroxaban could offer a single-drug approach that would simplify treatment by “eliminating the need to transition to a different anticoagulant, while preventing the occurrence of secondary blood clots in patients who have pulmonary emboli.”

Patients can be taught to inject themselves with heparin, and therefore be treated on an outpatient basis, but this is difficult to achieve in practice for many hospitals, Jack Ansell, chairman of the department of medicine at Lenox Hill Hospital in New York, said in an interview.

Patients with PE and DVT who are stable won’t need to be hospitalized; rather, they can be started on rivaroxaban as soon as they are diagnosed in the emergency department and sent home, without all the “problems and headaches that usually go along with combination therapy,” he said.

“If you do what they did in this study and go straight to rivaroxaban, you get exactly the effect of the injectable, with half the rate of bleeding. …This really sets a new standard of care,” Ansell said.
 

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