Further Phase III data from the EINSTEIN trials of Bayer/J&J's novel oral anticoagulant Xarelto (rivaroxaban) bolster its position as a single-drug option in the venous thromboembolism space.

The 3,400-patient EINSTEIN-DVT study, presented at the European Society of Cardiology meeting on Aug. 31, tested rivaroxaban as a single drug in patients with acute, symptomatic deep vein thrombosis for preventing recurrent venous thromboembolism. The test drug was pitted against the two-step standard of care of an initial treatment with injectable Lovenox followed by a vitamin K antagonist.

The study is significant in that it is not only looking at prevention of recurrent DVT, but also treatment of an active clot, the companies pointed out in announcing its results. Rivaroxaban proved as safe and effective as the standard of care in the study. And unlike today's options, it should not require routine anticoagulant monitoring and poses fewer problems with food and drug-drug interactions, the developers claimed.

A Factor Xa inhibitor, Xarelto is part of a revolution taking place in anticoagulant therapy. Among the drawbacks of the now widely-used warfarin, a vitamin K-dependent coagulation factor inhibitor, are the need for close monitoring, food-drug interactions and problems with tolerability. Sanofi's Lovenox, used in combination with warfarin for VTE, has the disadvantage of being injectable.

Of the up-and-comers, those closest to becoming the first novel anticoagulant to win approval in the U.S. market are rivaroxaban, Boehringer Ingelheim's direct thrombin inhibitor Pradaxa (dabigatran) and Pfizer/Bristol-Myers Squibb's Factor Xa inhibitor apixaban ('The Pink Sheet,' March 29, 2010).

Safer, easier-to-use drugs for prevention and treatment of VTE promise to grow the market significantly in the next decade. Research firm Decision Resources estimates sales of anticoagulants for VTE, including prevention and treatment indications, amounted $2.9 billion in 2008 and will grow to $5 billion by 2018. The prevention market for people at risk accounts for more than 70 percent, the firm estimates.

Rivaroxaban is in development for several indications including prevention and treatment of VTE. J&J/Bayer's massive development program encompasses more than 65,000 patients enrolled in late-stage trials. Of the total, about 9,000 are enrolled in EINSTEIN program of three Phase III trials exploring use in VTE prevention and/or treatment. EINSTEIN-DVT is the second portion to report out.

Proving comparability to an "incredibly effective drug" such as Lovenox is "no small feat," commented Matthew Killeen, Decision Resources analyst.

The trial design that tested rivaroxaban as a single drug may set it apart this indication over some rival drugs in late-stage development in this indication, Killeen said. For example, Boehringer Ingelheim tested its Pradaxa (dabigatran) in a similar indication in the RECOVER study, but tried its drug in combination with Lovenox.

Daiichi Sankyo is testing its novel anticoagulant endoxaban for prevention and treatment of VTE in the HOKUSAI trial in over 7,000 patients. But that study will also start patients out on enoxaparin or "unfractionated" heparin, an older type of heparin, and then randomize them to treatment with endoxaban or warfarin. So if Daiichi's drug was approved based on this study, an injectable drug would still be needed as part of treatment.

Bristol and Pfizer, however, have tested apixaban successfully in VTE as a single drug alternative to enoxaparin in the Advance-2 study.

Matching Standard Of Care

The EINSTEIN-DVT study of rivaroxaban included patients with acute DVT in the deep veins of the knee or thigh but who were asymptomatic for pulmonary embolism. Those in the rivaroxaban arm received a 15 mg dose twice-daily for three weeks and then 20 mg once daily. Patients were treated for up to 12 months.

The study's primary endpoint was incidence of symptomatic recurrent venous thromboembolism (non-fatal or fatal); the results were a 2.1 percent incidence for rivaroxaban and 3 percent for standard of care.

Rivaroxaban also met targets on the safety front. Incidence of major and non-major clinically relevant bleeding events was 8.1 percent for both arms of the study. Treatment-emergent cardiovascular outcomes were low for both treatment groups (0.7 percent for rivaroxaban and .8 percent for enoxaparin/vitamin K antagonist. Discontinuation rates were similar and low for both groups, researchers reported.

Compared to the standard of care, rivaroxaban had a significantly improved net clinical benefit, a pre-specified secondary outcome defined as the composite of the primary efficacy endpoint plus major bleeding.

EINSTEIN A Snooze Or Shot In The Arm?

Industry observers expressed mixed views on the implications of the EINSTEIN-DVT data. The market for anticoagulants in atrial fibrillation- expected to grow from $840 million in 2009 to $7 billion in 2019 according to Decision Resources - is the prized indication. Results from the Phase III ROCKET-AF study of rivaroxaban in atrial fibrillation are due at the American Heart Association meeting in November and are eagerly expected. Bristol and Pfizer stole the 2010 ESC show with their release of positive data from the AVERROES trial testing apixaban in patients with atrial fibrillation in order to prevent stroke (see related story).

In an Aug. 31 research note, Morgan Stanley's David Lewis seemed unimpressed with the EINSTEIN data, noting few implications for ROCKET-AF, which tests a similar, higher dose of rivaroxaban. The similar bleeding rates in the rivaroxaban and enoxaparin/vitamin K antagonist groups are a good sign, the analyst noted. But the average age of the patients was 73, versus an under-60 average for EINSTEIN-DVT, he observed.

"Attempts to draw conclusions about bleeds in ROCKET AF from the EINSTEIN-DVT data may be inappropriate," Lewis said.

Furthermore, Lewis concluded, the market opportunity in the EINSTEIN trial is limited and "traction may be difficult with incremental improvement over Lovenox, which will be available as a much cheaper generic."

However, Decision Resources' Killeen saw the results in a much more positive light. Killeen told "The Pink Sheet" DAILY he doubted that given the option of a single novel drug, practitioners would instead choose a generic injectable followed by the 50-year-old warfarin, even if it came at a lower price.

Furthermore, Killeen believes the results bode well for Xarelto's approval prospects with FDA. Already approved outside the U.S., the drug had been submitted unsuccessfully to FDA for an indication in hip and knee replacement surgery ('The Pink Sheet' DAILY, Feb. 26, 2010). The drug received a "complete response" letter despite a 15-2 positive vote in favor of approval from an advisory committee in March 2009. FDA's rejection reflected concerns about safety, liver toxicity and bleeding ('The Pink Sheet' DAILY, March 29, 2009).

Killeen argues that the EINSTEIN-DVT study supports the drug's safety. If the drug also proves to be safe in ROCKET-AF, EINSTEIN-DVT could help smooth the way for a planned resubmission in that indication by the end of this year, Killeen said.

Meanwhile, the EINSTEIN PE trial of rivaroxaban versus enoxaparin and vitamin K antagonists in 4,000 patients with acute, symptomatic pulmonary embolism for the prevention of recurrent PE continues. That study is due to wrap up this year. Positive results from EINSTEIN-EXT, the third portion of the program, in 1,197 patients who had been treated with a vitamin K antagonist for an acute episode of VTE were released in December 2009.

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