Johnson & Johnson subsidiary Janssen Inc. believes that its oral anticoagulant Xarelto (rivaroxaban) is on its way to having the broadest label of any of the novel anticoagulant agents.

With positive findings in treatment of symptomatic pulmonary embolism and prevention of recurrent events from the EINSTEIN-PE trial, it may be the first to crack an important indication that, until now, has been under the radar. The EINSTEIN-PE trial showed non-inferior efficacy for Xarelto and a 50% reduction in major bleeding compared to the standard of care. Based on that trial and two other studies previously published, Janssen is planning a second-quarter filing with FDA for treatment and secondary prevention of venous thromboembolism, including deep vein thrombosis (a blood clot in a deep vein, usually the leg) and pulmonary embolism, a blood clot in the lung(s).

Indications Targeted By Novel Oral Anticoagulants

Primary prevention of DVT, which could lead to PE, after orthopedic surgery
Prevention of stroke in patients with atrial fibrillation
Treatment of VTE and prevention of secondary events (PE and DVT)*
Prevention of cardiovascular events, including deaths, after recent acute coronary syndrome
Prevention of VTE in patients hospitalized for acute medical illness
Prevention of VTE in patients with mechanical heart valves

*Indications targeted for Xarelto in Janssen’s EINSTEIN program

Results of EINSTEIN-PE were presented at the American College of Cardiology meeting on March 26 and published online the same day in the New England Journal of Medicine ([A#14120326001]).The company noted that the trial was the largest done of a novel anticoagulant specifically in PE. The candidate is the only new oral anticoagulant to be studied in separate DVT and PE trials in this indication, a factor that could strengthen its value proposition in the clinic, said Decision Resources analyst Matthew Killeen.

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 of the attention has been on what is likely the largest and most profitable indication, prevention of stroke in atrial fibrillation, but the competitors also are staking out claims in smaller, albeit important, disease areas.

The market for stroke prevention in atrial fibrillation is set to grow from $1 billion in 2011 to $4.6 billion in 2020, according to Decision Resources. Xarelto and Boehringer Ingelheim GMBH’s Pradaxa (dabigatran) are both FDA-approved for this indication, and Bristol-Myers Squibb Co./Pfizer Inc.’s Eliquis (apixaban) is under FDA review for it as well Also see "Eliquis Delay Fuels Speculation About Advisory Committee Meeting" - Pink Sheet, 1 March, 2012..

The U.S. market for VTE treatment/secondary prevention is worth about $700 million and is set to grow to $1.3 billion by 2020, according to Decision Resources.

But VTE treatment and prevention of repeat episodes of venous thromboembolism, which includes pulmonary embolism and deep vein thrombosis, also has potential. The standard of care here currently is a five- to 10-day course of injectable heparin, including Sanofi’s low molecular weight heparin Lovenox, which just went generic, followed by a vitamin K antagonist, such as warfarin, for three to 12 months. U.S. drug sales for this indication amount to about $700 million (largely dominated by Lovenox) and are set to grow to $1.3 billion by 2020, according to Decision Resources.

The EINSTEIN series of trials generated data on about 9,400 patients in VTE treatment/secondary prevention, and was part of the broader Xarelto program, which included a total of about 75,000 subjects across a range of indications, including stroke prevention in AF. In VTE, Janssen and partner Bayer AG previously had unveiled the results for EINSTEIN-DVT of treatment of DVT and prevention of recurrent events, and EINSTEIN-EXT, a long-term study of Xarelto after treatment of DVT or PE for prevention of recurrent VTE (see sidebar on Phase III trials).

Xarelto was approved in Europe in December 2011 for treatment of DVT and secondary prevention of DVT and PE after DVT. Bayer plans to file specifically for PE treatment and prevention of recurrent VTE events after PE in Europe in the second quarter.

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In the U.S., FDA initially approved the drug in July 2011 for use after orthopedic surgery to prevent DVT, which can lead to PE, and then in November gave it a thumbs up for preventing stroke in patients with AF Also see "FDA Approval Of Xarelto Bodes Well For Drug’s Future Expansion" - Pink Sheet, 11 July, 2011.. J&J is waiting for an FDA decision on an indication for the drug in acute coronary syndrome; it was accepted for priority review following a filing in late-December 2011, with some speculating it could go before FDA’s Cardiovascular Drugs Advisory Committee in May.

The VTE treatment/secondary prevention opportunity is substantial, even if not on par with SPAF. Every year, an estimated 900,000 people in the U.S. have a VTE episode, one-third of which are fatal. According to Physicians Drug and Diagnostic Audit data, about 15% of the 1.3 billion annual daily doses of warfarin are directed toward VTE/PE, and warfarin currently may be significantly underused in VTE due to the cumbersome nature of its dosing, wrote UBS analyst Rajeev Jashnani in a March 26 note.

If successful, Xarelto could become the first novel oral anticoagulant to get this indication in the U.S. “If all four [indications] 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 Paul Burton, VP and cardiovascular franchise medical leader at Janssen.

Meanwhile, competitor Boehringer, which was first to get FDA approval of a novel anticoagulant, in October 2010, for the SPAF indication, has completed four trials of Pradaxa in VTE treatment and secondary prevention: RE-COVER and RE-COVER II for initial treatment/secondary prevention; and RE-MEDY and RE-SONATE for long-term secondary prevention. The most recent data were released from RE-COVER II in December 2011.

Private Boehringer Ingelheim has reported four trials of its Pradaxa in VTE treatment/secondary prevention, but will not comment on filing plans.

The company, which is private, has not disclosed its plans for regulatory filings, but says its VTE development program is now complete. Pradaxa is approved in 75 countries for primary prevention of VTE after orthopedic surgery but not approved in the U.S. for that indication, or anywhere yet for VTE treatment and secondary prevention.

Bristol and Pfizer are further behind in development of apixaban in VTE treatment and secondary prevention, with results from the Phase III AMPLIFY and AMPLIFY-EXT studies due to wrap up in March 2013 and August 2012, respectively.

A broad label for Xarelto is “probably underappreciated,” Jashnani wrote. While apixaban has shown a “compelling profile in the large a-fib indication, Xarelto’s label should ultimately span a-fib, VTE/PE & ACS,” he commented.

Based on its development program, Xarelto could wind useful to many specialists, including surgeons, cardiologists, electrophysiologists, hematologists and internal doctors, observed Decision Resources’ Killeen.

Differentiation By Trial Design

Trial design differences could provide room for differentiation among the various candidates in VTE treatment and secondary prevention.

Typically when a patient has DVT/suspected PE he or she is given an injection of heparin right away. When the diagnosis is confirmed, the patient is given warfarin and gradually weaned off heparin as warfarin takes effect. In the EINSTEIN studies, patients were allowed to have up to 48 hours of heparin prior to study entry, but then received only the study drug, so rivaroxaban has the possibility to be used with a much shorter course of treatment with heparin.

“If you do what they did in this study and go straight to rivaroxaban, you get exactly the same effect of the injectable, with half the rate of major bleeding,” said Janssen’s Burton.

Thought leaders perceive Xarelto’s one-drug approach to acute DVT and PE treatment “to be a major advantage that could significantly streamline care,” and help accelerate the trend toward treatment on an outpatient basis, Killeen said.

Currently, patients can be taught how to self-administer subcutaneous heparin, but this is difficult to achieve in practice, said Jack Ansell, chairman of the department of medicine at Lenox Hill Hospital in New York.

“There are people who go home, but it’s the minority. Most hospitals can’t achieve that and almost always admit patients for several days and then send them home. Now with this therapy, there is no need for that unless the patient requires admission for something else,” he said.

In contrast, Pradaxa and Daiichi Sankyo Co. Ltd.’s edoxaban were tested after treatment for five to 10/12 days with heparin.

In terms of the results for efficacy and safety in VTE treatment and prevention of Xarelto and Pradaxa – the only other new anticoagulant with Phase III results available for the indication – look broadly comparable, said Killeen, though there were some reports of additional cases of cardiovascular events in the Pradaxa studies.

Like Xarelto, apixaban is being tested as a one-drug approach for VTE treatment/prevention of recurrence, skipping the usual initial treatment period with heparin. The AMPLIFY-EXT trial is testing two different twice- daily doses of the drug – 2.5 mg and 5 mg – for a 12-month treatment period to prevent recurrence, flexibility that is likely to appeal to prescribing physicians if the trial succeeds.

“This could be a huge advantage for apixaban. It’s the only trial [in VTE secondary prevention] where two different doses of an anticoagulant are tested for a long period of time,” Killeen said.

Janssen Looks To Differentiate Anticoagulant Xarelto With Broad Label

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