FDA Approval Of Xarelto Bodes Well For Drug’s Future Expansion

The July 1 approval of Johnson & Johnson’s novel anticoagulant Xarelto for prevention of deep vein thrombosis is an important step for J&J and its ex-U.S. partner Bayer AG as they gear up to play in the highly promising but increasingly complicated world of novel anticoagulants.

FDA approved the drug for a narrow indication – prophylaxis of deep vein thrombosis, which may lead to a pulmonary embolism, in people undergoing total knee or total hip replacement surgery. An oral Factor Xa inhibitor, it is taken once daily for 35 days following hip replacement and for 12 days following knee replacement surgery, the periods when patients are most susceptible to hypercoagulation.

Superiority in DVT could change the standard of care, but there is stiff competition among the novel anticoagulants, especially in the larger markets.

Because this is short term therapy, analysts’ estimates of the U.S. market opportunity are low, ranging from $250 million to $500 million, relative to their overall projections for novel anticoagulants.

But despite the small size of the market, Xarelto (rivaroxaban) has the potential to change standard of care in this setting. The drug demonstrated superior efficacy in comparison to Lovenox (enoxaparin), the current standard of care, in a series of trials that clinicians and consultants describe as “robust.” Bleeding rates – the key safety indicator for anticoagulants – were slightly higher than for Lovenox, although not by a statistically significant amount.

The approval is a milestone, however, in part because it suggests that FDA has a favorable opinion of Xarelto, UBS analyst Rajeev Jashnani said in a July 1 note. The green light is all the more welcome because the drug has had some regulatory and clinical development setbacks, which could taint general perceptions as it faces increasingly tough competition.

Ultimately, of course, Xarelto’s success – like those of other novel antithrombotics – will depend not so much on DVT as on longer-duration, broader settings, notably prevention of stroke and systemic embolism in non-valvular atrial fibrillation, and treatment and ongoing prevention of venous thromboembolisms (chronic rather than acute uses).

The drug is currently pending at FDA for the atrial fibrillation indication, which has a review deadline at the beginning of November. Coincidentally, on July 5, FDA announced that the Cardiovascular and Renal Disease Advisory Committee plans to meet Sept. 8 to discuss the pending AF claim. While sending drugs for committee review can signal that FDA has significant concerns about a new drug prospect, it is also routine for major applications.

In addition, J&J anticipates filing in the U.S. in late 2011 and early 2012, respectively, for approval of the drug’s use in secondary prevention of cardiovascular events in patients with acute coronary syndrome and, secondly, for treatment and long-term secondary prevention of VTE. The first submission will be based on results of its ATLAS2 trial, and the second on a series of trials known as EINSTEIN. Data from ATLAS2 could be available later in 2011.

The drug also is pending review before the European Medicines Agency for both DVT treatment and preventing recurrence – the indication addressed by the EINSTEIN trials, and for the AF indication. It could be approved and launched for the former indication in the EU later this year, suggests Decision Resources analyst Matthew Killeen. J&J won’t benefit from EU approvals though—Bayer Healthcare, which initially developed the drug, retains all ex-U.S. rights to it.

Xarelto Making Headway In DVT In Europe

J&J holds exclusive marketing rights in the U.S. for all indications and is taking the lead there on commercial strategy, although Bayer expects to provide some support in specialty markets.

If Xarelto gets an AF approval, its total U.S. sales could reach $975 million by 2015, assuming a 40%-50% conversion from warfarin to novel drugs and a 20% to 25% market share for Xarelto, Jashnani predicted. About $300 million of that figure would come from non-AF indications, he estimated (Also see "Amid Torrent Of Next-Gen Anticoagulant Data, Trial Design Differences Complicate Comparisons Between Potential Competitors" - Pink Sheet, 8 Nov, 2010.).

Barclays Capital analyst Tony Butler pointed out just how big the total anticoagulation opportunity will be as more new drugs enter the market. He predicts total anticoagulant sales alone will reach $12 billion by 2020, of which 70% of sales will belong to AF. Xarelto could achieve sales of $1.4 billion for the DVT/pulmonary embolism acute and chronic indications alone by that date, he added.

Bayer sells Xarelto for the DVT indication in more than 110 countries, including the European Union, and derived global sales of €50 million ($66.5 million) from it in 2010 (all ex-U.S).

Bayer began the ex-U.S. launches in late 2008 or early 2009, and Xarelto is gaining traction in DVT, both against Lovenox, and other anticoagulants such as aspirin and warfarin, and against another newcomer, Pradaxa (dabigatran), made by Boehringer Ingelheim. Xarelto’s ease of use, its lack of need for routine monitoring, as well as its efficacy, are helping it to win over European clinicians, who have been comfortable with the traditional armamentarium.

Pradaxa has racked up some important wins of its own, notably in AF, for which it became the first of the novel anticoagulants to gain FDA approval in October 2010. The Boehringer drug is struggling overseas in the DVT setting, however, where it failed to show non-inferiority compared to Lovenox in a Phase III VTE trial called RE-MOBILIZE Killeen said; data from that study were presented in 2007. In later trials, it subsequently demonstrated non-inferiority in both bleeding and efficacy, but Xarelto’s superior results resonate with clinicians and overseas payers, he said.

In Canada, for example, the government (which is the sole payer) is reimbursing for Xarelto in the DVT setting based on its superior data, but is not covering Pradaxa, which is also approved there, said Jeffrey Weitz, a professor of biochemistry and biomedical sciences at McMaster University in Canada, and an investigator in some of the anticoagulant trials.

Xarelto's use in the DVT setting is based on four Phase III trials, known as RECORD 1-4, which assessed 10 mg rivaroxaban for DVT and PE events following major orthopedic surgery. FDA approval was based on the first three RECORD studies, two of which revolved around hip replacement procedures and one focusing on knee replacement.

It is clear that “RECORD was a well-designed program of four trials, which showed uniform and robust reduction in total VTE,” Weitz said. He estimated that about 65% of post-orthopedic surgery prescribers in Canada are switching from older medicines to Xarelto in the DVT setting, bypassing Pradaxa, even though on an out-of-pocket basis that drug is now less than half as expensive as Xarelto.

Xarelto Appears More Vulnerable In Other Indications

J&J launched the drug in the U.S. the week of July 4 at a WAC of $6.75 per unit, which is competitive in price with current standard of care, said Janssen Pharmaceuticals VP-Medical Affairs Paul Chang. J&J would not discuss whether it will maintain this pricing if it gains more approvals in the U.S. and as more competitors enter the market.

Nor would the company discuss the size of its commercial sales operations or its plans for market access, although it did note that, given that Xarelto is its first anticoagulant, it is tapping into expertise from its Biosense and DePuy medical devices businesses to better understand the orthopedics market dynamics.

The commercial focus is directed at orthopedic surgeons, who prescribe the bulk of post-orthopedic surgery anticoagulants, although in some hospital systems primary care physicians or hematologists are responsible for the coagulation care prescriptions and follow up, said Chang.

Because it is orally administered, Xarelto – and other novel anticoagulants – can help to improve compliance, which is problematic with the injectable Lovenox. Poor compliance leads to a higher-than-necessary rate of hospitalizations. CMS doesn’t reimburse hospitals for care of patients who are readmitted because of DVT after ortho surgery, so a drug that improves compliance and lowers the risk of embolisms can produce substantial cost savings for institutions, said Louis Kwong, a professor of orthopedic surgery at Harborside-UCLA Medical Center and a member of the steering committee for the pivotal trials for Xarelto.

Xarelto’s track record also has blemishes, which could be problematic in a therapeutic area where nuances are beginning to count. FDA issued a “complete response” letter for the DVT indication in late 2009 because of a variety of concerns about long-term safety and off-label utilization. J&J and Bayer then spent considerable time accumulating data to submit to FDA that would support both chronic and acute filings at the same time (Also see "Xarelto Back On Track: J&J Answers "Complete Response" Letter And Files For Atrial Fibrillation" - Pink Sheet, 5 Jan, 2011.).

Outside of DVT, Xarelto appears to be more vulnerable. It is one of a number of novel high-profile oral anticoagulants being studied in multiple indications. Pradaxa, a direct thrombin inhibitor, works differently than Xarelto and the other new Factor Xa inhibitors, and its approval in the U.S. last fall for the AF indication, by many accounts, gives Boehringer Ingelheim a first-mover advantage. Based on its trial results, labeling for Pradaxa includes language acknowledging the drug’s superior efficacy and similar bleed rates to warfarin, the standard of care in the AF setting, creating a high hurdle for followers.

Xarelto could be second to market in AF, but it may face an uphill battle against Pradaxa and Bristol-Myers Squibb/Pfizer’s Factor Xa inhibitor apixiban. Better-than expected top-line results of a pivotal study for apixiban released on June 22 demonstrated superior efficacy and bleeding rates over warfarin, the only one of the new drugs to do so to date.

Xarelto’s pivotal AF study, ROCKET-AF, demonstrated non-inferiority to warfarin on both efficacy and bleed rates. On a pre-determined analysis of patients who actually received treatment per protocol, Xarelto was superior to warfarin, but regulators prefer the more conservative intent-to-treat analysis, which showed only non-inferiority . That study was presented at the American Heart Association meeting in November 2010, but results have yet to be published in a peer-reviewed journal.

That said, the new drugs have not been compared head to head, so experts are reluctant to assess the benefits of one versus the other. Furthermore, the full apixaban data is not yet available – it will be presented at the European Society of Cardiology meeting on Aug. 28. And other factors, such as pricing, are likely to play a considerable role in the evolving market. All of the novel drugs have to compete against warfarin, which, whatever its faults, costs pennies on the dollar.

By Wendy Diller