As pivotal data on the new generation of anticoagulants continue to become public, differences in trial design and population are confusing attempts to predict competitive positioning for the new agents.

Complicated comparisons of trials using different endpoints, comparators, blinding, statistical analysis, and methods for measuring adverse events – particularly bleeding – make it difficult to predict which candidates are best positioned for commercial victory in what could become a cut-throat market.

Difficult comparisons between agents could, however, give an advantage to the sponsors best able to define and explain the data landscape with sophisticated promotional campaigns and effective sales reps – especially given the marketing heavyweights in the hunt.

Next up is the eagerly awaited presentation of full data from the pivotal ROCKET AF trial of Bayer/Johnson & Johnson’s Xarelto (rivaroxaban) on Nov. 15 at AHA.

Next up is the eagerly awaited presentation of full data from the pivotal ROCKET AF trial of Bayer/Johnson & Johnson’s novel anticoagulant Xarelto (rivaroxaban) on Nov. 15 at the American Heart Association meeting.

Xarelto, a factor Xa inhibitor, is one of many novel anticoagulants being positioned against the highly effective but error-prone, difficult-to-administer and unpopular generic warfarin. Other front-runners in the race to replace warfarin are Boehringer Ingelheim’s FDA-approved direct thrombin inhibitor Pradaxa (dabigatran) and another late-stage factor Xa inhibitor, Bristol-Myers Squibb/Pfizer’s apixaban.

The Phase III, double-blind, randomized ROCKET AF is a noninferiority study testing Xarelto against warfarin for stroke prevention in 14,000 patients with atrial fibrillation. Announcing positive top-line results from the study ahead of the meeting on Oct. 31, Bayer issued a brief press release noting just that the drug met its primary efficacy endpoint of noninferiority against warfarin, in terms of preventing a composite of stroke, non-CNS systemic embolism and vascular death. The safety endpoint, a composite of major and non-major clinically relevant bleeding risks, was comparable for both arms.

Disclosure was required for financial reporting reasons but due to AHA embargoes, further details were not made available. Thus, the full presentation at AHA is still needed to give a better picture on how Xarelto is shaping up vis-a-vis its competitors.

All data releases on the antithrombotic agents are being carefully scrutinized, as the new agents mark the first wave of change in decades for the sizeable market. Some research firms are projecting growth for the segment of novel oral anticoagulants from $1 billion in 2010 to $10 billion in 2015 (Also see "Oral Anticoagulants Market Snapshot: Big Bucks, But Payers Are On Guard" - Pink Sheet, 25 October, 2010.).

Novel anticoagulants are being tested in many indications, but the biggest ticket item is for stroke prevention in patients with atrial fibrillation, worth potentially $5 billion of the $10 billion, according to estimates from the U.K. firm Decision Resources.

Clinicians also say that this is the number one potential use by far for the novel oral anticoagulants. “It’s a common problem with large unmet need. Everything else plays second fiddle to that,” said Jefferey Weitz, McMaster University.

Pradaxa Ups The Ante With Show Of Superiority To Warfarin

A replacement for warfarin with the same efficacy and similar bleeding but without the administration errors and adverse events would have plenty of fans. With that bar in mind, most head-to-head trials for new drugs were designed to show noninferiority.

In the open-label RE-LY trial of 18,000 patients with atrial fibrillation, which tested two doses against warfarin in a noninferiority design, the higher 150 mg dose showed superior efficacy to warfarin – a reduction of 35%. A lower dose 110 mg met the noninferiority standard, but was not included in the approval after FDA's advisory committee expressed concern about making that dose available in light of the superiority of the higher dose (Also see "FDA's Pradaxa Quandary: Clearing Both Doses Could Mask Dabigatran's Superiority" - Pink Sheet, 27 September, 2010.). [Editor's note: This paragraph has been updated to correct the dosage strength and effect size.]

With the release of Xarelto’s ROCKET AF full results still to come on Nov. 15, speculation is centered on whether the Bayer/J&J drug will also show superior efficacy against warfarin in addition to the recently announced noninferiority finding.

“The finding of noninferiority is in line with our prior view, but commercial implications of ROCKET AF hinge upon whether the study shows superiority vs. warfarin, a dynamic not addressed in Bayer’s press release,” wrote Morgan Stanley analyst David Lewis in a Nov. 1 note.

However, Jefferies & Co. analyst Jeffrey Holford pointed out in a same-day note that ROCKET AF enrolled much higher-risk patients who could be considered more difficult to treat than those included in RE-LY. Also, studies suggest that warfarin performs better in a double-blind trial design, which could make it more difficult to achieve superiority in ROCKET AF versus the open-label RE-LY trial.

“Even if superiority is not gained (which is unclear at this point), Xarelto could be viewed as having a competitive clinical profile in the majority of patients,” Holford wrote.

Based on the Pradaxa RE-LY results, the “gauntlet was thrown down that noninferiority may not be good enough anymore,” said Jonathan Halperin, director of clinical cardiology services at the Mount Sinai Medical Center and a member of the executive committee of ROCKET AF.

All ongoing trials now need to consider demonstration of superior efficacy as an important criterion, Halperin says, but it’s also important to keep in mind that the trials for the various drugs have different limitations, i.e. the double-blind vs. open-label design.

A debate on which design is better has been ongoing in the cardiovascular community. Open-label arguably allows an analysis of performance in the real world and eliminates the complexities of double-blind designs, such as sham blood test monitoring, Halperin commented. Also, the double-blind design may be prone to overestimating warfarin’s performance.

But at the advisory committee review of Pradaxa, the panelists spent much of the day discussing the concerns about bias from open-label design. "It's not necessarily the most desirable approach," Cleveland Clinic's Steve Nissen stressed at the meeting. Committee Chair Michael Lincoff, Cleveland Clinic, gave the caveat that while it was an acceptable design, "for future development efforts [it] is a risky design."

The open-label design may also have limited the degree of Pradaxa's superiority claim. At the advisory committee meeting, Nissen urged FDA to be cautious about "using words like superiority in an open-label trial where there are other issues."

The label for Pradaxa includes language in the description of the clinical trial results noting that the drug was shown at the approved dose to be superior for stroke prevention to warfarin – a back door rather than overt superiority claim ([A#121609916884]).

In a foretaste of where Pradaxa marketing might go, Boehringer Ingelheim VP of Cardiovascular and Metabolic Disorders Marketing Wa’el Hashad commented that physicians understand the meaning of the language of the label, which clearly states that the magnitude of risk reduction is significantly greater with Pradaxa.

The Devil Is Always In The Details

Aside from the open-label vs. double-blind issue, there were other differences in trial design that could make it difficult to compare results across trials for novel anticoagulants; for example there are big variations in the way bleeding was assessed, Weitz commented. Consequently, the comparator warfarin should be an anchor, but instead results vary across trials.

Along with the primary endpoints, stakeholders such as FDA and prescribers will be equally interested in the comparative rate of stroke alone, major bleeding alone, and intracranial bleeding, Holford opined.

There is also interest in finding out how Xarelto fares when it comes to heart attack rates. A very slightly higher incidence of heart attack compared to warfarin had been reported for both doses of dabigatran (Also see "Heart Attack Signal Is Likely Focus For Panel Review Of Boehringer Ingelheim's Pradaxa" - Pink Sheet, 26 August, 2010.).

The data do not suggest that Pradaxa causes heart attacks but may suggest that warfarin could be better at preventing them, commented Alexander Graham Turpie, professor of medicine at McMaster and a lead investigator on trials of novel anticoagulants. However the difference is small and outweighed by the impressive reduction in intracranial hemorrhage and stroke.

Clinician experts don’t see this issue as being a serious issue for novel anticoagulants because the stroke risk is bigger than the danger of heart attacks. Nevertheless, experts are curious about whether data for factor Xa inhibitors, as with the direct thrombin inhibitor dabagatrin, will also suggest a lesser ability to prevent heart attack compared to warfarin. The AHA data may help shed light on that.

Dosing considerations could also come into play. Xarelto is given once-daily, whereas Pradaxa and apixaban are taken twice a day. Once-daily dosing could be a distinct advantage, particularly given that the target population includes elderly people and that medication dosing mistakes could have efficacy and safety implications. In general, patients are thought to prefer the convenience of once-daily dosing. [Editor's note: This paragraph was updated to correct dosing frequency for apixaban.]

On the other hand, twice daily dosing implies shorter half-life and greater reversibility of effects, which could be perceived as a distinct advantage given that antidotes are not yet available for the novel anticoagulants.

Boehringer marketing exec Hashad said that the company does not view twice-daily dosing as an obstacle to take-up of Pradaxa. Patients who take anticoagulants are typically on a number of other medications and are accustomed to BID dosing, he said in an interview.

Looking For The Net Clinical Benefit

Barclay’s analyst Tony Butler believes that rather than resting mainly on ability to show superior efficacy, the competitive profile of a new anticoagulant is going to be based on net clinical benefit, including a range of factors. For example, if a drug shows comparable efficacy but better safety than warfarin, that could offer a big advantage. So far in trials, Xarelto has shown similar bleeding rates as warfarin.

Butler cautiously believes Bristol/Pfizer’s apixaban may be able to achieve that feat, based on results from the AVERROES double-blind, randomized trial. The study tested the factor Xa inhibitor against aspirin for stroke prevention in 5,600 patients with atrial fibrillation who were considered intolerant of or unsuitable for a vitamin K antagonist like warfarin. A data monitoring body halted the study in June based on superior efficacy of apixaban and results were presented at the European Society of Cardiology meeting in August (Also see "Apixaban Impresses At ESC, Leading To Speculation About An Early Filing" - Pink Sheet, 31 August, 2010.).

Superior efficacy against aspirin would be expected because anticoagulants have previously been proven to far outperform anti-platelet drugs for this patient population. The AVERROES finding of similar bleeding to aspirin is what really caught the eye of investors. Aspirin is thought to have lower bleeding rates than warfarin. So some analysts surmised that apixaban could prove to have lower bleeding rates than warfarin, Pradaxa or Xarelto based on this study.

Clinicians expressed mixed views about the implications of the AVERROES study, with some saying that the data monitoring committee must have stopped the trial with a heavy heart. An anticoagulant would be expected to have higher bleeding rates and had the trial not been stopped on the basis of efficacy, the adverse event readings could have turned out differently.

Bristol responded to this concern by pointing out that the trial had one year follow-up data at the time it was stopped, which should be sufficient.

Waiting For The Wisdom Of ARISTOTLE

As encouraging as the AVERROES aspirin-comparison data are, the real test for apixaban will be the randomized, double-blind ARISTOTLE study testing apixaban against warfarin – but results won’t become available until the first half of 2011.

“Should this prove to be true with ARISTOTLE results, a superior-to-warfarin safety profile [would] set apixaban apart from the approved Pradaxa based on findings in RE-LY,” Butler wrote in a Nov. 1 note.

An exec at Bayer, one of the Xarelto sponsors, suggested that it is not appropriate to read too much into AVERROES. “The clinical utility I think clearly needs to be shown based on the comparison versus warfarin,” Frank Misselwitz, head of Bayer's cardiovascular therapeutic area, said in a call after the AVERROES release.

Nonetheless, Bristol announced in its third-quarter earnings call that FDA has agreed to review an application for apixaban based on the AVERROES data.

During the call, execs noted that Coumadin-like efficacy with increased safety should be a powerful message and highlighted the opportunity to dominate the market for the up to 50% of patients who can’t take warfarin (Also see "Bristol/Pfizer's Apixaban Gets A Chance At The Inside Track" - Pink Sheet, 26 October, 2010.).

More Info Needed On Aspirin Study

As the AVERROES data has come under the spotlight, experts also have raised questions about the suitability of aspirin treatment in the patient population enrolled in the trial. Risk for stroke and need for anticoagulation is based on CHADS₂ scores, which are related to co-morbidities. Scores range from the lowest risk of 0 to the highest at 6. The mean CHADS₂ score in AVERROES was 2.1, signifying moderate risk. Patients with this score would typically be advised to take warfarin and not aspirin. Even for patients with a score of 1, some professional guidelines prefer warfarin over aspirin, though aspirin is an option.

The mean CHADS₂ score in AVERROES was similar to that in the head-to-head RE-LY trial of dabigatran vs. warfarin.

Eligibility requirements for AVERROES included cases where previous therapy with vitamin K antagonists was unsuitable and discontinued for various reasons, such as poor anticoagulant control or adverse events. But patients who were unwilling to take a vitamin K antagonist or unlikely to adhere to restrictions on alcohol, diet or non-prescription medications were also able to take part.

Warfarin Under Used In Clinical Practice

Warfarin is under used in clinical practice, noted Jack Ansell, chair of medicine at the Lenox Hill Hospital in New York and founder of the Anticoagulation Forum, a national network of clinics.

“I have to look long and hard before I find patients who are not suitable candidates for warfarin. Many doctors will look at patients’ past history [and] risk factors and quickly assume patients are not candidates for warfarin because of an old history of bleeding or they fell once in the past. Or they are too old," he said.

“Many times it’s just an excuse to avoid use of warfarin, which is difficult and labor-intensive and complex to manage. Whether the patients in AVERROES truly should not have been on warfarin I can’t say,” added Ansell.

Halperin commented that he would like to know more about the patients and why they were not able to take warfarin. Full results have not yet been published but could shed light on this issue. Without that information and ahead of the release of ARISTOTLE data, it’s difficult to speculate about how the drug might be used in practice.

Bristol acknowledges that the mean risk score suggests anticoagulation would be more appropriate than antiplatelet agents, based on professional guidelines. But the company also points out that the enrollment reflected real-world practice, in which, unfortunately, some patients at even the highest risk are sometimes unable to take warfarin and instead prescribed aspirin.

The availability of a more manageable anticoagulant than warfarin could shrink the size of the patient population deemed to be unsuitable for warfarin.

Superiority Vs. Noninferiority

For the many sponsors with novel anticoagulants in early stage development, it's unclear whether it will be possible to test a novel anticoagulant against an antiplatelet agent in a moderate-risk population in the future, given that apixaban has shown superiority against aspirin and Pradaxa is now approved as an alternative to warfarin in atrial fibrillation.

The rules of the game are changing fast with the emerging data reports for the trio of front-runners – Pradaxa, Xarelto and apixaban.

If the full dataset from ROCKET AF at AHA reveals a superiority claim that Bayer/J&J was unable to reveal in releasing the top-line results, then it may have an advantage in having the evidence from a double-blinded study in a sicker population. But if all it has is noninferiority, than the marketing challenge becomes all the greater.

Because while noninferiority should still be sufficient to gain approval from FDA, now that Pradaxa is on the market with a superiority claim, having only noninferiority could leave future entrants in a vulnerable position.

– Emily Hayes (e.hayes@elsevier.com)

Amid Torrent Of Next-Gen Anticoagulant Data, Trial Design Differences Complicate Comparisons Between Potential Competitors

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