Pradaxa’s U.S. Label Updated To Cite Clinical Superiority To Warfarin In Stroke Prevention

Update of label not based on new post-NDA or post-marketing data, but on a fuller review of pivotal trial data and discussions between Boehringer Ingelheim and FDA.

After discussions with sponsor Boehringer Ingelheim GMBH and further study of pivotal trial data submitted with the NDA for Pradaxa, FDA has revised the anti-coagulant’s labeling to note that the oral direct thrombin inhibitor demonstrated superiority in prevention of ischemic and hemorrhagic stroke to warfarin.

Pradaxa (dabigatran etexilate mesylate) obtained FDA approval for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) in October 2010 (Also see "FDA Plays It Safe With Boehringer Ingelheim's Pradaxa By Approving A Single Dosing Option" - Pink Sheet, 20 Oct, 2010.). As of this spring, BI, a privately held German pharma, reported that the product had achieved blockbuster sales for the 12 months ending Feb. 29, 2012. In 2011, Pradaxa brought in €629 million, roughly $831 million.

In an interview, BI’s John Smith, senior VP, clinical development and medical affairs, noted that the label change, in the Clinical Studies section, is not due to any additional post-NDA or post-marketing data but reflects a fuller review by FDA of the data from the Phase III pivotal RELY trial.

“This is just a recognition of how robust the findings were across the two different stroke types in the stroke-reduction endpoint in RELY,” he said.

“We’ve maintained an ongoing dialogue with [FDA’s] cardio-renal division since the approval of Pradaxa,” Smith added. “What this does is … reiterate the significant reduction of stroke that we saw in the RELY trial, 35% reduction of stroke, including significant 25% reduction in the risk of ischemic stroke, which is the most common stroke type in patients with atrial fibrillation.” RELY also demonstrated significant reduction of risk for hemorrhagic stroke.

Pradaxa currently is the only approved anti-coagulant drug with efficacy data superior to warfarin, which was launched in the 1950s and still used widely to prevent stroke as a generic agent. Pradaxa was approved with a Risk Evaluation and Mitigation Strategy, including a Medication Guide which notes that it “can cause bleeding which can be serious, and sometimes lead to death.” Johnson & Johnson/Bayer AG’s anti-coagulant Xarelto (rivaroxaban) was approved last July, while Bristol-Myers Squibb Co. and Pfizer Inc. have a June 28 PDUFA date for their own new anti-coagulant, Eliquis (apixaban) (Also see "Boehringer Will Test How Pradaxa Stacks Up To The Competition In Real-World Study" - Pink Sheet, 3 May, 2012.).

Bristol/Pfizer Drug May Also Get Superiority Claim

Xarelto does not offer superiority in stroke prevention to warfarin, although its sponsors are trying to position it as a safer agent in terms of bleeding risk. Eliquis, however, may get approved with a label citing superiority in both efficacy and safety to warfarin, which would position it to take market share away from Pradaxa, Credit Suisse Group analyst Catherine Arnold wrote in a May 17 note.

Smith stressed that physicians should consider the revised superiority labeling – more clear-cut than what some termed a back-door superiority claim in the initial version – carefully in making their risk/benefit decisions as to whether or not they use Pradaxa.

One advantage warfarin (marketed as Coumadin) has is that if a bleeding episode occurs, its action can be reversed quickly by dosing vitamin K. The newer anti-coagulants at present do not have antidotes. Smith said BI continues to work on developing an antidote for its drug.

“We continue to do research in this area,” he said. “The current approach to a patient who is bleeding with Pradaxa is first to discontinue the drug. The drug is a reversible thrombin inhibitor, so with time that effect will decay. You need to make sure that renal function is preserved because the drug is cleared predominantly through the kidneys and then the treatment is as it would be in any patient who is bleeding, it’s supportive [care], maintaining blood volume with transfusions as necessary … We continue to look into options for more actively reversing the anti-coagulation effect of Pradaxa and at this point, this is an active area of investigation for us.”

In her note, Arnold said BI previously had shared in vitro and in vivo data for a prospective Pradaxa antidote, an antibody selective to the thrombin inhibitor. “There are no current updates recently; however, we believe that this agent is likely in development presently and likely to also enter the market in the 2014 timeframe,” she wrote.

Eliquis Expected To Eclipse Pradaxa, Xarelto By 2020

Smith declined to discuss how the Pradaxa label revision might affect head-to-head competition with Xarelto and, potentially, Eliquis, saying Boehringer Ingelheim typically does not discuss other companies’ products. Arnold, however, projects a heated battle during the remainder of this decade between Pradaxa and Eliquis, with Xarelto falling to a distant third position. She forecasts a $10 billion to $11 billion market for stroke prevention in atrial fibrillation by 2020, with Eliquis controlling about 45% of that market. Pradaxa will take between 15% and 20%, Arnold predicts, with Xarelto getting about 5%.

Arnold is bullish on Eliquis because she thinks it may be approved with labeling citing a mortality benefit, as well as the most attractive bleeding profile. Unlike Pradaxa or Xarelto, the Bristol/Pfizer drug shows statistically significant reduction in bleeding risk compared to warfarin, she wrote. “This reduces the risk threshold that physicians have to cross to try the agent, and makes them more likely to try the product,” she said.

Further, Eliquis is the only one of the three new anti-coagulants to show a mortality benefit in the atrial fibrillation patient segment. “In an open trial design, Pradaxa numerically beat Eliquis on several key efficacy outcomes, however, Eliquis’ data on mortality could give it a material edge in marketing the brand,” Arnold wrote. “Ultimately, we will see the extent to which FDA labeling enables this, but we see no reason why Eliquis could not claim a mortality benefit given the data from its ARISTOTLE study.”

Still, Arnold projects a bright shorter-term future for Pradaxa – it should surpass $2 billion in sales this year, she said. Treatment exposure should more than double this year to 1.1 million treatment years, and BI claims physician intent to prescribe the drug is very high – above 90% among cardiologists and around 90% for primary care physicians. “Despite the tempered growth in prescriptions over the last six months, the Pradaxa launch is strong by most measures,” Arnold wrote, adding that BI claims it to be the third biggest prescription drug product launch worldwide in the past decade.

AE Reporting Suggests Safety Trouble For Pradaxa

Pradaxa is safety-challenged, however, especially if one gives credence to adverse event reporting. In a May 31 report, the Institute for Safe Medication Practices noted that Pradaxa and Coumadin ranked first and second in 2011 in serious adverse event reports to FDA by companies, clinicians and patients. The Institute cautioned, however, that its data are not scientific – direct reporting of serious AEs to FDA is a valuable index of drug-safety risk, but should not be seen as a reliable indicator of the frequency of AEs with a specific drug. FDA estimates that less than 1% of serious AEs are directly reported.

In its Quarter Watch report, the Institute noted that Pradaxa accounted for 3,781 domestic serious AEs in 2011, including 542 patient deaths. These reports included 2,367 cases of hemorrhage, 291 cases of acute renal failure and 644 of stroke. Meanwhile, Coumadin was linked to 1,106 serious AEs and 72 deaths.

Post-market research is a big focus of BI’s efforts to increase user and patient confidence in Pradaxa. Later this year, the pharma plans to unveil data from its long-term safety study of Pradaxa called RELY-ABLE, while it also is establishing the GLORIA-AF patient registry to study NVAF patients being treated with oral anti-coagulants.

“We anticipate enrolling almost up to 10,000 patients [in GLORIA-AF], approximately a sixth of the patients globally,” Smith said. “This is an opportunity to observe the use of oral anti-coagulants in a real-world setting and again globally, and also allows for the serial collection of data that aren’t necessarily available from spontaneous reports. It should provide a rich data source for informing prescribers for years to come.”