Before the introduction of the first novel oral anticoagulant (NOAC), Boehringer Ingelheim's Pradaxa (dabigatran), in 2010, warfarin had been the dominant go-to oral anticoagulant for more than 50 years.
Pradaxa, which was first approved to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF), changed the paradigm for oral anticoagulation and set a new standard for innovation. It has a significantly broader therapeutic index than warfarin, making it easier to use clinically for both physicians and patients.
Not only does Pradaxa eliminate the need for frequent dose titration and monitoring, but it also has the advantage of very few serious drug and food interactions.
Innovation is contagious
The approval of Pradaxa was quickly followed by the introduction of several other NOACS, including the factor Xa (FXa) inhibitors Xarelto from Bayer and Johnson & Johnson in July 2011; Eliquis (apixiban) from Bristol-Myers Squibb (BMS) and Pfizer in March 2014; and Savaysa (edoxaban) from Daiichi Sankyo in January 2015.
Suddenly, there were multiple treatment options in this class. And although they were all approved for NVAF, there were noteworthy inter-drug differences in terms of pharmacokinetics, dosing, and specific indications. In addition, Pradaxa is a direct-thrombin inhibitor, while the other drugs are Factor Xa (FXa) inhibitors.
Uptake in this space was so successful that by mid-2013, 62% of all prescriptions written for an anticoagulant were for a NOAC, according to an article published in the American Journal of Medicine. Yet despite this success, there was a major problem associated with this class: Unlike warfarin, there was no reliable way to reverse the effect of the NOACs, leading to hard-to-control bleeding episodes, and in some cases, death.
Innovation means anticipating challenges before they happen
Between 2010 and 2015, there were roughly 1,400 reported Pradaxa-related adverse events, including uncontrollable bleeding, which lead to 280 deaths. BI eventually settled a $650 million class-action lawsuit related to those incidents.
But facing these challenges did not mean that BI’s work in the area of anticoagulation was any less innovative. In fact, even before Pradaxa was approved, BI scientists were already at work on a reversal agent for their anticoagulant-in-development.
"In 2008, BI scientists identified an opportunity to expand into anticoagulant reversal research," said Dr. Sabine Luik, Senior Vice President of Medicine & Regulatory Affairs at Boehringer, in an interview with BioPharma Dive.
"Conversations about the potential ability to reverse anticoagulant effects with a specific agent in patients who are in need of an emergency intervention while they are on anticoagulant therapy began following discussions at a scientific meeting. BI initiated research on idarucizumab in 2009, before Pradaxa and was approved and launched in the U.S., in 2010."
Innovative trial design, compelling clinical data
Dr. Charles Pollack (pictured above), professor of Emergency Medicine at Sidney Kimmel Medical College of the Thomas Jefferson University in Philadelphia, is the lead investigator on the ongoing phase 3 trial, which was one of the trials used as the basis for approval of Praxbind (idarucizumab) in October.
Overall, there were a total of three phase 1 studies in which a total of 283 healthy volunteers taking Pradaxa were given Praxbind. In addition, there is an ongoing phase 3 trial, RE-VERSE AD, which involves Pradaxa-treated patients.
When looking at patient reactions to Praxbind in the RE-VERSE AD trial, Pollack and his colleagues found that after taking Praxbind, there was an immediate reduction in the amount of Pradaxa in participants’ blood. In an interim analysis of 123 Pradaxa-treated patients who required Praxbind due to uncontrolled bleeding or because they required immediate surgery, the anticoagulant effect of Pradaxa was fully reversed in 89% of patients within four hours of receiving Praxbind.
“The study in at-risk bleeding patients was an all-comer study, with no limitations," said Pollack in an interview. "We found that the antibody idaricizumab was so safe and effective at reversing Pradaxa, that it removed all questions of efficacy.
"It’s notable that the FDA did not put any post-marketing requirement on us—and we received an approval 18 months after patients were initially recruited. This should be considered historic."
Leveling the playing field for FXa inhibitors
The ability to address safety concerns is a critical part of effective innovative—and something that the FDA takes very seriously.
It also confers competitive advantages. In the case of BI’s Pradaxa, reversibility now confers a distinct advantage over the FXa inhibitors—including Xarelto, which has long been the market leader, with $1.83 billion in sales last year.
Overall, the annual rate of bleeds with FXa inhibitors is in the 1% to 4% range, suggesting that there is an unmet medical need associated with FXa inhibitor reversibility. Between April 2014 and April 2015, there were more than 50,000 Xarelto- and Eliquis-treated patients admitted to hospitals for bleeding. (Since Savaysa was only approved earlier this year, this type of data is not yet available.)
"If you consider the fact that Pradaxa-related bleeding events are rare—and now you can reverse it, it gives Pradaxa an advantage that no other anticoagulant has in the marketplace," said Pollack.
Enter a new innovator
But given the work that another company, Portola Pharmaceuticals, has undertaken to develop a reversal agent for the FXa inhibitors Xarelto, Eliquis, Savaysa, as well as the low-weight molecular heparin enoxaparin, that advantage may diminish.
Andaxenet alfa is a recombinant protein which is specifically designed to reverse the anticoagulant activity of FXa inhibitors by acting as a decoy to target and sequester oral and injectable FXa inhibitors in the blood.
Like Praxbind, andaxenet alfa was given Breakthrough Designation by the FDA during the early stages of development. Currently, Portola is conducting a phase 4, single-arm, open-label confirmatory study in patients receiving an FXa inhibitor who present with an acute major bleed. Published data only includes analysis of andaxenet alfa in healthy patients taking an FXa inhibitor so far. Nontheless, Portola is on track to complete its rolling-admission BLA by the end of this year.
Innovation yields more innovation
In a key nod to an innovative approach to partnerships, Portola has an agreement in place with each of the companies that market an FXa inhibitor so that all of these firms may benefit from the approval of andaxenet alfa, which could become the company’s first approved product. The agreement is also intended to generate revenues while Portola continues the development of its own oral FXa inhibitor, betrixaban, which is currently in phase 3 development.
It is the nature of pharmaceutical research, development, and marketing to not only assess and respond to unmet medical needs, but to also anticipate challenges and take steps to be innovative at the earliest stages possible.
Although some level of failure is a built-in feature of pharma R&D, looking far into the future provides an advantage for companies determined to continue to innovate successfully and to ensure that patients have the safest, and most effective, treatment options.