Adcom backs Pradaxa but leaves questions unanswered


Pradaxa (dabigatran) moves to the head of the class. Boehringer Ingelheim's thrombin inhibitor received a unanimous vote from an FDA advisory committee yesterday, putting it ahead of Xarelto (rivaroxaban) and apixaban in the queue to launch in the stroke prevention in atrial fibrillation (SPAF) indication.

The vote was not without its question marks, however. Expert physicians questioned whether to endorse two dosages of Pradaxa and a statement of superiority over warfarin, the standard treatment in the indication. If the FDA allows only the higher 150mg dose and does not support a statement of superiority, as staff recommended in briefing documents, Pradaxa’s commercial potential could be affected, especially as a number of new products could enter the SPAF market within the next few years.

Dosing, superiority at issue

What emerged from a stew of official votes and straw polls was clear endorsement of Pradaxa (Event - Pradaxa adcom set for wide scrutiny, September 2, 2010). The panellists voted 9-0 that the product should be approved although issues over labelling and a lower dose, both of which were opposed in FDA staff documents but had some support from the experts on the panel, were unresolved.

For example a lower dosage of 110mg was not recommended by FDA staff. The FDA's position was that the 110mg dose did not significantly lower bleeding risk for at-risk patients when compared to 150mg dosage, whilst having poorer efficacy numbers. Observers watching the FDA’s meeting Monday said a straw poll showed marginal support for the lower dosage, but it was not an official question put to the panel.

Likewise, the FDA staff would not endorse a statement of superiority over warfarin for Pradaxa in product labelling in part because the pivotal RE-LY trial in 18,113 atrial fibrillation patients was an open-label test of warfarin vs blinded 110 and 150mg dosages of Pradaxa. Given the necessity of patient monitoring in warfarin because of variability in effectiveness and drug and diet interactions, anything but an open-label test appears difficult at best.

Panellists did not appear as bothered by the open-label nature of RE-LY and many appeared to support a claim of superiority, although others concurred it could introduce bias. Either way, should the drug receive final FDA approval without an explicit superiority claim the RE-LY data will be included in the product labelling, indicating superiority, analysts said.

Taking on warfarin

With an October 19 PDUFA date now ahead of it, Pradaxa is on track to be the first new drug to compete with warfarin in the SPAF indication in more than 50 years. Marketed in Europe since 2008 for prevention of venous thromboembolism following total hip or knee replacement surgery, Pradaxa’s sales are forecast to zoom from $385m this year to $1.99bn in 2016 in all indications, according to EvaluatePharma data.

An EU panel decision on Pradaxa in the SPAF indication also is expected by early next year, along with a US launch. Assuming a timely approval and launch, Pradaxa will be at the pointy end of the field in a race for anticoagulant market share (Therapeutic focus - Anti-thrombotics face a period of change, July 26, 2010).

The SPAF space is looking particularly competitive. Bayer and Johnson & Johnson’s Xarelto and Bristol-Myers Squibb’s apixaban, both Factor Xa inhibitors, are both in phase III trials, with Xarelto forecast for a launch in 2011. Combined, the other two drugs are forecast to sell $3.47bn worldwide in SPAF in 2016, signifying how matters such as launch timing or restrictive labelling could change the revenue picture for the four companies duking it out in the indication - particularly if Pradaxa's competitors can earn a superiority label.

Nevertheless, with support from the adcom, Pradaxa appears on track to gaining that all-important first-mover advantage.

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