On Thursday, March 24, Portola announced the top-line results from APEX, a large phase 3 trial of the novel oral anticoagulant betrixaban. With two other Factor Xa inhibitors already on the market (and no head-to-head comparison data) the findings of APEX are of more immediate interest to clinical trial designers than patients.
The drug itself may be a follower, but the design of APEX itself was cutting-edge. As the Portola press release proudly noted, APEX was the first trial of an anticoagulant to incorporate an enrichment design. The primary endpoint (the number of thrombotic events) would be compared with the standard-of-care arm first in a subset of patients considered at highest risk of thrombosis (those with elevated levels of the fibrinogen cleavage product called D-dimer). If betrixaban was superior in this sub-group consisting about half of all the randomized patients, the effect in a larger subgroup of intermediate risk patients would be tested, and finally if both these hurdles were passed, the effect in the whole population would be tested.
Such a design has the potential to increase the power for testing the primary hypothesis, and to avoid a common pitfall of late-stage trial design where a large effect in a particular sub-group is masked by a smaller effect in the remaining patients. Even if the population that responds to the drug is identified afterwards, the kind of post hoc data trawling required to identify it is rightly swatted away by the regulators. With the APEX design, if betrixaban was very effective in the high-risk group, but ineffective in the remainder, the positive result in the first cohort would have supported approval, albeit with a narrower label.
The impact of the trial design was therefore under the spotlight when the data was unblinded and the top-line results revealed.
Unfortunately, betrixaban failed to demonstrate superiority (by the smallest of statistical margins) in the first cohort, and so failed to trigger the cascade of tests in the larger populations.
Arguably, the pharma industry needs more innovation–but innovation in late-stage trial design has, it seems, cost Portola (and its investors) dear, as the stock fell 30% on the day the results were announced.
The problem lies in the second of the two hypotheses implicit in the trial design. With the enrichment design, APEX was not only testing the primary hypothesis that betrixaban was superior to standard-of-care, but in addition that the effect was materially larger in the high-risk population with elevated D-dimer.
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