Bristol-Myers Squibb and Pfizer’s try at using a factor Xa inhibitor in medically ill patients turned out no more successful than Bayer and Johnson & Johnson’s. Eliquis failed to show superiority to Lovenox in preventing deaths related to thrombotic events, and caused significantly more bleeding occurrences, in a challenging group of patients hospitalised for heart or respiratory failure and other serious illnesses.
Given the failure of Xarelto earlier this year, success for Eliquis would likely have been viewed as an unexpected bonus for the BMS-Pfizer drug (AHA Preview - Blood thinners and 'good cholesterol' boosters to take centre stage, November 9, 2011). However, researchers do not appear to be giving up on factor Xa drugs in this setting, saying trial designs have been flawed and failed to identify the highest risk patients who might benefit most.
Failed drug or failed trial?
The failure of Eliquis in the Adopt trial to show a clinical benefit in the population of very sick patients hospitalised for at least three days for serious illnesses was chalked up as much a failure of trial design as it was to Eliquis’ weaknesses, according to experts reviewing the study at the American Heart Association scientific sessions.
The outcome fits within a broader theme of seeking the “sweet spot” of usage for antithrombotic drugs, the therapeutic level that achieves significant reduction of venous thromboembolisms (VTEs) without increases in dangerous bleeding events like intracranial haemorrhages.
The Adopt trial did not hit the sweet spot, at least in the short follow-up period of 30 days – 2.7% of Eliquis patients died from a VTE-related event or suffered a VTE, compared with 3.1% of Lovenox patients, a non-significant finding, whilst being more than twice as likely to suffer a major bleeding episode. However, experts noted that there is a recognised risk extending to three months - indeed, the trends at 30 days showed that Lovenox patients were facing a greater risk of VTEs as time went on when compared to Eliquis patients.
“I think there’s some proof of principle in that post-discharge time you can certainly suppress thrombosis,” said Dr Mary Cushman, a professor of medicine at the University of Vermont, who was not involved in the trial. “Whether it is statistically significant or not you can see it.”
“There’s no reason to stop at 30 days,” said Dr Samuel Goldhaber, of Harvard Medical School, who chaired the trial’s executive committee. “40, 50, 60 days might be the right stopping point in future trials.”
Part of the issue is the diverse nature of the population – patients were hospitalised from conditions ranging from congestive heart failure to inflammatory bowel disease – which makes identifying the patients best suited for treatment with factor Xa inhibitors particularly problematic.
“In future we have an urgent need to develop validated risk prediction models so that we can design trials to better address this question,” Dr Cushman said.
Also troubling Adopt was the Lovenox usage that did not match standard of care – daily injections continued for at least six days instead of ending at discharge, a practice that may have favoured the Sanofi product.
The biggest weakness was likely the use of ultrasounds to identify VTEs at discharge, another practice not used in normal clinical routines. Many of the patients were too frail to undergo the ultrasound, Dr Goldhaber said, which meant that the trial was not large enough to detect a statistically significant difference. In addition, the ultrasounds likely detected VTEs that would not have been identified in normal clinical practice, and thus disrupted the “natural history” of the disease and trial.
“The next set of trials in this area have to be done without trying to mandate ultrasounds on individuals who are not symptomatic,” Dr Goldhaber said. “The approach in the next generation of trials should be the following: The day before a patient is discharged the patients deemed to be at high risk should be randomised to either anticoagulant or placebo, and then that patient should be followed for symptoms of DVT or pulmonary embolism.”
Is it worth it?
The population is a small but significant one. Analysts from UBS estimated the medically ill population represented $100m of Eliquis sales in 2015, for example. However, given the comparative importance of the stroke prevention population – for which Eliquis is expected to be filed soon - BMS and Pfizer may choose to cut their losses in the smaller population. A BMS spokesperson stated in an email that both companies "continue to evaluate the overall apixaban program in light of these data".
Hospitalised patients are at a greater risk of venous thromboembolisms during and after their stays because they are immobilised. Factor Xa drugs are indicated for use following the particularly high-risk procedures of hip and knee replacement surgery – for example, Eliquis is already approved in this indication in Europe. However, for other hospitalised patients the preventive effect has been harder to prove (Xarelto misses on Magellan, April 6, 2011).
As with Eliquis, Xarelto was associated with significantly more major bleeding events than Lovenox, but unlike Xarelto, which proved superior after 35 days, Eliquis could not prove the same efficacy.
Thus the decision to pursue further development may be more of a commercial one. Although specialists in the field clearly want another go at proving factor Xa drugs can work in this seriously ill patient population, it seems unlikely the pharma companies will think it is worth spending millions more dollars to prove their drugs work for such a relatively small commercial opportunity.