PHILADELPHIA—More than a year after Johnson & Johnson and Bayer pulled the plug on an open-label study for anticoagulant Xarelto in patients after a rare valve replacement procedure, the drugmaker is still grasping at straws for what exactly happened.
Patients treated with a Xarelto-added regimen after a transcatheter aortic valve replacement (TAVR) showed higher rates of bleeding, thromboembolic events and all-cause mortality than patients treated with standard-of-care aspirin. Those data led the pair to prematurely end their comparative Galileo study in October 2018, citing "imbalanced" safety results in the Xarelto arm of the studies. J&J and Bayer also recommended physicians not prescribe Xarelto for TAVR patients.
Now, more than a year later, Xarelto is still looking for answers with late-breaking data presented Saturday at the American Heart Association's Scientific Sessions. For James List, Janssen R&D's global therapeutic area head of cardiovascular and metabolism, the results––particularly patient deaths––are still somewhat of a mystery.
"We don’t totally understand the results," List said Friday. "We’re being very careful and cautious in stopping the study, but when you look at the events that occurred, most of the deaths came long after the study was discontinued."
Patients in Galileo were treated with a double therapy of Xarelto and aspirin one week after a TAVR, and then aspirin was dropped after three months. Patients then continued on Xarelto alone at a median follow-up duration of 17 months. From the beginning, the Xarelto arm of the study showed higher risks of bleeding, but the companies said subanalyses of Galileo did not show a direct relationship between those deaths and higher bleeding risks.
An imaging substudy dubbed Galileo-4D also showed that Xarelto reduced the risk of hypo-attenuated leaflet thickening in TAVR patients not indicated for an oral anticoagulant. However, due to the deleterious safety results, J&J and Bayer still do not recommend Xarelto for TAVR patients and have no plans to pursue that indication in the future.
"Sometimes negative studies come in when you’re doing science––and that’s important," he said.
Janssen said in a statement that it stood by its safety data in other approved indications.
"As the Galileo population was distinctly different from those participating in other Xarelto trials, the safety and efficacy profile of Xarelto across its eight FDA-approved indications remains positive," the company said.
RELATED: J&J, Bayer's Xarelto scores FDA nod to treat acutely ill patients during and after hospitalization
Cutting Galileo short was part of a series of Xarelto flops in late 2018, including J&J admitting in August the drug failed to top a dummy pill at fending off the potentially deadly blood clots it's designed to treat in two separate studies.
In the first, dubbed Mariner, Xarelto didn't pare down a composite endpoint of blood clots and blood-clot-related death in acutely ill patients—those suffering from conditions such as heart failure, infectious diseases or ischemic stroke—after their hospital stays.
However, Xarelto still scored an FDA nod to treat those patients without a high risk of bleeding in October of this year based on data from its Magellan study showing long-term Xarelto use topped long-term use of enoxaparin, known by brand name as Lovenox from Sanofi, at cutting clots. That trial’s results weren’t all rosy, either, though: They showed Xarelto increased bleeding risks, too.
In the second study, adding Xarelto to standard-of-care treatment didn’t reduce the risk of heart attack, stroke or death among heart failure patients whose symptoms had suddenly worsened.
The same month as the Galileo pull, Xarelto scored an FDA nod to reduce cardiovascular risks in patients with coronary artery disease or peripheral artery disease. That approval made Xarelto the first novel oral anticoagulant approved for that market, ahead of Pfizer and Bristol-Myers Squibb's Eliquis and Boehringer Ingelheim’s Pradaxa.
Aspirin is the current standard of care for these conditions, known as atherosclerosis. But findings from Xarelto's Compass trial showed that the drug, in combination with aspirin, could pare down the risk of death, stroke and heart attack by 24% versus aspirin alone. Specifically, Xarelto reduced the stroke rate by 52%, the CV death rate by 22% and the heart attack rate by 14%.
Editor's note: This story has been updated to include an additional comment from Janssen.