A new stroke preventer from Bayer and Johnson & Johnson – Xarelto moved one step closer to U.S. approval, but questions remained about restrictions on labeling and the need for more studies.
An Food and Drug Administration (FDA) panel advisory looked at the effectiveness and safety of blood thinner Xarelto compared to standard warfarin in the ROCKET-AF trial. They voted 9-2 on Thursday to recommend approval of the once-a-day anti-clotting pill, called Xarelto. They asked for further studies on how to transition off of Xarelto. FDA decision on the drug is expected by Nov. 4
Xarelto is one of several promising entrants angling to replace warfarin for people with dangerously irregular heart rhythms, called atrial fibrillation (AF). Warfarin is a problematic decades-old clot preventer originally developed as rat poison. AF patients' irregular heartbeats can cause blood to pool, increasing their risk of blood clots and strokes. But many are unwilling to take warfarin, which requires regular blood tests, or are unable to tolerate it.
The study involved 14,264 patients across 1,178 sites in 45 countries. Patients were diagnosed with persistent or paroxysmal AF with additional risk factors for stroke, and were randomly assigned to warfarin (Coumadin, Bristol-Meyers Squibb) or rivaroxaban (Xarelto, Johnson & Johnson). Patients who were assigned to rivaroxaban received a 20mg dose once daily, and warfarin was titrated to a target range of two to three.
Overall, a decreased rate of stroke and non-CNS embolism events were associated with rivaroxaban during treatments vs. warfarin (P=.015). In the intention-to-treat analysis, rivaroxaban was non-inferior to warfarin (P=.117). The rate of bleeding and adverse events was similar between the rivaroxaban and warfarin arms, but rivaroxaban was associated with less intercranial hemorrhage and fatal bleeding.
“I've seen the problems many patients face with warfarin,” said Dr. Philip Sager, a panel member and executive committee member of the Cardiac Safety Research Consortium in San Francisco. “I think there's a tremendous unmet medical need for new therapies.”
Panelists were divided on whether Xarelto, with the clinical name rivaroxaban, was as effective as warfarin. In clinical trials that compared Xarelto to warfarin, panelists and the FDA said the older drug was not always given in the proper dosing, making it more difficult to determine if Xarelto was just as good.
“I've heard nothing that convinces me that rivaroxaban should be first-line treatment for many patients,” said Allan Coukell, the patient representative on the panel and director for medical safety at Pew Health Group, adding that Xarelto's label should reflect that.
Earlier this week, FDA reviewers said for conditions such as stroke, which can cause irreversible harm, new drugs must be shown to be at least as effective as older treatments, and called for the agency to delay Xarelto's approval.
In Thursday's meeting, panel members also focused on risks for patients when they come off the drug. Patients who stopped taking Xarelto and resumed warfarin at the end of the main clinical trial had a higher risk of stroke, a so-called “rebound” effect.
“Additional data probably should be obtained regarding how to transition (off of Xarelto) prior to approval,” said Dr. Michael Lincoff, chair of the panel and professor of medicine at the Cleveland Clinic.
The FDA is set to make the final decision on Xarelto by Nov. 4, Johnson & Johnson said.
Dr Peter Dibattiste, global head of J&J's cardiovascular and metabolic division, said the company will discuss with the FDA the need for additional studies. A study looking at how long Xarelto lasted in patients could be relatively quick, “probably months,” he said.
A delay for Xarelto could give the edge to a rival treatment called Eliquis being developed by Bristol-Myers Squibb and Pfizer Inc. Eliquis, also called apixaban, showed superiority over warfarin in effectiveness, safety and saving lives in a clinical trial presented last month at a scientific meeting in Paris, affirming its place as the potential leader of the pack. Xarelto is approved in the United States and Europe for anti-clotting in patients after knee and hip surgery, a much smaller market than stroke prevention for AF patients.
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