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The pharma is seeking full approval for its anticoagulation reversal drug Andexxa, which the FDA granted accelerated approval in 2018 for patients who had been treated with apixaban or rivaroxaban.
AstraZeneca
had a tough day on Thursday, needing to allay clotting concerns associated with its anticoagulation reversal drug Andexxa (andexanet alfa) while also discontinuing a Phase II trial of its opioid use disorder therapy AZD4041.
The FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee convened on Thursday to look at AstraZeneca’s supplemental Biologics License Application (sBLA) for Andexxa to convert its accelerated approval to full approval. The panel of external experts were not asked to vote on any specific matter. Instead, they discussed Andexxa’s safety signals and its overall benefit/risk profile.
Andexxa
is a recombinant coagulation factor, Xa, that won the FDA’s accelerated approval in 2018 to stop bleeding in patients who had been treated with the anticoagulants rivaroxaban or apixaban. To back its bid for full approval, AstraZeneca
filed data from the Phase IV ANNEXA-I trial
, a randomized, open-label and multicenter trial that enrolled patients with acute intracranial bleeding treated with oral FXa inhibitors.
Results from ANNEXA-I showed that Andexxa could elicit significantly better hemostasis in patients than usual care, but the FDA’s internal reviewers, in a
briefing document
published ahead of the advisory committee meeting, raised several safety concerns. These included a twofold increase in the rate of thrombosis and thrombosis-related deaths in Andexxa-treated patients versus usual care.
Panelists on Thursday had trouble taking the efficacy and safety findings from ANNEXA-I—which was conducted in a specific subset of patients needing coagulation support—and making recommendations for the much wider population of patients who have access to Andexxa. “We almost don’t have the data to evaluate the serious risks,” Taby Ahsan, committee chair and vice president of Cell and Gene Therapy Operations at the City of Hope, said during the committee’s discussion.
The back-and-forth regarding Andexxa’s benefit/risk pro the study sample versus in the broader intended patient population reminded patient representative Joseph O’Brien, CEO of the National Scoliosis Foundation, of opioids.
“When the indication of opioids was to eliminate pain, it was clear that it did that,” O’Brien said during the meeting, noting that the situation now is the same for Andexxa, which in ANNEXA-I showed strong overall clinical benefit in the specific set of patients that were treated.
“But unfortunately, then we were left with two decades of side effects that have impacted patients more than anything else that we can find,” O’Brien continued, referring to opioids. Experts and regulators should be careful to avoid a similar outcome with Andexxa, he added: “Are we now exposing a very large population to the use of a drug that may in fact damage them or harm them? I think that’s a very legitimate question to ask.”
Still, many physicians during the meeting highlighted the value of Andexxa in the clinical setting, particularly when faced with a bleeding patient. Evan Snyder, director of the Center for Stem Cells and Regenerative Medicine at the Sanford Burnham Prebys Medical Discovery Institute, said that “when you’re confronted with a patient who’s bleeding, as an intensivist I know the first thing you want to do is simply to just stop the bleeding. Later on, you can deal with the downstream consequences.”
Also on Thursday, AstraZeneca announced that it has terminated a Phase II study for AZD4041, its investigational opioid use disorder medication, according to an update to the trial’s
clinicaltrials.gov page
.
In a statement to
Endpoints News
,
a company spokesperson said that the decision as driven by “a potential drug-drug interaction following a study to examine this risk.” These findings in turn “change the potential benefit-risk in this patient population and do not support further development of AZD4041 in opioid use disorder.”
