Andexanet alfa

Members of an FDA advisory committee were not asked to vote Thursday on AstraZeneca’s anticoagulant reversal drug Andexxa, but they did raise several safety and efficacy concerns. Last year, AstraZeneca began plans to shift Andexxa to a full approval from its accelerated approval after halting its confirmatory trial early due to positive efficacy. But the FDA explained in briefing documents and at the meeting that the confirmatory trial, known as ANNEXA-I, revealed “major safety findings,” including a “doubling of the rate of thromboses and thrombosis related deaths at Day 30 in the andexanet arm compared with” a standard of care clotting agent known as a prothrombin complex concentrate (PCC). While several hematologists on the adcomm explained how Andexxa does work at stopping serious bleeds, adcomm chair Taby Ahsan, VP of cell and gene therapy operations at City of Hope, said the committee generally indicated that there needs to be a better understanding of risks like thrombotic events. Committee members also questioned if the dose and the indicated population were understood well enough. While Andexxa demonstrated a statistically significant improvement in hemostasis in the confirmatory trial, the agency said that the “observed treatment difference between arms appears to be primarily driven by hematoma volume.” Panelist Rajiv Ratan, associate dean at Weill Cornell Medicine, said in the final discussion that “it doesn’t seem like the change in hematoma volume — especially because it was relatively large for patients who are untreated — is enough as a primary endpoint.” Others seemed to suggest that if the goal is the immediate reversal of the anti-coagulation drug, rather than long-term outcomes, then perhaps the drug should be converted to a full approval. “As a clinician this is a difficult decision,” said panelist Evan Snyder of Sanford Burnham Prebys Medical Discovery Institute. He stressed that other clinicians may want this drug in their toolbox, and potentially they would know that if a person is at high-risk for a thrombotic event they should not receive this drug. “We can be more nuanced with the indication,” Snyder said. Adcomm member Sanjay Ahuja of the Indiana Hemophilia and Thrombosis Center said that if a patient is bleeding on an anticoagulant, “the first thing you need to do is reverse that effect,” and Andexxa “does that. Looks like pretty well.” But thrombotic risk needs to be assessed before you place people at risk, panelist Thomas Ortel of Duke University Medical Center said. “There is no alternative here,” Ahuja said. “People use PCCs without any approval in that category and that actually complicates matters because a lot of physicians will use PCCs the way they want to use PCCs.”

The FDA on Thursday will convene an advisory committee to discuss the safety and efficacy of AstraZeneca’s Andexxa, which won accelerated approval in 2018 to reverse the anticoagulation effects of blood thinners that can cause life-threatening bleeding. The Cellular, Tissue, and Gene Therapies Advisory Committee will discuss the results of the confirmatory trial for the treatment. Also known as andexanet, it improved upon the standard of care but also revealed some safety issues and other concerns, FDA said in briefing documents released on Tuesday. The committee isn’t scheduled to vote on a recommendation. “Although andexanet showed superiority of the primary efficacy endpoint over UC [usual care] within the PEP [primary efficacy population], the superior efficacy at 12 hours did not predict longer-term benefit,” FDA said in its document. The FDA wants to hear more from the committee about increased rates of dangerous clotting and clotting-related deaths seen in a trial of Andexxa, compared with a standard of care reversal agent. And it’s looking for more discussion of the clinical meaningfulness of the benefit of Andexxa, and whether the benefit shown in the trial “outweighs the serious risks.” The treatment, a recombinant modified human factor Xa protein, is for patients treated with rivaroxaban or apixaban when rapid reversal of anticoagulation is needed because of life-threatening or uncontrolled bleeding. That could include, for example, when a patient needed urgent surgery because of a medical emergency or accident. Last year, AstraZeneca began plans to shift Andexxa to a full approval from its accelerated approval after halting its confirmatory trial early due to these efficacy findings. But FDA explained how the confirmatory trial, known as ANNEXA-I, revealed “major safety findings” including a “doubling of the rate of thromboses and thrombosis related deaths at Day 30 in the andexanet arm compared with” a standard of care clotting agent known as a prothrombin complex concentrate. Of the 239 patients treated with andexanet, FDA said, 14.6% of patients suffered thrombotic events versus 6.9% in the standard of care arm. While Andexxa demonstrated a statistically significant improvement in hemostasis, or the process to stop bleeding, compared with standard care, the agency also said that the “observed treatment difference between arms appears to be primarily driven by hematoma volume, with more patients in the andexanet arm compared to UC arm experiencing a ≤35% increase from baseline in hematoma volume at 12 hours (74% versus 60%).”