AstraZeneca Faces Safety Concerns Over Andexxa, Halts Opioid Use Disorder Drug Trial

Key Insights

• An FDA advisory committee reviewed AstraZeneca's application for full approval of Andexxa, raising concerns about increased thrombosis risk compared to standard care.
• Panelists debated the applicability of ANNEXA-I trial data to the broader patient population, questioning the overall benefit/risk profile of Andexxa.
• AstraZeneca discontinued a Phase II trial of AZD4041 for opioid use disorder due to potential drug-drug interactions altering the benefit-risk assessment.

AstraZeneca faced scrutiny regarding the safety profile of its anticoagulant reversal drug, Andexxa (andexanet alfa), during an FDA advisory committee meeting. Simultaneously, the company halted a Phase II trial for its opioid use disorder therapy, AZD4041.

Andexxa's Safety Profile Under Scrutiny

The FDA's Cellular, Tissue, and Gene Therapies Advisory Committee convened to discuss AstraZeneca's supplemental Biologics License Application (sBLA) seeking full approval for Andexxa, which currently holds accelerated approval. Andexxa is a recombinant coagulation factor Xa indicated to reverse the effects of rivaroxaban and apixaban in cases of uncontrolled bleeding. The application was supported by data from the Phase IV ANNEXA-I trial, a randomized, open-label, multicenter study involving patients with acute intracranial hemorrhage treated with oral FXa inhibitors.

While ANNEXA-I demonstrated that Andexxa led to significantly better hemostasis compared to usual care, FDA reviewers highlighted safety concerns, notably a twofold increase in thrombosis and thrombosis-related deaths in the Andexxa group. This discrepancy raised questions among the panel regarding the generalizability of the trial's findings to the broader population of Andexxa users. Taby Ahsan, committee chair and VP at City of Hope, noted the difficulty in evaluating the serious risks due to limitations in the available data.

The discussion evoked parallels to the opioid crisis, as highlighted by patient representative Joseph O'Brien, CEO of the National Scoliosis Foundation. He cautioned against exposing a large patient population to potential harm, even if the drug demonstrates benefit in a specific clinical setting.

Despite these concerns, some physicians emphasized Andexxa's clinical value in managing bleeding patients. Evan Snyder, Director at Sanford Burnham Prebys Medical Discovery Institute, stressed the importance of rapidly stopping bleeding, even if downstream consequences need to be addressed later.

AZD4041 Development Halted

In a separate development, AstraZeneca terminated a Phase II study of AZD4041, an investigational drug for opioid use disorder. The decision, according to a company spokesperson, was driven by potential drug-drug interactions identified during a study assessing this risk. These interactions were deemed to alter the benefit-risk profile, making further development in opioid use disorder unwarranted.