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While the Alzheimer's field waits for the FDA's decision on the investigational treatment aducanumab, drug developer Biogen has provided details and endpoints of , the drug's ongoing phase IIIb redosing study.

Aducanumab, a monoclonal antibody that selectively binds to aggregated forms of amyloid beta, has raised considerable controversy in the wake of findings from two identical phase III studies, and . The trials were terminated in March 2019 when a futility analysis determined aducanumab was unlikely to outperform placebo at completion. In October 2019, Biogen reversed its position, saying a review of previously unavailable data showed the drug actually reduced cognitive decline in EMERGE, but not in ENGAGE.

"Based on a larger dataset after the trials were terminated, it was determined that the assumptions in the futility analysis were not valid," said Carmen Castrillo-Viguera, MD, medical director of clinical development at Biogen, during a at the American Academy of Neurology virtual meeting. "One of the studies, EMERGE, met the primary pre-specified and secondary endpoints. While the other study, ENGAGE, did not meet its primary endpoint, post-hoc analysis of data from a subset of patients exposed to high-dose aducanumab supported the findings in EMERGE."

The drug currently is up for FDA review. In November 2020, an FDA advisory committee voted overwhelmingly against the data presented about the Alzheimer's drug candidate, saying the positive results seen in one of the two trials could not be considered alone, but must be taken together with its twin, which was clearly negative.

In the advisory committee meeting, Biogen's senior vice president Samantha Budd Haeberlein, PhD, attempted to account for the differences between EMERGE and ENGAGE, suggesting that failure in one trial did not detract from the findings of the other.

Billy Dunn, MD, director of the office of neuroscience in the FDA's Center for Drug Evaluation and Research, agreed, echoing what was presented in the FDA's briefing documents and emphasizing the urgent need for Alzheimer's treatment.

EMBARK will study Alzheimer's patients who were actively enrolled in aducanumab trials when they were halted in March 2019, including participants in EMERGE, ENGAGE, the long-term extension of the phase Ib study, and the safety study. Participants will be titrated to receive 10-mg/kg aducanumab by intravenous infusion every 4 weeks. The study includes an approximately 8-week screening period, a 100-week treatment period, and an 18-week safety and follow-up visit after the last dose.

"The EMBARK redosing study was really designed to assess two fundamental questions," Castrillo-Viguera said. "One is, what are the long-term safety and efficacy of aducanumab dosing with the highest dose tested in the phase III trials? And two, what are the changes in the clinical and biomarker measures during the treatment gap?"

Endpoints include number of adverse events and serious adverse events, adverse events leading to treatment discontinuation or study withdrawal, number of participants with amyloid-related imaging abnormalities (including edema, hemorrhage, or superficial siderosis), and number of participants with anti-aducanumab antibodies.

The study currently is enrolling and "is expected to be one of the largest clinical trials in Alzheimer's disease, with an estimated enrollment of 1,800 patients," Castrillo-Viguera said. As of March 9, a total of 1,361 people have enrolled.

The FDA is scheduled to decide aducanumab's fate by June 7 amid ongoing debate among experts, including those who agree with the agency's and those, , who think aducanumab should be approved and accompanied by a phase IV post-marketing surveillance study. If approved, aducanumab will be the first disease-modifying drug for Alzheimer's disease.

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