36: The Saga of the Lecanemab Adaptive Phase II Trial

In Episode 36 of "In the Interim…", Dr. Scott Berry and Dr. Don Berry analyze the Phase II trial of Lecanemab (BAN2401) in Alzheimer’s disease, focusing on the application of adaptive Bayesian methods following persistent failures in Alzheimer’s drug development. The conversation covers the specific design features of five active arms, response adaptive randomization, and a longitudinal Bayesian model driving interim decisions, as well as direct operational and statistical challenges encountered during the trial. The hosts address regulatory proceedings, critique from "experts" regarding adaptive methods on noisy cognitive endpoints, and the direct alignment of the trial’s Bayesian 18-month efficacy estimates with the subsequent Phase III results and regulatory approvals.

Key Highlights

• Alzheimer’s drug development context: Widespread Phase III failures prompted a retreat from conventional trial designs and a demand for greater rigor and adaptability.

• Lecanemab Phase II methodology: Five active arms, two dosing schedules, response adaptive randomization, and adaptive interim analyses at every 50 patients enabled real-time adjustment and efficient dose evaluation.

• Bayesian modeling and imputation: Use of a longitudinal model to address missing data, forecast 12- and 18-month outcomes, and inform both allocation and stopping criteria.

• Operational adaptations: The design accommodated unplanned safety restrictions, such as stratified randomization for APOE4-positive participants after ARIA signals.

• Expert skepticism: Addressed Paul Aisen’s concerns about adapting to noisy interim cognitive data, emphasizing safeguards against erroneous stopping or success.

• Regulatory outcome: The 18-month efficacy estimates from Bayesian modeling during Phase II matched Phase III findings; FDA granted accelerated approval based on amyloid reduction and later full approval after Phase III confirmation.