Alzheimer's Disease
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Introduction
Alzheimer’s disease presents challenges to trial design. While all too common, the progression of disease is relatively slow for clinical trials, historically we lacked quality biomarkers, and dosing strategies have important effects on both efficacy and safety. The slow rate of decline presents challenges for adaptive trials, requiring significant patient follow up and exposure. Trial designs must learn efficiently in this environment, and must carefully balance safety and efficacy. Berry has worked very hard in Alzheimer’s disease, including sporadic and familial, to improve the efficiency of designs, including the use of disease modeling, response adaptive randomization, adaptive stopping rules for efficacy and futility, use of external controls, and creation of innovative endpoints for understanding progression.
Berry Examples and Case Studies
The phase 2 study of lecanemab (Leqembi) investigated 5 dose and administration frequency combinations. This 5-arm study employed response adaptive randomization, employing periodic interim analyses that increased allocation to well performing arms and decreasing allocation to poorly performing arms. This methodology increases the statistical power of the trial and increases the probability of selecting the correct arm for the dose finding study. The endpoint for the study was the slowing of Alzheimer’s disease progression, where longitudinal modeling of disease progression was a critical factor in the success of the trial. A unique perspective on this trial was published in JAMA Network Open, showing each of the individual interim analyses and how allocation was changed at each decision point. The final analysis showed a 27% slowing in Alzheimer’s progression for the selected dose. This was an excellent prediction of the eventual results of the phase 3 study, which also showed a 27% slowing of progression. The phase 2 dose-finding trial originally formed the basis for accelerated approval from FDA, while full approval came with the subsequent phase 3 trial.
The DIAN-TU platform investigates dominantly inherited Alzheimer’s disease, a rare dominantly inherited form of Alzheimer’s disease affecting younger adults. This indication, while heartbreaking itself, has the incredible scenario that does not exist in sporadic Alzheimer’s disease, where the onset of disease can be predicted with strong accuracy based on the specific mutation, is an incredible testing ground in the development of Alzheimer’s disease drugs, and has been featured in media outlets like 60 Minutes. Disease progression was also included in DIAN-TU, as well as innovations in platform trial design allowing for the simultaneous evaluation of multiple therapies and the sharing of placebo arms. All of these features substantially reduced the required sample sizes in this limited population.
