Modernizing AD clinical trials: why are we designing studies for disease modifying treatments using the symptomatic treatment paradigm?

Abstract

AbstractBackgroundUntil the accelerated approvals of aducanumab and lecanemab, the only approved drugs for Alzheimer’s disease (AD) were symptomatic treatments, which showed relatively large improvements but did not alter disease progression. Multiple decades of designing and analyzing trials for symptomatic treatments have optimized the process for acetyl cholinesterase inhibitors and NMDA receptor antagonists, but this paradigm is not optimal for disease‐modifying therapies. As the AD research community continues to transition towards treatments with the potential to alter disease progression, significant course corrections in the design and analysis of clinical trials are required to ensure that treatments with the largest potential for impact do not fail because they’re being evaluated out of context.MethodSeveral design aspects from AD clinical trials are evaluated in the context of disease‐modifying treatments, including the expected effect size, patient population, outcomes, multiplicity adjustments, trial duration, use of biomarkers, and timing of visits. We use publicly available trial results to demonstrate that both the clinical trial process and public interpretation of data will result in costly losses unless significant improvements are accepted and implementedResultIn the context of donepezil’s expected 3‐point change on ADAS‐cog over 6 months, the results for lecanemab (1.5 points over 18 months) seem small, yet lecanemab improvements can be reasonably expected to match donepezil after three years of treatment and continue to increase. Symptomatic treatments were required to demonstrate significant improvement on multiple outcomes, but disease‐modifying treatments should address the underlying disease process. Trials of aducanumab, donanemab, and lecanemab show consistent disease modification of 5 to 6 months less progression over 18 months when outcomes are converted to units of time and combined. This time‐converted composite (which may include biomarkers) can show consistent results earlier in the disease course, allowing prodromal and early AD patients to be studied with greater success.ConclusionThe current message sent by recent approvals is that only sponsors with resources to field clinical trials with thousands of patients have a chance of gaining regulatory approval. By modernizing clinical trials, more sponsors will have a better chance of success, meaning better treatments available to more patients sooner.