Interpreting trial results in an era of disease‐modifying therapies: Efficacy of approved anti‐amyloid drugs in the context of the long‐term Alzheimer’s trajectory

Abstract

AbstractBackgroundEarly‐stage Alzheimer’s disease (AD) typically presents with slow progression of clinical symptoms. Approved high‐potency anti‐amyloid‐β (Aβ) therapies have demonstrated changes in the disease trajectory in these early stages and offer potential benefits beyond the period for which they have been studied in trials.MethodsBased on published results, the time‐slowing of disease progression based on change in CDR sum of boxes (CDR‐SB) was approximated. Disease progression modeling using long‐term cohort data was used to estimate the natural history trajectory of CDR‐SB in AD from the preclinical stages to severe dementia. Modeling of trial inclusion criteria was used to estimate the interval of the natural history trajectory of AD that were included in trials and different scenarios for long‐term treatment effects were explored.ResultsIn positive phase 3 studies, the high‐potency anti‐Aβ therapies appeared to slow disease progression 20‐30% resulting in a 4‐6‐month delay of progression during the 18‐month study period. Included patient populations were found to differ substantially, with the EMERGE and ENGAGE studies including an earlier group of patients than CLARITY‐AD. Consistent with trial subgroup analyses, natural‐history modeling suggested that more progressed patients would see an apparent greater absolute benefit during 18 months, but less absolute benefit over longer durations. Under an assumption of continued slowing beyond the study period, a treatment slowing disease progression by 30% (5.4 months delay in disease progression after 18 months) would lead to treatment differences on CDR‐SB of ‐0.42 and ‐0.72 points for typical MCI and mild dementia patients. With continued slowing beyond the length of the trial, typical MCI patients would have a treatment effect of ‐0.96 points once reaching the same disease stage as the mild dementia patients. Five‐year treatment differences would be approximately ‐2.5 and ‐3.2 points, well beyond all estimates of clinically meaningful differences. Even in the most conservative disease‐modifying scenario assuming no increased time delay after 18 months, observed treatment differences would still increase beyond 18 months due to the nonlinear trajectory of CDR‐SB.ConclusionDisease‐modifying effects of the magnitude observed in recent trials can potentially translate into clearly meaningful differences over a longer duration.