What's in It for Me? Contextualizing the Potential Clinical Impacts of Lecanemab, Donanemab, and Other Anti-β-amyloid Monoclonal Antibodies in Early Alzheimer's Disease

Abstract

A new era of disease-modifying therapy for Alzheimer's disease (AD) arrived in 2021 following the Food and Drug Administration's (FDA) decision to grant accelerated approval for aducanumab, an anti-β-amyloid (Aβ) monoclonal antibody designed to target Aβ aggregates, a biological component of AD. More recently, trial outcomes for lecanemab and donanemab, two additional antibodies of this drug class, have shown favorable and significant slowing of metrics for cognitive and functional decline. Lecanemab and donanemab have since received similar FDA approval to aducanumab in January 2023 and July 2024, respectively. Given that these therapies are a clearly emerging tool in the repertoire of clinicians treating AD and related dementias, a critical dialogue has been ongoing regarding the potential impacts and place for these therapies. Here, we seek to contextualize this debate by first considering factors involved in theoretically extrapolating current randomized control trial outcomes to estimate meaningful clinical impacts. In the process of this exercise, we outline a generally useful concept termed Summative Treatment-Associated Benefit measuring Long-term Efficacy/Effectiveness Area as a metric of summative benefits of treatment over the life course of an individual. Second, we consider current real-world factors, such as conditions of FDA approval and other points involved in clinical decision-making that will influence and/or temper the actual impacts of this drug class.

Keywords: Alzheimer’s disease; clinical efficacy; donanemab; lecanemab; minimal clinically important difference.

Figure 1.

Clinical benefits associated with slowing of cognitive decline. A, Assuming a consistent benefit of treatment with time, the delay to reach the same degree of cognitive impairment compounds with time in the treatment arm. B, The cognitive difference between treatment and placebo arms may compound with time. (Figure adapted from Assunção et al., 2022, Fig. 2 ). C, Summative clinical benefits are composed of both the time benefit and cognitive benefit. It is calculated as the area between the normal decline trajectory without treatment and the slowed decline with treatment. D, Possible summative clinical benefits in the event of a time-limited clinical effect of treatment.