Efficacy of Antiamyloid Therapies Shown Over Long-Term Alzheimer Trajectory

Lars Lau Raket, PhD

In a recent analysis presented at the 2023 Alzheimer’s Association International Conference, July 16-20, in Amsterdam, the Netherlands, findings showed that magnitude effects of approved disease-modifying therapies for Alzheimer disease (AD) have the potential to convert into positive meaningful and clear differences in patients over a long period of time.¹

The high-potency of anti-amyloid-β (Aβ) therapies assessed in positive phase 3 trials demonstrated between 20% to 30% slowing of disease progression, which resulted in a 4- to 6-month delay of progression in the duration frame of an 18-month study. Notably, the patient populations used in the analysis significantly differed as EMERGE (NCT02484547) and ENGAGE (NCT02477800) had an earlier group of patients compared with the Clarity AD trial (NCT03887455).

“Early-stage AD typically presents with slow progression of clinical symptoms. Approved high-potency anti-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,” lead author Lars Lau Raket, PhD, neurodegeneration researcher, Clinical Memory Research Unit, Lund University, Malmö in Sweden and colleagues wrote in its introduction.¹

The slowing of disease progression over time based on change in Clinical Dementia Rating sum of boxes (CDR-SB) was approximated using the published findings from the trials investigating the approved therapies of aducanumab (Aduhelm; Biogen) and lecanemab (Leqembi, Eisai). Additionally, disease progression from long-term cohort data was utilized for estimating the natural history trajectory of CDR-SB in AD from the preclinical stages to severe dementia. Modeling of trial inclusion criteria, used to explore long-term treatment effects in trials and different scenarios, was also applied for the estimation of the interval of the natural history trajectory of AD.

The natural-history modeling suggests that more patients who progressed further into disease severity would have a greater evident benefit during 18 months of treatment and a less apparent benefit over a longer period.^1,2 Authors noted that this finding was consistent with previous results from other subgroup analyses on the trials.

Assuming a continuation of the disease progression slowing after the study period, results showed treatment slowing disease progression by 30%, or 5.4 months of delay in after 18 months, would lead to treatment differences of –0.42 and –0.72 points on CDR-SB for patients with mild cognitive impairment (MCI) and mild dementia, respectively.. Beyond the trial, continued slowing of the disease progression in patients with MCI would have a treatment effect of -0.96 points once reaching the same disease stage as patients with mild dementia.

In the span of 5 years, treatment differences would translate to be approximately -2.5 and -3.2 points, which authors noted are well beyond all estimates of differences that are clinically meaningful. All told, even with the most conservative disease-modifying situation, under the assumption of no increased time of delay after 18 months, treatment differences observed would still increase beyond the study period because of the nonlinear trajectory of CDR-SB.

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REFERENCES
1. Raket LL, Cummings JL, Moscoso A, Schöll M, and Villain N. 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. Presented at: 2022 Alzheimer’s Association International Conference; July 16 to July 20; Amsterdam, the Netherlands. Abstract 74550.
2. Chaussalet TJ, Thompson WA. Data requirements in a model of the natural history of Alzheimer's disease. Health Care Manag Sci. 2001;4(1):13-19. doi:10.1023/a:1009689329661