Antiamyloid Therapies Tend to Perform Better in APOE e4 Carriers

Article

Using trials selected by amyloid positivity, amyloid-targeting therapies had slightly greater efficacy in APOE ε4 carriers than in noncarriers.

John R. Sims, senior medical director, Eli Lilly

John R. Sims

A recently published analysis of trials assessing potentially efficacious antiamyloid therapies for Alzheimer disease (AD) showed that patients who carry the apolipoprotein E (APOE) ε4 allele have similar or better response to treatment than noncarriers. Investigators concluded that the mechanism underlying these phenomena remains to be determined.

The pooled analysis included trials of aducanumab (Aduhelm; Biogen)(NCT02484547; NCT02477800), donanemab (Eli Lilly)(NCT03367403), lecanemab (Leqembi; Eisai)(NCT03887455), and solanezumab (Eli Lilly)(NCT01900665). Each of these trials enrolled patients with early symptomatic AD, with documented amyloid pathology as part of their inclusion criteria, and provided the APOE genotype therapeutic response. Led by John R. Sims, senior medical director, Eli Lilly, 5 clinical scales were used to evaluate the differences between APOE ε4 carriers and noncarriers.

Using Clinical Dementia Rating-Sum of Boxes (CDR-SB) and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), a Bayesian analysis revealed a greater probability of treatment difference relative to placebo in carriers than in noncarriers (CDR-SB: 0.79; ADAS-Cog: 0.68). Based on the aggregate data, investigators observed a standardized effect size of 0.14 (±0.044) and 0.13 (±0.037) on CDR-SB and ADAS-Cog, respectively, for carriers, vs effect sizes of 0.09 (±0.056) and 0.10 (±0.055), respectively, for non-carriers. The overall percent slowing with treatment compared with placebo was 18% in carriers vs 12% in non-carriers using CDR-SB, and 21% in carriers vs 17% in noncarriers using ADAS-Cog.

"As amyloid-positive noncarriers with early symptomatic AD had equal or greater clinical decline across multiple scales than carriers without treatment, the result cannot be explained by APOE ε4–mediated decline," the study authors wrote. "If there are other factors (i.e., co-pathologies) contributing to the decline in noncarriers, then it would stand to reason that trials with noncarriers, usually underrepresented in symptomatic amyloid-positive AD studies, will need to have larger sample size, longer treatment duration, or combination therapies to detect statistically significant benefits."

When assessing an amyloid-positive population of patients on placebo, findings showed greater decline across all scales in noncarriers. This group, comprised of individuals with similar baseline characteristics regardless of APOE ε4 status, performed significantly worse across various time points on ADAS-Cog13, CDR-SB, Mini-Mental State Examination scale, and Integrated Alzheimer’s Disease Rating Scale.

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Investigators found that the probability of study success could be hinged on the overall population of APOE ε4 carriers and noncarriers. Additionally, the success of a trial using CDR-SB as an outcome measure was predicted to suffer to a greater degree than the success of a trial using ADAS-Cog outcome as the noncarrier population increases. To have a 60% probability of trial success, a population of 70% carriers would require 2000 participants. A typical 18-month trial that has 1500 participants would require 80% and 90% carriers using CDR-SB and ADAS-Cog, respectively, to have a 60% probability of success.

Although the reasons for greater success in APOE ε4 carriers is not fully understood, investigators noted there are several different possible mechanisms that could contribute. “Some may attribute the greater treatment effect in carriers to the imbalance of amyloid-related imaging abnormalities–edema (ARIA-E) occurrence and potential unblinding,” Sims et al wrote. “However, the aducanumab data by APOE ε4 status after censoring subsequent to ARIA-Eappear to refute that hypothesis, as the differential impact in carriers of slowing disease progression in cognitive and functional assessments was maintained. Additionally, solanezumab, which does not cause significant ARIA-E, shows similar results. Thus, the possibility of ARIA-E having a large impact on the results is unlikely."

They added, "The aducanumab data also suggest that differential amyloid lowering is not an issue, as plaque removal was similar or numerically greater with high doses in noncarriers compared to carriers. Note that a higher total dose of aducanumab was permitted over the entire study period for noncarriers (160 mg/kg cumulative dose for noncarriers vs. 98 mg/kg for carriers)."

REFERENCE
1. Evans CD, Sparks J, Anderson SW, et al. APOE ε4’s impact on response to amyloid therapies in early symptomatic Alzheimer’s disease: analyses from multiple clinical trials. Alzheimers Dement. Published online May 19, 2023. doi:10.1002/alz.1328
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