Contributed by Joshua Grill, PhD
On the opening night of the Clinical Trials for Alzheimer’s Disease (CTAD) meeting, a packed room was abuzz with excitement. The evening included five presentations related to the Phase 3 CLARITY-AD trial of lecanemab, a monoclonal antibody against the beta amyloid protein that builds up in the brain of a person with Alzheimer’s disease. The excitement and anticipation were palpable, since the sponsor of the trial, Eisai, had announced in September that the results were positive. The presentations were accompanied by the full publication of the results in the New England Journal of Medicine and coverage by several major media outlets.
As for the results themselves? Few were disappointed. As indicated in the press release, lecanemab demonstrated significant and consistent benefit compared to placebo on its primary outcome measure as well as key secondary outcome measures in this large and well-powered trial. Lecanemab showed about a half-point benefit (27% slowing of decline) on the Clinical Dementia Rating Scale sum of boxes—an 18-point scale and the primary outcome of the trial. It also showed similar benefits on other outcomes, notably including a scale of Activities of Daily Living, suggesting that patients benefit not only in the rate of cognitive decline, but in the rate of functional decline as well. The benefits compared to placebo were statistically significant as early as 6-months after beginning treatment for many outcomes. Sensitivity analyses convincingly allayed concerns that the results might have been brought about by bias due to unblinding, or anomalies created by the COVID-19 pandemic. Subgroup analyses suggested highly consistent benefit across patient groups, with one possible exception—individuals carrying two copies of the e4 allele of the apolipoprotein (APOE) gene.
Lecanemab demonstrated a rapid and significant lowering of amyloid in the brain, as shown in earlier trials. But it also showed effects on a variety of other key biomarkers, including markers of amyloid in the cerebrospinal fluid and the blood, but also measure of tau in the CSF and PET imaging markers of tau (neurofibrillary tangles) in the brain, especially in the temporal lobe. This is a major piece of evidence to support the amyloid cascade hypothesis, which postulates that amyloid is an upstream event that leads to downstream neurodegeneration and that interventions targeting amyloid could slow that neurodegeneration.
The safety risks of lecanemab were recently emphasized in the press. The safety profile for lecanemab in the double-blind portion of the trial was acceptable. As known to occur with anti-amyloid monoclonal antibodies, the main safety concern was amyloid-related imaging abnormalities (ARIAs), evidence of leakage (ARIA-E, for effusion) or bleeding (ARIA-H, for hemorrhage) from the brain’s blood vessels after treatment. About 12% of participants treated with lecanemab experienced ARIA-E (compared to 2% of participants treated with placebo) and 14% of participants treated with lecanemab experienced ARIA-H (compared to 8% of participants treated with placebo). Most of the ARIA-H cases in the lecanemab treated arm of the study were also ARIA-E cases and, in fact, there was no statistically significant difference between the study arms in isolated microhemorrhages (9% vs. 8%). The risk of ARIA was greatest for carriers of the APOE e4 gene, particularly those who carried two copies. Six participants treated with lecanemab died during the trial, compared to 7 treated with placebo.
Overall, the results were highly convincing. There remains need for studies of lecanemab, to further explore its efficacy and safety, particularly in APOE e4 homozygotes; to test other modes of administration (e.g., subcutaneous injections compared to the intravenous infusions used in the study); and to understand the longer-term benefits of treatment. It is likely, however, that the conversation will now turn to the clinical meaningfulness of the demonstrated benefit; the likely approval of lecanemab by the FDA and other regulatory agencies; the price of the drug; and who will pay for it. The results will also lead to important conversations about how to design trials of new and still much needed therapies for Alzheimer’s disease, when a disease modifying drug is available for clinical use.