Could lecanemab offer a ray of hope?

As I have discussed in previous posts, many drugs designed to remove beta-amyloid from the brains of people with Alzheimer’s disease have been designed and tested over the last twenty-plus years. Most of these have been very effective in animal models of Alzheimer’s, but results in humans have been frustratingly negative in slowing cognitive decline. Aducanumab came tantalizing close with mild slowing of cognitive impairment in one of two identical phase 3 trials but had no benefit in the other trial. Although aducanumab was approved by the FDA, its use outside of further clinical trials remains controversial. 

Last week, there was an exciting press release from Eisai and its partner Biogen describing positive results in a phase 3 trial of the anti-amyloid monoclonal antibody lecanemab. All research subjects had either mild cognitive impairment or early dementia due to Alzheimer’s disease. The primary endpoint was the Clinical Dementia Rating – Sum of Boxes (CDR-SB). This is a numeric scale used to quantify the severity of symptoms of dementia. It is based on interviews of people living with dementia and their caregivers by qualified professionals who assess cognitive and functional performance in six areas: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. The total score of the six areas is the score of the CDR-SB. After 18 months, those receiving lecanemab had 27% less decline of the CDR-SB compared to those receiving placebo. This was highly significant statistically (p = 0.00005). Brain swelling (ARIA-E) occurred in 12.3% of subjects, about one third the occurrence rate seen in the aducanumab phase 3 trials. 

Why should lecanemab be more effective than any of the other anti-amyloid MABs tested so far? Early anti-amyloid MABs such as crenezumab targeted soluble beta-amyloid whereas more recent anti-amyloid MABs such as aducanumab, gantenerumab, and donanemab bind most firmly to aggregated amyloid in plaques. Lecanemab uniquely binds to an intermediate form called protofibril amyloid that is found in astrocytes. Interestingly the development of lecanemab was based on the discovery of the rare “Arctic” mutation in the gene for amyloid precursor protein (APP). This mutation causes a disease clinically identical to Alzheimer’s except that it is associated with high levels of amyloid protofibrils and the relative absence of amyloid plaques.

Is lecanemab a breakthrough? It may well be. But so far, we have only the press release to go by. Further details of the study including biomarker data will be presented at a meeting in November. Among the twenty-four comments by Alzheimer’s experts following an article in Alzforum there was almost universal excitement balanced by some caution that we need to see all the data before celebrating.  Still, the amyloid hypothesis seems to have received a timely life ring just as drowning had appeared imminent.