A glimmer of hope from a new anti-amyloid monoclonal antibody: closing the barn door before the horses get out

As I have mentioned in a previous post, the beta-amyloid plaques of Alzheimer’s disease can be seen in the brain up to 20 years before the onset of cognitive decline. The amyloid hypothesis holds that as amyloid accumulates in the brain, it eventually triggers the production of tau-containing neurofibrillary tangles within nerve cells, eventually leading to decreased function and then death of these cells. This results in progressive worsening of cognition. Animal studies have supported this hypothesis, and a variety of methods of blocking production of amyloid or removing amyloid after it has been deposited have successfully reversed cognitive decline in some of these models of Alzheimer’s in mice and other animals.  Over the last 20 years or so many trials of anti-amyloid medications have been tried in humans, and for the most part they have failed.  Anti-amyloid monoclonal antibodies were designed to remove the amyloid plaques once they have formed.  Doses have been cautiously limited to prevent side effects, and up till now, only one, aducanumab, has been shown to decrease the amyloid burden and modestly slow cognitive decline. But there is uncertainty in the interpretation of the data as one of two identical phase 3 trials showed a modest benefit in slowing cognitive decline and the other did not. This drug is under review by the FDA, but I suspect that a third trial will be required before possible approval. I volunteered as a subject in the aducanumab trial, and I described my experiences in detail in A Tattoo on my Brain.

The newest anti-amyloid monoclonal antibody is Eli Lilly’s donanemab. The results of a phase 2 trial were just published in the March 13 issue of the New England Journal of Medicine. An excellent summary of the results along with expert commentary can be found at AlzForum. While this is just a small, phase 2 trial with only 257 subjects split between the drug and placebo groups, there are some very interesting features.  The subjects were monitored with both amyloid and tau PET scans so the amyloid plaques and the tau-containing neurofibrillary tangles could be evaluated. This antibody binds only to the beta-amyloid that is within a plaque, and it is very effective at removing those plaques.  Once the plaques were gone, the donanemab was stopped, and the plaques didn’t return, at least for the duration of the study. There was also a slight reduction in neurofibrillary tangles in some parts of the brain as seen on the tau PET scans in subjects who received donanemab.  Most exciting was a modest reduction in cognitive decline ranging from 21% using the Mini Mental Status Exam (MMSE) to 39% with another cognitive test, the ADAS-cog13. This protection against cognitive decline was not seen in subjects who had the most tau burden. In other words, the subjects with more advanced Alzheimer’s did not benefit.

Promising results of phase 2 clinical trials often cannot be replicated in the more robust phase 3 trials containing several thousand subjects, so I’m not holding my breath. But what is most exciting to me is the hint that disease-modifying drugs for Alzheimer’s like donanemab and aducanumab are likely to be most successful as preventative treatments, given before there has been loss of too many nerve cells and before cognitive impairment has begun. I think we will finally have success against Alzheimer’s when we learn how to close the barn door before the horses get out.