Another anti-amyloid monoclonal antibody trial disappoints, but there may still be hope

I last posted on my blog three weeks ago.  A few days after that, I came down with what was probably just a bad cold.   It was mainly in my chest with a lot of coughing. It wasn’t Covid, and I never had a fever or decrease in oxygen in my blood.  For the last week or so, I have tried to write about the failure of another anti-amyloid monoclonal antibody, gantenerumab, but I just couldn’t concentrate enough to get my thoughts together. Today I feel almost back to normal so I’ll give it a try.

Gantenerumab is the latest anti-amyloid monoclonal antibody to complete twin, phase 3 trials in subjects with early, symptomatic Alzheimer’s disease. Gantenerumab binds to the same general region of the beta-amyloid molecule as do aducanumab and lecanemab. All three of these anti-amyloid monoclonal antibodies are effective at reducing amyloid in the brain, but so far, only lecanemab has shown a small but statistically significant slowing of cognitive decline. Donanemab, another anti-amyloid monoclonal antibody that targets a different part of the amyloid molecule found only in plaques (N-terminally truncated pyroglutamate-modified amyloid β), is by far the most effective medication in eliminating amyloid plaques in the brain. In subjects with mild Alzheimer’s disease defined as a mild or moderate tau burden on PET scans, there was a 35.1% slowing of cognitive decline based on the integrated Alzheimer’s Disease Rating Scale. However, in subjects with high tau burden, in other words those with more severe Alzheimer’s disease, there was no benefit.

Dr. Lon Schneider, writing in a New England Journal of Medicine editorial that accompanied the results of the gantenerumab trials, suggests that “depending on one’s perspective, the results of the antibody trials to date either reinforce confidence in this therapeutic approach and its clinical meaningfulness or support a view that the effects are small, unreliable, and barely distinguishable from no effect. Or, if a meaningful effect is not apparent after 1.5 to 2 years of treatment, there may be hope that it manifests in the future.” I am in the cautiously optimistic camp. I’m especially impressed by the effects seen with donanemab.  It is the most effective drug so far in removing amyloid plaques, and in subjects with mild Alzheimer’s, it seems to have a significant effect in slowing cognitive decline.  Lecanemab appears to be effective as well, but the slowing of cognitive decline is probably not as robust as that seen with donanemab. It should be emphasized that none of these drugs reverse cognitive impairment. At best, they slow cognitive decline. Lecanemab has already received full FDA approval, and donanemab is likely to receive FDA approval soon.

Finally, there is a strong indication that these drugs, when they work, are most effective in the earliest stages of Alzheimer’s disease. Two important studies using subjects who have amyloid biomarkers in the brain but no cognitive impairment yet, people with preclinical Alzheimer’s disease, are now underway. The AHEAD 34-5 Study is testing lecanumab, and the TRAILBLAZER-ALZ-3 Study is testing donanemab. Results for both studies will not be available until 2027.  I’m keeping my fingers crossed, not for me, but for the millions of people with preclinical Alzheimer’s who may someday get an unequivocal benefit.