Immunotherapies Targeting Amyloid-β May Produce Brain Shrinkage
Immunotherapies offer great potential, but are not without side-effects as presently implemented. This is well demonstrated in the cancer field, where a chance of severe short-term, or even lasting immune-related issues is a risk that patients are willing to take given the alternatives on the table. Here, researchers suggest that the immunotherapies tested against Alzheimer's disease in clinical trials are producing an accelerated shrinkage of brain tissue, perhaps because of raised inflammation. In recent years, these immunotherapies have succeeded in clearing extracellular amyloid-β, but have not improved patient outcomes. Alzheimer's disease is complex, and it remains to be seen as to whether amyloid-β is truly important in the disease process, or whether it is a side-effect of the real disease processes. Immunotherapies will remain an important part of clinical development for neurodegenerative conditions, and so I'm sure it is concerning to many in this part of the field to see potential issues of this nature.
Researchers identified 31 published clinical trials of so-called antiamyloid Alzheimer's drugs. All aim to eliminate beta amyloid, whose buildup many consider a driver of the disease. The drugs fell into two categories. One, secretase inhibitors, are traditional small-molecule drugs that target an enzyme that produces beta amyloid from a larger protein. These compounds have largely been abandoned because they didn't pan out in trials. The second category included monoclonal antibodies like lecanemab that directly target various forms of beta amyloid. Another antiamyloid antibody in the analysis, aducanumab, was approved in 2021 amid much controversy, and still others are in trials. Sixteen of the 31 trials researchers analyzed involved these lab-generated immune proteins.
Alzheimer's disease frequently causes the brain to shrink as the illness progresses. But the researchers found both types of antiamyloid drugs generally caused clinical trial participants to lose more brain volume than what was seen in Alzheimer's patients on a placebo. Lecanemab and another antibody, donanemab, currently in late-stage trials, both accelerated whole brain volume loss. People in two large lecanemab trials on the highest drug dose recorded, on average, a 28% greater brain volume loss relative to placebo after about 18 months. This translated to a loss of an extra 5.2 milliliters (mL) in brain matter. The authors also reported that the antiamyloid antibodies - but not the secretase inhibitors - led to an increase in the size of brain ventricles, indicating they were filling with extra fluid. This can happen when nearby brain tissue atrophies. In people taking the now-approved dose of lecanemab, brain ventricle size increased by 36% more that it did in people on placebo - or an additional 1.9 mL.
Researchers then studied whether a type of brain swelling and bleeding called amyloid-related imaging abnormalities (ARIA), a well-documented side effect of the antibodies, was associated with the other brain changes. ARIA occurred in 21% of the 898 people taking lecanemab in a pivotal trial (as well as 9% on a placebo); most had no symptoms, but some did become severely ill and at least two died after extensive brain swelling and bleeding. Researchers found the experimental therapies with a higher rate of ARIA also generated a bigger average increase in the size of the ventricles. There's a logic behind this, though the connections haven't been proved. ARIA shows up on brain scans as inflammation, and generally, it's not controversial that neuroinflammation would lead to neurodegeneration.
Could reduced size actually be related to alleviation of inflammation? Inflammation causes the brain to swell a bit, so it stands to reason that alleviating the inflammation should result in a one-time reduction in brain volume.
I hope someone gives covalent bioscience some additional funding soon to try their covalent catabodies in a human trial.