The rationale for investigating monoclonal antibodies and BACE inhibitors for the treatment of patients with Alzheimer disease.
Ronald C. Petersen, MD, PhD: When you think about drugs that are still in development against amyloid, there are numerous agents. There are 2 general classes of these. With 1 class, we can block the deposition of amyloid, or the abnormal processing on the front-end side. Or we can try to remove amyloid once it’s been deposited abnormally in the brain.
On the input side, we’re approaching the BACE [beta secretase] enzyme. This is one of the enzymes that cleaves the amyloid precursor protein in an abnormal spot. We can block that enzyme with BACE inhibitors. If they are effective, that stops the accumulation of the abnormal protein. The other attack is to use an antibody to remove the amyloid once it’s been deposited in the brain, or remove it in its formation phase—the soluble to insoluble forms, the aggregate forms—early in the process. So we can take those 2 avenues of approach, and there are still active programs on both ends.
Alireza Atri, MD, PhD: Most recently, the approaches that are anti-amyloid approaches have fallen into 2 bins, for the most part. Those are the BACE inhibitors that are really kind of trying to turn down the spigot of toxic amyloid production, and then there’s the approach with the antibodies of trying to take out the plaques and many monomers, or oligomers, and protofibrils. Unfortunately, as I mentioned, a number of programs, including aducanumab and crenezumab this year, have either read out or reported to be negative or futile. We’re still waiting to see if there are signals, for example, in individuals where there was plaque removal to a certain level and whether there were any congruent changes in cognition or clinical benefit. That data still has to come through.
As far as the BACE inhibitors, or the spigot approach, of the 7 programs, 5 of them have either read out as futile or have shown small signals of a small detriment in cognitive function. But 2 of the programs are still ongoing. They have not read as negative, so we’re waiting eagerly to see whether those programs can show a signal at the later stage. Some of these drugs are also in development for earlier stages in secondary prevention of Alzheimer disease—people at risk or who already show a disease pathway but really don’t have a tremendous amount of symptoms. That is still outstanding: Whether early enough some of these interventions can modify the trajectory. Certainly, with the current readouts, it becomes a bit more pessimistic, but I don’t think that answer has been found yet.