Alzheimer’s Physician Newsletter May 2019

We continue to fight for a disease modifying treatment in Alzheimer’s disease despite recent setbacks.

by Dr. David C. Weisman, MD

In tragic news, two recent Alzheimer trials have been halted for futility. In both cases, the study drug was a monoclonal antibody directed against b-amyloid, the toxic protein fragment which appears to cause Alzheimer’s. So why did it fail? One reason may be that this hypothesis—that amyloid causes the disease—may be therapeutically wrong. (It may remain correct as a necessary cause, but removing the cause later in the disease will not help). If this is the case, then removing amyloid will not change the disease. But there are reasons to think that these drugs failed and hope other similar mechanisms can succeed.

This trial joins a field of other trials investigating anti-amyloid antibodies, some ongoing, some negative, and one positive. Full comprehension is impossible given the limited data, and we should learn to suspend judgement until we have a complete picture. So far, we don’t have answers to important questions: do differences in the monoclonal antibodies, their target epitope, their spine, their dosages, their titration schedule? What is an appropriate time course to measure this slow-moving disease? Is a 1.5- to 2-year trial not long enough? Was there too much symptomatic ARIA (leaky vessels giving rise to swelling in the brain) despite titration? A few cases of symptoms from this swelling could have dragged treatment group down. What relevant species of amyloid oligomers and protofibrils should be targeted for removal? One of the trials used a functional endpoint of CDR-SOB, which is a hard one to move. This metric is difficult and was barely changed between groups on the single positive mab trial with BAN (see slide 14 from the slideshow linked below).

Eisai (ESALY) BAN2401 Phase 2 Data Analysis in Early AD Subjects

Were the populations too mild or non-progressive? Did the placebo do too well? Was CDR preserved in early disease?

Yes, let’s keep multiple lines of inquiry alive. Tau drugs look promising. As does polytherapy, neuroprotectives. Let’s never give up. But let’s fully know that we hit the target, right drug, right pharmacokinetics, in the right people, right stage, using the right metrics before giving up. I realize it is easy to say, hard to do, but patients deserve it. More data will come.

Thanks to all investigators, the teams at Biogen, and the subjects who put their lives on the line. All heroes, the subjects most of all, and deserve our deepest admiration.


New York Times: An Alzheimer’s Drug Trial Gave Me Hope, and Then It Ended

I was a small piece in the search to find a cure. Now I feel as if I’m getting erased, and medical science doesn’t have any answers.

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