1. Reports of the death of the amyloid hypothesis are exaggerated. Here's why. statnews.com/2019/03/21/alz…
2. Background: two Biogen Alzheimer trials failed using an monoclonal antibody that looked like it engaged amyloid with a unique binding interface. This was an important trial. Disclosure: I did not participate as a site PI for them but do others. alzheimersanddementia.com/article/S1552-…
3. There are a few possibilities here, one of which is that amyloid hypothesis is therapeutically wrong. But there are other possibilities that one should explore. Full comprehension is hard given limited data, but impulsive radicalism is not good solution.
4. This trial joins a field of other trials, some ongoing, some negative (CREAD, bapi, sola), and one positive (BAN2401). The differences are important. The following questions are unanswered at this time (also true of Mueller report), but are very important:
5. Was the titration too long? If there was not enough time in such a slow moving disease, then a 1.5 year trial perhaps was not long enough. clinicaltrials.gov/ct2/show/recor…
6. Was there too much symptomatic ARIA despite titration? A few cases of symptomatic ARIA could have dragged treatment group down.
7. Amyloid is complex. We don't know all the relevant species of amyloid oligomers and protofibrils. If adu hit wrong target, it may have removed the wrong amyloid species. This might not be true of other mabs.
8. Endpoint of CDR-SOB (on both trials) is a very hard one to move. (Lose only 0.5-1 points per year.) This metric is difficult and was barely changed between groups on the single positive mab trial with BAN (slide #14), c/w ADAS (#13): seekingalpha.com/article/419069…
9. Was the population too mild or non-progressive? Did the placebo do too well (CDR can be preserved in early disease)? What were other metrics? Did the drug clear amyloid?
10. For all the Monday am quarterbacks, don’t hear much on what to do next - other than more science. Back to the drawing board, but where? Yes, let's keep multiple lines of inquiry alive. Tau drugs look promising. As does polytherapy, neuroprotectives. Let's never give up..
11. ...But let's fully know that we hit the target, right drug, right pharmakokinetics, in the right people, right stage,, right metrics before giving up. I realize it is easy to say, hard to do, but patients deserve it. More data will come.
12. 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 you have my deepest admiration. nytimes.com/2019/03/22/wel…
