Why do we keep investing in anti-amyloid therapies for Alzheimer’s disease?

One can not help but think of Queen’s 1980 hit Another One Bites the Dust when reading some of the latest headlines about the failures of anti-amyloid therapies for Alzheimer’s disease. Just this week, Biogen reported that their block-buster anti-amyloid immunotherapy, aducanumab failed its major phase 3 trials, essentially tanking its market cap and inducing irritable bowel syndrome in its investors.

The raw data are not out yet, but will be published at the next scientific meeting. The goal of the two multicenter studies (ENGAGE and EMERGE) was to determine if monthly doses of aducanumab could slow cognitive decline in patients with early stage Alzheimer’s disease. The idea behind passive immunotherapy is to remove amyloid-beta from the brain. How these antibodies accomplish this is still under investigation. Interestingly, phase 1 studies of aducanumab showed impressive reduction of brain amyloid-beta using positron emission tomography — a growing technology for looking at biomolecules in live tissues. Additionally, these studies, although underpowered, suggested a possible slowing of cognitive decline.

Predictably, once the antibody was used in a larger cohort, this therapeutic effect disappeared. A quote from Biogen’s CEO Michel Vounatsos, sums up the failure nicely (emphasis on complexity my own):

“This disappointing news confirms the complexity of treating Alzheimer’s disease and the need to further advance knowledge in neuroscience.”

It is frustrating to see failures like this, especially when so many lives are affected and so much money is spent. However, it is also frustrating that we keep ramming our heads into the same brick wall with the same tools, hoping that this time it will fall. In the same breath Vounatsos also says:

“Biogen’s history has been based on pioneering innovation, learning from successes and setbacks.”

I fail to see the innovation or wisdom gained from setbacks here. Aducanumab is another IgG1 monoclonal antibody just like bapineuzumab and solanezumab, both of which have similarly failed miserably in clinical trials. In fact, the pattern is quite striking. There have been no successful clinical trials using anti-amyloid therapy in non-autosomal dominant Alzheimer’s disease at any stage of progression, except for prior to the onset of symptoms.

And yet(!), oh so laughably, not even 24 hours after the latest failure — I cannot put enough sarcasm on this line — Eisai and Biogen are forging ahead with another clinical trial testing the already controversial BAN2401 in patients with mild cognitive impairment or early Alzhiemer’s. BAN2401 is yet another (shaking my head at the irony) monoclonal IgG1 antibody that recognizes larger forms of amyloid fibrils. There was initially some excitement for this therapy as it was the first to show significant slowing of cognitive decline (about 30%) — until the raw data were actually published and it was realized that the study authors left out patients with the important genetic risk factor for Alzheimer’s, ApoE4, in the high dose arm of the study. In other words, it was difficult to tell if slowing of progression was actually due to the drug, as the patients with the highest risk for progression were not even studied.

Nevertheless, the devotees of the Holy Church of Amyloid continue to trudge forward through the valley of cognitive dissonance, seeking salvation in the waters of anti-amyloid. I can no longer tell if it is to protect their own pride that they resist letting go of their precious theory or if they merely want to recover all of the money spent by any means necessary. Either way, precious resources, including morale, are being squandered on a dead-end theory that is repeatedly smacking us in the face with therapeutic failure after failure. And to add insult to injury, you have the CEOs of the companies spending all of this money telling us (and patients) that they are committed to innovation and learning from their previous mistakes. I think not. We can not keep going the route of “well maybe this trial will be The One.” Maybe this next BAN2401 will be the one, but a lot of science (and a lot of history) tells us it probably won’t. And what if it does show a significant result? A blind squirrel finds a nut every once in a while. It will probably bring up more questions than it answers.

Good luck Biogen and Eisai.