How the amyloid hypothesis holds its grip

Why pharmas can’t let go of the amyloid hypothesis of Alzheimer’s disease

By now, two things are clear about the amyloid hypothesis of Alzheimer’s disease: one is that the amyloid peptide is somehow involved; the other is that it’s a terrible target.

β amyloid has had an irresistible pull on drug developers because human genetic data strongly argue the peptide causes the disease. But at least 20 failed Phase III trials, and zero successful ones, argue equally strongly that it’s not the path to success.

Yet the hypothesis appears here to stay for the foreseeable future. Even Biogen Inc.’s April 24 announcement that it would call off all Phase III studies of aducanumab, widely considered the most promising anti-amyloid candidate to date, does not represent an abandoning of the hypothesis. The biotech and its partner Eisai Co. Ltd. have two other amyloid-lowering therapies in late-stage trials.

For the believers, what’s left is to define whether there is a “kill experiment” whose results would persuade them to walk away from β amyloid as a focus for therapeutic intervention. So far, with each failed trial of a β amyloid-lowering therapy, these companies and their academic collaborators have concluded that either the compound or the trial design was at fault (see “Amyloid: How Did We Get Here And What We Can Learn?”).

“Billions of dollars are being spent on a target that really in any other indication would have died.”

Howard Fillit, ADDF

At least nine pharmas or biotechs remain committed to development of agents that aim to block β amyloid or prevent its production, and over a dozen compounds are in clinical development, according to BioCentury’s BCIQ database.

“Billions of dollars are being spent on a target that really in any other indication would have died,” Howard Fillit, founding executive director and CSO of the Alzheimer’s Drug Discovery Foundation, told BioCentury. “I applaud

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