6:42 PM
May 03, 2019
 |  BioCentury  |  Product Development

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 the industry for keeping at it, but on the other hand, in doing so they are taking resources that could be used for novel targets.”

Even the staunchest advocates of the amyloid hypothesis are starting to hedge their bets, and smaller biotechs are exploring a wide range of new approaches. About two thirds of the 78 AD candidates in the clinic are targeted outside the amyloid pathway (see “Baby Steps Beyond Amyloid”).

Nevertheless, all 10 academic and industry KOLs who spoke to BioCentury remain convinced that amyloid causes or at least plays a major role in the disease. Most likely, it is the trigger, they say. The problem is that the peptide builds up for decades before symptoms start, and by the time a patient seeks help, other mechanisms are in the driver’s seat. The prime suspects are tau aggregation, the second major hallmark of the disease, and neuroinflammation, which has been implicated by genome-wide association studies (GWAS).

Still, there’s little agreement among the KOLs on what -- if anything -- would convince them to jettison β amyloid. Two argued the field should have already moved on, and another three were not ready to describe an exit strategy. The rest are reserving judgment until even more data are available.

The greatest agreement was that the best play left for the amyloid hypothesis is in disease prevention. At least five Phase II or III trials in presymptomatic patients are slated to read out between 2020 and 2024 (see Table: “Still Plugging Away at Amyloid”).

Even if all these fail, it may not mark the end of the hypothesis. One pharma suggested the results, positive or negative, could spur additional studies, and several KOLs think combinations of amyloid inhibitors with other...

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