Will Beta-Amyloid Drugs for Alzheimer's Succeed?

The pharmaceutical industry has invested billions of dollars in drugs targeting beta-amyloid, which is found in plaques that are a hallmark of Alzheimer's disease. But recent drug trial failures have called into question the role of beta-amyloid in Alzheimer's and the chances that other drugs targeting it will help Alzheimer's patients.

What is Amyloid?

Amyloid is a general term for proteins that misfold in a specific way, causing them to get sticky and clump together. When these sticky proteins collect inside tissues, they become toxic and can cause amyloidosis, a family of diseases that occur throughout the body and, in severe cases, result in organ failure. Approximately 60 known proteins can cause amyloidosis, including beta-amyloid, the type implicated in Alzheimer's disease. Among all forms of amyloidosis, there are few effective treatments.

In the brain, beta-amyloid clumps into toxic plaques that damage nearby neurons. These plaques were discovered in 1906 by Alois Alzheimer, who called them "senile plaques." It wasn't until 1984 that researchers identified beta-amyloid as the plaques' primary (though not only) component.

These early discoveries form the basis of the "amyloid hypothesis," which posits that beta-amyloid in plaques cause Alzheimer's. But questions remain about whether plaques are a cause or merely an effect of Alzheimer's disease. It's possible that plaques are a result of brain inflammation, which also damages neurons and is a potential cause of Alzheimer's. And some researchers theorize that beta-amyloid proteins accumulate into plaques because of a failure to clear them from the brain.

How Do Beta-Amyloid Drugs Work?

Because beta-amyloid was discovered relatively early in Alzheimer's research, it became the focus of the earliest drug discovery efforts in Alzheimer's and, consequently, today those drugs are some of the most developed. The majority of drugs targeting beta-amyloid have taken one of three approaches. The first is to reduce the production of the protein using gamma-secretase or beta-secretase (BACE) inhibitors. Merck's drug verubecestat—expected to complete a large phase 3 trial this summer—is a BACE inhibitor. The second approach is to bind to and remove soluble beta-amyloid proteins (called monomers and oligomers) that are a precursor to plaques. Eli Lilly's failed drug solanezumab tried this and several similar drugs are still in clinical trials, including crenezumab (Genentech) and CT1812 (Cognition Therapeutics). The final approach—used by Biogen's drug aducanumab and Roche's gantenerumab—involves removing beta-amyloid plaques once they have aggregated in the brain.

Will Any of These Drugs Succeed?

Findings from early-stage clinical trials provided strong evidence that Biogen's aducanumab can remove plaques, and that Merck's verubecestat can slow the production of beta-amyloid. While these results show that the drugs "worked" as intended, we still don't know whether they have any effect on the clinical progression of Alzheimer's disease. Will these anti-amyloid drugs restore or slow the decline in cognitive function? The results of these Phase 3 clinical trials—Merck is expected to release findings this summer and Biogen in 2018—should provide the answers.

But even if these anti-amyloid drugs fail, the pipeline of potential Alzheimer's treatments in clinical trials is more diverse than it's ever been. Aging is the primary risk factor for Alzheimer's disease. And more and more Alzheimer's drugs are targeting the biological processes involved in aging—such as increased inflammation, epigenetic changes, and neuronal energy failure.

The Alzheimer's Drug Discovery Foundation, where I lead the scientific portfolio, was an early funder of beta-amyloid programs. We supported CTS-21166, developed by Dr. Jordan Tang and CoMentis, which was the first BACE inhibitor program to reach clinical trials. But in 2010—as the pharmaceutical industry began to make significant investments in anti-amyloid clinical trials—we strategically chose to stop funding anti-amyloid drugs and focus our investments on other, more innovative areas of drug research. We believe that a combination of drugs focused on the underlying, age-related causes of Alzheimer's (which may ultimately include anti-amyloid therapies) have the potential to slow its progression enough that, in a typical lifespan, most people will never develop the disease. Thanks to our funding, numerous drugs have reached clinical trials and could be available to patients in as little as five years.

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