Experimental Alzheimer’s drug delivers promising Phase 2 trial results

Although yet to be published in a peer-reviewed journal, pharmaceutical company Eli Lilly has announced promising results from one of its Phase 2 human trials testing an experimental Alzheimer’s disease drug designed to slow cognitive decline.

The two-year Phase 2 trial, dubbed TRAILBLAZER-ALZ, was testing a novel drug called donanemab, which targets the amyloid protein clusters many researchers hypothesize are the primary cause of neurodegeneration associated with Alzheimer’s. But the drug's mechanism of attack is a little more focused than many prior experimental anti-amyloid drugs.

Donanemab is a monoclonal antibody that homes in on a very specific form of amyloid-beta protein known as N3pG. The idea is N3pG acts as a signpost of toxic protein clusters, and the antibody treatment helps the body rapidly clear out those damaging aggregations.

This Phase 2 trial enrolled 273 subjects with early-stage symptomatic Alzheimer’s disease. The primary endpoint looked at cognitive changes from baseline after 76 weeks. According to the new data, only detailed so far in a press release from the company, donanemab slowed cognitive decline by 32 percent compared to placebo.

"This unique mechanism and antibody for clearing plaques, discovered at Lilly, has the potential to provide high levels of durable amyloid plaque clearance after limited duration dosing," explains Lilly’s chief science officer Daniel Skovronsky. “The positive results we have obtained today give us confidence in donanemab and support its rapid and deep plaque clearance for the potential treatment of Alzheimer's disease."

A second Phase 2 trial called TRAILBLAZER-ALZ 2 kicked off in early 2020. The trial hopes to recruit around 500 subjects and will run until at least 2023.

Of course, until the results are comprehensively delivered in a peer-reviewed journal it is difficult to interpret the true success of the trial. In an interview with The New York Times, Michael Weiner, a researcher from the University of California, San Francisco who is not affiliated with the donanemab work, suggested the results certainly need larger replication but these findings are undeniably “big news.”

One of the key reasons these results may generate a wave of cautious optimism among some Alzheimer’s researchers is they seem to indicate targeting amyloid clusters can directly slow cognitive decline. Over the last few years, following a near-constant stream of failures of anti-amyloid drugs in clinical trials, many scientists have begun to question the overriding amyloid hypothesis that has guided the majority of Alzheimer’s research for several decades.

As multi-million-dollar clinical trials failed, and big pharma companies started putting Alzheimer’s research into the "too hard" basket, a number of alternative hypotheses gained momentum. Researchers are now looking at everything from the gut microbiome and viruses, to immune dysfunction and high iron levels, in the search for a way to treat this increasingly common neurodegenerative disease.

These preliminary Phase 2 findings undeniably offer a boost to those still working with the amyloid hypothesis but there is a long road ahead before donanemab can be broadly found effective at slowing Alzheimer’s-related cognitive decline. Even with successful subsequent Phase 2 and 3 trial results, the experimental drug is at least seven to 10 years away from clinical applications.

Source: Eli Lilly