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Drug Development

Lilly Alzheimer’s drug fails

The firm will not seek regulatory approval for solanezumab

by Lisa M. Jarvis
November 23, 2016 | APPEARED IN VOLUME 94, ISSUE 47

Credit: Lilly
A Lilly researcher in New York City.

In yet another blow to the amyloid hypothesis, Eli Lilly & Co. said today that its Alzheimer’s treatment solanezumab failed in a Phase III study. Shares of Lilly were down as much as 15% on the news.

For more than a decade, Alzheimer’s drug developers have focused their efforts on trying to prevent or remove the amyloid plaques coating the brains of people with the disease. Solanezumab, which binds to soluble, monomeric forms of amyloid-β, had already tanked in two Phase III studies. But Lilly decided to push on with a third trial based on signs that people with early stage Alzheimer’s benefited from the drug.

In this latest study, the drug failed to slow down the cognitive decline seen in the disease. Lilly said it would no longer file for regulatory approval for the drug, which, if approved, would easily have enjoyed multi-billion-dollar sales.

“This result will no doubt cast a shadow over Lilly’s Alzheimer’s disease pipeline portfolio, which is heavily based on the beta-amyloid hypothesis,” Leerink stock analyst Seamus Fernandez told clients. The news is also hitting Biogen, which has aggressively moved ahead late-stage studies of aducanumab, an antibody targeting aggregated amyloid-β. Biogen’s stock was initially down more than 8% this morning.

The solanezumab failure adds to a graveyard of Alzheimer’s disease treatments. Indeed, Lilly already had plots there: Solanezumab is the third Alzheimer’s drug the firm has dropped from its neuroscience pipeline. In 2010, the company pulled the plug on semagacestat, a small molecule that blocks γ-secretase, after two failed Phase III studies. Three years later, Lilly ended development of LY2886721, a BACE inhibitor that had made it to Phase II.

Many are wondering whether solanezumab’s failure should be seen as the final word on the amyloid hypothesis. Sam Gandy, an amyloid expert at Mount Sinai’s Alzheimer’s Disease Research Center who for months had predicted the failure, noted the interventions were likely happening too late in the disease. “By the time an amyloid scan is positive,” he says, microscopic clumps of amyloid- β “may have been there for decades.”

Other Alzheimer’s experts say solanezumab itself may be the problem. “It is not truly surprising, as sola was always known to be a ‘weak’ antibody in terms of its ability to mobilize amyloid from the brain,” says Dennis Selkoe, a Harvard neurologist who was among the first to put forward the amyloid hypothesis in the early 1990s.

Selkoe argues that Biogen’s aducanumab, “which appears to be much more effective at mobilizing amyloid- β,” and a small molecule from Merck still hold promise.

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Comments
Oliver (November 24, 2016 12:06 AM)
The problem with molecule drugs, pills, is that when swallowed, there are myriad factors that will alter the molecule - from hydrocloric acid (digestive enzymes) to a host of other chemicals in the body and by time it gets to any brain or neural or brain region - it has been wholly compromised, broken down, made moot.
Robert (November 24, 2016 4:55 AM)
While this is a relevant concern for oral drugs, there are an abundance of examples, where the drug passes from the gastro-intestinal tract into the cardiovascular one unchanged.
In this case, this does apply as solanezumab is apparently adminstered by infusion directly into the bloodstream. Obviously, it being a monoclonal antibody, it is probably much more sensitive than a small molecule drug.
The blood-brain barrier would be the main obstacle.
Bour (November 27, 2016 6:30 PM)
Oliver, I think that most of these biologics are injected.
Jessica (November 26, 2016 4:17 PM)
Oliver, I think you need to read up a little more on medicinal chemistry and the drug discovery process before making such comments. Stability studies are a standard part of lead optimisation, taking into account how the drug dissolves, its stability in a range of biologically relevant conditions, be they acidic, alkaline, or neutral. Drug clearance is also minimised for oral drugs during this phase of development, designing molecules that are cleared less rapidly, with properties capable of carrying them across the blood brain barrier, where necessary, as in this case.

Hydrochloride acid and digestive enzymes are not the same thing, as you suggest, but do happen to coexist in the stomach.

I hope that you can see that drug discovery needs the support of the public to increase funding and inspire the next generation of scientists. Negative and false comments like yours do not help in this manner, and I hope you will think more carefully in future.

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