PhIII Alzheimer’s drug goes bust — and a major setback at Eli Lilly and AstraZeneca may doom the class

Another big Phase III Alzheimer’s program is being scrapped at Eli Lilly $LLY and AstraZeneca $AZN, offering fresh evidence that the entire BACE class may be completely useless in slowing or preventing the disease in symptomatic patients.

Dan Skovronsky

The drug this time is lanabecestat, which Lilly grabbed close to 4 years ago in a $500 million pact with AstraZeneca — a modest $50 million in cash. At the time, Lilly was plugging a gap in its Alzheimer’s pipeline after the failure of its own BACE effort due to toxicity issues with that particular medication.

This time, fingers are pointing to the entire class in a flop that will likely cause fresh angst over a huge question: Is amyloid beta really the culprit here?

The BACE theory is easy enough to understand. Moving upstream in the biological process for the production of amyloid beta, researchers hoped to bend the course of the disease by closing the tap on toxic proteins. Merck was the first to try it in a pair of Phase III studies and simply concluded it was a bust, probably only theoretically useful now in pre-symptomatic patients or as a combo.

Eli Lilly will now move to shutter two big trials — the AMARANTH trial, in early Alzheimer’s disease, and the DAYBREAK-ALZ trial, in mild Alzheimer’s disease dementia — after the monitoring committee called it on futility.

The failure of Lilly and AstraZeneca’s drug may sound the death knell on a solo BACE strategy in early and mild patients, even though Biogen just touted its Phase II BACE study heralding the biomarker success on amyloid beta alongside an absence of a statistically significant impact on cognition — much the same as what Merck was tracking.

In lanabecestat’s case, we only know that the drug appeared safe and ineffective, no hard data are available yet.

Why keep trying after more than a decade of failures? AstraZeneca answered that question when Pascal Soriot once estimated that this drug could earn $5 billion a year. 

That’s not going to happen, of course. But developers keep hammering away at it — even as big players remain puzzled about what causes the disease. 

Following the failure of solanezumab in three straight pivotal studies, Eli Lilly doesn’t have much of a credible pipeline left in the field. And after Pfizer bowed out following big retreats at GSK and AstraZeneca, Big Pharma may be doing some additional soul searching about its role in R&D. Lilly, though, vows to soldier on after spending billions on failure.

“Lilly remains dedicated to Alzheimer’s disease research as we have been for the last three decades,” says R&D chief Daniel Skovronsky. “We won’t give up on finding a solution for Alzheimer’s patients.”

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Research Scientist - Immunology
Recursion Pharmaceuticals Salt Lake City, UT
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Atlas Venture Cambridge, MA

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