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.