In the early 2000s, researchers from Washington University in St. Louis and drugmaker Eli Lilly started testing in mice an experimental drug they hoped could disable a protein thought to be the root cause of Alzheimer’s disease.
On Wednesday, after nearly 20 years of costly and unsuccessful research, Lilly conceded a final defeat for the drug, called solanezumab. Researchers running one last study determined that solanezumab, when given to people whose brains harbored that suspect protein but hadn’t yet shown clinical signs of Alzheimer’s, failed to slow cognitive decline.
The trial, dubbed “A4,” began in 2013 and enrolled more than 1,100 older adults in the U.S., Canada, Australia and Japan. Despite hopes solanezumab could prevent or delay Alzheimer’s onset, the data showed no benefit to treatment, according to Lilly.
“Results of the A4 study clearly showed that the primary and secondary endpoints were not met,” said John Sims, Lilly’s head of the drug’s medical and global brand development, of the trial run by the University of Southern California and the Alzheimer's Clinical Trials Consortium. “Therefore, the A4 Study concludes our clinical development of solanezumab.”
The announcement serves as a coda for Lilly’s efforts to develop solanezumab, once the prize of the drugmaker’s pipeline, into a blockbuster medicine for the many millions of people with Alzheimer’s.
Along the way, Lilly enrolled thousands of people in multiple Phase 3 trials comparing solanezumab to a placebo, betting that removing a protein called amyloid from the blood could help treat Alzheimer’s. Two of those studies failed in 2012, but Lilly scientists dug through the data and found reason to hope the drug could work better when given to patients with milder disease.
That finding led to a third large Phase 3 trial which failed four years later in 2016. Another, investigator-led study came up short in 2020.
These trials taught researchers that targeting amyloid that was insoluble in the blood might also be necessary, and raised questions about whether reducing amyloid brain accumulation was sufficient for treating Alzheimer’s. Their failure also pushed researchers to explore earlier treatment and develop new ways to measure the disease’s progression.
Despite the billions of dollars Lilly has spent on ultimately futile Alzheimer’s research, the company hasn’t been deterred from investing further. The company is developing another drug called donanemab that could win Food and Drug Administration approval should trial data expected this year confirm earlier positive findings. (The agency recently rejected an application based on those early results, choosing to wait for the follow-up data.)
Lilly also has another amyloid-targeting drug, called remternetug, in Phase 3 testing and a third that blocks another protein implicated in Alzheimer’s and is currently in Phase 2.
In the company’s view, solanezumab’s failure doesn’t diminish the prospects of donanemab and remternetug, even though those drugs are also aimed amyloid, noting how solanezumab wasn’t expected to remove deposited amyloid plaques.
“Donanemab and remternetug ... are different from solanezumab in that they specifically target deposited amyloid plaque and have been shown to lead to plaque clearance in treated patients,” Lilly said in its statement.
Yet the company is now behind rivals Eisai and Biogen, which jointly developed and won an expedited FDA approval of an amyloid-targeting drug called Leqembi earlier this year.
While pharmaceutical companies have now broken through with Alzheimer’s drug approvals, they still face skepticism from insurers and from physicians. Aduhelm, an Alzheimer’s drug from Biogen that secured an accelerated FDA OK in 2021, never won support from payers and sales remain negligible.
That pushback has forced Eisai, Biogen and Lilly to focus on securing full approvals to better secure their drugs’ place on the market. The FDA is currently reviewing Eisai and Biogen’s application for a traditional clearance and expects to make a decision later this year.