The anti-amyloid agent solanezumab failed to meet its primary endpoint in the highly anticipated EXPEDITION3 trial, drugmaker .
Patients with mild dementia who were given the monoclonal antibody didn't have a significant slowdown in cognitive decline as measured by the ADAS-Cog14 compared with those given placebo (P=0.095), the company said.
Lilly said based on the results, it won't pursue regulatory submissions for solanezumab in mild dementia due to Alzheimer's disease. But the company didn't rule out continued development for other indications, saying that "next steps for the remaining elements of the solanezumab development program have not yet been determined."
John Lechleiter, PhD, chairman, president, and CEO of Eli Lilly, said in a statement that the results "were not what we had hoped for and we are disappointed for the millions of people waiting for a potential disease-modifying treatment for Alzheimer's disease."
The company noted that some secondary endpoints favored solanezumab but the magnitude of treatment difference on these outcomes was usually small.
The failure raises questions about the amyloid hypothesis itself, and could have implications for other trials of solanezumab as well as other amyloid-targeting drugs, particularly Biogen's aducanumab.
, of the Mayo Clinic in Rochester, Minn., said the implications for the amyloid hypothesis "are not good."
Since the study "was done as well as it could have been for very mild symptomatic people," Knopman said, the fact that clearing amyloid had no benefit "is really very disappointing."
, of Mount Sinai Hospital in New York, said the results will likely "increase enthusiasm for tau-reducing drugs and anti-inflammatories either in combo with, or instead of, amyloid-lowering drugs."
But Knopman noted this failure isn't the final nail in the coffin: "This trial still did not go early enough in the disease. That is why the A4 study is the definitive one."
Gandy said the problem with the A4 study is that it requires a positive amyloid scan "and by then the pathology is advanced and has been there for decades," but he noted that questions about whether the drug works in the earliest, pre-clinical stages of the disease would remain.
It is unclear at this time whether there will be any repercussions for the A4 trial, which is being run by Reisa Sperling, MD, at Brigham & Women's Hospital in Boston.
Lechleiter said in the statement that the company will "evaluate the impact of these results on the development plans for solanezumab and our other Alzheimer's pipeline assets."
The impact on aducanumab is less clear, although that anti-amyloid agent works by targeting insoluble beta amyloid; solanezumab targets soluble protein.