22 Jan 2014

Phase 3 trial results of Eli Lilly and Co.'s solanezumab and Janssen/Pfizer's bapineuzumab will appear tomorrow in the January 23 New England Journal of Medicine. Both monoclonal antibodies failed to slow cognitive or functional decline in patients with mild to moderate Alzheimer’s disease. However, each drug hinted at smaller benefits and bolstered the idea that amyloid-related treatments, if they are to work, must be applied early in the disease process, perhaps before cognitive symptoms emerge. “We need to understand the similarities and differences between the bapineuzumab trials and the solanezumab trials to infer new insights,” wrote Eric Karran, director of research for the charity Alzheimer’s Research U.K., and John Hardy of University College London, in an accompanying editorial. Neither was involved in the trials. “Both give useful data regarding diagnostic accuracy and biomarkers.”

Last August, scientists reported that solanezumab had missed its cognitive and functional endpoints in two Phase 3 studies (see Aug 2012 news story). However, when the researchers pooled and analyzed the data from the mildest patients in both studies at once, a slight cognitive benefit emerged. The finding gave the field its first clue that removing amyloid could help treat Alzheimer’s, and encouraged scientists to apply these types of therapy earlier in the disease process (see Oct 2012 news story). In January, researchers announced that they would test solanezumab in cognitively normal, at-risk participants as part of the A4 secondary prevention trial (see Jan 2013 conference news). 

In both solanezumab and bapineuzumab trials, PET imaging revealed that about a quarter of patients lacked fibrillar amyloid pathology at baseline, suggesting that they did not have Alzheimer’s in the first place. Eli Lilly and Co. has since started a third Phase 3 clinical trial for solanezumab, called EXPEDITION 3, in patients with mild AD and evidence of amyloid burden. “This will greatly increase the potential to show efficacy,” wrote Karran and Hardy. Researchers plan to have data available sometime in 2016. “The solanezumab findings give us reason to be optimistic,” Hardy told Alzforum.

Bapineuzumab missed its primary cognitive and functional endpoints in both ApoE4 carriers and non-carriers (see Jul 2012 news story; Aug 2012 news story), prompting the companies to halt clinical development. Scientists previously told Alzforum that the lack of efficacy could have been partly due to a lowered dose, which the researchers implemented after patients receiving a higher dose developed vasogenic edema. 

In spite of the disappointing cognitive and functional results, biomarker analyses hinted at a small reduction in amyloid accumulation, as seen in PET imaging, as well as lowered cerebrospinal fluid tau (see Sep 2012 conference story). This is a noteworthy finding, Hardy said, because recent research has shown that CSF tau increases in aging APP-transgenic mice in the absence of tangles, indicating that CSF tau elevation is a downstream marker for the presence of plaques.—Gwyneth Dickey Zakaib