29 Jun 2017

Ever since Eli Lilly’s anti-Aβ antibody solanezumab fell short on slowing cognitive decline in Phase 3 Alzheimer’s studies, researchers have wondered about the fate of ongoing secondary prevention trials testing this drug. For the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease trial—A4 for short—trial, which enrolls cognitively normal people with amyloid accumulation, the word is now in: The study will continue, and will boost solanezumab exposure. “We believe that by increasing the dose and extending the study, we will be able to provide more definitive answers,” study director Reisa Sperling at Brigham and Women’s Hospital, Boston, said in a press release.

Eli Lilly announced in late 2016 that solanezumab had failed to meet its primary endpoint in the Phase 3 EXPEDITION studies, though treated participants trended toward slower decline on the ADAS-Cog14 (Nov 2016 news). Later analyses confirmed that solanezumab treatment nudged down the rate of decline on all clinical outcomes, with some secondary measures reaching significance. The findings raised speculation that a higher dose of the drug might accomplish more (Dec 2016 conference news). 

Based on these data, A4 researchers decided to quadruple the dose of solanezumab from 400 to 1,600 mg, given intravenously every four weeks. They will monitor participants closely for any adverse effects such as ARIA, a buildup of fluid in the brain that has plagued previous anti-amyloid trials.

The dosage hike follows a trend in antibody studies. Genentech researchers recently said they had quadrupled the dose of their anti-Aβ antibody crenezumab in the Phase 3 CREAD trial (Dec 2016 conference news). Likewise, Roche researchers upped gantenerumab dosing fourfold in Phase 3 after analysis of the negative Scarlet RoAD trial showed hints of benefits at higher doses (see Nov 2015 conference news). 

In addition to the dosage change, the A4 study will lengthen by 72 weeks, for a total duration of more than 4½ years. This is because observational studies such as the Harvard Aging Brain Study and the Alzheimer’s Disease Neuroimaging Initiative have found that a time frame of three to five years is necessary to detect accelerated cognitive decline among people with preclinical AD, the researchers noted. A4 began in 2014 and is still enrolling participants. Researchers have not yet analyzed any interim data.—Madolyn Bowman Rogers