BOSTON – Another Eli Lilly–sponsored trial of solanezumab is in the works, bolstered by a subanalysis of two failed studies that picked up an efficacy signal among patients with mild Alzheimer’s.
"Although our primary objectives in those trials were not met, this prespecified secondary analysis did show a significant benefit" for patients who took the drug, compared with those who took placebo, Christopher Carlson, Ph.D., said at the Alzheimer’s Association International Conference 2013.
Dr. Carlson, an employee of Eli Lilly, presented the pooled analysis of EXPEDITION I and II. It found a 34% decline in cognitive slowing and a 17% decline in functional slowing, compared with placebo, among the 2,042 patients with mild disease.
Angina was the only adverse event seen in more than 1% of patients, which was also significantly different between the groups; it occurred in 1% of the solanezumab group and in 0.2% of the placebo group.
Dr. Christopher Carlson
Amyloid-related imaging abnormalities (ARIAs) were numerically more common among those taking solanezumab, but the between-group differences were not statistically significant. Any increase of ARIA-H (microhemorrhage) in size or number over baseline occurred in 9% of the solanezumab patients and 7.5% of the placebo patients. ARIA-E, a measure of vasogenic edema and/or sulcal effusion, developed in 1.1% of those taking solanezumab and 0.5% of those taking placebo.
Dr. Carlson said the combination of some cognitive benefit and the low rate of adverse events was enough to prompt further study of the monoclonal antibody.
"The cognitive and functional effects and safety profile provide a favorable risk/benefit level. So we are now in the process of planning a large, multinational phase III trial for patients with mild Alzheimer’s and evidence of amyloid pathology."
Lilly announced its plans for the study during a July 12 webcast.
The new study – EXPEDITION III – will enroll 2,100 patients with mild Alzheimer’s. Treatment will consist of one 400-mg infusion of solanezumab or placebo every 4 weeks. Like EXPEDITION I and II, EXPEDITION III will run for 80 weeks and will be followed by an open-label extension study.
Co–primary endpoints will be the Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog)-14 and the Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADAS-ADL), and Instrumental Activities of Daily Living scales (IADL). Secondary endpoints include a variety of cognitive, functional, and quality of life measures, as well as changes in amyloid brain deposition as measured by florbetapir PET scan, changes in CSF biomarkers, and volumetric brain changes as measured on magnetic resonance imaging.
The trial design of EXPEDITION III includes a few changes that Lilly researchers hope will decrease noise in the data, making it easier to pinpoint any benefits the drug may confer. The failed EXPEDITION trials contained an unknown number of patients with mild disease who may not have had amyloid pathology – a problem that could have diluted the drug’s positive effects, Dr. Eric Siemers said on the Lilly conference call.
In those studies, "We tested a small subgroup of the mild patients with florbetapir PET. Among them, almost 26% were negative for amyloid pathology," said Dr. Siemers, senior medical director of the company’s Alzheimer’s disease team. It’s doubtful that an antibody designed to eliminate amyloid plaques could benefit a patient without such deposits, he said.
Another admission qualification of the new study – a Mini Mental State Examination score of 20-26 – will further help ensure that only patients with mild Alzheimer’s enter the trial, he added.
The tightened entry requirements mean that more patients will have to be screened for entry, Dr. Siemers noted. "The screen failure rate for EXPEDITION I and II was just under 25%. In EXPEDITION III it could be up to 50%." That means it could take 22 months to find the full complement of 2,100 patients.
"This would place the last patient visit around the end of 2016," he said.
Eli Lilly is the sponsor of all the solanezumab EXPEDITION trials.