24 August 2012. The other shoe dropped today on Phase 3 monoclonal antibody trial results expected this summer. Eli Lilly and Company announced that solanezumab did not reach its cognitive or functional endpoints in either of two double-blind, placebo-controlled trials in patients with mild to moderate Alzheimer's disease (AD). It is the second in a one-two punch that casts doubt on the ability of these antibodies to treat symptomatic AD. Earlier this month, Janssen Alzheimer Immunotherapy had halted all studies of intravenous bapineuzumab in patients with mild to moderate AD (see ARF related news story). There may be a glimmer of hope, however. According to a Lilly press release, prespecified analysis of data pooled from the EXPEDITION and EXPEDITION2 solanezumab trials suggests cognitive decline slowed in people with mild, but not moderate, AD, hinting that earlier treatment could provide some benefit. "The fact that there would be any benefit in a population of people who already have cognitive deficits is a huge win for the amyloid hypothesis," said Ryan Watts, Genentech, San Francisco, California. "I am cautiously optimistic," he told Alzforum. Lilly will discuss the next steps with federal regulators, according to their press statement. Unlike bapineuzumab studies, solanezumab trials have not been terminated. An open-label extension study will apparently go ahead as planned.
Many researchers believe that Aβ plays a key role in AD pathology, but so far no amyloid immunotherapy has proven effective in slowing cognitive decline in AD patients. "Up until now we've had all discouraging results; there was no clear cognitive benefit, even in mild groups," said Stephen Salloway, Brown University, Providence, Rhode Island. "This is the first possible evidence that there is a cognitive benefit in a mildly affected population."
The EXPEDITION trials enrolled more than 2,050 people age 55 and older. Those randomly selected for active treatment received 400 milligrams of intravenous solanezumab every four weeks for 80 weeks. In neither trial did mild or moderate AD patients benefit in outcomes that measure cognition (Alzheimer's Disease Assessment Scale—Cognitive subscore) or function (Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory). But when scientists combined data from both studies, those with the mildest disease showed evidence of a modest slowing in cognitive decline, according to ADAS-Cog data.
"The fact that there isn't a functional benefit probably isn't that surprising because in milder patients, there's less of a functional deficit in the first place," said Watts. Plus, even though it was necessary to pool the data to find what is likely a very modest effect, the hint of one in early stages of the disease argues that going earlier may even be better, suggested Watts. Salloway agreed: "If there is a mild benefit, and the biomarker effect matches it, it would support the idea that at earlier stages we may have a bigger impact," he told Alzforum.
How early the treatment would need to start is unclear. Several prevention trials are on the horizon (see ARF related news story), including one that will test the efficacy of Genentech’s antibody therapy, crenezumab (see ARF related news story).
However, all researchers interviewed for this article said they would wait for biomarker data before they get too excited over the slight benefit in mild AD patients. It would be important to make sure that cerebrospinal fluid analysis, brain volumetric analysis by magnetic resonance imaging, and positron emission tomography to estimate plaque burden reflect the somewhat crude measurements of cognitive benefit, said Ranjan Duara, Mount Sinai Medical Center, Miami Beach, Florida. Lilly has shared some of the trial data, including CSF, amyloid PET, and MRI measures, with the Alzheimer's Disease Cooperative Study (ADCS) for independent study. The ADCS analysis will be presented at the American Neurological Association Annual Meeting in Boston, Massachusetts, and at the Clinical Trials on Alzheimer's Disease Meeting in Monte Carlo, Monaco, both taking place next October.
Today's top-line disclosure includes no in-depth data. One question pundits might be asking is how the placebo groups fared, given that faster-than-expected decline in cognition in the control groups in a Phase 2 study raised hopes that bapineuzumab would work—at least in those free of the ApoE4 allele. Eric Siemers of Eli Lilly told Alzforum that the placebo controls declined "as expected” in the solanezumab trials.
On the safety side, some mild side effects occurred more often in the drug compared to placebo groups; these included lethargy, rash, and malaise in the EXPEDITION1 group, and angina in EXPEDITION2. Vasogenic edema, which limited dosing in bapineuzumab trials, did not emerge as a major concern. The limited success of solanezumab may have to do with dosing, which can be much higher with solanezumab, said Watts. The two antibodies also target different Aβ epitopes.
Meanwhile, in the extension trial, EXPEDITION-EXT, 1,275 volunteers from the two Phase 3 trials will continue to get the same solanezumab dose every month for 100 more weeks. That study will wrap up in July of 2014. "Given the fact we are encouraged by efficacy data, and that the safety profile is quite good, we felt that it was appropriate to continue with the extension study while we're further evaluating the data," said Siemers.—Gwyneth Dickey Zakaib.