Solanezumab, a monoclonal antibody that targets amyloid plaques, did not slow cognitive decline in patients with mild Alzheimer’s disease.
Although the drug did reduce soluble amyloid beta by 40%, compared with placebo, that change did not translate into a clinically meaningful cognitive benefit, Eric Siemers, MD, said in a press briefing called by Eli Lilly & Co., which manufactures solanezumab. The company did not release specific cognitive data from the highly anticipated Expedition 3 trial, except to say that changes on the ADAS-Cog14 (Alzheimer’s Disease Assessment Scale–cognitive subscale-14), the main cognitive endpoint, had a nonsignificant P value of 0.095 [Corection: Changed from 0.95 in original posting]. Functional data were also withheld.
Courtesy NIH
The entire clinical picture won’t emerge until Dec. 8, when Lilly presents full data at the annual Clinical Trials in Alzheimer’s Disease meeting in San Diego. But, in the meantime, Dr. Siemers did say that Lilly won’t be pursuing a Food and Drug Administration New Drug Application for solanezumab as a disease-modifying therapy for mild Alzheimer’s. However, it’s not the end of the road for solanezumab. Lilly is still investigating it in ExpeditionPro, a trial which will employ the antibody in patients with prodromal AD.
Solanezumab is also part of two very important public/private partnership studies: The Anti-Amyloid Treatment in Asymptomatic Alzheimer’s study (A4 study), investigating its effect in cognitively healthy elders with Alzheimer’s risk factors, and the Dominantly Inherited Alzheimer’s Network (DIAN) study of patients with autosomal dominant mutations in Alzheimer’s genes.
It’s unclear what impact the failed Expedition 3 could have on those, Dr. Siemers said. “These studies are also funded by the National Institute on Aging in collaboration with academic institutions, so we will need to sort through the data very carefully and speak with our academic colleagues before making any decisions on this.”
If solanezumab was successful in either one of those trials – if they continue – Lilly could still apply for approval in those patient groups, Dr. Siemers noted.
The results are disappointing, but not entirely unexpected in the research community. Many felt that Expedition 3 was founded on shaky clinical ground from the start. The study was based on subgroup analyses of Expedition 1 and Expedition 2, both of which failed to meet their primary endpoints in patients with mild-moderate AD. But when researchers pooled both groups of mild patients, they found that solanezumab conferred a 34% slowing of cognitive decline in one cognitive measure, the ADAS-Cog14. This translated to a clinical change of less than 2 points on the scale, however.
Lilly very carefully drafted Expedition 3 to come as close to recreating those findings as possible, said Lon Schneider, MD, of the University of Southern California, Los Angeles.
“By taking the ideal patients from two studies and combining them as if they were from one study, Lilly predicted that they could find a 1.5-2.0 point [Correction: Changed from 1.5 in original posting] difference in one particular outcome, the ADAS-Cog14, [Correction: the ADAS-Cog14 not included in previous posting] in a study of more than 2,000 patients,” Dr. Schneider said in an interview.
This is the research equivalent of Heraclitus’ adage that one can never step in the same river twice: These could never be the same patients, from the same places, at the same time, with the same clinical picture, Dr. Schneider said – especially since Expedition 3 had a purified cohort of only amyloid-positive patients, while close to 25% of patients in the earlier studies probably had no brain amyloid at all.
“This is what happens when we rely on subanalysis to create drug trials. We slice it and dice it until we find some patients for whom the drug is better than placebo, and then say, ‘We have a winner.’ ” Even in the best-case scenario, he said, Expedition 3 would have found only the same modest benefit as its predecessors. “Then we would be in the difficult situation of saying we have a disease-modifying therapy that is associated with only very small clinical changes.”
Dr. Siemers rejected the idea that Expedition 3’s failure is another nail in the coffin of the amyloid hypothesis, or at least in the idea that taming amyloid can prevent dementia or rescue cognition. “You can’t disprove a hypothesis based on one study done in patients with mild dementia,” he said.
Dennis Selkoe, PhD, the Vincent and Stella Coates Professor of Neurologic Diseases at Harvard Medical School, Boston, said Expedition’s failure does not negate the amyloid hypothesis or the appropriateness of amyloid as a therapeutic target.
“Like others, I am disappointed for our patients that solanezumab failed to meet its clinical endpoint by just a little bit. But it is not truly surprising, as this drug was always known to be a ‘weak’ antibody in terms of its ability to mobilize amyloid from the brain,” he said in an interview.
Research into antiamyloid therapies should continue, he said.
“This outcome does nothing to alter the overwhelming genetic, neuropathological and biomarker evidence that amyloid beta protein buildup acts to precipitate the AD process, and it also does not alter the potential promise of current agents in trials: Merck’s beta secretase inhibitor and Biogen’s aducanumab antibody, which appears to be much more effective in mobilizing amyloid beta. Other approaches, in addition to antiamyloid agents, are very much desired and are gradually moving forward, which is good news. But for the time being, antiamyloid treatments will be those most examined in trials, for scientifically and technically sound reasons.”
Dr. Schneider has served as a consultant for Eli Lilly & Co in the past. Dr. Selkoe is a founding scientist and director of Elan Pharmaceuticals.
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