A second phase 3 trial investigating bapineuzumab IV in patients with mild to moderate Alzheimer’s disease (AD) has been stopped, essentially spelling the end of the program to investigate this agent in patients with this type of dementia.
The 18-month, randomized, double-blind, multicenter studies were examining the efficacy and safety of bapineuzumab, a monoclonal antibody that targets beta-amyloid (Aß), in patients who carry the apolipoprotein E epsilon 4 (ApoE4) genotype and in those who do not.
The study involving ApoE4 carriers (Study 302) failed to meet co-primary clinical endpoints of change in cognitive and functional performance compared with placebo; topline results were released July 23.
The phase 3 trial of those without the ApoE4 genotype included some 1300 patients, and the study of carriers included about 1100 subjects. The co-primary clinical endpoints for both studies were the change in the AD Assessment Scale–Cognitive Subscale (ADAS-Cog) and in the Disability Assessment for Dementia (DAD).
These studies were led by Janssen Alzheimer Immunotherapy R&D LLC (Janssen AI), a partner with Pfizer Inc in the Alzheimer’s Immunotherapy Program (AIP). Based on results of these trials, the Janssen AI and Pfizer Joint Steering Committee for the AIP “has decided to discontinue all other bapineuzumab IV studies in patients with mild-to-moderate Alzheimer’s disease,” the statement said.
These clinical findings and the decision to discontinue the other trials have, “been shared with regulatory authorities and study investigators.” No new safety signals were seen in these trials, the statement notes.
Pfizer was conducting 2 additional phase 3 trials, primarily outside of North America, that also enrolled patients with mild to moderate AD with and without the ApoE4 risk allele. The statement notes that all patients in the discontinued studies will undergo a follow-up evaluation, and final data analyses will be conducted.
Data from both phase 3 trials are expected to be presented in September at the European Federation of Neurological Societies (EFNS) meeting in Stockholm.
The decision to pull the plug on this research came as no surprise to some experts in the field, some of whom maintain that the intervention was introduced too late in the disease process to make a difference.
Sam Gandy, MD, PhD, director of the Mount Sinai Center for Cognitive Health, Mount Sinai chair in Alzheimer’s disease research, and professor of neurology and psychiatry at Mount Sinai School of Medicine in New York City, is one of these. He told Medscape Medical News that he was not surprised by the news that the trials were being disbanded; however, he was not discouraged by it.
He pointed to one potential new strategy for addressing AD — lowering amyloid-beta. This development arises from the recent discovery by a team of researchers in Iceland of an amyloid precursor protein (APP) mutation that may protect against AD. He noted mounting evidence of the importance of physical exercise and social engagement in preserving cognition — and even reversing the effects of ApoE4 in the case of social engagement.
Understanding how these interventions affect the brain at the molecular level is an important new research direction, said Dr. Gandy.
Dr. Gandy says he feels “more optimistic than ever” that scientists eventually will find a way to lower amyloid-beta to preserve cognition throughout one’s entire life. “I think that controlling one’s amyloid-beta is likely to be a lifelong endeavor, just like controlling one’s cholesterol.”
Reisa Sperling, MD, professor of neurology at Harvard Medical School, and director of the Center for Alzheimer Research and Treatment, at Brigham and Women’s Hospital, in Boston, Massachusetts, was lead investigator in the study involving ApoE4 carriers and served as a member of the steering committee for the study of noncarriers.
When topline results of the study in ApoE carriers were released in July, Dr. Sperling told Medscape Medical News that the lack of clinical efficacy perhaps was not surprising, “given the significant pathology by this stage of the disease in this genetic risk group.”
She said she hoped to see “at least a signal” of clinical effect in the noncarrier study, but “ultimately, I suspect we will have to treat Alzheimer’s disease at least 5 to 10 years earlier in the disease process to really affect the clinical course.”
Brendon Boot, MD, a neurologist at the Center for Alzheimer’s Research and Treatment at Brigham and Women’s Hospital, pointed out that results of these trials will be disappointing for patients living with AD and their families. However, he said that he and others in the field believe that there is still hope for successful treatment of the disease.
“It may be that these treatments are biologically active, but that we need to begin treatment earlier — possibly even before cognitive symptoms begin,” he told Medscape Medical News.
A large consortium of academic units is working on such a plan “as we speak,” said Dr. Boot.
In the press release, Steven J. Romano, MD, senior vice president and head of the Medicines Development Group, in the Global Primary Care Business Unit at Pfizer Inc, said that he and others are “obviously very disappointed” in the outcome of the research.
“We are also saddened by the lost opportunity to provide a meaningful advance for patients afflicted with mild to moderate Alzheimer’s disease and their caregivers,” he said. “Yet these data and the subgroup and biomarker analyses under way will further inform our understanding of this complex disease and advance research in this field.”