Pfizer has announced the co-primary clinical endpoints—change in cognitive and functional performance compared to placebo—were not met in the Janssen Alzheimer Immunotherapy R&D (Janssen AI)-led phase III trial of intravenous (IV) bapineuzumab in patients with mild-to-moderate Alzheimer's disease who carry the ApoE4 (apolipoprotein E epsilon 4) genotype (Study 302). Pfizer and Janssen AI are partners in the Alzheimer's Immunotherapy Program (AIP).
These clinical findings have been shared with regulatory authorities and study investigators so participants in the ongoing clinical program can be informed. Because in this study clinical efficacy was not demonstrated in ApoE4 carriers, the Janssen AI and Pfizer Joint Steering Committee for the AIP has decided participants from this study who enrolled in a follow-on extension study will no longer receive doses of bapineuzumab. However, these patients will have a follow-up evaluation.
Based on a comprehensive review of the data by the independent safety monitoring committee, all other ongoing Janssen AI and Pfizer bapineuzumab studies are continuing as planned and without modifications.
Study 302 is the first of four placebo-controlled phase III studies to complete in the comprehensive development program of bapineuzumab IV. Janssen AI is leading two phase III studies of patients who are ApoE4 carriers (Study 302) and non-carriers (Study 301) at sites primarily in North America. Pfizer is conducting two phase III studies of patients who are ApoE4 carriers (Study 3001) and non-carriers (Study 3000) at sites primarily outside of North America.
The alliance will expedite the completion of an interim analysis for the ongoing, Pfizer-conducted phase III study of ApoE4 carriers (Study 3001) based on the results of Study 302.
The topline results from Study 301 in patients with mild-to-moderate Alzheimer's disease who do not carry the ApoE4 genotype are expected to be announced later this summer.
"While we are disappointed in the topline results of Study 302, a more complete understanding of bapineuzumab and its potential utility in mild-to-moderate Alzheimer's disease will be gained following the availability of additional data, including data from the soon-to-be available non-carrier Study 301," said Steven J. Romano, M.D., senior vice president and head of the medicines development group, global primary care business unit at Pfizer. "We recognize that Alzheimer's disease is very complex, but Pfizer, along with our partner Janssen AI, remains committed to advancing the science of Alzheimer's disease, with the ultimate goal of delivering innovative and meaningful new treatment options to patients."
Data from both the ApoE4 carrier (Study 302) and non-carrier (Study 301) studies have been accepted as a late-breaker and will be presented in September at the European Federation of Neurological Societies meeting in Stockholm.
The presence of the ApoE epsilon 4 genotype is a genetic risk factor for Alzheimer's disease and is associated with increased beta-amyloid plaques in the brains of patients with the disease. Topline results of Study 302 indicate that among patients treated with bapineuzumab IV the most commonly observed serious adverse events which occurred more commonly than placebo and with an incidence of at least 1% were ARIA-E and dehydration. ARIA-E (amyloid-related imaging abnormalities-edema or effusion) refers to changes in the brain that may be due to fluid (water and protein) leaking from blood vessels, which can be detected using magnetic resonance imaging (MRI) of the brain.
There are four placebo-controlled phase III studies in the bapineuzumab clinical development program. Janssen AI is leading two 18-month, phase III, multi-center, randomized, double-blind, placebo-controlled, parallel-group, efficacy and safety studies of patients who are ApoE4 carriers (Study 302) and Apoe4 non-carriers (Study 301). The two co-primary clinical endpoints are change in the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), a validated measure of cognition, and the Disability Assessment for Dementia (DAD), a validated instrument to measure function. Study 302 included approximately 1,100 patients who carry the ApoE4 genotype and Study 301 includes approximately 1,300 patients who do not carry the ApoE4 genotype.
In addition to the Janssen AI-led studies, Pfizer is conducting two primarily ex-North America 18-month, phase III, multi-center, randomized, double-blind, placebo-controlled, parallel-group, efficacy and safety studies of patients with mild-to-moderate Alzheimer's disease who are ApoE4 non-carriers (Study 3000) and carriers (Study 3001).
Bapineuzumab IV, an investigational therapy being studied for the treatment of mild-to-moderate Alzheimer's disease, is an antibody that targets beta-amyloid (AB), a protein that can exert toxic effects in the brain and is believed to play a central role in the pathology of Alzheimer's disease.
The Alzheimer's Immunotherapy Program of Janssen Alzheimer Immunotherapy and Pfizer is an equal collaboration committed to researching and developing selective products for the treatment and/or prevention of neurodegenerative conditions, including Alzheimer's disease.