Pfizer Inc has announced topline results of a phase 3 trial of bapineuzumab showing treatment failed to meet the co-primary endpoint of change in cognitive or functional performance versus placebo in patients with mild to moderate Alzheimer’s disease (AD) who are positive for the apolipoprotein E4 (ApoE4) risk allele.
Bapineuzumab is an investigational monoclonal antibody that targets amyloid-ß (Aß) under development by the Alzheimer’s Immunotherapy Program (AIP), a partnership between Janssen Alzheimer Immunotherapy R&D LLC (Janssen AI) and Pfizer Inc.
“These clinical findings have been shared with regulatory authorities and study investigators so that participants in the ongoing clinical program can be informed,” a statement from the companies notes. “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 that 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.”
The findings would appear to mirror phase 2 study results with bapineuzumab that had missed the same primary endpoints but showed a suggestion of benefit only in ApoE4 noncarriers.
“The lack of clinical efficacy in the ApoE4 carriers at the stage of dementia is very disappointing, but perhaps not surprising, given the significant pathology by this stage of the disease in this genetic risk group,” Reisa Sperling, MD, professor of neurology at Harvard Medical School, and director, Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital, in Boston, Massachusetts, told Medscape Medical News. Dr. Sperling was lead investigator on the study.
She said they hope to see “at least a signal” of clinical effect in the noncarrier study, on which she is also a member of the steering committee, “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.”
Dr. Sperling pointed out that it will be important to investigate biomarker data from the trial, including positron emission tomography (PET) imaging and cerebrospinal fluid markers, to better understand the biological effects of treatment in both carriers and noncarriers. “We plan to present these data in early September,” she noted.
Topline results of a second trial, Study 301 in noncarriers, are expected later this summer, the Pfizer statement notes, adding that both Study 302 and Study 301 have been accepted as late breakers for presentation at the upcoming European Federation of Neurological Societies meeting in Stockholm, Sweden, in September. The AIP plans to expedite completion of the interim analysis of Study 3001 in ApoE4 carriers based on results of the current study.
This phase 3 trial, called Study 302, is one of 4 studies examining the efficacy of bapineuzumab in AD. Janssen AI is leading Study 302 in ApoE4 carriers, as well as Study 301 in noncarriers, with AD. Pfizer is conducting 2 additional phase 3 trials, primarily outside of North America, also enrolling patients with mild to moderate AD who are ApoE4 noncarriers (Study 3000) and carriers (Study 3001).
“Based on a comprehensive review of the data by the independent safety monitoring committee, all the other ongoing Janssen AI and Pfizer bapineuzumab studies are continuing as planned and without modifications,” the statement notes.
Study 302 included 1100 patients with the ApoE4 risk allele. The co-primary endpoints were change in the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) and in the Disability Assessment for Dementia (DAD). No data were released at this time, but the treatment did not meet either endpoint.
The most common adverse events that occurred with higher frequency with treatment than with placebo at an incidence of at least 1% were amyloid-related imaging abnormalities suggestive of edema or effusion (ARIA-E) on magnetic resonance imaging — an effect that has been a concern with bapineuzumab in the past — and dehydration.
Aß Hypothesis
Passive or active immunotherapy against Aß is one of the major strategies being evaluated as a disease-modifying therapy for AD, and several other companies have immunotherapies in phase 2 and 3 investigation. The hope is to bind and clear amyloid from the brain, but the question has begun to arise of whether Aß is the real culprit in the disease process.
To date, amyloid-clearing therapies have not been able to stop cognitive or functional decline associated with the disease, despite evidence that they are successfully clearing amyloid. Many speculate that treatment is coming too late in the process, once cognitive and functional symptoms appear.
Earlier detection of Aß deposition using PET tracer agents that have recently been approved or that are in late stages of development may provide an opportunity to remove amyloid before symptoms appear, researchers suggest.
Dr. Sperling was head of the writing committee that recently published a new guideline proposing diagnostic criteria for a preclinical stage of Alzheimer’s disease. They are considering the possibility of using bapineuzumab in a large prevention trial that is now being planned in those with early, preclinical disease, Dr. Sperling noted.
Progress ‘Incremental’
In a statement, the Alzheimer’s Association noted that the results are disappointing, but not surprising.
“While we have high hopes for every Alzheimer’s and dementia therapy trial, history shows that progress is incremental and we will have setbacks along the way. These setbacks also provide critical information to the research community for application in future studies,” the statement notes. “The Alzheimer’s Association is not surprised by these newly announced results based on reports from earlier studies in carriers of the ApoE4 Alzheimer’s risk gene.
“While not the overall positive results we would all hope for, a positive finding is that the side effects profile appears to be manageable based on the data currently released,” the Association statement adds. “This gives us hope for the potential usability of drugs of this type (immunotherapies that target a protein called beta amyloid in the brain) in future studies.”
Trials of several Alzheimer’s drugs with varied mechanisms of action have shown differing results in carriers versus noncarriers, they add, and “this may also be the case with bapineuzumab. We learn more about Alzheimer’s disease from every study, and results from additional phase 3 studies of this drug, in an additional population of people who carry the ApoE4 gene as well as people who do not carry the gene, are expected soon.”
The Association “remains unwaveringly committed to finding better therapies and prevention for Alzheimer’s disease and related disorders as well as providing 24/7 support for people and families facing Alzheimer’s disease today.
“We are eager for the launch of upcoming Alzheimer’s disease prevention trials, which were featured at the just-concluded Alzheimer’s Association International Conference (AAIC), and also about how the field will benefit from projects such as the worldwide Alzheimer Disease Neuroimaging Initiative, which now includes whole genome sequencing for all participants, and the International Genomics of Alzheimer’s Project,” the statement concludes. (Susan Jeffrey)