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.

Not Surprising

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.

More Optimistic

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.”

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)