September 19, 2012 — Following disappointing initial results of trials investigating intravenous bapineuzumab, a monoclonal antibody that targets beta-amyloid, more recent biomarker analyses have provided some reason for optimism, at least for some experts.
Results of biomarker substudies included in the bapineuzumab trials showed significant differences in the amount of amyloid in the brain and phospho-tau in cerebrospinal fluid between patients with Alzheimer's disease (AD) carrying the apolipoprotein E ε4 (APOE4) genotype who received bapineuzumab and those taking placebo.
"We are encouraged that there was evidence of target engagement, and evidence of an effect on secondary markers of neurodegeneration," one of the study investigators, Stephen Salloway, MD, director of Neurology and the Memory and Aging Program, Butler Hospital, professor of neurology and psychiatry, Brown University, Providence, Rhode Island, told Medscape Medical News.
"I think we should seriously consider bapineuzumab and other drugs like it that can be used earlier in preclinical AD or in mild cognitive impairment (MCI) stages, which may produce more of a clinical benefit."
Full results of the bapineuzumab phase 3 trials, along with the biomarker subanalyses, were presented at the 16th Congress of the European Federation of Neurological Societies meeting in Stockholm, Sweden.
Trials Failed to Meet Endpoints
Results of 2 large phase 3 randomized, double-blind trials of bapineuzumab (Johnson & Johnson and Pfizer Inc.) in patients with mild to moderate AD showed that the treatment failed to meet co-primary clinical endpoints of change in cognitive and functional performance compared with placebo in APOE4 carriers and noncarriers, respectively.
In the wake of those results, it was announced earlier this year that this research investigating the agent would be stopped in patients with mild to moderate AD.
Subsequently, topline results of 2 phase 3 trials showed that a similar drug from Eli Lilly & Co., solanezumab, also failed to improve cognition and memory among patients with mild to moderate AD. Subanalysis of those data suggested a slowing of cognitive decline in mild but not moderate disease, the company reported. Full results of those trials will be presented at the American Neurological Association's annual meeting in Boston next month.
The phase 3 study that included APOE4 carriers randomly assigned 1121 patients with mild to moderate AD to receive bapineuzumab (0.5 mg/kg) or placebo by intravenous infusion.
The new biomarker analysis with bapineuzumab shows that in carriers, there was a "clear difference" in the amount of amyloid deposition seen on contrast positron emission tomography (PET) at the end of the trial in those treated with the drug compared with those who weren't treated, said Dr. Salloway.
"Patients who got the treatment seemed to stay the same so there was no increase or decrease from baseline, and in the placebo group, there was an increase in the amount of amyloid," he noted.
Also in carriers, there was a clear decrease in the amount of phospho-tau, a marker for neural degeneration, in the cerebrospinal fluid of patients in the treated group, while the untreated group "pretty much stayed the same," amounting to a significant difference between the 2 groups, said Dr. Salloway.
As for brain volume, measured by magnetic resonance imaging, the new analysis showed similar volume loss among patients receiving the drug and those receiving placebo.
The noncarrier study, also presented at the meeting, randomly assigned 1331 patients with mild to moderate AD to receive bapineuzumab (0.5 mg/kg or 1.0 mg/kg) or placebo. In both studies, the participants were followed for 78 weeks.
In contrast to the carrier study, biomarker analyses in the noncarrier study showed no significant differences between groups when doses were combined, although there was some decrease in the amount of amyloid deposition on PET at the highest dose, said Dr. Salloway. However, the follow-up study may have been too small to show much of an effect.
In this noncarrier group, some 36% of participants did not meet the cutoff for being positive on amyloid PET scan, said Dr. Salloway. "Either it's a measurement issue — and we will re-evaluate the measurements — or these subjects just didn't have that much amyloid."
This is an important finding, he stressed, because "going forward we're recommending that amyloid cutoffs be used to make sure that we include people who have amyloid pathology in clinical trials."
In the noncarriers, there was a nonsignificant reduction in phospho-tau compared with placebo when the doses were combined.
"But when we looked at each dose, there was a significant reduction in the higher dose suggesting that, especially in noncarriers, you need a higher dose to get the disease-modifying effect," said Dr. Salloway, although he pointed out that the higher dose was associated with more side effects. "One thing that came out of these data is that dose may matter."
William Thies, PhD, chief medical and scientific officer, Alzheimer's Association, said that in light of the new findings, administering antiamyloid therapies earlier in the continuum of AD, such as in people with MCI "deserves to be tested." The new results will benefit the research community and contribute to the planning of future clinical trials, said Dr. Thies.
Although progress in the field of AD research is incremental and can be slowed by setbacks along the way, "we learn more about Alzheimer's from every study," he said. "The Alzheimer's Association encourages the companies — and all clinical trial sponsors — to share the data from their trials as widely as possible, for the benefit of the entire field."
Dr. Thies stressed that his association remains "unwaveringly committed" to finding better therapies for AD. "Scientists need the resources to vigorously pursue this and other therapeutic targets, and to discover additional therapeutic targets."
The new biomarker results can be interpreted in different ways, depending on one's preconceived notions about the amyloid cascade hypothesis, said Ron Petersen, MD, PhD, director of the Mayo Alzheimer's Disease Research Center, Rochester, Minnesota. To an adherent of this philosophy, he says, the findings demonstrate that the antibodies reached and removed amyloid in the brain, as shown on the PET scans, and that there was less of a downstream effect from amyloid deposition as seen from measures of phospho-tau in the cerebral spinal fluid.
"If you're a believer in this hypothesis, then these results would say, yes that's what's supposed to happen; it's all very reasonable and interpretable, but there was no clinical effect and therefore we just jumped into the cascade, jumped into the clinical progression, too late."
From a scientific standpoint, the evidence that the amyloid process can be altered "is reasonably strong and compelling and enticing," and the weight of that evidence is sufficient to warrant investigations at earlier stages, said Dr. Petersen. However, he added, even if drugs could affect amyloid earlier in the cascade process, they wouldn't completely wipe out AD.
"Amyloid is probably an important component, and an extremely important component in young onset disease, in the truly familial form, but it's not the be all and end all," he said.
While scientifically the evidence argues for earlier interventions, the economics of funding such additional research using this monoclonal antibody is an issue to be embraced by shareholders of companies sponsoring such research, said Dr. Petersen.
Dr. Salloway noted that there are already 3 different compounds being tested in earlier stages of dementia, including Roche's gantenerumab.
"The bottom line is that the field is in transition; we're moving toward earlier stage treatment which is very consistent with what we do with other chronic diseases like heart disease and cancer where we believe that intervention early on is going to have biggest impact on disease course," he said. "We have to test that first, but I guarantee that we will find treatment that will be used early that will modify the course of this disease."
Dr. Salloway added that he's confident that there will eventually be combination therapies for different stages of AD that could include 1 or more antiamyloid drugs, agents with other targets such as tau, and perhaps other neuroprotective drugs.
Meanwhile, to skeptics of the amyloid hypothesis, the new results provide no hard evidence that even if amyloid were to be successfully removed, there would be any clinical effect, said Dr. Petersen. Some maintain that the biomarker findings were not that strong and, given that the amyloid theory has not been proven, resources may be better spent on pursuing other lines of research.
"Setbacks to Stepping Stones"
Late last week, the Pharmaceutical Research and Manufacturers of America (PhRMA) released 2 new reports looking at drug development in the Alzheimer's field, and specifically at the ratio of drug successes to failures.
The first report, "Alzheimer's Research" Setbacks and Stepping Stones," points out that between 1998 and 2011, 101 treatments have been investigated but failed to ultimately reach patients, whereas 3 have been approved over the same period for the symptomatic treatment of AD, a ratio of failure to success of 34 to 1.
"Setbacks in Alzheimer's research are disappointing to many, including the scientists carrying out the studies, but these unsuccessful attempts are critical stepping stones to advancing understanding of this extremely complex disease," PhRMA president and CEO John J. Castellani said in a statement.
"The reality is that so-called failures in the development of new drugs for Alzheimer's are helping redirect research — providing new information that allows science to move forward."
A second report, "Medicines in Development for Alzheimer's Disease," notes that biopharmaceutical companies are currently investigating or developing 93 new drugs for patients with Alzheimer's or other dementias, including gene therapy and vaccines.
"For this critical innovative work to continue and to help curb the costly impact of this disease on our healthcare system, policymakers must support policies that foster medical advancements for patients and value innovative engines of growth such as the biopharmaceutical sector," Castellani concluded.
Dr. Salloway chaired the investigator Steering Committee for the Janssen AI phase 3 bapineuzumab program and was a site investigator. He also consults for Janssen, Pfizer, and Elan. He reports he owns no stock or equity interest in any pharmaceutical company and no patent or royalty rights related to any compound. Dr. Thies has disclosed no relevant financial relationships. Dr. Petersen reports no conflicts with regard to the bapineuzumab therapies but chairs the Data Monitoring Committee for another Pfizer immunotherapy trial of active immunization, ACC-001.
16th Congress of the European Federation of Neurological Societies. Abstract SC312. Presented September 11, 2012.
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Cite this: Hope for Bapineuzumab in Alzheimer's? - Medscape - Sep 19, 2012.