Although the phase 3 trials of the antiamyloid therapies bapineuzumab (Pfizer Inc, Johnson & Johnson) and solanezumab (Eli Lilly) failed to meet their respective primary endpoints in patients with mild to moderate Alzheimer's disease (AD), the new research nevertheless adds important information in the search for a successful treatment for this debilitating and increasingly prevalent disorder, according to study authors.
"We always want to get a home run, especially for a bad disease like Alzheimer's disease, but you have to learn as much as you can and there are a lot of things we got out of these studies that we are incorporating into new trials," said lead author of the bapineuzumab study, Stephen Salloway, MD, professor, neurology and psychiatry, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
Results from the humanized monoclonal trials, reported previously at medical meetings, are now published in the January 23 issue of the New England Journal of Medicine (NEJM).
Both antibodies target β-amyloid (Aβ). Bapineuzumab targets both soluble and aggregated Aβ species, while solanezumab recognizes soluble but not plaque Aβ.
Although the results of the randomized, double-blind, placebo-controlled bapineuzumab and solanezumab trials were ultimately disappointing, they reinforce the message that amyloid accumulation likely starts many years before the onset of symptoms and raise the question of whether using modified versions of these monoclonal antibodies, or combining them with other drugs, such as anti-tau agents now being developed, might be the best treatment approach going forward, said Dr. Salloway.
As well, researchers now know that patients with AD tolerate this type of intravenous medication very well and that the drugs in some ways do hit their intended target, he said.
For example, an analysis of apolipoprotein E (APOE) 4 carriers found a decreased rate of accumulation of amyloid in the brain in a subset of patients taking bapineuzumab who had positron emission tomography (PET) imaging using Pittsburgh compound B, although the difference was smaller than that seen in phase 2 studies using a higher dose of the drug. And, among carriers, bapineuzumab was associated with reduced concentrations of cerebrospinal fluid (CSF) phospho-tau, a marker of neurodegeneration.
"We were getting some target engagement and that's encouraging," said Dr. Salloway. "But we were limited in our ability to lower amyloid because of the dose-related side effects."
Amyloid-Related Side Effects
He was referring to differences in the incidence of amyloid-related imaging abnormalities with edema — and in potential efficacy — that were found between APOE 4 carriers and noncarriers in the phase 2 study that had prompted researchers to conduct 2 separate phase 3 trials of bapineuzumab. One trial involved carriers (getting a dose of 0.5 mg per kg of the drug or placebo) and the other noncarriers (receiving 0.5 or 1.0 mg/kg of the drug or placebo). The higher dose of 2 mg/kg used in earlier trials was eliminated from the phase 3 trials.
It's not clear what caused the adverse effects, but it could be that whereas bapineuzumab stimulates cells to remove amyloid plaque from the brain, it also binds to amyloid in the vasculature, which may weaken the vessel walls or cause "leakiness."
Despite some signals of target engagement, the bapineuzumab study overall showed no significant group differences from baseline to week 78 with respect to the co-primary outcomes.
In the carrier study, the mean difference from placebo on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11) total score was –0.2 (95% confidence interval [CI], –1.4 to 1.0; P = .80; higher scores indicate greater cognitive impairment). The mean difference in Disability Assessment for Dementia (DAD) total score was –1.2 (95% CI, –3.8 to 1.3; P = .34; higher scores indicate less impairment).
In the noncarrier study, the mean difference in ADAS-cog11 score was –0.3 (95% CI, –1.8 to 1.1; P = .64) and the mean difference in DAD score was 2.8 (95% CI, –0.2 to 5.8; P = .07).
The annual rate of brain volume loss did not significantly differ between the treatment and placebo groups in either carriers or noncarriers.
Although investigation on bapineuzumab is not going forward for patients with AD, it's possible that this drug, or a modified version, would have better success in patients with a milder form of the disease, said Dr. Salloway. "One take-away from these 2 trials is that we should be using these drugs earlier. We can now use amyloid PET scans and see who's building up amyloid even before there are any symptoms."
The other monoclonal antibody — solanezumab, which was tested at a dose of 400 mg in 2 phase 3 studies, EXPEDITION 1 and EXPEDITION 2 — appeared to have more success in providing cognitive benefit for patients with milder disease.
"We found that in each study, there were some positive statistically significant values or trends on either cognition or function, and we found that there was a certain consistency across these studies," said lead author of the solanezumab paper, Rachelle S. Doody, MD, PhD, professor, neurology, Baylor College of Medicine, Houston, Texas.
For example, in patients with mild AD in the 80-week EXPEDITION 2 study, the between-group difference in the ADAS-cog14 (the subscale that is a better measure of cognitive change in patients with mild AD) score was –1.7 points (95% CI, –3.5 to 0.1; P = .06), with a significant difference favoring solanezumab at week 64.
Also in EXPEDITION 2, there was a significant treatment effect on the change in the AD Cooperative Study–Activities of Daily Living (ADCS-ADL) score in patients with mild AD, with a difference between groups of 2.3 points (95% CI, 0.2 - 4.4; P = .04) at week 80 (with lower scores indicating worse functioning.)
"The totality of the analysis suggests that the therapy should be explored earlier," Dr. Doody told Medscape Medical News. "We did get indicators that this may work in milder patients."
As with bapineuzumab, though, the analysis failed to show clinical benefit overall.
In EXPEDITION 1, the mean difference between groups in the change from baseline to week 80 was –0.8 points for the ADAS-cog11 score (95% CI, –2.1 to 0.5; P = .24) and –0.4 for the ADCS-ADL score (95% CI, –2.3 to 1.4; P = .64).
In EXPEDITION 2, the mean between-group difference was –1.3 points for the ADAS-cog11 score (95% CI, –2.5 to 0.3; P = .06) and 1.6 points for the ADCS-ADL score (95% CI, –0.2 to 3.3; P = .08).
Because it does not directly target fibrillar amyloid plaques, solanezumab was associated with relatively little of the amyloid-related edema or hemorrhage that was so evident with the bapineuzumab studies. "Solanezumab was quite remarkably well tolerated when it came to those brain changes; there were very, very few of them, probably not more significant than placebo," said Dr. Doody.
Its relative safety, as well as its signals for efficacy in patients with mild AD, might be the reason solanezumab was chosen for an upcoming National Institutes of Health–sponsored prevention trial.
The multisite Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) trial will test solanezumab, another anti-Aβ antibody (gantenerumab, Roche), and a third, as yet undetermined, drug, in patients who have an inherited form of AD and a positive PET scan but who don't have symptoms or are in the earliest stages of the disorder.
Other prevention trials are in the works, too. One involving genetically at-risk participants using Genentech's antibody crenezumab has begun in Colombia, and others are being carried out in the normal population, including one testing low doses of the oral diabetes drug pioglitazone, said Dr. Doody.
"This all goes to show that we have entered the era of prevention studies and that it's reasonable to take the monoclonals and move them early, but this is all in context of many other studies with different mechanisms of action that may benefit Alzheimer's disease," she said.
However, it's likely that any results from these prevention trials will not be available for another 4 or 5 years.
In the current studies, solanezumab did not have treatment effects on hippocampal or total brain volumes or on amyloid accumulation, as seen on PET scans, which is consistent with its not targeting fibrillar amyloid. Also consistent with its targeting soluble brain amyloid were "large, sustained increases" of Aβ in plasma, the authors write.
The drug was also linked to changes in CSF levels of Aβ — decreased levels of free (unbound) Aβ40 and increased levels of total (bound and unbound) Aβ40 and Aβ42 in patients receiving solanezumab, which suggests some transfer of Aβ to the periphery, they note.
In addition to starting antiamyloid treatment earlier in the disease, another take-home message from these trials, said Dr. Salloway, is that a single treatment isn't going to cut it when it comes to getting a robust response.
He suggested that combining a monoclonal antibody such as solanezumab or bapineuzumab with another drug that decreases deposits of amyloid, for example, a β-secretase inhibitor, which targets an earlier step on the amyloid pathway, might have superior results. Combining antiamyloid therapies with drugs that target tau might also provide more benefit, he said.
These approaches will require a paradigm shift in the way drugs are developed, as well as more cooperation among drug companies carrying out trials of prospective therapies, said Dr. Salloway.
"One company may have a β-secretase inhibitor and another may have a monoclonal antibody and another company may have a tau drug, so they will have to work together and share information," he said.
Such a multipronged approach is standard in other areas of medicine, he added. "In heart disease and cancer and HIV, we combine drugs with multiple targets to get the biggest effect, and I think we will have to do the same in Alzheimer's disease, which is a complex disease and difficult to treat."
Already, plans are underway to create the research "infrastructure" for testing a combination approach in AD, said Dr. Salloway.
One proposal for future studies is to ensure that they include only patients with documented amyloid. The studies published in NEJM only tested for the presence of amyloid using PET scans in a subset of patients. Together, the results showed that about 20% of the patients didn't meet the cutoff for being amyloid positive, and most of these participants probably didn't have AD, said Dr. Salloway.
"These patients were not building up amyloid," he said. "It just makes sense that in a future trial you would not want to include patients who don't have amyloid in an amyloid-based treatment."
That message is apparently being heard. Another study of solanezumab — EXPEDITION 3 — is rolling out in patients with mild AD who must have positive results on PET amyloid imaging to be enrolled. The co-primary outcome measures for this study are the changes in scores on the ADAS cog-14 and ADCS-ADL scales.
Dr. Salloway wanted to emphasize that despite some setbacks, there's a palpable sense of momentum building among AD investigators as 2025 — the target year for finding a successful AD treatment — fast approaches. "There is a sense of optimism among researchers and they will work as hard as they can to meet that 2025 goal," he said.
Authors of an accompanying editorial in the same issue of NEJM agreed that the antibody studies provide useful data, but they also question the interpretation placed on some biomarkers, especially the CSF level of phospho-tau, and also brain volume.
"If elevated CSF levels of phospho-tau and changes in brain volume are mediated through multiple mechanisms, including as a response to plaque deposition, then the lack of a treatment effect is not so surprising," write Eric Kerran, PhD, and John Hardy, PhD, Department of Molecular Neuroscience, University College London, United Kingdom.
"Possibly, in mild Alzheimer's disease, solanezumab reduces the process of ongoing Aβ aggregation, and it is this — rather than the presence of plaques — that triggers downstream pathologic processes that later become Aβ-independent."
The editorialists conclude that they "advocate continuing to investigate ways to modulate Aβ levels in the brain," while accepting that they "lack clarity on the roles that different forms of Aβ play in the disease."
The bapineuzumab trial was supported by Janssen Alzheimer Immunotherapy Research and Development and Pfizer. The solanezumab trial was supported by Eli Lilly. Dr. Salloway chaired the investigator steering committee for the bapineuzumab trials and consults for Lilly (<$5000); his hospital receives research support for clinical trials of solanezumab and other AD treatments and biomarkers. Dr. Doody reports paid consultancy relationships with and grants from several companies, not including Eli Lilly. Disclosures for all investigators are available at www.nejm.org. Dr. Hardy reports personal fees from Eli Lilly and Esai outside the submitted work. Dr. Karren has disclosed no relevant financial relationships.
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Cite this: The Good News on Antiamyloid Alzheimer's Therapies - Medscape - Jan 22, 2014.