Researchers at Washington University School of Medicine in St. Louis, working with mice, discovered an antibody that removes amyloid plaques from brain tissue and blood vessels while not increasing the risk of brain bleeds.
Researchers at Washington University School of Medicine in St. Louis, working with mice, discovered an antibody that removes amyloid plaques from brain tissue and blood vessels while not increasing the risk of brain bleeds. Beta-amyloid is a type of amyloid plaque associated with Alzheimer’s disease. It accumulates in the brain of Alzheimer’s patients. They also form around brain blood vessels in aging people, called cerebral amyloid angiopathy, and increase the risk of stroke. They published their research in the journal Science Translational Medicine.
The single strongest genetic risk factor for late-onset Alzheimer’s disease is the E4 allele of the apolipoprotien E (APO3). This allele influences the development of beta-amyloid pathology.
The researchers studied the potential therapeutic effects of the anti-human APOE antibody HAE-4, which targets human APOE that is deposited along with beta-amyloid in cerebral amyloid angiopathy (CAA) and parenchymal amyloid pathology. They also evaluated if HAE-4 increased the risk of brain hemorrhages, a component of amyloid-related imaging abnormalities (ARIA). ARIA is an adverse effect secondary to treatment with anti-beta-amyloid antibodies that can show up in blood vessels with CAA.
The research team used 5XFAD mice that expressed human APOE4+/+ with significant CAA and parenchymal plaque pathology.
“Alzheimer’s researchers have been searching for decades for therapies that reduce amyloid in the brain, and now that we have some promising candidates, we find that there’s this complication,” said David Holtzman, the Andrew B. and Gretchen P. Jones Professor, head of the Department of Neurology, and senior author of the study.
Holtzman went on to say, “Each of the antibodies that removes amyloid plaques in clinical trials is a little different, but they all have this problem, to a greater or lesser degree. We’ve taken a different approach by targeting APOE, and it seems to be effective at removing amyloid from both the brain tissue and the blood vessels, while avoiding this potentially dangerous side effect.”
Generally, the clinical trials of antibodies against beta-amyloid have been failures. At the moment, the big question is Biogen’s aducanumab, an anti-amyloid antibody.
Earlier this year, the U.S. Food and Drug Administration (FDA) extended the review period for Biogen and Eisai Co.’s Biologic License Application (BLA) for aducanumab for Alzheimer’s disease. The drug has been fraught with controversy—and unexpected hopes. The decision by the FDA on the drug application was expected on March 7, but is now delayed until June 7, 2021.
In March 2019, Biogen and Tokyo-based Eisai, announced they were discontinuing the global Phase III clinical trials, ENGAGE and EMERGE, of aducanumab in patients with mild cognitive impairment for Alzheimer’s and mild Alzheimer’s dementia. They were also discontinuing the EVOLVE Phase II trial and the long-term extension PRIME Phase Ib trial. An independent data monitoring committee indicated they were unlikely to hit their primary endpoint.
It appeared to be the final nail in the amyloid theory of Alzheimer’s disease. Aducanumab is an antibody targeting beta-amyloid, one of the proteins that accumulates in the brains of Alzheimer’s patients.
But in October 2019, the two companies announced plans to pursue regulatory approval for the drug. It turned out, the Phase III EMERGE trial met its primary endpoint, showing a significant decrease in clinical decline. Biogen presented the findings in the final data analysis in a December conference, and although there was still some skepticism about the overall data, it did appear to be enough to file for a BLA and the company planned to do so in the second quarter of 2020.
What they presented was that the Phase III EMERGE trial met its primary endpoint, showing a significant decrease in clinical decline. Biogen said the data from a subset of patients that received a high enough dose of the drug had significant benefits on measures of cognition and function, including memory, orientation, and language, as well as benefits on activities of daily living.
Although many had issues with some of the data, which was very complex, the companies felt they had a strong enough case to submit it to the FDA and were expected to do so this spring.
Then, in April 2020, they announced that although the company had begun to submit parts of the BLA, they did not expect to complete it until the third quarter of this year.
The submission was completed in August 2020 with ongoing collaboration with the FDA and include data from the Phase III EMERGE and ENGAGE trials, as well as the Phase Ib PRIME study. Biogen had also requested Priority Review.
In November 2020, the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee slammed the drug submission, voting 1 yes, 8 no and 2 uncertain on the question, “Does Study 302 (EMERGE), viewed independently and without regard for Study 301 (ENGAGE), provide strong evidence that supports the effectiveness of aducanumab for the treatment of Alzheimer’s disease?” It also voted 0 yes, 7 no and 4 uncertain on whether Study 103 (PRIME) supported the effectiveness of the drug. Again and again, the committee voted against the drug.
Although the FDA isn’t obligated to follow the recommendation of their advisory committees, they usually do.
Not everyone is as skeptical.
“There were clear cognitive benefits on a number of end point measures, which [is] unprecedented in a Phase III Alzheimer disease trial, and furthermore, there was a very clear indication of target engagements, as measured by a dose-dependent reduction in amyloid plaques on amyloid PET,” said Thomas Wisniewski, professor of neurology, and director, Pearl I. Barlow Center for Memory Evaluation and Treatment, who was not associated with the studies, told NeurologyLive. He added that the potential of the drug was “game-changing” and even though the effect size was not large, “it does look like it’s disease-modifying and of cognitive benefit.”
Apparently the newest delay is related to the FDA requesting additional analyses and clinical data. Biogen complied, and the FDA considered it a Major Amendment to the application, thus requiring additional review time.
