Research Highlights from Padmaja Genesh September 2021
AlzeCure Gets Green Light for 3rd Phase 1 Study of ACD856
The study is designed to test multiple and increasing doses of the medication. The primary goal is to evaluate the tolerability and safety of ACD856 after repetitive dosing, as well as to determine early efficacy by looking at brain activity.
ACD856 is being developed to improve cognitive function by enhancing neurotrophin signaling in the brain. Neurotrophins are a group of proteins that regulate the development and maintenance of nerve cells, and their levels are impaired early in Alzheimer’s disease.
Preclinical studies have shown that ACD856 strengthens the communication between nerve cells and improves cognitive function, including memory. A first Phase 1 study of ACD856 showed positive results in terms of how the medication moves throughout the body. ACD856 also was found to be suitable for further clinical development as an oral medication for Alzheimer’s.
A second Phase 1 study with a single ascending dose also confirmed the therapy’s tolerability, safety, and good bioavailability, which means it is well-absorbed and used by the body.
The mechanism of action of these therapies may have other potential indications, including in depression and cognitive impairment in Parkinson’s disease, traumatic brain injury, and sleep disturbances.
Congress Asks FDA for More Information on Aduhelm Approval
Federal lawmakers are asking the U.S. Food and Drug Administration (FDA) to provide additional data and documents related to the agency’s controversial decision to grant accelerated approval to Biogen‘s Aduhelm (aducanumab) as a treatment for Alzheimer’s disease.
Aduhelm is an antibody-based therapy designed to clear amyloid-beta plaques- a hallmark of Alzheimer’s disease from the brain.
Early clinical trial data indicated that Aduhelm could effectively clear these plaques, leading Biogen to launch two Phase 3 clinical trials to test whether the therapy might affect cognition. One of these trials revealed that Aduhelm had significantly slowed the decline in cognition and function — namely in terms of memory, orientation, and language, as well as in activities of daily living, but that no such benefit was seen in the other trial.
Despite these inconsistent results, Biogen decided to seek FDA approval of Aduhelm in late 2019. An FDA advisory committee voted strongly against approving the medication in late 2020, saying that the available data were not enough to ensure the medicine’s efficacy.
Nonetheless, earlier this year, the FDA granted Aduhelm a conditional approval, requiring further studies to confirm efficacy.
In the 13-page letter to FDA, the members of Congress requested that the FDA answer 15 separate and multipart questions about the agency’s approval of Aduhelm. The deadline for providing the information to lawmakers is Sept. 16.
Omega-3 Supplements May Slow Memory Decline
Six months of daily supplements of omega-3 increased the levels of two biomarkers of inflammation and nerve damage in the cerebrospinal fluid (CSF) of people with Alzheimer’s disease, according to a post-hoc analysis of data from the OmegAD clinical trial.
Omega-3 is a polyunsaturated fatty acid, a type of healthy fat found in foods such as fatty fish (salmon, tuna, mackerel), walnuts, and some seeds. Omega-3 is key to cells’ structure and has been shown to help prevent heart disease.
Previous studies in animal models suggested that omega-3 supplementation may have beneficial effects in cognitive function and reduce the levels of beta-amyloid — the protein that forms toxic clumps in Alzheimer’s — in a mouse model of the disease.
While these preliminary findings suggest that omega-3 supplements may be associated with higher inflammation and nerve damage, previous OmegAD data showed that patients with very mild cognitive decline saw their memory stabilize over six months, while those not given omega-3 experienced memory decline.
Notably, no cognitive benefits were observed among patients with greater cognitive impairment, suggesting that omega-3’s benefits may be limited to people with early stage disease and milder cognitive problems.
Larger studies are needed to confirm these findings and clarify the therapeutic potential of omega-3 supplements in early stage Alzheimer’s.
NIH Funds 2 New Centers Joining Alzheimer’s Research Network
Research institutions in North Carolina and Texas have become the newest members of a national network of Alzheimer’s Disease Research Centers (ADRCs), which are at the forefront of research into Alzheimer’s and related dementias.
The ADRCs, a project funded by the National Institute on Aging (NIA), have “been at the heart of progress in Alzheimer’s and related dementias research in the U.S. for more than three decades,” Richard J. Hodes, MD, NIA director, said in a NIA press release.
The new ADRC research hubs are: the Duke/University of North Carolina Alzheimer’s Disease Research Center and the South Texas Alzheimer’s Disease Center, bringing the total number of ADRCs to 33 nationwide, plus four exploratory centers.
The two new centers were each granted $14.8 million over five years to focus on risk factors for Alzheimer’s and related dementias, and ways to reduce the burden of these disorders particularly in Mexican-American Hispanics and Black/African-Americans. These groups are understudied, and yet among the fastest-growing older populations in the U.S., according to NIA.
Semorinemab Slows Decline in Cognition, Top-line Results Show
Treatment with the investigational anti-tau monoclonal antibody Semorinemab significantly slowed decline in a measure of cognition among people with mild-to-moderate Alzheimer’s disease in the Phase 2 LAURIET clinical trial, top-line results show.
By binding to the tau protein, Semorinemab is designed to stop the tangles from forming and growing, thereby halting disease progression.
The LAURIET clinical trial (NCT03828747), sponsored by Genentech, enrolled 272 adults with mild-to-moderate Alzheimer’s at 43 study centers around the globe. Participants were randomly assigned to receive either Semorinemab or a placebo for 49 weeks, or about one year.
Top-line results showed that Semorinemab treatment significantly reduced the rate of decline in activities of daily living by 43.6% compared with the placebo.
However, the treatment did not significantly affect scores on the ADCS–ADL. Semorinemab treatment also did not significantly affect scores on two secondary measures of cognition, the Mini-Mental State Examination (MMSE) and the Clinical Dementia Rating–Sum of Boxes (CDR-SB).
Further analyses of the trial data are ongoing, according to the researchers.
Athira to Begin Open-label Extension Studies of ATH-1017
Both clinical trials — the Phase 2/3 LIFT-AD (NCT04488419) and Phase 2 ACT-AD (NCT04491006) — are investigating ATH-1017, a small molecule designed to enhance the effect of hepatocyte growth factor (HGF), and its receptor, MET. Both are expressed in the central nervous system.
HGF works on specific cell types via its receptor to promote cell growth, cell migration, and new blood vessel formation. The hope is that by enhancing the activity of this receptor pair, brain health and function will be improved.
In previous preclinical studies, ATH-1017 was well-tolerated in all tested doses and was able to regenerate nerve cells and improve cognitive function.
These two studies are evaluating the safety and efficacy of ATH-1017 in patients with mild-to-moderate Alzheimer’s disease.
The goal of the new open-label extension study (NCT04886063) is to determine the safety and tolerability of ATH-1017 in patients who completed 26 weeks of treatment in both of the studies. Researchers are hopeful this trial can provide additional, longer-term safety and tolerability information regarding ATH-1017 administration up to one year in this patient population.
Amyloid-beta Produced in the Liver May Play Role in Alzheimer’s
Amyloid-beta produced in peripheral organs, specifically the liver, may be implicated in the brain neurodegeneration observed in Alzheimer’s disease, according to a mouse study.
Deposits of amyloid-beta in the brain are a hallmark of Alzheimer’s. However, given that both the brain and liver produce amyloid-beta, it has been challenging for scientists to determine the source of amyloid-beta found in the brain of Alzheimer’s patients or animal models of the disease.
In humans, peripheral amyloid-beta from the liver travels through the blood as part of a complex with triglyceride-rich lipoproteins (TRLs), basically a way to transport fat-soluble particles through the bloodstream.
In this study, researchers genetically engineered mice to produce human amyloid-beta only in their livers, this way allowing them to detect whether the liver or the brain was the potential cause for the neurodegeneration.
These animals had significantly higher amounts of circulating amyloid-beta in their blood (roughly 30% more than healthy controls) and this circulating form of human amyloid-beta was complexed with TRLs, just as it does in humans.
Additionally, there was significantly more inflammation and more neurodegeneration in the brains of mice that produced human amyloid-beta versus healthy control mice.
These mice also showed increased inflammation in the blood vessels of the brain, in addition to increased dysfunction in those same blood vessels, all of which is commonly seen in Alzheimer’s. Moreover, mice with increased circulating levels of amyloid-beta were also more likely not to perform as well in learning tests where they were required to form new memories.
This study seems to show that peripherally-derived amyloid-beta, specifically from the liver, contributes toward the neurodegeneration and neuroinflammation seen in Alzheimer’s disease.
Virtual Mayo Clinic Conference on Brain Health Set for Oct. 29
People affected by Alzheimer’s disease and related dementias are invited to register for the Mayo Clinic Conference on Brain Health and Dementia, which also pays tribute to all that the community has been going through during the COVID-19 pandemic.
The conference coordinators are encouraging patients, caregivers, and all those interested in supporting those affected by Alzheimer’s or other related dementias to attend. Continuing education credits are available.
The program’s highlights include a presentation by Jason Karlawish, MD, author of “The Problem of Alzheimer’s: How Science, Culture and Politics Turned a Rare Disease Into a Crisis and What We Can Do About It” and Hopefest, a celebration of new programs to help improve the welfare of those affected by dementia. Experts from the Mayo Clinic, the University of Minnesota, AARP, and the Alzheimer’s Association will be discussing the latest research on Alzheimer’s, associated dementias, and brain health. An optional workshop will follow the main conference proceedings.
The conference will serve to bring together both practical applications for those affected by Alzheimer’s, as well as cutting edge science and expert advice.
The Mayo Clinic’s Alzheimer’s Disease Research Center focuses on promoting research and education about healthy brain aging, among other things. AARP works on supporting adults as they age, and the Alzheimer’s Association supports those affected by Alzheimer’s.
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