Research Highlights by Padmaja Genesh January 2022

Published: Feb 02, 2022
  • UBC researchers launch first-in-Canada testing program for Alzheimer’s disease

For the first time, Canadians can access a new test to diagnose Alzheimer’s disease, thanks to a study led by research team headed by Dr. DeMarco, at UBC’s faculty of medicine.

In Alzheimer’s disease, the proteins amyloid-beta and tau clump together in the brain to form amyloid plaques and tau tangles, respectively, which cannot be seen using regular imaging techniques. The new test measures the level of these proteins in the cerebrospinal fluid, using them as biomarkers that help with earlier and more accurate diagnosis of Alzheimer’s disease.

Through the study, called IMPACT-AD, the research team developed a key component of the biomarker test and worked with individuals with lived experience with dementia, along with health care providers and other partners, to implement a comprehensive diagnostic testing strategy.

The team recently achieved one of their major goals by making the test available for people across Canada. The test must be ordered by doctors specializing in dementia care, who may recommend it for individuals experiencing mild to moderate symptoms suspected to be caused by Alzheimer’s disease.

Early and accurate diagnosis of Alzheimer’s disease is critical to enable patients timely access to health care and community services, which could lead to more effective treatment and improve quality of life. The current approaches for diagnosis rely on expensive and inaccessible imaging tests and observation of the signs and symptoms of the disease.

As part of the study, patients are also able to provide their perspective on how the test results impacted their lives. With additional input from patients’ families and their doctors, DeMarco and her colleagues hope to address barriers to uptake and use in the Canadian healthcare system.

Source: https://www.med.ubc.ca/byline-date-only/ubc-researchers-launch-first-in-canada-testing-program-for-alzheimers-disease/

  • Lecanemab for Early Alzheimer’s Granted the FDA’s Fast Track Status

Lecanemab, an investigational antibody also known as BAN2401, has been granted a fast track designation from the U.S. Food and Drug Administration (FDA), which may help speed up its development for the treatment of early Alzheimer’s disease.

The antibody, developed jointly by Biogen and Eisai, is designed to bind to the protein amyloid-beta, allowing the immune system to clear amyloid before it forms plaques that drive the death of nerve cells  in the brains of those with Alzheimer’s.

The FDA granted its breakthrough therapy designation to Lecanemab in mid-2021. In September, Eisai started a rolling submission for a biologics license application, based on data from Study 201, a Phase 2b clinical trial (NCT01767311) that enrolled 856 patients with mild cognitive impairment or dementia and a confirmed presence of amyloid-beta clumps in the brain.

The data showed that Lecanemab reduced amyloid-beta clumps in the brain and slowed clinical decline, which qualifies amyloid-beta as a surrogate marker that could facilitate quicker approval of Lecanemab for early Alzheimer’s.

Under the accelerated approval program, the FDA also requires Lecanemab to be tested in a confirmatory clinical trial to verify its clinical benefit  in more patients.

A Phase 3 clinical trial (NCT03887455), called Clarity AD, is testing the safety and efficacy of Lecanemab  (10 mg/kg) every two weeks versus a placebo in up to 1,795 patients with early Alzheimer’s. Another Phase 3 clinical study (NCT04468659), called AHEAD 3-45, is testing the efficacy of Lecanemab versus a placebo in up to 1,400 patients with preclinical Alzheimer’s disease and intermediate or high levels of beta-amyloid.

Source: https://alzheimersnewstoday.com/2022/01/04/lecanemab-early-alzheimers-granted-fda-fast-track-status/

  • FDA Approval Again Wanted for Nuplazid in Easing Psychosis

Acadia Pharmaceuticals intends to request FDA approval for oral Nuplazid to treat hallucinations and delusions,  associated with Alzheimer’s disease. Nuplazid is approved to treat hallucinations and delusions associated with Parkinson’s psychosis.

 

Its planned request to the U.S. Food and Drug Administration (FDA), in the form of a resubmitted supplemental new drug application (sNDA), follows the FDA’s rejection last year of Nuplazid in treating hallucinations and delusions in dementia-related psychosis.

The FDA raised concerns regarding the lack of evidence of significant benefits in dementia forms, other than Alzheimer’s Disease, in the Phase 3 HARMONY study.

Nuplazid is a selective serotonin inverse agonist, which can bind and block the activity of serotonin 5-HT2A receptors. These receptors are involved in psychosis, commonly consisting of delusions and hallucinations, depression, and other neuropsychiatric disorders.

The resubmitted sNDA will include data from two placebo-controlled studies, the Phase 3 HARMONY study (NCT03325556) and the Phase 2 ACP-103-019 trial (NCT02035553).

HARMONY evaluated the safety and effectiveness of Nuplazid in 392 people with the five most common forms of dementia-related psychosis.

HARMONY met its main goal, significantly lowering the risk of a psychosis relapse by 2.8 times compared with placebo. It also met a key secondary endpoint, significantly reducing by 2.2 times the risk of patients leaving the study for any reason, including treatment tolerability.

In the ACP-103-019 trial, 181 people with Alzheimer’s-related psychosis were treated with either Nuplazid or placebo for 12 weeks. Nuplazid was shown to significantly reduce patients’ psychosis scores, particularly in those with more severe symptoms, at six weeks of treatment relative to placebo, meeting the trial’s main goal. However, these benefits were not sustained at 12 weeks.

Source: https://alzheimersnewstoday.com/2022/01/06/fda-approval-again-wanted-nuplazid-treat-alzheimers-disease-psychosis/

  • Diet Inflammatory Index and Dementia Incidence- A Population Study

The present study aimed to explore the associations between the inflammatory potential of diet, assessed with an easily applicable, population-based, biomarker-validated diet inflammatory index (DII), and the risk for dementia in community-dwelling older adults.

Individuals from the Hellenic Longitudinal Investigation of Aging and Diet (HELIAD) were included in the present cohort study. Participants were recruited through random population sampling and were followed up for a mean of 3.05 (standard deviation 0.85) years. Those with baseline dementia or missing cognitive follow-up data were excluded from the analyses.

The inflammatory potential of diet was assessed through a DII score that considers literature-derived associations of 45 food parameters with levels of proinflammatory and anti-inflammatory cytokines in the blood; higher values indicated a more proinflammatory diet.

Consumption frequencies were derived from a detailed food frequency questionnaire and were standardized to representative dietary intake normative data from 11 different countries. Analysis of dementia incidence as a function of baseline DII scores was performed by Cox proportional hazards models.

Results Analyses included 1,059 individuals (mean age 73.1 years, 40.3% male, mean education 8.2 years), 62 of whom developed incident dementia. Each additional unit of DII score was associated with a 21% increase in the risk for dementia incidence. Compared to participants in the lowest DII score tertile, participants in the highest one (maximal proinflammatory diet potential) were 3 times more likely to develop incident dementia. The test for trend was also significant, indicating a potential dose-response relationship (p = 0.014).

 In the present study, higher DII scores (indicating greater proinflammatory diet potential) were associated with an increased risk for incident dementia. These findings might avail the development of primary dementia preventive strategies through tailored and precise dietary interventions.

https://doi.org/10.1212/WNL.0000000000012973

  • Predictors of Incident Mild Cognitive Impairment and Its Course in a Diverse Community-Based Population

The purpose of this study was to investigate sociodemographic and medical predictors of incident mild cognitive impairment (MCI) and subsequent course of MCI at follow-up.

Within a community-based cohort, diagnoses of MCI were made with a published algorithm. Diagnosis of dementia was based on clinical consensus.  Approved statistical methods were used to estimate hazard ratios of incident MCI associated with several predictors, and relative risks associated with predictors of diagnostic status at follow-up after incidence.

Results:  Among 2,903 cognitively normal participants at baseline, 752 developed MCI over an average of 6.3 years (incidence rate 56 per 1,000 person-years).

Presence of APOE e4 and higher medical burden increased risk of incident MCI, while more years of education, more leisure activities, and higher income decreased this risk.

Of the incident MCI cases, after an average of 2.4 years of follow-up, 12.9% progressed to dementia, 9.6% declined in functioning and did not meet the algorithmic criteria for MCI but did not meet the clinical criteria for dementia, 29.6% continued to meet MCI criteria, and 47.9% no longer met MCI criteria.

Multidomain MCI, presence of APOE e4, depressive symptoms, and antidepressant use increased the risk of progression to dementia.

Conclusions: This community-based study showed that almost half of the individuals with incident MCI diagnoses were classified as cognitively normal at follow-up. Predictors of incident MCI demonstrably differed from those of subsequent MCI course; these findings can refine expectations for cognitive and functional course of those presenting with MCI.

Source: Neurology® 2022;98:e15-e26. doi:10.1212/WNL.0000000000013017

  • Sex Differences in the Association Between Midlife Cardiovascular Conditions or Risk Factors With Midlife Cognitive Decline

 

The prevalence of mid-life cardiovascular conditions and risk factors are higher in men than women. Associations between mid-life cardiovascular conditions or risk factors and mid-life cognitive decline has been reported, but few studies have assessed sex differences in these associations.

The researchers included 1,857 participants enrolled in the population-based Mayo Clinic Study of Aging, who were aged 50-69 years at baseline. Participants were assessed every 15 months by a coordinator, for neurologic evaluation, and neuropsychological testing.

The neuropsychological testing used nine tests to calculate global cognitive and domain-specific (memory, language, executive function, and visuospatial skills) scores. Nurse abstractors reviewed participant medical records to determine the presence of cardiovascular conditions (coronary heart disease, arrhythmias, congestive heart failure) and risk factors (hypertension, diabetes, dyslipidemia, obesity, ever smoking). Linear mixed-effect models evaluated the association between baseline cardiovascular conditions or risk factors and global and domain-specific cognitive decline. The models were adjusted for demographics, APOE genotype, depression, and other medical conditions. Interactions between sex and each cardiovascular condition or risk factor were examined, and results were stratified by sex.

Results: Overall, 1,465 (70.3%) participants had at least one cardiovascular condition or risk factor; the proportion of men was higher than women. Cross-sectionally, coronary heart disease and smoking were associated with a lower visuospatial score. Longitudinally (over the period of study duration), several cardiovascular conditions and risk factors were associated with declines in global and/or domain-specific scores, but not visuospatial scores.

 Most cardiovascular conditions were more strongly associated with cognition among women: coronary heart disease, and other cardiovascular conditions were associated with global cognition decline only in women. Additionally, diabetes, dyslipidemia, and coronary heart disease were associated with language score decline only in women. However, congestive heart failure was associated with language score decline only in men.

Conclusions: Mid-life cardiovascular conditions and risk factors are associated with mid-life cognitive decline. Moreover, specific cardiovascular conditions and risk factors have stronger associations with cognition decline in mid-life for women than men despite the higher prevalence of those conditions in men.

Source: https://n.neurology.org/content/early/2022/01/05/WNL.0000000000013174

  • Clinical Trial Set for Gantenerumab in Early-onset Alzheimer’s Disease

An international clinical trial for Gantenerumab aimed at preventing inherited, early-onset Alzheimer’s disease is being launched at the Washington University School of Medicine in St. Louis.

The trial, called the Primary Prevention Trial, is enrolling people with a family history of early-onset Alzheimer’s and its associated genetic mutations up to 25 years before their expected onset of dementia, starting at age 18.

The study will investigate whether Gantenerumab — an investigational antibody under development for Alzheimer’s disease — can prevent and clear amyloid beta buildup.

Gantenerumab has been granted breakthrough therapy status by the U.S. Food and Drug Administration (FDA) in order to accelerate its development and treatment of early Alzheimer’s. It has shown potential in clearing beta amyloid, a key protein involved in Alzheimer’s progression due to its aggregation, or clumping, in the brain.

This new clinical trial for Gantenerumab use is the second international Alzheimer’s prevention trial led by WashU’s School of Medicine.

Both trials are being conducted in association with the Dominantly Inherited Alzheimer Network (DIAN)  involving nearly 40 research institutes across North America, Australia, Europe, Asia, and South America.

This new trial will be recruiting 230 people from families who carry genetic mutations that lead to early-onset Alzheimer’s. These individuals, with a 50% chance of inheriting a gene associated with Alzheimer’s, are almost guaranteed to develop dementia near the same age as their parent if any of these genes are inherited. Those interested can email the DIAN Expanded Registry.

The participants will have few to no amyloid plaques and will be seen in sites on five continents over the course of four years. The goal is to determine whether early treatment targeting amyloid can prevent familial, inherited Alzheimer’s disease.

Source: https://alzheimersnewstoday.com/2022/01/11/clinical-trial-set-gantenerumab-early-onset-alzheimers-disease/

  • Phase 2a Trial Initiated for Lomecel-B in Mild Alzheimer’s Disease

Longeveron is initiating a Phase 2a clinical trial for its Lomecel-B treatment — an investigational, bone marrow-derived, medicinal signaling cell (MSC) — in patients with mild Alzheimer’s disease.

The first patient has already given consent to participate in the trial, and further patient screening has begun.

Lomecel-B MSCs are stem cells derived from the bone marrow of healthy adult donors. The company believes that by using the same cells that promote normal tissue repair, organ maintenance, and immune system function, it can address several features of Alzheimer’s, including brain inflammation, the function of blood vessels in the brain, brain damage due to disease progression, and regenerative responses.

Lomecel-B is given via an intravenous infusion and is thought to work by secreting bioactive molecules, such as growth factors and anti-inflammatory cell-signaling molecules, at the site of inflamed and damaged tissue.

This new trial builds upon data from a previous Phase 1 trial (NCT02600130), which showed Lomecel-B was safe and well tolerated and could slow cognitive decline and the loss of daily life abilities in patients with mild Alzheimer’s, relative to those given a placebo. Additionally, the levels of pro-vascular (formation of new blood vessels) and anti-inflammatory markers significantly increased in those treated with Lomecel-B.

This placebo-controlled Phase 2 study is designed to measure brain anatomy using imaging techniques such as magnetic resonance imaging (MRI) and includes assessments of the inflammatory and vascular systems thought to contribute to Alzheimer’s progression. It will be conducted at a minimum of six different centers and will be led by Mark L. Brody, MD, of Brain Matters Research in Florida.

The study will further assess the therapy’s safety and tolerability as well as other endpoints, including cognitive function and biomarkers. The study will compare single or multiple infusions of Lomecel-B with placebo in patients with mild Alzheimer’s.

Source: https://alzheimersnewstoday.com/2022/01/18/phase-2a-trial-initiated-lomecel-b-mild-alzheimers-disease/

  • Stroke Therapy Candidate 3K3A-APC Holds Promise for Dementia

3K3A-APC, an investigational therapy for stroke about to enter Phase 3 clinical testing, may also help to protect the brain against Alzheimer’s disease and other forms of dementia.

3K3A-APC is a modified version of a human protein called activated protein C, or APC, which normally helps to lessen inflammation and protect brain cells from damage. Berislav Zlokovic, MD,  professor at the University of Southern California  co-discovered the brain-protecting effects of APC.

In preclinical studies using a mouse model of the disease, Zlokovic and other scientists showed that treatment with 3K3A-APC improved memory and markedly reduced amyloid-beta plaques, the irregular clumps of protein in the brain that are thought to drive Alzheimer’s. The therapy also has been shown to decrease inflammation in the brain, and to improve the health of the brain’s blood vessels and blood flow in the brain.

Now, Zlokovic and other scientists tested the investigational therapy in a mouse model of vascular dementia. They found that 3K3A-APC protects white matter tracts and oligodendrocytes  (support cells that protect white matter health) from ischemic injury, in certain parts of the brain. They also found that this effect was dependent on two proteins in the brain called PAR1 and PAR3.

A Phase 2 clinical trial that tested 3K3A-APC in 110 stroke patients  reported  that the investigational therapy reduced bleeding in the brain by up to 86.5% compared with a placebo.

3K3A-APC’s safety and potentially efficacy is being tested in a small Phase 2 (NCT05039268) trial in patients with amyotrophic lateral sclerosis (ALS), and a Phase 3 clinical trial in stroke patients is planned to launch this year. According to USC, the therapy has received fast-track designation from the U.S. Food and Drug Administration.

Source: https://alzheimersnewstoday.com/2022/01/24/stroke-therapy-candidate-3k3a-apc-holds-promise-alzheimers/

  • First Patient Dosed in Resumed Trial of Montelukast for Alzheimer’s

The first patient has been dosed in the resumed Phase 2a clinical trial of montelukast for mild to moderate Alzheimer’s disease. IntelGenx, the company running the study known as BUENA (NCT03402503), suspended the trial in late 2020 due to increased concern regarding the COVID-19 pandemic.

Montelukast, an approved asthma drug, is a leukotriene receptor antagonist, which helps prevent some inflammatory processes. Previous research has shown that it can boost the production of nerve cell progenitors.

IntelGenx is repurposing the therapy for treating neurodegenerative diseases, and  is reformulating the medication into an oral film with the use of its proprietary VersaFilm technology.

Montelukast VersaFilm may have advantages over tablets, including easier mode of administration, increased medication concentration at the affected site, being absorbed directly into the blood stream, allowing the use of lower doses, and avoiding toxicity.

Phase 1 trials indicated that this oral film formulation is safe and tolerable in healthy subjects. Additionally, it had a 52% higher bioavailability as compared with regular montelukast.

The reformulated therapy also demonstrated that it can cross the blood-brain barrier — the thin, highly selective permeable membrane that controls what crosses into the brain from the bloodstream — which is an important feature for treating neurodegenerative diseases.

The Canadian Phase 2a BUENA study, which was started in 2018, is now resuming across multiple sites. The study includes patients over age 50 who have mild to moderate Alzheimer’s and are on a stable treatment with Aricept (donepezil)Exelon (rivastigmine), or Razadyne (galantamine) for at least three months.

Recruited participants will be randomly given either montelukast or placebo film. Treatments will be administered once or twice daily for 26 weeks.

At week 26, patients will be assessed through a battery of neuropsychological tests. All patients will be followed for any safety concerns for an additional four weeks following

Source: https://alzheimersnewstoday.com/2022/01/27/first-patient-dosed-resumed-trial-montelukast-alzheimers/