Research Highlights from Padmaja Genesh - April 2021

Published: Apr 30, 2021

EMBARK Trial to Again Test Safety, Efficacy of Aducanumab  

A new Phase 3 clinical trial, called EMBARK, will evaluate the long-term safety and efficacy of Aducanumab, an investigational therapy for Alzheimer’s disease in patients who took part in its previous clinical studies. 

Aducanumab, being co-developed by Biogen and Eisai, is an investigational Alzheimer’s treatment currently under review for approval in the U.S., Europe, and Japan. The therapy is designed to remove toxic clumps of proteins found in the brains of Alzheimer’s patients, which are believed to drive the disease. 

Biogen had launched two Phase 3 clinical trials to test the safety and efficacy of aducanumab in Alzheimer’s patients: ENGAGE (NCT02477800) and EMERGE (NCT02484547). These studies were terminated in 2019, after an independent advisory committee analyzed data from these studies and determined that the investigational medication was unlikely to provide a meaningful benefit.  However, a later analysis that included more data indicated that EMERGE had, in fact, achieved its main goal of improving cognition and function, including memory, orientation, language, and daily living activities, relative to a placebo. 

Biogen initiated EMBARK (NCT04241068) as an open-label clinical trial in patients who were active participants in EMERGE, ENGAGE, or other clinical studies of aducanumab when they were discontinued. This is to assess 2 fundamental questions- what is the long-term safety and efficacy of highest dose Aducanumab, and what are the changes in clinical and biomarker measures during the treatment gap.

The trial is expected to enroll (by invitation) about 1,800 participants at over 300 sites in 20 countries — which would make it one of the largest ever clinical trials conducted in Alzheimer’s disease. 



Lecanemab Safely, Quickly Lowers Amyloid Clumps in Trial 

Eisai and Biogen’s experimental therapy Lecanemab (BAN2401) safely leads to rapid and sustained reductions in the brain levels of beta-amyloid — the protein that forms toxic clumps in Alzheimer’s — in people in early disease stages, according to one-year, preliminary data from a Phase 2 trial’s ongoing extension phase. 

These findings add to previous trial results showing that the therapy slowed disease progression and cognitive decline in Alzheimer’s patients, and further support the continued development of Lecanemab, which is now being evaluated in two Phase 3 trials- Clarity AD  (NCT03887455) and AHEAD 3-45 (NCT04468659). 

Lecanemab is an antibody designed to specifically bind to a soluble, damaging version of the beta-amyloid protein that clumps into toxic plaques in the brain, contributing to Alzheimer’s.  By binding to this form of beta-amyloid, the antibody is expected to “tag” it as harmful in the “eyes” of the immune system, promoting its clearance before it clumps and forms toxic plaques, which could slow Alzheimer’s progression. 

The international Phase 2 Study 201, designed to evaluate Lecanemab’s safety and effectiveness, enrolled 856 Alzheimer’s patients with mild cognitive impairment or dementia, who had amyloid protein accumulation in the brain. Patients were recruited at nearly 170 sites across 11 countries, including the U.S., Canada, and those of Europe. 

Amyloid drops during the extension appeared to be dependent on placement in the core study, with patients initially assigned to placebo showing the greatest reductions. 

Among those switching from placebo to Lecanemab, the therapy rapidly reduced brain amyloid, with effects noted as early as three months. 



A New Monoclonal Antibody Shows Promise in Early Alzheimer's Disease 

The monoclonal antibody Donanemab was effective in clearing amyloid-beta plaque in patients in the early stages of Alzheimer's disease; it was also associated with slower rates of cognitive decline, according to a phase 2 clinical trial. 

The patients taking the experimental drug had a significantly 32 percent slower rate of cognitive decline, compared with patients on a placebo dose, said Mark A. Mintun, MD, a senior scientist at Eli Lilly and Company, which sponsored the study.  This is equivalent to slowing the course of the disease by about six months. 

This study, called TRAILBLAZER-ALZ, was also the first to enroll people using two PET scans, one for abnormal amyloid  (Abeta) and one for misfolded tau—to choose only those patients with a low level of tau tangle formation that they believed would give them a better chance of showing a positive effect from lowering Abeta levels. 

The investigators used post-scan data to identify a marked reduction in the brain's amyloid burden. Almost 70 percent of the patients on the drug converted from amyloid-positive to amyloid-negative during the first 18-months of the study. 

Based on the results from this phase 2 study, the company is already enrolling about 1000 patients for a phase 3 clinical trial.

This was the first study to use tau-PET to select patients in the earliest clinical stages of AD.



Cardiovascular Risk Factors Across the Life Course and Cognitive Decline- A Pooled Cohort Study 

(Kristine Yaffe, Eric Vittinghoff, Tina Hoang, Karen Matthews, Sherita H. Golden, Adina Zeki Al Hazzouri )

Cardiovascular risk factors (CVRFs) are associated with increased risk of cognitive decline, but little is known about how early adult risk factors and those across the life course might influence late-life cognition. To test the hypothesis that CVRFs across the adult life course are associated with late-life cognitive changes, the researchers pooled data from 4 prospective cohorts (n = 15,001, ages 18–95). 

They plotted trajectories of body mass index (BMI), fasting glucose, systolic blood pressure (SBP), and total cholesterol (TC) for older adults. They used linear mixed models to determine the association of early adult, midlife, and late-life CVRFs with late-life decline on global cognition (Modified Mini-Mental State Examination) and processing speed (Digit Symbol Substitution Test [DSST]), adjusting for demographics, education, and cohort. 

 Elevated BMI, Fasting Glucose, and SBP (but not TC) at each time period were associated with greater late-life cognitive decline. Early life CVRFs were associated with the greatest change, an approximate doubling of mean 10-year decline (an additional 3–4 points for both global cognition and processing speed).

Late-life CVRFs were associated with declines in early late life (<80 years) but with gains in very late life (≥80 years). After adjusting for CVRF exposures at all time periods, the associations for early adult and late-life CVRFs persisted. 

The researchers found that cardiovascular risk factors across the life course, especially in early adulthood, were associated with greater late-life cognitive decline. Their results suggest that CVRF treatment in early adulthood could benefit late-life cognition, but that treatment in very late life may not be as helpful for these outcomes. 



FDA Rejects Nuplazid to Treat Dementia-related Psychosis 

The U.S. Food and Drug Administration (FDA) has rejected Acadia Pharmaceuticals’ request that Nuplazid (pimavanserin) be the first approved treatment of hallucinations and delusions associated with dementia-related psychosis. 

While the FDA’s complete response letter (CRL) did not mention any safety issues, it raised concerns regarding effectiveness data from the Phase 3 HARMONY trial (NCT03325556), which mainly supported the application. 

These included the lack of significant benefits in some dementia forms and the small number of patients with less common subtypes, which led the agency to conclude evidence was insufficient to support Nuplazid’s approval for this indication at this point. 

Classified as a selective serotonin inverse agonist, Nuplazid works by specifically blocking the activity of serotonin 5-HT2A receptors, which are involved in psychosis — commonly consisting of delusions and hallucinations, depression, and other neuropsychiatric disorders. 

The oral therapy was approved by the FDA to treat Parkinson’s disease-related psychosis in 2016. 

The latest application drew mainly on positive data from the pivotal Phase 3 HARMONY trial, which evaluated the safety and effectiveness of Nuplazid in 392 people with the five most common forms of dementia-related psychosis.  HARMONY enrolled patients with the most common forms of dementia-related psychosis, including Alzheimer’s disease-related dementia (which accounted for 76% of all trial participants), Parkinson’s disease dementia, dementia with Lewy bodies, vascular dementia, and frontotemporal dementia. 

Top-line results showed that Nuplazid-treated patients were significantly less likely (by 2.8 times) to experience a psychosis relapse compared with those on a placebo. 

The trial also achieved a key secondary goal, with the therapy significantly reducing by 2.2 times the risk of patients leaving the study for any reason.  Nuplazid was generally well-tolerated, and not associated with common side effects of conventional antipsychotics, including cognitive decline or daytime sedation. 

These findings show the trial met its main and secondary goals, an FDA prerequisite for the dementia-related psychosis indication, Acadia stated. 
Source : 


GV1001 Treatment Shows Promise for Moderate to Severe Alzheimer’s 

Six months of treatment with GemVax & KAEL’s investigational GV1001 provided benefits in the cognition and daily life activities of adults with moderate to severe Alzheimer’s disease, who take Aricept (donepezil) for dementia, according to data from a Phase 2 clinical trial. 

Originally developed as a cancer vaccine, GV1001 was shown to have neuroprotective properties, mediated through anti-cell death, anti-inflammatory, anti-aging, and antioxidant effects. 

The Phase 2 clinical trial (NCT03184467) evaluated the safety and effectiveness of GV1001 in 96 adults (59 women and 37 men) with moderate to severe Alzheimer’s, who were on a stable dose of Aricept. Participants were recruited at 13 hospitals across South Korea and had a mean age of 70.9 years (range of 56–85 years). 

The study’s main goal was to assess changes in patients’ cognitive function using the Severe Impairment Battery (SIB) scores. Secondary goals included safety assessments and other validated measures of several aspects of disease severity.

Efficacy analyses were performed in the entire treated patient population and in the group of 73 (76%) participants who completed the six-month treatment period. 

Results showed that while patients on placebo showed a mean decrease of 6.9 to 7.3 points in the SIB scores (indicating cognitive function worsening) after six months, those treated with the high dose of GV1001 had stable scores, with a mean drop of 0.1 to 0.3 points. 

Notably, GV1001’s significant, beneficial effect on cognition was already observed at week 12, both for the entire patient population and for those who completed treatment. No significant differences in the SIB score were observed between the low-dose group and the placebo group throughout the study. 

These findings meant that the trial met its main goal for GV1001’s high dose, which also resulted in significant reductions in dementia-related behaviors at week 12, as assessed with the NPI, compared with a placebo. GV1001 was generally well-tolerated, with rates of most common adverse events similar to those reported in the placebo group, and no reports of severe or clinically significant adverse events. 

The launch of a Phase 2a trial (NCT03959553) in people with moderate Alzheimer’s has already been approved in the U.S. and a Phase 3 trial in South Korea is planned to start later this year. 



Safety Seen in Trial of Oral Treatment, Anavex 2-73, for Early Alzheimer’s 

Following a positive review of preliminary data, an independent board recommended the Phase 2b/3 study investigating oral Anavex 2-73 (blarcamesine) in people with early Alzheimer’s disease continue without modification.  

Anavex 2-73, being developed by Anavex Life Sciences, is a small molecule designed to activate a receptor called sigma-1. Alzheimer’s patients have fewer of these receptors in their brains compared to people of the same age without the disorder. 

Activation of sigma-1 may lessen clinical symptoms, marked by a progressive loss of the ability to learn, communicate, reason, and carry out daily activities. Activation is also thought to protect against neurologic changes by targeting protein misfolding, problems with mitochondria (a cell’s energy producers), inflammation, and oxidative stress — an imbalance between the production of metabolic byproducts, such as reactive oxygen species, and a cell’s ability to detoxify them.  

Preclinical animal studies demonstrated Anavex 2-73’s potential to stop or reverse Alzheimer’s progression. Its use also showed protection against convulsions, amnesia, neurological damage, and depression, suggesting it might also treat other conditions, including Parkinson’s disease and epilepsy.  

Anavex 2-73-AD-004 is a placebo-controlled safety and efficacy study underway in Australia, Canada, Germany, the Netherlands, and the U.K., with more than 92% of its estimated 450 patients enrolled. Participants are those with cognitive impairment, or early stage and mild dementia, due to Alzheimer’s, ranging in age from 60 to 85. More information about site locations and contacts is here.  

This study demonstrated dose-dependent improvement in endpoints of cognition and function. 

Patients who complete Anavex 2-73-AD-004 will be invited to enroll in the open-label ATTENTION-AD study, in which all will be given the treatment for two years. 



Neuropsychiatric symptoms in early and late onset Alzheimer’s Disease (2452) 

(Neus Falgàs Martínez, Isabel E. Allen, Joel Kramer, Howard Rosen, Bruce Miller, Gil Rabinovici, Lea Grinberg, Thomas Neylan, Christine Walsh) 

The objective of the study was to determine the differential trajectories of the neuropsychiatric symptoms in Early onset AD (EOAD) and Late onset AD(LOAD), in a cohort of amyloid positive patients.

The faster rates of cognitive decline and the predominance of atypical forms in early onset Alzheimer’s Disease (EOAD) suggests that neuropsychiatric symptoms (NPS) could be more common in EOAD than in late-onset AD (LOAD). However, prior studies based in non-biomarker diagnosed cohorts show discordant results. 

115 participants meeting criteria for AD, using amyloid-PET, were recruited at Memory and Aging Center, UCSF. Participants were classified as EOAD (age of onset ≤ 65 years; n=69) or LOAD (> 65 years; n=46). The caregiver-reported Neuropsychiatric Inventory – Questionnaire (NPI-Q) was assessed at baseline and follow-up (annual visits, from 1 to 8 years).

Results: There were no differences between EOAD and LOAD for gender (51 vs 59%), global cognition (MMSE 23.4±5 vs 24.7±5) or functional performance (CDR Total 0.6±0.2 vs 0.6±0.3). At baseline, both the NPI Total scores and certain subdomains scores (anxiety, irritability and nighttime behaviors) were higher in EOAD compared to LOAD.

Longitudinally, EOAD predicted higher scores in NPI Total, nighttime behavior and motor disturbances. Non-amnestic (non-memory related) EOAD showed higher anxiety than amnestic (memory-related) EOAD. 

Conclusions: Neuropsychiatric symptoms are more severe in Early Onset AD than Late-onset AD along the disease course, independent of the disease stage. Certain domains such as anxiety, irritability, nighttime behaviors and motor disturbances contribute to the differential pattern of NPS, suggesting there is a need to develop more tailored treatment strategies to address these clinical manifestations in Early-Onset AD. 



Quality of Plant-Based Diet and Risk of Total, Ischemic, and Hemorrhagic Stroke 

(Megu Y. Baden, Zhilei Shan, Fenglei Wang, Yanping Li, JoAnn E. Manson, Eric B. Rimm, Walter C. Willett, Frank B. Hu, Kathryn M. Rexrode) 

The objective of the study was to determine whether a healthful plant-based diet is related to lower stroke risk. The researchers examined the associations of plant-based diet quality with risk of total, ischemic, and hemorrhagic stroke. 

The participants were 73,890 women in Nurses' Health Study (NHS; 1984–2016), 92,352 women in NHSII (1991–2017), and 43,266 men in Health Professionals Follow-Up Study (1986–2012) without cardiovascular disease and cancer at baseline.

Plant-based diet quality was evaluated by the overall plant-based diet index (PDI), the healthful PDI (hPDI), and the unhealthful PDI (uPDI). Participants who reported that their meat and/or fish intakes were 0 or <1 serving per month were categorized as vegetarians, and others were classified as nonvegetarians. Strokes with available medical records were subtyped as ischemic or hemorrhagic. 

During the follow-up, 6,241 total stroke cases (including 3,015 ischemic and 853 hemorrhagic strokes) were documented.  The researchers found that lower risk of total stroke was observed by those who adhered to a healthful plant-based diet.