Research Highlights From Padmaja Genesh (July 2020)

Published: Aug 05, 2020

Investigational Agitation Treatment AXS-05 Named FDA Breakthrough Therapy

The U.S. Food and Drug Administration (FDA) has granted breakthrough therapy designation to Axsome Therapeutics‘ AXS-05, an investigational oral therapy for the treatment of agitation in people with Alzheimer’s disease.

This designation is intended to accelerate the development and review of potential therapies for serious diseases, and includes more intensive FDA guidance throughout treatment development, and eligibility for priority review, which can speed the approval process.

AXS-05, an oral candidate therapy to treat this symptom, is composed of two main active components: dextromethorphan and bupropion. Dextromethorphan works by modulating the activity of neurotransmitters such as Glutamate, Serotonin, and, Norepinephrine, which are known to play a role in the cognitive and behavioral changes in people with Alzheimer’s.

Bupropion stabilizes dextromethorphan, boosting its efficacy. It also increases the availability of dopamine and norepinephrine, and acts on another neurotransmitter called acetylcholine, also thought to be involved in agitation.

The FDA’s decision was based on recent top-line results from the Phase 2/3 ADVANCE-1 trial (NCT03226522). 

The top-line results showed that, after five weeks, patients in the AXS-05 group underwent a statistically significant 48% reduction in their agitation scores, compared with 38% drop in those in the placebo group.  Importantly, 73% of the participants who received AXS-05 achieved a clinical response defined as a 30% or greater improvement in their agitation score, compared to 57% of patients who achieved a clinical response in the placebo group.



Biogen, Eisai Seek FDA Approval of Aducanumab for Alzheimer’s

Biogen and Eisai have submitted a biologics license application (BLA) to the U.S. Food and Drug Administration (FDA) requesting the approval of aducanumab (BIIB037) for the treatment of Alzheimer’s disease.

If approved, aducanumab will become the first therapy with the potential to slow the clinical decline seen in patients with Alzheimer’s, as well as the first to demonstrate that reducing the buildup of amyloid plaques in the brain of patients may lead to better outcomes.

Aducanumab is an investigational treatment for Alzheimer’s that is currently being developed by Biogen in collaboration with Eisai. As a monoclonal antibody, the treatment is specifically designed to bind to the toxic clumps of beta-amyloid that are thought to be the underlying cause of neuronal degeneration in Alzheimer’s.

The BLA submission was based on data from two Phase 3 trials — EMERGE (NCT02484547) and ENGAGE (NCT02477800) — which assessed the efficacy of two doses of aducanumab in patients at early stages of the disease, who had mild cognitive impairment due to Alzheimer’s and mild Alzheimer’s dementia.

EMERGE met its primary goal, with patients given the highest dose of aducanumab experiencing a significant reduction in the progression of cognitive and functional impairments, compared with a placebo, at 78 weeks.


This was accompanied by significant reductions in other measures of clinical progression, including the Mini-Mental State Examination (MMSE) and the Alzheimer’s Disease Assessment Scale-Cognitive Subscale 13 Items. The treatment also slowed the rate at which patients lost their ability to perform daily life activities, including managing their personal finances, performing household chores, and traveling independently.



Nation-wide retrospective, cohort study of epilepsy and incident dementia

The purpose of the study was to determine the association of epilepsy with incident dementia. The researchers conducted a nation-wide retrospective data-linkage, cohort study, to examine whether the association varies according to dementia subtypes and investigate whether risk factors modify the association.

The researchers used linked health data from hospitalization, mortality records and primary care consultations to follow-up 563,151 Welsh residents from their 60th birthday to estimate dementia rate and associated risk factors. Dementia, epilepsy and covariates (medication, smoking, comorbidities) were classified using previously validated code lists.

The researchers studied rate of dementia and dementia subtypes in people with epilepsy.

The persons with epilepsy had a 2.5 times higher hazard of incident dementia, a 1.6 - 1.4 times higher hazard of incident Alzheimer’s disease (AD), and a 3.1 times higher hazard of incident Vascular dementia (VaD).

A history of stroke modified the increased incidence in persons with epilepsy. Persons with epilepsy who were first diagnosed at age 25 years or younger had a similar dementia rate compared to those diagnosed later in life. Persons with epilepsy who had ever been prescribed sodium valproate compared those who had not, were at higher risk of dementia  and VaD  but not AD.

Conclusion: People with epilepsy, compared to those without epilepsy, have an increased dementia risk.


Global Phase 3 Trial Will Test BAN2401 in Early-stage Asymptomatic Alzheimer’s

BAN2401, an experimental treatment for Alzheimer’s disease (AD), will be tested in the new global AHEAD 3-45 clinical trial, its developers have announced.

The Phase 3 study — to be conducted in the U.S., Canada, Japan, Australia, Singapore, and Europe — will test the therapy in people who are in the early stage of the neurological disorder and do not yet show symptoms.

AHEAD 3-45 (NCT04468659) will evaluate the therapeutic effect of BAN2401 on the progression of Alzheimer’s in patients who are clinically normal (asymptomatic) but have intermediate or elevated levels of beta-amyloid protein fiber aggregates, or clumps — a hallmark of the disease — in their brains. 

The therapy, which is jointly being developed by Eisai and Biogen, is an antibody-based treatment designed to bind, neutralize, and eliminate these beta-amyloid clumps selectively. 

Currently, BAN2401 is being studied in the pivotal Clarity AD Phase 3 clinical study (NCT03887455). Participants in that trial also have early-stage Alzheimer’s, but do show disease symptoms.

BAN2401 also is being evaluated in a large, ongoing, Phase 2 clinical trial (NCT01767311) called Study 201, which began in 2012, involving Alzheimer’s patients with mild cognitive impairment or dementia. 

The results from the first 18 months of the trial, involving 856 participants, showed a statistically significant decrease in cognitive decline as well as reduced accumulation of beta-amyloid in the brains of treated patients, compared with those given a placebo.

AHEAD 3-45 will enroll an estimated 1,400 participants. It will test BAN2401 against a placebo in two separate trials — named A3  (involving people without any signs of cognitive impairment who have a moderate amount of beta-amyloid in their brains)  and A45 ( enrolling people with little-to-no cognitive impairment, but who have elevated levels of beta-amyloid in the brain) — based on the level of beta-amyloid in the brain, for approximately four years.



FDA to Consider Nuplazid to Treat Dementia-related Psychosis

The U.S. Food and Drug Administration (FDA) has accepted a request by Acadia Pharmaceuticals‘ that  Nuplazid (pimavanserin) be approved for a new indication: the treatment of delusions and hallucinations associated with dementia-related psychosis.

The company’s supplemental new drug application, which was submitted in June, was granted standard review status. The FDA’s decision is expected by April 3, 2021.

If approved, Nuplazid would be the first therapy indicated for the treatment of hallucinations and delusions associated with dementia-related psychosis.

Nuplazid is a selective serotonin inverse agonist (SSIA) that specifically binds to serotonin 5-HT2A receptors and blocks their activity. These receptors have been shown to be involved in psychosis, depression, and other neuropsychiatric disorders.

Nuplazid was approved in 2016, under FDA’s breakthrough therapy designation, to treat hallucinations and delusions associated with psychosis in people with Parkinson’s disease. 

Results from three clinical trials support the application, including the pivotal Phase 3 HARMONY trial (NCT03325556), which included people with Alzheimer’s disease, Parkinson’s disease, Lewy Body dementia and frontotemporal dementia.

The study found that patients given Nuplazid, compared with those given a placebo, were 2.8 times less likely to experience a relapse of psychosis, a statistically significant reduction. Nuplazid was well-tolerated, and was not associated with cognitive decline over the nine-month testing period.



Flu, Pneumonia Vaccinations Linked to Reduced Risk of Alzheimer’s, Researchers Say

Vaccines against the flu and pneumonia are associated with a lower risk of developing Alzheimer’s disease, while infections are generally linked to increased mortality among people with dementia, according to three research studies presented at this year’s Alzheimer’s Association International Conference, which is being held virtually this week.

Albert Amran, a medical student at McGovern Medical School in Houston, and his colleagues searched 9,066 medical records for evidence of a possible link between flu vaccine and Alzheimer’s study in their study, “Influenza Vaccination is associated with a reduced incidence of Alzheimer’s Disease.”

They found that people who consistently got their annual influenza or flu shot had a lower risk of developing Alzheimer’s. Their data revealed that  the more consistently people got their shots, the less likely they were to develop Alzheimer’s later.

While a single injection translated to an approximately 17% reduction in Alzheimer’s risk, more frequent shots added another 13% reduction. The researchers also observed that vaccines seemed to offer better protection when received at a younger age.

Another team of researchers investigated whether existing vaccines could be repurposed for Alzheimer’s prevention in a study. The team, led by Svetlana Ukraintseva, PhD, a professor of aging research at Duke University, discovered that receiving pneumococcal (pneumonia) vaccination between the ages of 65 and 75 reduced the risk of developing Alzheimer’s by 25%–30%, depending on individual genes.

They observed the largest reduction in Alzheimer’s risk (up to 40%) among people vaccinated against pneumonia, who did not carry the risk gene (TOMM40 gene, called the rs2075650 G allele).

Finally, another research team discovered the risk of dying after infections was higher in people with dementia than those without dementia in their study.

They found that people who had dementia and visited the hospital for infections had a 6.5 times higher mortality rate than those without those conditions.

Patients with dementia or infection had a threefold higher mortality rate which was highest within the first 30 days after their hospital visit. Mortality rates remained higher for 10 years after the initial infection-related hospital visit for people with dementia.




Healthy lifestyle and the risk of Alzheimer dementia- Findings from 2 longitudinal studies

The objective of the study was to quantify the impact of a healthy lifestyle on the risk of Alzheimer dementia.

Using data from the Chicago Health and Aging Project (CHAP; n = 1,845) and the Rush Memory and Aging Project (MAP; n = 920), the researchers defined a healthy lifestyle score on the basis of nonsmoking, ≥150 min/wk moderate/vigorous-intensity physical activity, light to moderate alcohol consumption, high-quality Mediterranean-DASH Diet Intervention for Neurodegenerative Delay diet (upper 40%), and engagement in late-life cognitive activities (upper 40%), giving an overall score ranging from 0 to 5.

Results During a median follow-up of 5.8 years in CHAP and 6.0 years in MAP, 379 and 229 participants, respectively, had incident Alzheimer dementia. In multivariable-adjusted models, the pooled hazard ratio of Alzheimer dementia across 2 cohorts was 0.73 per each additional healthy lifestyle factor.

Compared to participants with 0 to 1 healthy lifestyle factor, the risk of Alzheimer dementia was 37% lower  in those with 2 to 3 healthy lifestyle factors and 60% lower  in those with 4 to 5 healthy lifestyle factors.

Conclusion A healthy lifestyle as a composite score is associated with a substantially lower risk of Alzheimer's dementia.

Source: First published June 17, 2020, DOI:;