Research Highlights from Padmaja Genesh - January 2021

Published: Jan 31, 2021

Phase 3 Trial of Diabetes Treatment in Early Alzheimer’s Patients Planned  

Novo Nordisk is planning to initiate a pivotal Phase 3a trial of oral Semaglutide, a diabetes treatment, in people with early Alzheimer’s disease, by mid-year. 

Semaglutide is an orally administered diabetes medication approved in the U.S., EU, and Japan, under the name Rybelsus, to treat adults with type 2 diabetes.

Semaglutide is a long-acting analog (structurally similar) of glucagon-like peptide 1, a hormone that stimulates insulin signaling. Increased insulin signaling is thought to improve the transport of glucose in the brain, and to potentially reduce nerve cell death. As such, researchers believe insulin might also play a role in Alzheimer’s progression. 

In preclinical animal studies, treatment with GLP-1 improved memory function and lowered phospho-tau protein accumulation, a hallmark of Alzheimer’s disease. Semaglutide has also been shown to ease neuroinflammation, which may affect cognition and neural function. 

The Phase 3a trial will enroll about 3,700 people in the early stages if Alzheimer’s disease, and will evaluate the efficacy and safety of 14 mg of oral Semaglutide, compared with a placebo, taken once daily. The study is anticipated to run for about two years. 

In three large cardiovascular trials — LEADER (NCT01179048), SUSTAIN 6 (NCT01720446) and PIONEER 6 (NCT02692716) — that included 15,820 patients with type 2 diabetes (median follow-up of 3.6 years), treatment with liraglutide (another GLP-1 analog) or Rybelsus was associated with a statistically significant lower rate (by 53%) of developing dementia compared with those given a placebo.  



Axsome Launches AXS-05 Phase 3 Trial for Alzheimer’s-associated Agitation 

Axsome Therapeutics has launched a Phase 3 trial that will assess the safety and efficacy of AXS-05, the company’s investigational oral treatment for agitation associated with Alzheimer’s disease. 

According to the company, top-line data from the study, called ACCORD, is expected in 2022. 

AXS-05 is based on a proprietary formulation of two active ingredients, dextromethorphan and bupropion. Dextromethorphan is able to control the activity of multiple neural signals that are thought to influence the cognition and behavior of people with Alzheimer’s. Bupropion, in turn, also regulates the activity of these neural chemicals, and is thought to increase the stability and effectiveness of dextromethorphan. 

The therapy’s safety and efficacy in patients with agitation associated with Alzheimer’s were previously investigated in a recently completed Phase 2/3 trial, called ADVANCE-1 (NCT03226522). Top-line data from ADVANCE-1 showed AXS-05 was safe, and significantly and rapidly lessened agitation in Alzheimer’s patients.

These promising results led the U.S. Food and Drug Administration (FDA) to grant AXS-05 the designation of breakthrough therapy. Following the FDA’s recommendation, Axsome has now launched ACCORD, the second pivotal study that is expected to support the therapy’s future approval.

ACCORD will follow a randomized-withdrawal design, in which patients will first complete a nine-week open-label treatment course in which everyone receives AXS-05. Those responding to the treatment will then be randomly assigned to either continue receiving AXS-05 or switch to a placebo, for up to 26 weeks (about six months) or until experiencing an episode of agitation. 

The study’s main goal will be to assess the effects of treatment on the time it takes for patients to experience a relapse of agitation following their randomized selection for differing treatments. Additional study goals will include evaluating the therapy’s safety, as well as its effects on patients’ agitation levels, which will be determined based on their scores on the Cohen-Mansfield Agitation Inventory (CMAI). 



Donanemab Found to Slow Cognitive, Functional Decline in Early Alzheimer’s 

Donanemab (LY3002813), Eli Lilly’s experimental antibody-based immunotherapy, slowed cognitive and functional decline in patients at the earlier stages of Alzheimer’s disease, according to data from a Phase 2 trial. 

Donanemab is designed to bind to beta-amyloid protein  clumped together in plaques in people with Alzheimer’s. By doing so, Donanemab is expected to trigger an immune response against these harmful plaques and help the body eliminate them. This, in turn, is expected to slow Alzheimer’s progression. 

TRAILBLAZER-ALZ is an ongoing Phase 2 trial that’s assessing the safety, tolerability, and efficacy of Donanemab in patients with early symptomatic Alzheimer’s. A total of 272 older adults, ages 60–85, with early Alzheimer’s, were randomly assigned to receive either Donanemab, or a placebo, both given intravenously (into the vein) over approximately 18 months. 

The study’s main goal was to assess changes in the participants’ scores on the Integrated Alzheimer’s Disease Rating Scale (iADRS), a composite measure of cognition and daily life functioning. Score changes were monitored from the start of the trial until week 76, or over the course of about 1.5 years. 

Additional study goals included assessing changes in other measures of cognition, memory, and activities of daily living. The effects of treatment on the number of amyloid plaques also were assessed through brain imaging scans. 

Data from TRAILBLAZER-ALZ, now announced by the company, showed that Donanemab slowed patients’ cognitive and functional decline, based on their iADRS scores, by 32% compared with a placebo. Consistent improvements in the scores of all other cognitive and functional measures, also were observed in the patients treated with Donanemab. 

This group saw the number of amyloid  plaques drop from an average of 108 centiloids at the study’s start to 24 centiloids at week 76, deemed as amyloid negative in PET scans.  

Safety assessments demonstrated a favorable safety profile, which was consistent with reports from previous trials. 



BXCL501 Led to Fast, Safe, Durable Drop in Agitation in Dementia Patients 

BXCL501, BioXcel Therapeutics’ experimental therapy for the treatment of agitation associated with dementia, was found to be well-tolerated and able to rapidly and sustainably lower agitation in patients with different forms of dementia, including Alzheimer’s disease. 

A proprietary orally dissolving formulation of dexmedetomidine, BXCL501 is a selective agonist of alpha-2a adrenergic receptors, with potent anti-anxiolytic and sedative properties.

The study enrolled a total of 54 patients, ages 65 and older, living in assisted living residencies, who had episodes of acute agitation associated with dementia. Most of them (87%) had Alzheimer’s.  The participants were randomly assigned to receive an under-the-tongue (sublingual) dissolving thin film containing one of three doses — 30, 60, or 90 mcg — of BXCL501 or a matched placebo. 

Safety assessments revealed BXCL501 was well-tolerated and did not cause any severe or serious side effects. Daytime sleepiness, known clinically as somnolence, was the most common side effect reported in the trial, and was classified as mild in most cases. Some patients treated with the therapy’s higher dose also experienced dizziness and episodes of orthostasis, or low blood pressure shortly after standing. 

When given at a dose of 60 mcg, BXCL501 significantly reduced the scores of three scales — the Positive and Negative Syndrome Scale-Excitatory Component (PEC), the Pittsburgh Agitation Scale (PAS), and the Modified Cohen-Mansfield Agitation Inventory (Mod-CMAI) — that were used to measure patients’ agitation levels. 

These clinically meaningful reductions were observed in a period of two hours following dosing. In the case of PEC scores, differences between patients treated with BXCL501 at a dose of 60 mcg and those given a placebo started to be seen as early as 30 minutes following dosing. The differences became significant after one hour, and lasted up to eight hours post-treatment.  

Statistically significant improvements in the scores of two other agitation scales — the Agitation and Calmness Evaluation Scale (ACES) and Clinical Global Impression-Improvement Scale (CGI-I) — also were seen in patients treated with BXCL501 at a dose of 60 mcg, compared with those given a placebo, within two hours following dosing.  

Patients receiving BXCL501 at a lower dose of 30 mcg also saw their scores improve on all scales.



Non-invasive Neurostimulation Device Wins FDA’s Breakthrough Status 

Cognito Therapeutic’s neurostimulation device — a next-generation digital therapeutic designed to treat memory and cognition symptoms in Alzheimer’s disease — has been granted a breakthrough device designation by the U.S. Food and Drug Administration. The device, part of a new class of disease-modifying digital therapies, uses proprietary, non-invasive neurostimulation technology developed by Massachusetts Institute of Technology professors. 

The device uses gamma frequency technology — called GENUS, for gamma entrainment using sensory stimuli — as a way to stimulate the brain in a non-invasive way. This can be done as an auditory (via sound) or visual (via light) stimulation. 

The neurostimulation correlated with a reactivation of the neuroprotective effects of microglia, the immune cells of the brain, along with a reduction in amyloid-beta plaques and tau tangles, key hallmarks of the disease. 

Cognito launched the Overture trial (NCT03556280) in 2018 to evaluate the combination of auditory and visual GENUS, compared with a sham treatment, in 60 people with Alzheimer’s or mild cognitive impairment due to the disease.

A second trial, called Etude (NCT03661034) compared different dosing regimens in 20 people with the disease, or with mild cognitive impairment due to Alzheimer’s.

FLICKER (NCT03543878), a third study, evaluated the tolerability of the combination of auditory and visual stimulation for one hour per day for 10 people with mild cognitive impairment.

The FDA’s Breakthrough Devices program is meant to expedite the review of medical devices that have the potential to be an effective treatment or diagnostic tool for life-threatening or irreversibly debilitating diseases. This designation allows these devices to reach the market faster. 



New Technique May Enable Early Diagnosis of Alzheimer’s 

A newly developed technique could make it easier to measure very small concentrations of molecules, which may have implications in early diagnostic testing for Alzheimer’s and other diseases. 

One of the most common techniques used in biomedical laboratories is the enzyme-linked immunosorbent assay (ELISA),  which allows researchers to measure the amount of a given disease marker using antibodies that specifically recognize and bind to that target molecule. Antibodies cannot be seen binding to their targets, so the antibody in an ELISA is attached to an enzyme that, when exposed to certain substances, creates a color change. Thus, researchers can indirectly measure how much of the target is present by the extent of color change induced by the enzyme. 

Usually, the color-changing antibody used in ELISAs is horseradish peroxidase (HRP), which is found in the horseradish plant.

While HRP-based ELISAs have been effectively used in research, these ELISAs can’t reliably detect very small quantities of their targets. 

In Alzheimer’s, the protein amyloid beta 1-40 (Aβ 1-40) in the blood is a disease marker, believed to be present in the blood at very early stages of the disease but at such low concentrations that ELISAs cannot reliably detect them.

The team designed an artificial enzyme called a single-atom nanozyme (SAN), composed of single iron ions embedded in nitrogen-coated carbon nanotubes. The SAN functions similarly to HRP but,  is more efficient. The SAN is also more resistant to changes in temperature and acidity than the natural enzyme. 

The researchers then incorporated their SAN into an immunoassay functionally identical to an ELISA, which they called a SAN-LISA (SAN-linked immunosorbent assay). 

The SAN-LISA was able to detect Aβ 1-40 levels as low as 0.88 picograms (pg)/mL. This was more than 10 times lower than the limit of detection for a commercial ELISA kit (9.98 pg/mL). 



Bi-directional association between epilepsy and dementia - The Framingham Heart Study 

The objective of the study was to assess the risk of incident epilepsy among participants with prevalent dementia and the risk of incident dementia among participants with prevalent epilepsy in the Framingham Heart Study (FHS). 

The researchers analyzed prospectively collected data in the Original and Offspring FHS cohorts. To determine the risk of developing epilepsy among participants with dementia and the risk of developing dementia among participants with epilepsy, they used separate, nested, case–control designs and matched each case to 3 age-, sex- and FHS cohort–matched controls. They used Cox proportional hazards regression analysis, adjusting for sex and age. In secondary analysis, they investigated the role of education level and APOE ε4 allele status in modifying the association between epilepsy and dementia. 

 A total of 4,906 participants had information on epilepsy and dementia and dementia follow-up after age 65. Among 660 participants with dementia and 1,980 dementia-free controls, there were 58 incident epilepsy cases during follow-up. Analysis comparing epilepsy risk among dementia cases vs controls yielded a hazard ratio (HR) of 1.82 (95% confidence interval.  Among 43 participants with epilepsy and 129 epilepsy-free controls, there were 51 incident dementia cases. Analysis comparing dementia risk among epilepsy cases vs controls yielded a HR of 1.99. In this group, among participants with any post–high school education, prevalent epilepsy was associated with a nearly 5-fold risk for developing dementia compared to controls of the same educational attainment. 

Conclusions There is a bi-directional association between epilepsy and dementia. with either condition carrying a nearly 2-fold risk of developing the other when compared to controls. 



Neuropathologic burden and the degree of frailty in relation to global cognition and dementia 

The objective of the study was to test the hypothesis that degree of frailty and neuropathologic burden independently contribute to global cognition and odds of dementia. 

This was a secondary analysis of a prospective cohort study of older adults living in Illinois. Participants underwent an annual neuropsychological and clinical evaluation. The study included 625 participants (mean age 89.7 ± 6.1 years; 67.5% female) who died and underwent autopsy. 

The researchers quantified neuropathology using an index measure of 10 neuropathologic features: β-amyloid deposition, hippocampal sclerosis, Lewy bodies, tangle density, TDP-43, cerebral amyloid angiopathy, arteriolosclerosis, atherosclerosis, and gross and chronic cerebral infarcts. Clinical consensus determined dementia status, which was coded as no cognitive impairment, mild cognitive impairment, or dementia. A battery of 19 tests spanning multiple domains quantified global cognition. They operationalized frailty using a 41-item frailty index and employed regression analyses to model relationships between neuropathology, frailty, and dementia. 

Results Both frailty and a neuropathology index were independently associated with global cognition and dementia status. These results held after controlling for traditional pathologic measures in a sample of participants with Alzheimer clinical syndrome. Frailty improved the fit of the model for dementia status and explained an additional 11%–12% of the variance in the outcomes. 

Conclusion Dementia is a multiply determined condition, to which both general health, as captured by frailty, and neuropathology significantly contribute. This integrative view of dementia and health has implications for prevention and therapy; specifically, future research should evaluate frailty as a means of dementia risk reduction. 



Apathy and risk of probable incident dementia among community-dwelling older adults 

Meredith A. Bock, Amber Bahorik, Willa D. Brenowitz, Kristine Yaffe 

Objective To evaluate the association between baseline apathy and probable incident dementia in a population-based sample of community-dwelling older adults. 

The researchers studied 2,018 white and black community-dwelling older adults from the Health, Aging, and Body Composition (Health ABC) study. They measured apathy at year 6 ( study baseline) with the modified Apathy Evaluation Scale and divided participants into tertiles based on low, moderate, or severe apathy symptoms. Incident dementia was ascertained over 9 years by dementia medication use, hospital records, or clinically relevant cognitive decline on global cognition. 

They examined the association between apathy and probable incident dementia using a Cox proportional hazards model adjusting for demographics, cardiovascular risk factors, APOE4 status, and depressed mood. They also evaluated the association between the apathy group and cognitive change (as measured by the modified Mini-Mental State Examination and Digit Symbol Substitution Test over 5 years) using linear mixed effects models. 

Results:  Over 9 years of follow-up, 381 participants developed probable dementia. Severe apathy was associated with an increased risk of dementia compared to low apathy (25% vs 14%) in unadjusted (hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.5–2.5). Greater apathy was associated with worse cognitive score at baseline, but not rate of change over time. 

Conclusion:  In a diverse cohort of community-dwelling adults, apathy was associated with increased risk of developing probable dementia. This study provides novel evidence for apathy as a prodrome of dementia.