Research Highlights from Padmaja Genesh - February 2021

Published: Feb 28, 2021

FDA Extends Its Aducanumab Review With Decision Expected in June

The U.S. Food and Drug Administration (FDA) has extended its review period for Aducanumab, an investigational therapy for Alzheimer’s disease being co-developed by Biogen and Eisai.

The three-month extension means the new deadline to review the compound’s biologics license application (BLA), also known as the Prescription Drug User Fee Act action date, is June 7, 2021.

Aducanumab is a synthetic, or man-made, antibody designed to remove the misfolded beta-amyloid proteins seen in brains of those with Alzheimer’s. By targeting a region of beta-amyloid that is only accessible when the proteins clump together, the antibody is expected to leave healthy beta-amyloid unaffected.

If approved, it would become the first therapy to potentially slow Alzheimer’s progression.

The experimental therapy’s path to approval has been tumultuous.

Two Phase 3 trials of Aducanumab — ENGAGE (NCT02477800) and EMERGE (NCT02484547) — were terminated in 2019, after an independent advisory committee determined that the investigational medication was unlikely to provide patients with a meaningful benefit. However, an analysis of a larger dataset, which became available after trial termination, 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.

Based on this and the results of the Phase 1b PRIME study (NCT01677572), which showed evidence that Aducanumab could slow cognitive decline, Biogen and Eisai asked the FDA, as well as its European counterpart, the European Medicines Agency, to consider approving Aducanumab.

As part of the ongoing review, Biogen submitted additional analyses and clinical data as requested by the FDA. The agency classified it as a “Major Amendment” to the medication’s application, which requires that the review period be extended.



Phase 3 Trial of Therapy for Inflammation, Insulin-sensitivity in Alzheimer’s to Open

NeurMedix has announced it will soon open a pivotal Phase 3 clinical trial of its lead investigational therapy, NE3107, for people with Alzheimer’s disease, following authorization by the U.S. Food and Drug Administration (FDA).

The trial (NCT04669028), to be conducted at about 30 clinical U.S. sites, will be looking to recruit up to 316 people with mild to moderate Alzheimer’s.

Increasing evidence supports inflammation and insulin resistance — a condition in which cells no longer respond to the action of insulin, a hallmark of type 2 diabetes — play a major role in Alzheimer’s development.  Inflammation and a defective insulin response lead to a poor uptake of sugar (glucose) by brain cells, affecting their normal function, and possibly to Alzheimer’s dementia and progression.

Despite the established role of inflammation in the disease; however, approved anti-inflammatory agents are ineffective, either due to their inability to cross the blood-brain barrier and reach the brain, or because they lack broad anti-inflammatory activity.

NE3107 is a small molecule, oral treatment designed to act as an anti-inflammatory and insulin-sensitizing agent. It works by targeting three major inflammation signaling pathways, those controlled by the extracellular signal regulated kinase (ERK), nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB), and tumor necrosis factor (TNF).

In clinical studies of people with type 2 diabetes, NE3107 inhibitory activity of ERK and NF-κB lessened insulin resistance and lowered the levels of C-reactive protein, a marker of systemic inflammation. NeurMedix believes that NE3107’s ability to reach the brain, allied with its ability to halt inflammation without additional immunosuppressive effects, makes it an attractive possibility for Alzheimer’s.

In the trial, people with mild to moderate Alzheimer’s (age range, 55 to 85) will be randomly assigned to 20 milligrams (mg) of NE3107 or a placebo capsule, twice a day for 30 weeks.

The study’s main goals include changes in the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) and the Alzheimer’s Disease Study Cooperative Study – Clinical Global Impression of Change (ADCS-CGIC), which measure cognitive function and cognitive functional and behavioral characteristics, respectively.



Troriluzole Fails to Ease Cognitive Impairments in Phase 2/3 Trial

Troriluzole, an investigational oral symptomatic treatment developed by Biohaven for Alzheimer’s disease, did not work better than a placebo in alleviating cognitive impairments and reducing brain volume loss in patients with mild-to-moderate disease, according to top-line data from a Phase 2/3 trial.

Troriluzole (BHV-4157) is a precursor of riluzole, an oral therapy that has been approved to slow the progression of amyotrophic lateral sclerosis (ALS). This therapy was designed to control the activity of glutamate, one of the most abundant and important neural chemicals in the brain.

Although glutamate plays a key role in learning and memory by stimulating brain cells, abnormal sensitivity or excessively high levels of this brain chemical can damage and even destroy nerve cells.

Treatment with Troriluzole lowers glutamate-mediated nerve cell stimulation by promoting the chemical’s reabsorption at synapses, the places where nerve cells contact and communicate with each other.

The T2 Protect AD (NCT03605667) trial sought to assess the safety and efficacy of Troriluzole at easing cognitive impairments and reducing brain volume loss, a sign of Alzheimer’s progression, in a group of patients with mild to moderate forms of the disease.

Participants were randomly assigned to receive either oral capsules containing 280 mg of Troriluzole, or a matched placebo, for 48 weeks (nearly one year).

Earlier data from the study showed Troriluzole had the potential to be superior to the placebo at improving patients’ cognition and reducing brain volume loss.

However, top-line data from the T2 Protect AD trial, now announced by Biohaven, showed that despite being safe and well-tolerated, Troriluzole failed to show superiority over the placebo at improving cognition and lowering brain volume loss in the overall population of patients participating in the 48-week study.

Yet, a subgroup analysis performed only in a subset of patients with mild Alzheimer’s demonstrated that Troriluzole led to some improvements in cognition and brain volume preservation at week 48.

Biohaven is now planning to amend the trial’s long-term extension study, which is currently underway, to allow participants with mild Alzheimer’s to be able to continue treatment. This change will allow the company to continue gathering data on Troriluzole’s potential health benefits for this patient population.



Oral Simufilam Found to Improve Cognition, Behavior After 6 Months’ Use

Simufilam, an investigational oral medication being developed by Cassava Sciences, improved cognition and behavior in people with Alzheimer’s disease after six months of dosing in a clinical trial, interim data show.

Simufilam is a small molecule that has been designed to bind to an abnormal form of the protein Filamin A (FLNA). This protein is commonly misfolded in the brains of people with Alzheimer’s. It is believed to be involved in biological processes that drive the disease. By binding to FLNA, simufilam is designed to restore the protein’s normal structure and activity.

The new interim analysis is based on data from the first 50 evaluable participants in an open-label Phase 2 clinical trial (NCT04388254) launched in March 2020. The trial, which is recruiting 100 people with mild to moderate Alzheimer’s, is now approximately 80% enrolled, Cassava said.

The medication is given to trial participants as 100 mg tablets, taken twice daily.

Results from the interim analysis showed improvements in cognition and behavior scores after six months of treatment with simufilam.

Specifically, mean scores on the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) improved by 10% at six months relative to the start of the study. At the same time, mean scores on the Neuropsychiatric Inventory (NPI) improved by 29%.

In people with Alzheimer’s, these scores usually get worse over time. Thus, Cassava stressed that an improvement is particularly noteworthy.

The interim analysis did not raise any new safety concerns about the medication. There were no serious side effects (adverse events); all reported adverse events were mild and resolved in time.

Based on this data, the estimated enrollment for this clinical trial is being expanded — from an initial goal of 100 participants up to 150.

Cassava said that the data will support further clinical development of simufilam, with a Phase 3 clinical trial planned to start later this year.



Prospective Analysis of Leisure-Time Physical Activity in Midlife and Beyond and Brain Damage on MRI in Older Adults

The objective of the study was to test the hypothesis that greater levels of leisure-time moderate to vigorous intensity physical activity (MVPA) in midlife or late life are associated with larger gray matter volumes, less white matter disease, and fewer cerebrovascular lesions measured in late life. The researchers utilized data from 1,604 participants enrolled in the Atherosclerosis Risk in Communities study.

Methods Leisure-time MVPA was quantified using a past-year recall, interviewer-administered questionnaire at baseline and 25 years later and classified as none, low, middle, and high at each time point. The presence of cerebrovascular lesions, white matter hyperintensities (WMH), white matter integrity, and mean diffusivity [MD]), and gray matter volumes were quantified with 3T MRI in late life. The odds of cerebrovascular lesions were estimated with logistic regression. Linear regression estimated the mean differences in WMH, mean FA and MD, and gray matter volumes.

Results Among 1,604 participants (mean age 53 years, 61% female, 27% Black), 550 (34%), 176 (11%), 250 (16%), and 628 (39%) reported no, low, middle, and high MVPA in midlife, respectively. Compared to no moderate to vigorous physical activity in midlife, high levels of moderate to vigorous physical activity was associated with more intact white matter integrity in late life. High moderate to vigorous physical activity in midlife was also associated with a lower odds of lacunar infarcts (a sign of reduced blood flow in the brain). High levels of physical activity of moderate to vigorous intensity was not associated with gray matter volumes.

Conclusion Greater levels of physical activity in midlife may protect against cerebrovascular sequelae in late life.



Dementia Patients Have a Greater Risk of Contracting COVID-19

A recent large retrospective study indicates that adults with dementia are two times more likely to contract COVID-19 than adults who don’t have the cognitive disorder.

The study took into account more than 60 million medical records across the U.S. Medical data from 317,000 providers and 360 hospitals in all 50 states were used in the study, which represents about 20% of the country’s population.

More than 1 million of the senior patients out of 61,916,260 people had dementia. Of that number, 810 had both dementia and COVID-19. The study was definite in its findings, and specific. People with vascular dementia have the greatest risk, according to the research, followed by presenile dementia, Alzheimer’s disease, senile dementia, and post-traumatic dementia.

One might argue that the study’s findings could be skewed because of the natural commonalities between dementia and COVID-19. However, the study accounted for these factors, including advanced years and living in a care home.

Following adjustments for age, sex, and risk factors commonly associated with COVID-19, African Americans with dementia emerged as the demographic that is most likely to contract the virus when compared with white patients with dementia. Similar findings also accompanied Alzheimer’s disease and vascular dementia.

The study notes that “preexisting dementia, especially with involvement of blood vessels in the brain (vascular dementia), predisposes patients to greater risk of morbidity and mortality from COVIDÔÇÉ19.”

Family caregivers should be vaccinated to help protect their loved ones. In the meantime, the best you can do is to make an appointment for a frail senior who is at risk. A vaccination will help protect them in the event that you become ill with COVID-19.



Grants of $4.6M to Support Trials of Cancer Therapy in Early Alzheimer’s

The National Institute of Aging (NIA) and the Alzheimer’s Drug Discovery Foundation (ADDF) have awarded $4.6 million to a team of researchers studying the potential of the cancer therapy Revlimid (lenalidomide) in treating people with early stage Alzheimer’s disease.

Two clinical trials, each supported by one of these grants, are planned. The first is now recruiting up to 30 eligible adults at its single site in Nevada.

Revlimid is an FDA-approved immunomodulatory treatment developed by Celgene (part of Bristol Myers Squibb) to treat blood cancers, such as multiple myeloma. It targets cells by binding to a specific protein called cereblon, which is involved in regulating the activity of proteins related to cell adhesion, metabolism, and division.

By binding to cereblon, Revlimid triggers the death of cancer cells by affecting these processes.

Revlimid also works as an immunomodulatory therapy, meaning it is capable of modifying and regulating certain immune system functions. It also blocks the formation of new blood vessels around tumors, preventing their growth.

The research project, “Repurposing Lenalidomide for Early Alzheimer’s Treatment,” is divided in two complementary clinical trials that aim to determine if Revlimid is safe, and if can reduce inflammation and disease biomarkers while improving cognition in patients with early stage Alzheimer’s.

The first Phase 2 trial (NCT04032626), named MCLENA-1 and sponsored by the Cleveland Clinic in cooperation with the NIA, will evaluate the safety, tolerability, and efficacy of long-term treatment with lenalidomide (10 mg daily, taken orally) compared to a placebo.

The trial is currently recruiting patients at the Cleveland Clinic Lou Ruvo Center for Brain Health, in Las Vegas.

The second study, supported by the ADDF, will also be a Phase 2 trial to evaluate the safety and effects of short-term treatment with lenalidomide in 45 patients with MCI.

In this study, patients will be randomly assigned to either lenalidomide (5 mg daily) or a placebo for six months, followed by one month washout. Researchers will measure lenalidomide’s effects on biomarkers in blood and cerebrospinal fluid, the liquid surrounding the brain and spinal cord.



Compiled by Padmaja Genesh, Learning Specialist.