Research Highlights from Padmaja Genesh (September 2020)

Published: Sep 30, 2020

Technique That Opens Blood-Brain Barrier May Help Target Treatment, Study Says

A new non-invasive technique that can temporarily “open” the blood-brain barrier may make it easier for promising therapies to enter the brain of people with Alzheimer’s disease, a study reports.

The blood-brain barrier is made of a “wall” of cells tightly bound together by protein structures called tight junctions that act like a kind of “cement.”

This barrier surrounds blood vessels in the brain and spinal cord (central nervous system or CNS) to separate the bloodstream from the tissues within the CNS and prevent the passage of cells, particles, or microbes that might disrupt the normal function of the CNS.

However, the blood-brain barrier also limits the use of potentially effective medicines, immunotherapy, gene therapy, and other treatments, which may not be able to enter the brain in the necessary amounts.

In recent years, scientists have developed a technique called magnetic resonance-guided focused ultrasound (MRgFUS), that would allow a non-invasive, reversible “opening” of the blood-brain barrier in precise areas of the brain.

To do this, doctors inject microscopic bubbles into the patient’s bloodstream, which are then exposed to a focused ultrasound through a treatment helmet attached to a magnetic resonance imaging (MRI) table. This causes the bubbles to start oscillating and open small “holes” in the “cement” that joins together the cells of the blood-brain barrier. In a previous Phase 1 clinical trial (NCT02986932), the MRgFUS technique was shown to safely open the blood-brain barrier in Alzheimer’s patients. Now, researchers at the institute, in partnership with the Weill Cornell Medical Center, are conducting a multicenter Phase 2 clinical trial (NCT03671889) with the goal of evaluating the safety and feasibility of using MRgFUS to temporarily open the blood-brain in the hippocampus and the entorhinal cortex in people with early-onset Alzheimer’s disease. Although the trial is still ongoing and recruiting, the team has now reported on results from six patients with early Alzheimer’s disease (five women and one man between 55 and 73 years old) who participated in the study.

Each MRgFUS session was administered two weeks apart, with each patient receiving two to three sessions, for a total of 17 treatment sessions. In all sessions, there was an immediate opening of the blood-brain barrier and the barrier was seen to close again within 24 hours without any adverse cognitive changes or neurological events, in the short-term and even after 15 months.



First Patients Dosed in Annovis Bio’s ANVS401 Trial, Delayed Due to COVID-19

The first three patients have been dosed in a Phase 2a clinical trial investigating Annovis Bio‘s lead compound ANVS401 as a treatment for people with early Alzheimer’s and Parkinson’s diseases, the company said.

The trial (NCT04524351) will recruit up to 68 participants at 15 sites scattered across the U.S. Thus far, only the sites in Florida and Utah are open for enrollment. The remaining sites are in high COVID-19 areas and will open when the disease is less rampant.

Diseases like Alzheimer’s and Parkinson’s are characterized by the buildup of toxic protein aggregates, or clumps, that interfere with normal neuronal processes, and eventually causes the premature death of nerve cells. In Alzheimer’s, both beta-amyloid and tau accumulate in the brain, while clumps of the alpha-synuclein protein are the hallmark of Parkinson’s. ANVS401 is an oral medication that prevents all three proteins from being made, acting as a potential treatment for both conditions. In addition to lowering the brain levels of these proteins in humans and animals, ANVS401 — which also is known as Posiphen — was seen to restore memory and learning in Alzheimer’s mouse models and to lessen gut problems in models of Parkinson’s. An ongoing Phase 2a trial called DISCOVER (NCT02925650) is investigating ANVS401 in people with early Alzheimer’s disease. Up to 24 participants will be enrolled and randomly assigned to receive one of three ANVS401 doses – 60 mg, 120 mg, or 180 mg – or a

placebo. The goal is to determine the safety and tolerability of this 23-25 day treatment, and to determine changes in disease biomarkers, cognitive and mental status, and neuropsychiatric symptoms.

Initial data from this trial is expected in early 2021, and final data by late summer 2021.



Phase 3 Trial of AXS-05 to Treat Agitation in Alzheimer’s Likely by Year’s End

Axsome Therapeutics announced plan to soon open a Phase 3 clinical trial of AXS-05, its investigational oral treatment for Alzheimer’s disease-related agitation, after U.S. Food and Drug Administration (FDA) officials confirmed an earlier study was pivotal.

Results from this new efficacy trial, to open before year’s end, are expected to support a new drug application (NDA) seeking regulatory approval of AXS-05 from the FDA. Feelings of agitation are common symptoms of Alzheimer’s, experienced by up to three-quarters of people with the disease. AXS-05 has two active components: dextromethorphan and bupropion. Dextromethorphan works by modulating the activity of neurotransmitters (signaling molecules in the brain) that are believed to impact behavior and cognition in people with Alzheimer’s, including glutamate, serotonin, and norepinephrine.

Bupropion, an antidepressant, also affects the activity of neurotransmitters. It is believed to stabilize dextromethorphan, increasing its effectiveness.

Top-line results from the Phase 2/3 ADVANCE-1 clinical trial (NCT03226522) showed that AXS-05 was generally safe and well-tolerated by Alzheimer’s patients. Treatment significantly eased agitation, with significantly more people given AXS-05 showing a clinical response (defined as a 30% or greater change in CMAI scores), compared with those given placebo (73% vs. 57%). Based on these results, AXS-05 was designated a breakthrough therapy by the FDA. In this case, Axsome reported that the FDA at a meeting confirmed that favorable results of an additional Phase 3 trial, comparing AXS-05 tablets with a placebo, would likely support an NDA. The upcoming trial will follow a randomized-withdrawal design: first, all participants will be given AXS-05 in an open-label manner. Then, those patients who respond to treatment will be randomly assigned, in a double-blind manner, to either continue treatment with AXS-05 or switch to a placebo.

The basic idea behind this study design is to see whether those who initially experience a benefit stop doing so when moved to a placebo, indicating that the therapy itself is effective — as opposed to results being due to a placebo effect.



Sumifilam Lowers Levels of Multiple Biomarkers of Disease Activity, Trial Shows

Sumifilam, formerly known as PTI-125, is a proprietary small oral molecule that has been designed to bind and restore the normal shape and function of filamin A (FLNA), a protein that is misfolded in patients with Alzheimer’s and is thought to contribute to the accumulation of toxic protein clumps (aggregates) inside nerve cells. Data from a previous open-label Phase 2a study (NCT03748706) had shown that, when given at a dose of 100 mg twice per day, Sumifilam was able to lower the levels of several disease biomarkers in 13 patients with mild-to-moderate Alzheimer’s within a period of 28 days.

These promising findings led the company to launch a larger, double-blind, placebo-controlled Phase 2b trial (NCT04079803) to confirm the positive effects of Sumifilam on Alzheimer’s disease biomarkers. Funded by the National Institutes of Health (NIH), the study enrolled 64 patients with mild-to-moderate Alzheimer’s who were randomly assigned to receive one of two doses (50 or 100 mg, twice daily) of Sumifilam or a placebo, for a period of 28 days.

The study’s main goal was to assess if Sumifilam would be superior to the placebo at lowering the levels of several biomarkers of disease activity, neurodegeneration, and inflammation in the cerebrospinal fluid (CSF). Among the disease activity biomarkers assessed were total and phosphorylated tau and beta-amyloid protein. Neurogranin and neurofilament light chain were two neurodegeneration biomarkers evaluated, while YKL-40, sTREM2, and interleukin 6 were inflammation biomarkers that were assessed. The levels were examined over the 28-day period. Although top-line data from the trial failed to show Sumifilam was superior to a placebo at lowering the levels of certain disease biomarkers, updated study findings (based on a new analysis) now showed that, compared with a placebo, both doses of Sumifilam were able to significantly lower the CSF levels of all biomarkers within a period of 28 days. In general, reductions tended to be stronger in patients receiving the highest dose of the therapy. These responses were seen in 98% of the study participants who were given Sumifilam during the trial.

From all biomarkers assessed, the ones whose levels dropped the most, in the higher dose group, were sTREM2 (up to 46%), neurogranin (up to 43%), and neurofilament light chain (up to 34%). The ones that dropped the least, in the higher dose group, were phosphorylated tau protein (up to 11%), interleukin-6 (up to 11%), and YKL-40 (up to 12%). Sumifilam also improved patients’ cognitive abilities, particularly their episodic and spatial working memory, compared with the placebo (effect size of 46% vs. 17%). These improvements in cognition also were found to be correlated with reductions in the CSF levels of phosphorylated tau 181 (p-tau181). Treatment with Sumifilam also was found to be safe and well-tolerated. A Phase 2 open-label extension study (NCT04388254) is currently ongoing. This long-term extension study aims to enroll approximately 100 participants to evaluate the long-term safety and efficacy of Sumifilam, when given at a dose of 100 mg twice per day, for one year.



Specific Tau Protein Shows Potential as Blood Biomarker in Early Studies

A specific form of the tau protein, called phosphorylated-tau-217 or p-tau217, may function as a blood biomarker of Alzheimer’s disease, and allow the development of blood tests to accurately diagnose the disease at earlier stages. These are the findings of three studies presented during the recent Alzheimer’s Association International Conference (AAIC) 2020.

The brains of those with Alzheimer’s disease show accumulation of tau protein aggregates, which are thought to precede the loss of nerve cells, shrinkage of the brain, and cognitive impairment. P-tau217, a modified form of tau which is phosphorylated at residue 217, seems to be the most specific to Alzheimer’s and the earliest to show measurable changes. Researchers with the University of Lund, in Sweden, found evidence that blood levels of p-tau217 might serve as an early diagnostic biomarker for Alzheimer’s.

Their study examined over 1,400 cases and blood p-tau217 distinguished Alzheimer’s from other neurodegenerative disorders with a diagnostic accuracy between 89 and 98 percent.

According to the team, “the diagnostic precision of blood p-tau217 was as high as established diagnostic methods, including positron-emission tomography (PET) imaging and cerebrospinal fluid biomarkers, which are invasive, costly and less available.”

P-tau217 levels measured in both CSF and blood outperformed other experimental biomarkers, including p-tau181, neurofilament light chain, the amyloid beta 42/40 ratio and established magnetic resonance imaging (MRI) in differentiating Alzheimer’s dementia from non-Alzheimer’s neurodegenerative diseases.

The researchers also found that changes in p-tau217 seen in blood samples associated with Alzheimer’s-related brain changes — thought to be related to amyloid plaque accumulation — were also observed in tissue samples analyzed after death. Importantly, in individuals with a particular Alzheimer’s-causing gene, PSEN1 , levels of p-tau217 began to increase about 20 years before the onset of cognitive impairment.

In another study, “Mass spectrometry measures of plasma Aβ, tau and p-tau isoforms relationship to amyloid PET, tau PET, and clinical stage of Alzheimer’s disease,” researchers with Washington University School of Medicine in St. Louis suggested that a blood test measuring both amyloid and tau may lead to earlier and more accurate dementia diagnoses.

The team reported that only some p-tau variants measured in the blood correlated with levels found in cerebrospinal fluid (CSF) and measured by PET imaging. Of these, p-tau217 correlated with the growth of amyloid plaques in the brain more than that of the better-known p-tau181.

These data came from a study of 1,100 participants in the greater St. Louis area, to help guide development and validation of blood-based Alzheimer’s biomarkers. Finally, researchers with the UCSF Memory and Aging Center] reported that blood plasma levels of both p-tau217 and p-tau181 could distinguish between Alzheimer’s and a neurodegenerative disease known as frontotemporal lobar degeneration (FTLD) or frontotemporal dementia.

Overall, p-tau181 demonstrated a 91% accuracy and p-tau217 a 96% accuracy in predicting whether a person had a tau positive brain scan, reflecting the results obtained through PET imaging of the brain.


Compiled by Padmaja Genesh, Learning Specialist