Research Highlights by Padmaja Genesh October 2021

Published: Nov 01, 2021

Eisai Starting Rolling Submission to FDA for Lecanemab Approval 

Eisai has started work on a rolling submission to the U.S. Food and Drug Administration (FDA) for a Biologics License Application (BLA) for Lecanemab (BAN2401), its antibody treatment for early Alzheimer’s disease. As a rolling submission, Eisai will submit each portion of its application as it is completed. 

Lecanemab, being jointly developed by Eisai and Biogen, is an investigational antibody administered directly into the bloodstream. It is designed to specifically bind to a soluble, damaging version of the beta-amyloid protein that builds up into toxic plaques in Alzheimer’s disease

By binding to this form of beta-amyloid, Lecanemab may promote its clearance before it can create the deposits that are a key hallmark of Alzheimer’s disease. This is thought to slow disease progression in people with early Alzheimer’s. 

This rolling submission agreement for Lecanemab was based mostly on clinical evidence of benefit from Study 201, a Phase 2b (NCT01767311) trial that enrolled 856 patients who had mild cognitive impairment or dementia and a confirmed presence of beta-amyloid deposits in the brain. 

Lecanemab now is being tested in two ongoing Phase 3 trials: Clarity AD (NCT03887455) in early Alzheimer’s and AHEAD 3-45 (NCT04468659) in asymptomatic individuals who  



Hyperbaric Oxygen Therapy Found to Improve Memory in Older People 

 Hyperbaric oxygen therapy, the administration of 100% oxygen at a pressure greater than one atmosphere, has been found to prevent the biological processes responsible for the development of Alzheimer’s disease in a study using a mouse model. 

Inspired by the animal study, the team examined the ability of hyperbaric oxygen therapy to change brain blood flow and impact cognitive function in older adults. The human study (NCT02790541), called ANGIOHBOT, had enrolled 62 participants at Asaf Harofeh Medical Center, in Israel.  

HBOT was conducted for 60 daily sessions at five sessions per week within three months. Each session included 100% oxygen at two atmospheres for 90 minutes with a five-minute air break every 20 minutes. 

MRI scans showed hyperbaric oxygen therapy significantly increased blood flow in several brain areas from 16 to 23%, compared with before treatment. After HBOT, there was a significant increase in the overall cognitive score in which memory, attention, and information processing speed scores were most improved. Furthermore, the post-HBOT mean memory scores improved from 86.6 to 100.9. 

Conditions such as diabetes, obesity, smoking, and high blood pressure, affect the health of blood vessels and increase the risk of Alzheimer’s disease and cognitive decline during aging. 

Thus, treatments such as HBOT that improve blood vessel health may help enhance cognitive abilities in people experiencing declines in cognition due to Alzheimer’s or other related conditions. 



1st Phase 3 Simufilam Trial Enrolling Patients; 2nd Expected by Year’s End 

Cassava Sciences has launched the first of two Phase 3 clinical trials evaluating the safety and efficacy of Simufilam, its investigational oral treatment for Alzheimer’s disease.  

Simufilam is a small molecule designed to bind to an abnormal form of the protein Filamin A, called FLNA, found with an abnormal shape — a 3D structure — in the brains of people with Alzheimer’s. FLNA is believed to participate in the processes driving the disease. By binding to FLNA, Simufilam is designed to restore the protein’s normal structure and activity. 

The first Phase 3 trial, called RETHINK–ALZ (NCT04994483), aims to enroll around 750 people, ages 50–87, with mild to moderate Alzheimer’s across 39 clinical sites in the U.S. and Canada.  

Participants in this first study will be randomly assigned to receive either a placebo or 100 milligrams (mg) tablets of Simufilam, twice daily, for 52 weeks, or one year. 

The trial’s main goals are to determine whether Simufilam can improve cognition and participation in daily life activities compared with the placebo. 

The second Phase 3 trial, called REFOCUS–ALZ (NCT05026177), that would be launched towards the year end, will evaluate the safety and effectiveness of two doses of Simufilam — 50 and 100 mg — versus a placebo, delivered twice daily for 78 weeks (18 months).  

Previous results included in an interim analysis of an open-label Phase 2 clinical trial (NCT04388254) showed that six months of dosing with 100 mg tablets, taken twice daily, improved cognition and behavior in people with mild to moderate Alzheimer’s. 



FDA Grants Breakthrough Therapy Designation to Gantenerumab 

The U.S. Food and Drug Administration (FDA) has granted breakthrough therapy status to gantenerumab, a human antibody that’s expected to slow or even prevent cognitive decline and memory loss in Alzheimer’s disease. The FDA designation is intended to accelerate the development and review of candidate therapies with clinical evidence of substantial improvement over approved treatments for serious diseases. 

Gantenerumab, developed by Roche and its U.S. affiliate Genentech, is designed to bind and reduce amyloid-beta plaque formation in the brain, a hallmark of Alzheimer’s. 

Since it is administered under the skin (subcutaneously), the antibody has the potential to be given to patients at home, according to Roche. 

The FDA’s decision was based on clear clinical evidence from several studies, including early findings of two open-label extension (OLE) Phase 3 clinical trials, Scarlet RoAD (NCT01224106) and Marguerite RoAD (NCT02051608), and the DIAN-TU-001 Phase 2/3 clinical trial (NCT01760005). 

These Phase 3 trials showed that gantenerumab reduced the accumulation of amyloid plaques in the brain of patients with sporadic Alzheimer’s disease, as shown by positron emission tomography (PET) scans. 



Safety Board Recommends Trial of Anavex 2-73 Continues as Planned 

An independent safety board has recommended that Anavex Life Sciences continues a trial, without modification, of its oral therapy Anavex 2-73 (blarcamesine) in people with early Alzheimer’s disease.  

Anavex 2-73 is a small molecule that works by activating sigma-1, a protein receptor in the brain. Activating this receptor may lessen clinical symptoms and is 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. 

While levels of sigma-1 typically increase with age, people with Alzheimer’s tend to have lower levels of the protein receptor than their similarly aged peers. 

Anavex is expecting that top-line data from the Phase 2b/3 clinical trial, called Anavex 2-73-AD-004 (NCT03790709), will be available in the second half of 2022, according to a press release

The trial has enrolled 509 participants who have mild cognitive impairment or early-stage mild dementia due to Alzheimer’s disease, at 54 locations in Australia, Canada, Germany, the Netherlands, and the U.K. All participants are 60 to 85 years old and  

The trial is evaluating the effect of Anavex 2-73 on patients’ cognitive function and their ability to go about daily life activities. Safety and tolerability are being monitored as well. The treatment is also being tested in trials for Parkinson’s disease, Parkinson’s disease with dementia, and Rett syndrome. 



Nuravax Acquires Rights for MultiTEP Vaccine Platform Tech 

The nonprofit Institute for Molecular Medicine (IMM) has licensed its universal vaccine platform technology — called MultiTEP — to Nuravax, a biotech developing therapies for Alzheimer’s disease and other disorders of the central nervous system. 

MultiTEP is a vaccine platform that can generate very high levels of antibodies against toxic proteins that clump together in the brains of older people, driving neurodegenerative diseases. 

In the case of Alzheimer’s, the vaccines are targeted against toxic clumps of amyloid-beta and tau proteins, the two hallmarks of the disease. 

The platform combines a dozen antigen fragments (epitopes) used in previously established vaccines. An antigen is a molecule or a molecular structure that can bind to cells of the immune system and trigger an immune response.  

Together the antigen fragments induce a potent immune response and boost the production of high antibody titers by activating key cells of the immune system, namely T helper cells. 

As people age, their immune systems produce fewer of these naïve T helper cells, which are key to recognizing antigens that will trigger an immune response.  

Prior preclinical studies showed that immunization with two experimental vaccines targeting the toxic forms of amyloid-beta and tau protein triggered an immune response that reduced the levels of both proteins in the brain of a mouse model of the Alzheimer’s. 

According to Nuravax, the levels of antibodies detected in the blood of animals treated with its vaccines were significantly higher than 50,000, which is several times greater than the levels obtained with other vaccines being tested in clinical trials. 



Portable Neurostimulator Safe With Home Use, Alzheimer’s Trial Finds 

Changes in brain waves — the synchronized, electrical pulses used by nerve cells to communicate with each other — and particularly in the gamma frequency are known in people with Alzheimer’s and other neurodegenerative diseases. 

Gamma brain waves, which are subdivided in slow (range between 25-60 hertz) and fast oscillations (60–135Hz), are involved in different aspects of cognition, such as working memory or attention. 

In mouse models of Alzheimer’s as well as in patients, restoring low gamma waves has been shown to lessen cognitive symptoms, inflammation, and amyloid deposition, an Alzheimer’s hallmark.  

Actipulse Neuroscience reports that its non-invasive and wearable headset delivers fast gamma waves , which correlate with working memory in humans,  directly to the skull via its Fast Gamma Magnetic Stimulation (FGMS) technology. This is intended to activate the brain region involved with working memory. 

Particularly, the device is able to apply high-frequency and low-intensity magnetic pulses at fast-gamma frequencies directly to the skull. 

The pilot clinical trial (NCT03983655) enrolled 34 adults (age 65 and older), with mild cognitive impairment (MCI) or mild Alzheimer’s disease at a single site in Mexico. 

Participants were randomly assigned to twice daily sessions of FGMS (17 patients; mean age of 80.47) or to a sham procedure (17 patients; mean age of 82.24) for six months. 

Patients were able to use the portable headset at their home without supervision. The device is equipped with a wireless sensor, allowing researchers to evaluate treatment compliance. 

No significant differences were seen in cognition, daily life activities or depression between these groups, likely due to the small number of people evaluated, the researchers wrote. 

These findings support the safety of Actipulse’s neurostimulation device when used in the home without a healthcare’s provider supervision, the team concluded, and in an elderly population with MCI and mild Alzheimer’s. 



ACT-AD Phase 2 Trial Fully Enrolled with Results Expected Next Year 

Athira Pharma has completed enrollment in its ACT-AD Phase 2 trial evaluating the safety and efficacy of ATH-1017 in adults with mild-to-moderate Alzheimer’s disease. 

Topline results of the ACT-AD trial (NCT04491006) are expected to be available in the first half of 2022. 

ATH-1017 is a small molecule designed to improve the effects of hepatocyte growth factor and its receptor, MET, which are expressed throughout the central nervous system (brain and spinal cord). Athira hopes that ATH-1017 can help promote brain health and function. 

The investigational compound (also known as NDX-1017) is being tested in the LIFT-AD Phase 2/3 trial (NCT04488419) and was shown to be able to regenerate nerve cells and improve cognitive function in previous studies

The ACT-AD trial has enrolled 77 patients with mild-to-moderate Alzheimer’s across 14 sites in the U.S. and Australia. Patients will be given a placebo or a high (70 mg/day) or low (40 mg/day) dose of ATH-101, as a subcutaneous (under-the-skin) injection, over the course of 26 weeks. 

Patients will be evaluated for improvement in cognition, as well as global and function assessments. Additionally, electroencephalogram, quantitative electroencephalogram, and Event-Related-Potential (ERP P300), a functional measure of working memory processing speed, will be used to assess brain function.