Promising Treatment Developments for Neurodegenerative Diseases

By: Quantis guest author Dr. Nash Rochman, Computational Biologist

Forward by Rick Gurz: I am excited to bring in a guest author today, Dr. Nash Rochman. He is a research fellow at the National Institutes of Health. Dr. Rochman will discuss how a few novel approaches targeting diverse aspects of Alzheimer’s disease onset and progression are likely to dramatically alter the landscape of treatment for neurodegenerative diseases.

The Costs of Alzheimer’s Disease

The statistics for people battling neurodegenerative diseases are sobering. Approximately 30% of individuals 85 and older in the U.S. are battling Alzheimer’s. Parkinson’s disease affects up to 2% of individuals over the age of 65. While less common, there are up to 15,000 people living with ALS (also known as Lou Gehrig’s disease) in the U.S. While each condition and every individual affected is unique, much like different cancers, neurodegenerative diseases share many things in common and the study of one may lead to improved therapies for others bringing enormous social and economic impact.

The lifetime cost of Alzheimer’s care is estimated at nearly $350,000 which far exceeds treatment costs for most individuals affected by cancer or heart disease. There are currently over 250 ongoing clinical trials on Alzheimer’s disease and related dementias. These trials are collaborative efforts among universities and hospitals as well as at least 28 private and 2 public companies with many seeking novel approaches for Alzheimer’s treatment. Even nearer to reaching patients, Biogen and Eli Lily both have drugs that have recently been approved or received breakthrough therapy designation from the FDA.

The Road to a Cure

How does Alzheimer’s affect the brain? Plaque, primarily composed of beta amyloid protein, accumulates in the brain. Directly clearing beta amyloid from neurons is extremely challenging. Biogen’s anti-plaque antibody Aducanumab (sold as Aduhelm), as well as Eli Lily’s Donanemab, broadly work by binding to these plaques and breaking them up through direct action as well as eliciting an immune response. These drugs are bringing renewed hope that anti-plaque therapeutics may finally bring significant improvements to patient health. However, anti-plaque therapies have a long history yet have demonstrated limited success to date, motivating other groups to seek alternative approaches including Cassava Sciences and Athira Pharma.

On the road to plaque formation, beta amyloid interacts with another protein called tau, which can interrupt normal tau function and lead to the disruption of microtubules, which play a critical role in maintaining the “skeleton” of the cell. These interactions with tau involve other proteins as well which are more readily targeted than beta amyloid itself. One of these proteins is called Filamin A, which takes on an altered shape when influenced by beta amyloid.

Cassava’s Approach

  • Cassava’s pharmaceutical Simufilam works by restoring the normal shape of Filamin A, making it more difficult for beta amyloid to disrupt the cell skeleton. In clinical trials, Simufilam has been demonstrated to reduce Alzheimer’s biomarkers and has the potential to improve cognition.
  • Additionally, Cassava is working on a blood test, SavaDx, which may be used to measure the amount of altered Filamin A and could potentially detect Alzheimer’s disease before symptoms appear. They are demonstrating promising early clinical results.
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Athira’s Approach

  • Athira’s lead therapeutic candidate, ATH-1017, targets a repair pathway called HGF/MET. ATH-1017 increases HGF activity, which may result in broad, significant improvements to brain health. The HGF/MET pathway is involved in immune regulation and blood flow in the brain as well as maintaining or restoring connections between neurons. ATH-1017 has the potential to rapidly improve memory function and is being investigated for use in the treatment of Parkinson’s disease as well.
  • One of the challenges associated with the development of therapeutics for neurodegenerative disease is the measurement of cognitive function. Athira is able to leverage traditional clinical tools which measure electrical activity in the brain to investigate the early effects of therapeutic intervention. These measurements can be thought of as a “middle ground” between blood tests (which are only useful if the proteins tested for are an accurate measure of cognition) and explicit cognitive tests. While explicit memory and response tests are ultimately what must be demonstrated to prove efficacy, intermediate measurements of cognitive health enable faster, standardized assessments.

In the future, first-generation interventions focused on plaque clearance including Biogen’s Aducanumab and Eli Lily’s Donanemab may be combined with those preventing plaque formation and others that boost existing repair pathways, together leading to the maintenance and restoration of cognition.

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