Understanding the Cost of Aducanumab for Alzheimer's Prevention
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The recent expedited approval of Biogen's Aducanumab by the FDA has sparked hope among some Alzheimer's patients. However, this approval has not come without its share of debate, as highlighted by the Los Angeles Times:
> "In a decision driven as much by optimism as by scientific evidence, the FDA approved a drug aimed at treating Alzheimer’s disease despite minimal proof of its effectiveness in alleviating patient symptoms."
The absence of clear clinical benefits following two late-stage trials led an FDA advisory panel to recommend against the drug’s approval. When the vote shows 10 out of 11 members opposing it yet the decision goes ahead, it raises questions about the motives involved.
Now, let’s delve into the science behind Alzheimer's disease.
What is Alzheimer's Disease?
Alzheimer's disease is a significant challenge for many aging individuals, characterized by the accelerated death of neurons in the brain. These neurons play a crucial role in processing various types of sensory information, and their decline leads to a noticeable reduction in cognitive function and mental sharpness.
A key factor in Alzheimer's is the presence of amyloid beta aggregates. To illustrate, consider the transformation of a raw egg into a cooked one. A raw egg, composed of about 12.5% protein and 76% water, appears translucent and fluid. Cooking it removes some water and causes the proteins to refold into a stable configuration, resulting in a white, opaque solid.
Similarly, as electrical wires are prone to tangling when left unattended, amyloid beta proteins can misfold and aggregate in the brain.
Protein folding is influenced by numerous factors, including:
> "Many factors affect the process of protein folding, including conformational and compositional stability, cellular environment (temperature and pH), primary and secondary structure, solvation, hydrogen bonding, salt bridges, hydrophobic effects, van der Waals (vdW) forces, ligand binding, cofactor binding, ion binding, chaperones, and post-translational modifications."
The accumulation of amyloid beta aggregates in the brain indicates two main issues:
- The environment is fostering rapid misfolding of amyloid beta proteins, leading to aggregation.
- The mechanisms responsible for clearing these aggregates are not functioning effectively.
So, who is to blame for this situation?
What is Aducanumab, and What Can It Do?
Aducanumab is classified as a monoclonal antibody, as indicated by the “mab” in its name. Like many other biologic drugs, it is protected by a 20-year patent, allowing the patent holder to set a high price.
As a biochemical engineer, I understand the complexities of manufacturing biologic drugs. Many production processes are similar, but the significant cost increase is largely due to the protection of intellectual property through patents.
For example, Adalimumab (marketed as Humira) was the top-selling prescription drug in the U.S. in 2020, generating over $16 billion in sales. This drug manages rheumatoid arthritis symptoms remarkably well financially.
According to Biogen’s Executive Vice President of Research & Development, Aducanumab is designed to:
> "Specifically bind to aggregated forms of beta-amyloid and identify amyloid plaques in brain tissue."
In studies with transgenic mice, Aducanumab successfully penetrated the brain and attached to beta-amyloid deposits, leading to a significant and dose-dependent reduction of these pathological features.
However, the details of the clearance mechanism remain unclear.
The Natural Clearance of Amyloid Beta Plaques
Healthy human brains contain microglial cells, which function similarly to macrophages in the rest of the body. These cells perform phagocytosis to clear cellular debris and biomolecules. In the brain, microglial cells are responsible for eliminating amyloid beta plaques, thus preventing their accumulation.
However, the efficiency of this process can be compromised. If there is an accelerated rate of misfolding, the microglial cells may struggle to manage the overload of plaques, leading to their buildup.
Inflammation also plays a significant role in promoting the aggregation of amyloid beta (Alzheimer's) and alpha-synuclein (Parkinson's). While Aducanumab may assist in clearing amyloid beta plaques, it does not address the aggregation of alpha-synuclein plaques.
Could this lead to an increased risk of developing Parkinson's? Elevated levels of the pro-inflammatory cytokine tumor necrosis factor alpha (TNF-?) may pose a significant concern. Chronic inflammation in the body could weaken the blood-brain barrier (BBB), allowing harmful substances to infiltrate the brain.
The BBB serves as a protective barrier, but it can deteriorate over time. Conditions like Type 2 diabetes or heart disease can heighten pro-inflammatory cytokine levels, compromising the BBB's integrity.
As a result, substances that typically cannot cross the BBB may begin to enter the brain. Microglial cells respond by producing their own pro-inflammatory cytokines to alert other immune cells about these toxic invaders. Excessive stress can trigger similar inflammatory responses.
What happens when the concentration of these cytokines reaches a critical level? Neurons may undergo premature apoptosis, resulting in declining cognitive function over time.
If that isn't indicative of Alzheimer's, then what is?
The Need for Lifestyle Changes
Alzheimer's does not solely manifest as a cognitive decline in older age; it often stems from lifestyle choices made much earlier in life. Many habits adopted in our 30s or even earlier can contribute to this risk, especially those linked to inflammation, such as poor sleeping patterns, unhealthy eating habits, and excessive work-related stress.
Will Aducanumab help? If it functions as intended, it could facilitate the more efficient clearance of amyloid beta plaques. Yet, it does not tackle the underlying inflammatory or aggregation issues present in the brain.
At a cost of $56,000 per year, Biogen’s CEO describes this price as “fair.” This is concerning, particularly when many individuals aspire to earn $50,000 annually. Wall Street analysts had predicted a price between $10,000 and $25,000.
If the fundamental inflammatory and aggregation problems remain unaddressed, one thing is certain: while the patient's mental health may not improve, their financial situation will likely take a hit due to the ongoing expense of this partial solution.
The easiest change to implement and maintain is a healthier diet. You might be interested in exploring nutrients that support brain health in "12 Brain-Boosting Nutrients and How They Work For Supporting Brain Health."
Joel Yong, Ph.D., is a biochemical engineer/scientist, educator, and writer. He has authored five ebooks (available on Amazon.com in Kindle format) and co-authored six journal articles in internationally peer-reviewed scientific journals. His focus is on elucidating the biochemical mechanisms in the body that are often overlooked in medical education, making them accessible for better understanding.
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