Aducanumab: Promising New Treatment For Alzheimer’s Disease
Written By: Nathaniel Nguyen; Edited By: Anastasia Leones and Sherin Lajevardi
For the first time in 20 years, the FDA has approved a new therapeutic treatment for Alzheimer’s disease. Developed by the pharmaceutical company Biogen, Aducanumab (common name Aduhelm) aims to revolutionize the Alzheimer’s treatment process. While there is no currently approved cure for Alzheimer’s disease, results of early phase clinical trials indicate a promising future.
A well known characterization of Alzheimer’s disease throughout its progression is the connection with Beta-Amyloid plaque buildup. The term beta-amyloid refers to a peptide chain thought to be involved in various cellular processes, from cholesterol transport to kinase activity in the cell. Degradation of the beta-amyloid molecule has been observed to typically occur during sleep, however in Alzheimer’s disease, it has been observed to occur at a slower rate. Beta-amyloid buildup in the brain forms plaque structures that lead to an effect on calcium ion channel homeostasis (known as the BAD hypothesis). Due to the prominent role of calcium balance in the cell signaling pathway, plaque buildup poses a great issue to brain health and function. When this balance is disrupted, neural cells are unable to trigger necessary signals for cells to function and receive important nutrients or removal of waste products, resulting in massive cell deaths. As Alzheimer’s progresses further, more neural cells are gradually lost leading to overall body function deterioration, typically signified by memory loss.
Existing treatments mainly target ways to control and contain symptoms of Alzheimer’s, specifically memory recollection difficulties. With Aducanumab, pharmaceutical company Biogen, becomes the first to get any form of FDA approval for a treatment designed to eliminate and prevent the spread of Alzheimer’s altogether. Aducanumab is an antibody treatment that marks these amyloid plaques for degradation. The immune system then acts to break up the plaque to reduce their densities in patients’ brains.
Recent peer-reviewed literature does reveal that from an imaging standpoint, Aducanumab does appear to successfully reduce plaque. Human clinical trials of Aducanumab reveal that there does appear to be a reduction in beta-amyloid plaques during treatment. To evaluate Aducanumab in relation to beta-amyloid plaque buildup, an experimental clinical trial was conducted over a one year period. Evidence of beta-amyloid presence was evaluated based on PET scan image results. Quantification of data was analyzed using PET standard uptake value ratio (SUVR; a measurement of expression/absorption readings) taken at baseline (Week 0) and after one year (Week 54). In a PET scan, beta-amyloid plaque presence would correspond with a higher SUVR value. The average initial SUVR reading was reported to be 1.44 at baseline and 1.16 after one year period (Sevigny et al, 2016). Over the course of one year of Aducanumab usage, there was an observed 20% decrease in the SUVR measurement. The difference between the two readings was determined to be statistically significant, indicating that there does appear to be a clear correlation with aducanumab usage and the reduction of beta-amyloid.
As with most treatments, targeting essential organs in the human body can often lead to detrimental side effects. The most common side effects of neurological medications are amyloid-related imaging abnormalities (ARIA) and brain edema evidenced in MRI scans. ARIA’s refer to regions of the brain that appear to have breakdown of epithelial tissue of the blood-brain barrier, signifying edema (fluid/pressure buildup) or hemorrhaging. Researchers investigated Aducanumab dosages of 0, 0.3, 1, 3, 10, 20, 30 , 60 mg/kg and correlation with ARIA-E (ARIA of the cerebral cortex specifically) collected data via a clinical trial in a double-blind study of early to mid stage Alzheimer’s patients. Each treatment group involved 6 patients. ARIA-E’s were observed to be 14%, 17%, 17%, 0%, 17%, 17%, 50%, and 100% (Ferrero et al, 2016). Based on the indicated results, it appears that there is no significant difference in the ARIA-E risk for dosages below 30 mg/kg, while having extreme risk for ARIA-E at high dosage (60 mg/kg). The extreme levels observed in the results may be caused by the small sizes of the treatment groups involved.
Currently, there remains strong opposition towards the FDA’s early approval of Aducanumab. The argument made is that the FDA has granted approval too early in the process, citing how the side effect rates of edema and brain swelling are still too high to be considered safe. The main worry is that the standard for efficacy has been gradually decreasing as there has been a drought in the well of progress for new Alzheimer’s treatment in recent years.
Whether or not the FDA’s approval of Aducanumab is a step in the right direction is open for debate. However, one thing remains clear: there is a need for further clinical trials investigating Aducanumab. Most early phase trials of Aducanumab involved short time frames typically lasting around one year. Lengthier studies would be necessary to determine long term effects of Aducanumab and whether the treatment can still be successful. Another concern with a majority of the current studies of Aducanumab is that multiple external factors were unable to be controlled and accounted for (Sevigny et al, 2016; Ferrero et al, 2016). Due to the old age of the group of interest, most patients have other underlying health conditions or were taking other medications that may have impacted their treatment process. This led to differences observed in effectivity and tolerance between mentioned sources. Further studies looking into how other medications work in conjunction with Aducanumab are necessary to understand effects and implications. Additionally, these studies can be expanded to test the viability of Aducanumab with other Alzheimer’s therapeutic remedies (specifically with those that reduce the risk of edema) to determine whether more effective or safer outcomes can be achieved.
Biogen is currently looking to conduct confirmatory trials of Aducanumab and will release completed results on the safety and effectiveness of their product in 2030. While research into Aducanumab effectivity and tolerance still has a long way to go, the treatment has shown great progress in early phase research successes.
References:
[1] Sevigny, J., et al (2016, August 31). The antibody aducanumab reduces AΒ plaques in alzheimer’s disease. Nature News. https://www.nature.com/articles/nature19323
[2] Ferrero J, et al. First-in-human, double-blind, placebo-controlled, single-dose escalation study of aducanumab (BIIB037) in mild-to-moderate Alzheimer’s disease. Alzheimers Dement (N Y). 2016 Jun 20;2(3):169–176. doi: 10.1016/j.trci.2016.06.002. PMID: 29067304; PMCID: PMC5651340.
[3] Cajigal S, et al. What FDA’s Controversial Accelerated Approval of Aducanumab Means for Other Neurology Drugs. Neurology Today. https://journals.lww.com/neurotodayonline/fulltext/2021/08050/what_fda_s_controversial_accelerated_approval_of.1.aspx
[4] Andrew E. Budson, M. D. (2021, July 15). A new alzheimer’s drug has been approved. but should you take it? Harvard Health. https://www.health.harvard.edu/blog/a-new-alzheimers-drug-has-been-approved-but-should-you-take-it-202106082483
