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  • 10Mar

    Could new drug Aducanumab be the future for Alzheimer’s treatment?

    Alzheimer’s: the dreaded disease that is affecting more and more people as the population ages. At present, 850,000 people in the UK suffer from this form of dementia which generally begins in individuals from the age of 65 [1]. To begin with, patients incur short term memory loss and disorientation, but as the disease progresses, mood swings, hallucinations and loss of bodily functions occur eventually leading to death [2].

    Most cases of Alzheimer’s have no known cause, however, some cases are believed to have a genetic origin due to mutations in the genes. These genes code for proteins that are responsible for the pathology of this disease. These proteins are called β-amyloid, which form plaques around the outside of neurones (brain cells), and tau which forms neurofibrillary tangles inside the neurones [3]. The proteins interfere with communication in the brain and can result in neurodegeneration [4].  At present, there are no effective Alzheimer’s treatments that can prevent or reverse this disease, they are only capable of relieving the symptoms temporarily. So, could the newly researched drug, Aducanumab, break the mould and be the future treatment?

    What is Aducanumab?

    Aducanumab is a monoclonal antibody that is selective only for aggregated forms of β-amyloid in the brain. It enhances the activity of microglia, immune cells that digest debris in the central nervous system [4]. This drug was created by the pharmaceutical company Biogen, with headquarters in Massachusetts. The drug has successfully gone through phase 1 and 2 clinical trials. It’s awaiting phase 3 trials where the drug is tested on large numbers of patients with Alzheimer’s disease. Dr Alfred Sandrock, the chief medical officer at Biogen commented, “This is the first time an investigational drug for Alzheimer’s disease has demonstrated a statistically significant reduction on β-amyloid plaques as well as a statistically significant slowing of clinical impairment in patients with mild disease” [5].

    Evidence of its Success

    Biogen first tested Aducanumab on mice that had been genetically engineered to mimic having Alzheimer’s disease. Here they found that the drug entered the blood-brain barrier and reduced the levels of β-amyloid.

    Subsequently, this gave the green light to test the drugs on humans. A total of 166 patients in the USA with prodromal (symptoms but not the full disease) and mild Alzheimer’s disease were intravenously given either the drug at increasing doses or a placebo. The trial was double-blind so neither the scientists or patients knew what they were receiving, and lasted a duration of 54 weeks.

    This study not only measured the levels of β-amyloid in the volunteers, but also any improvements in cognition. Results showed that, compared to the placebo group, β-amyloid levels were reduced with aducanumab. The highest dose of the drug, 10 mg/kg, had the largest effect at clearing this damaging protein.

    Mini Mental State Examinations were carried out on patients to assess the drug’s ability to reduce memory and cognitive impairments. This is a 30 point questionnaire, where the lower the score, the worse the mental impairment. The individuals taking the placebo produced an average decline of 3.14 points over the trial compared to the 0.58 point average decrease shown by those taking the highest dose of aducanumab [5]. This can be used as evidence that aducanumab not only reduces levels of β-amyloid, but it also has a role in improving cognition and slowing down disease progression.

    Side Effects

    Generally, this drug was well tolerated. However, 22% of those taking aducanumab compared to 5% of the placebo group, complained of headaches [4]. There were also a few cases of urinary tract and respiratory tract infections though these were not considered severe [6]. Other adverse effects were amyloid-related imaging abnormalities (ARIA). This involves brain swelling, and was most prominent in patients receiving the highest dose of aducanumab. It was classified as being a severe effect but fortunately no patients needed to be hospitalised [4]. Therefore these undesired effects will need to be refined before it becomes available to the general public.

    The Future

    So far, this drug has proven successful in preventing the progression of Alzheimer’s in patients with prodromal or mild forms of this disease. However, there is still a long way to go until aducanumab can be sold on the market as it first has to complete phase 3 trials, which may reveal that the ARIA side effects are too serious for the drug to continue. The long term side effects will not be discovered for a while yet, but it is hoped that this method of reducing β-amyloid levels is the way forward in Alzheimer’s treatment research. Other monoclonal antibody drugs, such as Crenezumab and Gantenerumab, have shown to be safe and well tolerated after phase I clinical trials.

    By Ellen Temple, Third Year Medical Sciences

    Edited by Luke Smith

    References:

    [1] Alzheimer’s Society, (2014). Dementia 2014 report statistics. [online] Available at: https://www.alzheimers.org.uk/statistics Accessed 15 September, 2016.

    [2] Burns, A, (2009). Alzheimer’s Disease. British Medical Journal. 338 p158.

    [3] Goldgaber, D. et al. (1987). Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimer’s disease. Science. 235 (4791) pp.877-880.

    [4] Sevigny, J et al. (2016). The antibody aducanumab reduces Aβ plaques in Alzheimer’s Disease. Nature. 537 (7618) pp. 50-56.

    [5] Netzer, W, (2016). Experimental Alzheimer’s drug, Aducanumab, slows cognitive decline in early trials. [online] Available at: https://www.alzinfo.org/articles/diagnosis/experimental-alzheimers-drug-aducanumab-slows-cognitive-decline-in-early-trials/ Accessed 15 September, 2016.

    [6] Owens, S, (2016). Intravenous Aducanumab reduces Abeta plaque accumulation in patients with Alzheimer’s disease. [online] Available at: http://journals.lww.com/neurotodayonline/blog/breakingnews/pages/post.aspx?PostID=575 Accessed 15 September, 2016.

    Image: http://www.alzheimer.gen.tr/alzheimer-evreleri.html

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