Alzheimer's Drug Aducanumab

Results hint that this drug can slow Alzheimer's disease


I dislike writing articles about dementia and Alzheimer's disease. Alzheimer's disease is a sad disease.  It progresses relentlessly. The FDA-approved drugs to treat this disease like Aricept, Nemenda, and Cognex do little to slow its clinical course.

Most neurologists know that medications are of very limited value to their patients with Alzheimer's disease. Nevertheless, loved ones request these medications with the hope that these meds can help in some small way.

Ultimately, the best treatment for those with Alzheimer's disease is compassionate caregiving which not only preserves decent quality of life for the person with the disease but also quality of life for the caregiver herself.

Despite my general aversion to writing articles about Alzheimer's disease, I've agreed with myself to cover the disease only if some clinical drug trial suggests a slowing the cognitive decline in those who have the disease. Recently, very early results from trials involving Biogen's aducanumab demonstrate that this monoclonal antibody may hinder the clinical progression of Alzheimer's disease.

Alzheimer's disease is the most common form of dementia. In the United States, an estimated 5 million Americans aged 65 and older live with the disease. The course of Alzheimer's disease is slow and irreversible. Over time, Alzheimer's erodes memory, thinking, and reasoning. Eventually, a person with this terrible disease is left unable to perform even the simplest tasks and activities of daily living.​

Our current explanation for the pathology of Alzheimer's disease is limited to the "amyloid hypothesis." Specifically, neurodegeneration is attributable to the deposit of amyloid-beta (Aß) peptides in brain-tissue plaques. Accumulation of Aß drives Alzheimer's disease pathogenesis. Another contributing factor involves neurofibrillary tangles composed of tau protein.

An imbalance between Aß production and Aß clearance leads to the formation of these tangles.

To date, a bevy of different antibodies have been developed to combat Alzheimer's disease by targeting amyloid. Specifically, the antibody aducanumab works by triggering Fc-receptor–mediated phagocytosis of Aß plaques. In other words, aducanumab stimulates our own body's phagocytes to digest Aß.

In recent years, the "amyloid hypothesis" has been seriously questioned and labeled by many experts as oversimplified. We still have no clinical validation for the hypothesis, and many believe that the accumulation of Aß may be part of a larger and ill-understood process that causes neurodegeneration. More specifically, in those with Alzheimer's disease, Aß deposit precedes cognitive decline by 10 to 15 years thus clouding the proposition of a simple cause-and-effect relationship. Furthermore, the metabolism of amyloid precursor protein (APP) results in not only Aß but also other fragments which could play a role in Alzheimer's pathogenesis.

Based on interim results of a Phase 1b clinical trial of aducanumab called PRIME, Biogen has committed to a Phase 3 clinical trial of the drug. Here are some of these interim results:

  • Treatment with aducanumab resulted in a reduction of amyloid plaques in people with prodromal or mild Alzheimer's disease.
  • Reduction in plaques was visualized using PET imaging, and this reduction was dose- and time-dependent.
  • After one year of treatment, participants with early Alzheimer's disease showed a clinically significant slowing in cognitive impairment as scored by Mini-Mental Status Examination (MMSE) and Cognitive Dementia Rating.
  • The safety and patient tolerance of aducanumab was acceptable. Some adverse effects included headache and ARIA (amyloid-related imaging abnormalities).

In order for an Alzheimer's drug or any other new medication to be approved by the FDA, it must pass through Phase 3 clinical trials. As discussed in a recent article titled "Pivotal trials for b-secretase inhibitors in Alzheimer’s" from Nature Biotechnology, some drug manufacturers of Alzheimer's drugs rush to Phase 3 trials. This practice is risky because clinically insignificant results from a Phase 3 trial will shut down a drug's development. After all, nobody wants to invest in a "burnt" drug.

Just because a drug fails to show clinically significant results during one specific Phase 3 trial does not necessarily mean that the drug doesn't work. For example, it's possible that a drug could be effective at doses different from those tested. Or, some drugs work best on certain populations. Instead of passing the Rubicon and committing to a Phase 3 trial, it's a good idea to do an exploratory Phase 2 trial and better understand the drug and its effects. In contrast, Biogen has decided to proceed with Phase 3 clinical trials in light of encouraging interim results from (lower-powered) Phase 1b trials.

If you or a loved one suffers from Alzheimer's disease, please read this article within context and without false hope. Biogene is still some time away from garnering approval for aducanumab, and we still need plenty of more clinical results. Although early results concerning aducanumab are promising, Alzheimer's drugs are notorious for failing to cut the mustard, and we have yet to realize a truly effective treatment aimed at slowing this disease's progression.

Selected Sources

Article titled “The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Promise on the Road to Therapeutics” by J Hardy and DJ Selkoe published in Science in 2002.  Accessed on 3/22/2015.

Ropper AH, Samuels MA, Klein JP. Chapter 39. Degenerative Diseases of the Nervous System. In: Ropper AH, Samuels MA, Klein JP. eds. Adams & Victor's Principles of Neurology, 10e. New York, NY: McGraw-Hill; 2014. Accessed March 22, 2015

Article titled “Pivotal Trials for ß-secretase inhibitors in Alzheimer’s by Cormac Sheridan published in Nature Biotechnology in 2015.  Accessed on 3/22/2015.

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