Monograph

4. Promising Drug Study Offers Hope to Alzheimer's Patients!

A recent drug study published in Nature has shared exciting findings in the battle against Alzheimer's disease. The Phase I clinical study aimed to investigate the safety of a human monoclonal antibody called aducanumab in patients suffering from Alzheimer's, and heartening clinical changes were detected in the process. Although preliminary data from the trial was presented at the 2015 Alzheimer's & Parkinson's Disease International Conference and the American Academy of Neurology's 67th Annual Meeting, Nature has now offered more details about the investigational drug.

As part of the double-blind, placebo-controlled study, 165 patients who were clinically diagnosed with either early onset or mild Alzheimer's were randomly given the drug or a placebo each month over a period of one year (from October 2012 to January 2014). The drug was administered to them intravenously in different doses, with patients receiving either 1, 3, 6, or 10 mg/kg. At the beginning of the study period, the patients' PET scans clearly showed beta-amyloid (amyloid beta) plaque buildup in their brains, which is largely thought to cause the cognitive impairment that is characteristic of Alzheimer's disease. After 54 weeks, patients who had been treated with aducanumab showed PET imaging with visibly reduced amyloid beta plaque in a dose and time-dependent manner. Those who had been given the highest dosage of the drug at 10 mg/ kg showed barely any plaque in their PET scan by the study's end. Furthermore, although researchers did not intend to measure clinical effects of the drug, patients scored high on a Clinical Dementia Rating and Mini Mental State Examination, indicating that they experienced a slowing down of clinical cognitive decline.

These results are prompting many experts to consider aducanumab as a possible breakthrough in the often disappointing road to finding a treatment for this debilitating neurodegenerative disease, which is the most common form of dementia. Overtime, progressive brain cell death leads to cognitive decline and memory loss, and eventually an inability for Alzheimer's patients to perform daily activities and care for themselves. Although a definitive cause of brain cell death has not yet been found, a large body of genetic, neuropathological, and cell biological evidence from post-mortem examinations of the brain points to the accumulation of amyloid beta plaque as the culprit. This type of plaque is formed when protein deposits clump together on neurons, essentially clogging up the brain and leading to synaptic dysfunction and cell death. For this reason, therapeutic agents that specifically target this toxic amyloid beta plaque have been sought after. Until now, however, it has been a challenge both to find an effective antibody that selectively targets amyloid plaques in the brain and to choose the right patient population...

Aducanumab is one of three experimental antibodies (the others being solanezumab and gantenerumab) that have been studied as candidates for Alzheimer's treatments in both mice and humans in recent years, and has been the most encouraging when it comes to benefiting Alzheimer's patients. It was developed by the multinational Massachusetts-based biotechnology company Biogen, Inc., which initiated European Medicines Agency's Priority Medicines (PRIME) Program. The program was an effort to boost development of treatments for illnesses that lack good therapeutic options. The first human trial for the drug was supported by pre-clinical investigation of amyloid plaque reduction in transgenic mice. In these mice, aducanumab penetrates the brain and binds to amyloid beta plaque, also reducing it in a dose-dependent manner. The drug is currently in the midst of Phase III clinical trials, and has a long way to go before gaining approval from the FDA. At this point, the goal is to further determine the clinical effectiveness and side effects of aducanumab, as initial trials were meant to simply ascertain how safe and tolerated it is in humans. Increasing the size of the study cohort is especially important to determine statistical significance of early phase results, because throughout the course of the Phase I trial, 20 patients dropped out due to adverse side effects. The most common of these side effects, which were mild and appeared in a dose-dependent manner, included headaches, urinary tract infections and respiratory tract infections. These were caused by what is known as amyloid-related imaging abnormalities (ARIA). Swelling of the brain is possible in severe cases of ARIA, but there were no drug-related hospitalizations or deaths of patients involved in the study. Phase III trials are ongoing in several locations around the globe, with 1350 participants involved this time around.

A number of mechanisms of action are hypothesized for aducanumab. The most likely scenario is that the drug enhances the recruitment of microglia, a glial cell that is the main immune defense cell in the central nervous system. The microglia are macrophages, which phagocytose (or eat up) amyloid beta plaque. In addition to the therapeutic effects of the drug, its mechanism of action has also provided further proof that amyloid plaque is to blame for the disease and that focus on this aspect of the disease is merited.

Despite the optimism that many experts are showing for the drug, it has its critics. After all, the track record for drug treatments aimed at Alzheimer's disease is not a good one. For over more than twenty years, upwards of 100 candidate drugs have failed in delivering positive results for those with cognitive decline, making some experts quick to caution aducanumab's potential. However, it is difficult not to feel optimistic given this latest data on the drug, especially since in just over one year, it diminished amyloid plaque that may have accumulated over decades. Despite there being some drugs which temporarily ease symptoms associated with cognitive changes in Alzheimer's patients, none have yet to cure, prevent, or halt the disease in its tracks. Commonly prescribed drugs for varying stages of Alzheimer's patients include cholinesterase inhibitors such as donepezil, galantamine, and rivastigmine as well as memantine, which regulates the glutamate receptor NMDA that is associated with learning and memory function in the brain.

For the millions of people presently living with Alzheimer's worldwide and their loved ones, any glimmer of hope is being embraced - however cautiously.

Canadians and Dementia By the Numbers

1. 564,000 people currently living with dementia

2. 25 000 new dementia diagnoses EACH year

3. 65% of pts with dementia over 65 are women

4. 937,000 projected total pts living with dementia in 15 years

5. 1.1 million people are directly or indirectly affected by dementia.

6. 10.4 bill. annual cost to canadians to care for those with Alzheimer's