Over 10 years ago the last drug for use in people with Alzheimer’s Disease was licensed. As there are still no treatments to halt or cure the disease, the search for treatment continues. In this blog, we will explore the drug Aducanumab, which has shown promise in a recent Phase 1b trial. Recruitment for the Aducanumab Phase 3 trial , which is run by Biogen, is currently ongoing.
What is Aducanumab?
Aducanumab or BIIB037 is an antibody designed to target amyloid, the protein that builds up in the brains of people with Alzheimer’s disease at an early stage in the disease process. Antibodies are proteins that bind to other proteins, and they are mainly involved in immune processes, helping the body defend itself. As we discussed in our previous blog, many previous drugs have targeted amyloid to try and reduce the buildup of this protein in the brain. So far these drugs have been unsuccessful.
Why target amyloid?
According to the amyloid hypothesis the aggregation of amyloid is a major cause of synaptic dysfunction in the brain, which is when the communication between nerve cells is disturbed. This is thought to eventually lead to neurodegeneration, the progressive loss of structure and function of nerve cells. If this hypothesis is correct, then getting rid of amyloid should improve the outcome for patients with Alzheimer’s disease.
Phase 1b Trial: a success story?
In 2015 Aducanumab was trialled in a double-blind placebo-controlled randomised trial. This means that neither researchers nor participants were aware of whether they were taking the real drug or a placebo replacement. Participants were randomly assigned to a group at the beginning of the trial, and only at the very end, it was revealed whether they were given the medication or a harmless substitute.
In this Phase 1b trial, Biogen aimed to test different doses, and make sure that Aducanumab was safe and well tolerated in people with early memory problems and mild Alzheimer’s disease. 165 people enrolled in the trial, and received monthly injections of Aducanumab at doses of 1, 3, 6 and 10 mg/kg or a placebo for 54 weeks. One of the criteria for participation in the trial was that people had to have evidence of high levels of the amyloid protein in the brain as visible on brain scans. During the trial participants underwent brain scans, blood tests, and memory and thinking skill assessments.
The study showed that the highest dose of Aducanumab had the best effect in reducing levels of amyloid on brain scans. The image below taken from the original paper shows the dose-dependent reduction of amyloid plaques (red colour) in the brain of a participant:
Not only were the levels of protein reduced, but there also appeared to be a dose-dependent slowing the rate of decline in memory and thinking skills. Specifically, after 54 weeks participants who received the placebo did worse on the Mini-mental state exam (MMSE), a standardised test used to assess memory, than those that received Aducanumab. However, the study was too small to allow for statistical analyses. It is also noteworthy that although there was a generally dose-dependent effect, at the dose of 6mg/kg, participants seemed to do worse than at either 3 or 10 mg/kg.
Although Aducanumab was considered safe for continued development, and generally was relatively well tolerated, almost 50% of participants on the highest dose of Aducanumab experience a condition called amyloid-related imaging abnormalities (ARIA). ARIA is characterized by leakage of fluid from the blood into the brain. Other common adverse effects included headache, urinary tract infection and upper respiratory tract infection.
The results of this study were published in a paper in August 2016 in the Nature magazine. It is important to bear in mind that although Aducanumab seemed to affect memory and thinking ability and it was considered safe enough for continued trial, there were some severe side effects depending on the dose administered. In addition, the differences in memory and thinking ability were not statistically significant due to the relatively small sample size.
Current status: Phase 3 Trial
Biogen is currently recruiting participants for the Phase 3 clinical trial of Aducanumab. Participants have to be aged between 50 and 85 years and have to have a confirmed diagnosis of mild cognitive impairment or mild Alzheimer’s disease. During the trial they will undergo testing for risk genes, brain scans, blood tests, and monthly visits to the research centre to receive either the trial drug or the placebo intravenous infusion. The estimated study completion date is March 5, 2022.
As with any drug trial, there are various inclusion and exclusion criteria that determine the eligibility of a participant. These eligibility criteria are in place to enrol participants with similar characteristics, which helps ensure that any observed changes are due to the drug being tested and not due to other factors. In this manner, these criteria can help researchers achieve more accurate and meaningful results.
It is not clear whether the Phase III trial of Aducanumab will succeed. Clearly, dosage and side effects are major issues that need to be considered. However, it is a step in the right direction. Especially, since it does seem like reducing amyloid plaques in the brain is actually leading to an improvement in memory function. Although this is no cure, it may be a treatment that can slow the progression of Alzheimer’s.
In an ideal world, treatment would start at a much earlier stage, before any clinical symptoms appear. It is thought that by the time the disease manifests with signs such as memory impairment or behaviour change, changes in the brain have already been occurring for 10 to 20 years. We need to find a way to identify people at risk early on so that treatment can be preventative.
If you would like to make a contribution and volunteer for dementia research, have a look at the dementia research website or call Alzheimer’s research UK on 300 111 5 111