Thursday, 30 July 2015

Are we Nearing an Effective Treatment for Alzheimer's Disease?

Alzheimer’s disease (AD) is the most common form of dementia worldwide, with 500,000 people currently living with the disease in the UK alone and, with an ageing population, this number is only going to increase. Despite huge efforts, there are relatively few treatments for AD and so far these all only treat specific symptoms of the disease and don’t combat the disease itself. For example, some current drugs allow brain cells (neurones) to keep communicating with each other for longer without dying, but inevitably these cells will be overwhelmed by the disease. Other people have tried to treat the disease by replacing the lost cells with new ones, but without removing the disease these cells will still die after a time too.  What is needed is a treatment that actually combats the cause of the disease itself.

This has been a very difficult task with AD, as it is not entirely certain how the disease works. It is generally believed that the misfolding of a protein, called β (beta) amyloid, is important in some way or another; generally it is believed that this is due to the formation of toxic plaques (called amyloid plaques) between brain cells although there are some other ideas about what might be going on (that’s a whole post or series of posts in itself!). But in the last few days, the news has been abuzz with what could potentially be something quite exciting, a drug that actually slows the progression of AD.

You can find some general information about the news on basically any news website, but very few of them go into any real detail about how the drug is supposed to work, or any real detail about the results and how the trials were carried out. In a sentence; after looking more closely at previous trials researchers found an effect in mild patients, so they looked into it further and found that this may actually be a disease modifying drug, there is already another trial underway that is due for completion in 2016.

This cartoon represents how amyloid plaques build up in Alzheimer's disease  
For those who want a bit more detail, I did the leg work and found the actual sources rather than just the press releases to try and see what was really going on. First there’s the drug (Solanezumab), which is an antibody against the misfolded β amyloid protein to stop it from forming plaques. Between 2009 and 2012, two clinical trials were conducted to investigate the efficacy (how effective it is) of the drug, named EXPEDITION and EXPEDITION 2. They were randomised placebo controlled trials (which means that participants (pts) were randomly assigned to be in the placebo or treatment group) with about 1000pts in each trial. The participants were all diagnosed with AD only and were not in a serious or unstable state. The primary measure (which determines whether a trial was successful or not) was the change in a cognitive score called the Alzheimer's Disease Assessment Scale - Cognitive Subscore 14-Item Scale (ADAS-Cog14) after 80 weeks of treatment. Both of these studies failed to show a statistically significant improvement in this score, and therefore officially failed as a trial. However, after doing a secondary analysis in mild patients that were caught early, there did seem to be a benefit. So an extension trial was conducted with mild patients from the trials regardless of whether they were in the treatment or placebo group, the results of which are what has been hitting the news recently.

The brain of patients with AD has severe shrinkage compared to the healthy brain, also notice the large 'gaps' in the AD brain where large areas of grey matter dedicated to functions such as memory and language have been lost. 

Because there was already a number of patients who had already been treated and an existing placebo group, they were able to perform a ‘delayed start trial’, as some participants had already been given the treatment. This was useful because it allowed the researchers to determine whether the drug was really slowing the progression of the disease or not. For example, if a drug only affects the symptoms and it has its maximal effect after 2 months, you would expect the delayed group to catch up to the early start group once the drug has had its maximal effect. But if the drug actually slows the progression of the disease, both groups will benefit, but the early start group will always remain better off, because the disease has been slowed for longer and the delayed group can’t catch up.  This is what happened in the extension trial. Because they already had data from the other trials, they could see that the difference in the cognitive scale (ADAS-Cog14) score between the early start and delayed start groups was similar to that at the end of the failed trials. This means that after 28 weeks of treatment, the delayed-start didn’t catch up (although they did see an improvement). This difference between the two groups remained statistically significant for 52 weeks, which means that the delayed start group certainly did not catch up to the early-start.

In order to further research the idea that Solanezumab really does slow disease progression, a third trial (EXPEDITION3) is already underway that uses a very similar design. There is an early-start group, a delayed-start group and a placebo group. If the primary measure (the cognitive score) is shown to be significantly improved in both treatment groups compared to placebo and that the early-start group has a significant improvement over the delayed-start, then it can be said with reasonable certainty that this drug really is disease modifying. I would then expect the drug to be approved a few years after that, which could be very, very good news indeed. 


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