Bar a few bacteria usually found hitching a ride on our dental plaque and digestive system, every living cell in the human body needs oxygen. Some cells need more oxygen that others, dependent on much energy they need to produce to function. Neurones are particularly active cells (the brain uses a fifth of all the oxygen consumed by the human body) and motor neurons are amongst the most energy hungry of all.
Unfortunately, the process of producing cellular energy isn’t 100% efficient: a small but constant amount of waste products called free radicals (yep, those things that the beauty product industry bangs on about) can build up in the cells. If not kept in check, they can start to wreak havoc within the cell.
Our cells have quite effective ways of dealing with free radicals, but these ‘cellular defences’ become less and less efficient with age. As we age, our energy production processes lose efficiency, causing a ‘double-whammy’ of not only more free radicals being produced, but also less effective ways of dealing with them. When neurones are damaged, as happens with neurodegenerative diseases, then everything gets exacerbated even further, leading to a vicious cycle of events.
This series of cellular events is commonly known as oxidative stress and there is plenty of evidence that it plays a role in motor neurone disease (MND) and other neurodegenerative diseases. However, turning the theory into treatments has proven difficult. Several antioxidant treatment strategies have been tested in clinical trials, but none have been effective. But maybe there are signs that things are changing.
Edaravone trial in MND
Japanese clinicians working with Mitsibushi Tanabe Pharma ran a 9 month study of the free radical scavenger Edaravone, which is used in the treatment of stroke. They presented their results on the final day of the Symposium.
The trial involved over 200 MND patients (half taking the drug, half on placebo). The trial, however, did not show any statistically significant benefit, although there was a trend towards slower progression with the drug. This hint of an effect led the investigators to analyse the data more thoroughly and they identified a subgroup of patients that appeared to obtain some benefit.
There is a saying that “if you torture your data long and hard enough, you can make it tell you anything” and this is particularly true in medicine, where such ‘post hoc analysis’ is always taken with a large pinch of salt. The next step therefore was to carry out a further study focused on the particular subgroup of patients. Over 130 participants took part in this trial, receiving intravenous infusion of Edaravone. The results showed a statistically significant slowing of disease progression (assessed using the Revised ALS Functional Rating Scale) over the 24-week treatment period.
Whilst these results give a glimmer of hope after so many years of negative and inconclusive trials, there are some questions that need to be answered. Why does the drug only appear to show some effect in a subgroup? Can the trial results be confirmed and, if so, can a longer term effect be demonstrated? Does the drug have an effect on survival? In addition, the drug has to be given intravenously, which may be impractical for many, plus there are key differences in the way that the Japanese population metabolises drugs compared with Caucasians, so very different doses may need to be considered for different populations.
Hopefully, some of these questions will be answered through another study. The Dutch company Treeway is developing a formulation that can be taken orally and has been shown to be safe in preliminary (Phase 1) studies. The company is aiming to start a phase 2/3 study in 2016.