Edaravone – a month on since the FDA announcement

It’s been over a month since the announcement by the FDA of their decision to licence edaravone / Radicava for people with MND in the USA. The speed of the FDA’s decision took the drug company MT Pharma and the MND research community by suprise. It is encouraging that edaravone has been licenced to treat MND after two decades of failed drug trials. Since the FDA announcement the effects of the drug and what it means for people with MND has been extensively discussed and some of the trial data has been published.

This blog is an update on what studies have been done on edaravone and the likelihood of people with MND noticing a beneficial effect if they were to receive it.

What do we know about the edaravone clinical trial?
In the last month a Lancet Neurology research paper has been published by the scientists at MT Pharma. This research paper described the latest of a series of clinical trials of edaravone. The trial compared those receiving the edaravone intra-venous infusions to a group of people who received the placebo, saline infusion.

The study was conducted in 137 people with ALS living in Japan, of these 69 received the drug and 68 received the placebo. Most people were taking riluzole (in each group 6 people weren’t). Those taking part received the drug for 14 days via an IV infusion for an hour every day, then had a 14 day break. Participants received five further ‘cycles’ of daily IV infusion in a pattern of 10 days of receiving the drug and 14 day breaks. People were receiving the drug or placebo for approximately 6 months.

The clinical trial was designed to see statistically significant changes in a ‘rating scale’ used to measure the symptoms of MND, called the ‘ALS Functional Rating Scale’ (ALSFRS). At the end of the 6 months of treatment those receiving edaravone had not lost quite so much function as those that were on the placebo.

How were people selected to take part in the study?
For every research study there will be ‘rules’ for selecting who is eligible to take part, known as ‘inclusion’ and ‘exclusion’ criteria. These are set up for a number of reasons, including to see whether the effect is a real one and also to protect those taking part in the study. (For example, if it is known that the new drug changes the action of existing drugs people may be taking, or makes an existing condition worse, then people who are on the conflicting drug or have that condition will be excluded from taking part). There are also lots of statistical methods used in clinical trials for working out whether any effect of the drug being tested is true or real.

How people were chosen to take part in the latest edaravone trial was based on the results of earlier clinical trials of the drug. The first trial of edaravone had a wider selection criteria. When the pharma company scientists applied their pre-agreed statistical tests, there was no overall benefit to people with MND. However, when they looked at their results in more detail, they found that there was a smaller group of people who seemed to do better than other people receiving the drug. These people had had MND for less than two years and their MND hadn’t progressed very much (according to the ‘ALSFRS’ I mentioned above). The last trial only recruited people with MND in this subgroup.

What does a change in the rating scale mean?
The results of the second clinical trial showed that people receiving edaravone had a better ALSFRS score than those who received the placebo.

The score of the ALSFRS is out of 48, where 48 is the best score anyone can get. People with MND lose points on this scale as their disease progresses. On average people receiving edaravone lost less points (loss of 5 points) than those on the placebo (loss of 7.5 points). Those on edaravone were 2.5 points ‘better off’.

The scale gives people a mark out of 4 for 12 different things (where 4 is good). The 12 categories range from handwriting, to climbing the stairs, to what your breathing is like. The published data doesn’t say which of these 12 categories the 2.5 points are saved from.

How have MND researchers reacted to the news?
From the information that we’ve seen and heard, what this 2.5 points saving in the ALSFRS means has debated a lot, both in questions that we’ve received into the Research team at the MND Association and also by neurologists. To MND researchers and clinicians it doesn’t feel like a big effect.

When the results were published in the Lancet Neurology paper mentioned above, a separate comment article was published alongside it, giving the views of the authors on the edaravone clinical trial. The article was written by Professors Orla Hardiman and Leonard van den Berg from Trinity College Dublin and Utrecht Medical Center in The Netherlands respectively.

They highlighted a number of limitations of the research so far. These include the strict rules for including people in the study, the way that the group of people who were included were selected and the (short) length of time that people received the drug. I’ve given more information on their comments below:

Strict rules for including people – From data from the population registers of MND in Ireland and The Netherlands, Professors Hardiman and van den Berg estimate that as few as 7% of all people with MND would have met the rules for taking part in this study. This suggests that there is only evidence of an effect in a very small number of people with MND.

Selection of who to include in the study – Increasingly, researchers think that sub-groups of people with MND may react differently to different drugs. There is a great deal of research underway in looking at ways of identifying these subgroups of people. This has focussed on being able to group people together according to a common set of biomarkers – these might be a specific pattern of chemicals in the blood or in the cerebrospinal fluid (CSF). (CSF is a fluid that surrounds the brain and spinal cord). The researchers comment that no chemical markers were used to identify the group of people with MND who received edaravone, and so questioned how accurate or robust the allocation of the sub-groups were.

Short length of time drug was tested for – Many MND clinical trials run for 12 to 18 months – a requirement set out by the licencing authority in Europe the European Medicines Agency (EMA). Studying the effects of a drug over this length of time allows more detailed information to be collected. This includes the effect (good or bad) of the drug on people with MND for longer periods of time – including how long people with MND live with the disease. The researchers conducting the edaravone trial didn’t look at whether the drug meant that people with MND lived for longer if they took the drug. As the edaravone study ran for approximately six months, we do not have any information on the longer term effects.

Getting edaravone in Europe
For the drug to be available in Europe it would require the drug company to request that the EMA review their clinical trial data. In turn the EMA would have to approve the drug. For the UK this would then need MHRA approval and an assessment of the health benefits / cost effectiveness of the drug by NICE. Currently we’re uncertain of progress or plans in this area. We don’t know whether MT Pharma have begun conversations with the EMA (we have asked them). EMA have stricter guidelines than the FDA on approving drugs – including, as mentioned above, that they like to see data over a long period of time, and also on whether the drug can extend life.

We will be posting updates on edaravone on this research blog as we learn more.