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.

Collaborating to find treatment for MND

21 June – MND Awareness Day

Each year, the MND Association dedicates the month of June to raising MND awareness. This year, we focus on the eyes – in most people with MND the only part of their body they can still move and the only way left for them to communicate. Alongside the Association-wide campaign, the Research Development team selected six most-enquired about topics, which we will address through six dedicated blogs. 

It is at the heart of the Association to fight MND by funding and promoting research into understanding the disease so that we can defeat it. However, we would not be able to fight this battle on our own and the support of various people is crucial to defeat this MND monster.

Everyone working in the field of MND research has one aim – to find what causes this disease and find a treatment to cure it. We have already written about the long elaborate process behind developing and licensing new drugs but we have not yet talked about the people who are essential for this process to run successfully. Continue reading

Life of an MND researcher: part 1

Each year, the MND Association dedicates the month of June to raising MND awareness. This year, we focus on the eyes – in most people with MND the only part of their body they can still move and the only way left for them to communicate. Alongside the Association-wide campaign, the Research Development team selected six most-enquired about topics, which we will address through six dedicated blogs.

We all know that rigorous research is the key to finding a cure for MND. Scientists are working hard every day to find the causes of MND, developing new treatments that would help tackle the disease and also looking for new ways to improve the quality of life of people currently living with the disease. But what does it take to have research at heart of everything you do? What is the typical day in the life of a researcher and what does carrying out a research study actually involves?

We asked eight researchers to give us an idea of what their research is all about and what their typical day looks like. Read about four of them in the following blog and keep an eye out for ‘Part 2: PhD edition‘ in the next few days… Continue reading

How is tissue donation helping us to solve the MND puzzle?

Each year, the MND Association dedicates the month of June to raising MND awareness. This year, we focus on the eyes – in most people with MND the only part of their body they can still move and the only way left for them to communicate. Alongside the Association-wide campaign, the Research Development team selected six most-enquired about topics, which we will address through six dedicated blogs.

Last year, I wrote about our trip to a brain bank. Here, we learned about how people can arrange to donate their tissue (brain and spinal cord) to tissue banks after they die, and how it is stored and used in MND research all around the UK.

What you might be asking is: what can tissue actually tell us about MND, and how will this help us find new treatments?

To find new drugs that can beat this disease we first need to understand what is going on in the brain, which is very difficult to study in living people. This is why post-mortem tissue from people with MND is an invaluable resource. Below are four reasons why tissue donation is so important. Continue reading

Stem cells and MND

Each year, the MND Association dedicates the month of June to raising MND awareness. This year, we focus on the eyes – in most people with MND the only part of their body they can still move and the only way left for them to communicate. Alongside the Association-wide campaign, the Research Development team selected six most-enquired about topics, which we will address through six dedicated blogs.

In this blog I’ve chosen to write about two examples of how stem cells are used in MND research – one example from a stem cell therapy clinical trial and the other example from how stem cells are used in the lab. Before explaining these in more detail, I felt it would be helpful to have a brief introduction to stem cells – and signpost you to other sources of information along the way.

Introducing stem cells
Stem cells are basic cells that have the potential to grow into any cell type – whether that’s heart cells or liver cells, muscle or motor neurones. Another way of putting it is that stem cells are cells that don’t know what they want to be when they grow up. To realise their potential and to convert themselves into other cell types, stem cells need triggers from the body – or chemicals added in the lab – that push them towards becoming more specialised cells. Continue reading

The journey of a drug – what it takes to be approved

Each year, the MND Association dedicates the month of June to raising MND awareness. This year, we focus on the eyes – in most people with MND the only part of their body they can still move and the only way left for them to communicate. Alongside the Association-wide campaign, the Research Development team selected six most-enquired about topics, which we will address through six dedicated blogs.

So far, there is no cure for MND. In the past 22 years, we have only seen approval of two drugs that were either shown to prolong the life of MND patients by several months (riluzole in 1995 in the US) or to slow down symptom progression (edaravone in 2015 in Japan). It is only reasonable that you might wonder ‘what is taking so long?’ or ‘why are there not more drugs available?’.

It is very competitive in the world of medicinal drugs. From thousands of chemical compounds that are gradually eliminated as they go through different stages of drug development, only one makes it near the finish line. This line represents approval for marketing authorisation and there is no guarantee that this ‘top compound’ will actually make it to the end. So let’s have a closer look at the individual stages that a potential drug has to go through in order to be crowned the champion. Continue reading

Edaravone (Radicava) approved to treat MND in USA – what does this mean for people with MND in the UK

On Friday 5 May in America, the FDA, the organisation that approves drugs, announced that they’d granted a licence for the drug known as a Edaravone (to be marketed as Radicava ) for the treatment of MND. It’s unexpected news and we’re currently working out what this means for people with MND in the UK. Below is more information on what we know so far:

Continue reading

ANXA11 – another gene closer to understanding ALS

A new research paper has been published today in the Science Translational Medicine journal, describing a new gene implicated in developing MND. What is this gene and why is it important for our fight against MND?

Although they are not the sole cause of MND, genes play a big role in someone’s probability of developing the disease. A number of such genes that make a person susceptible to developing MND have already been identified, with most of them causing the rarer, inherited form of the disease.

A new addition to a list of genes that are related to development of ALS, the most common form of MND, has been discovered by researchers from King’s College London. Dr Bradley Smith and colleagues screened genetic data of an unusually high number of people of European origin: 751 with inherited – familial – ALS (fALS) and 180 with non-inherited – sporadic – ALS (sALS). Detailed analysis of this data found that specific mutations in the ANXA11 gene are associated with around 1% of all fALS and 1.7% of all sALS cases. Continue reading

What goes wrong with electrical signalling in MND?

Last year, we introduced a PhD Studentship that we are funding at the University of St Andrews. Under the supervision of Dr Gareth Miles and Prof Siddharthan Chandran, the student working on this project, Amit Chouhan, is investigating why electrical signalling goes wrong in MND.

As the project enters its second year, Amit and the team have made some important discoveries… Continue reading

Epi Epi Epi, Oi Oi Oi

Mention the word Epidemiology and instantly my mind conjures up the Centre for Disease Control (CDC) in America being swarmed by zombies or men in bright orange astronaut-type suits in The Crazies.  While it’s true that it includes studying highly infectious diseases and how they spread (zombies and end of world scenarios aside!), it can be applied to any disease.

Having spent much of my time in the last year working on the data that was collected from our recent epidemiology study, I was keen to shout about the fact that the data is now ready for researchers to use. The analysis of this data will add great value to samples that we already have in our DNA Bank.

What is Epidemiology?

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