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.

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:

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ALS/MND Clinical Trial Guidelines: your opportunity to comment!

A few months ago we wrote an article about the ALS Clinical Trials Workshop which took place in Virginia, USA. Since then the Guidelines Working Groups have been busy turning the large number of issues debated into a first draft of a new set of guidelines. This is open for comment from 1- 31 August.

The guidelines will be posted on this website, and comments can be sent to guidelines.public.comments@gmail.com.

The guidelines are divided into sections:

  • Preclinical studies
  • Study design and biological and phenotypic heterogeneity
  • Outcome measures
  • Therapeutic / Symptomatic interventions in clinical trials
  • Patient recruitment and retention
  • Biomarkers
  • Different trial phases and beyond – (there are two sections on this)

Within each of these sections, there are many recommendations. The Clinical Trials Guidelines Investigators want to ensure that all interested people and stakeholders have an opportunity to provide input – whether you are a researcher, clinician or person with MND.

Thank you very much for your help.

For more information, please see a copy of their press release below: Continue reading

Clinical trials update from Symposium

Clinical trials determine if potential treatments are safe and aim to prove beyond reasonable doubt whether a drug is beneficial. They are therefore the gold standard of treatment research.

More information on the different types of clinical trial can be found on our website and in our information sheet on the topic.

This year the Symposium session on clinical trials looked at three drugs and one therapy. Dr Brian Dickie has posted a separate blog on one of these drug treatments – Edaravone.

A summary of the results from the drugs and treatments discussed is below. More information on each of them in detail is later on in this blog.

Ibudilast: This drug was safe and well tolerated in those who were not using non-invasive ventilation. However, these are results from an early stage trial so more research is needed to establish possible long-term benefit.

Methylcobalamin (Vitamin B12 injections): If this treatment is given early (within 12 months of diagnosis) then it showed an effect at increasing survival in a small sub-group of those taking part in the trial. This effect was not seen when the treatment was given further on from diagnosis.

Stem cell therapy: This small, early Phase 1/2 trial was testing the safety of bone-marrow derived stem cell injections into the spinal cord. The researchers found this treatment had no major side effects. Further studies are needed to evaluate the effectiveness and safety of this treatment over the long-term.Clinical trial flow chart

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Edaravone trial presentation sparks interest

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. Continue reading

Understanding more about GM604

20141020_MND Kings College_290The MND Association’s Director of Research, Brian Dickie explains more about ‘GM6’, also known as ‘GM604’, a drug in development by an American pharmaceutical company Genervon.

The Association funds a wide range of research that leads to new understanding and treatments, which may one day, bring us closer to a cure for MND. We are hopeful that the increasing international research effort into the disease will accelerate the development of an effective treatment for MND. However for non scientists I also fully appreciate how the ‘system’ often seems designed to impede rather than assist this process.

There has been much discussion online about the results of a small scale study of a drug called GM604, or GM6, produced by the American pharmaceutical company Genervon. You can read some general comments about the drug on our website. I’ve written this blog to explain in a little more detail why the research community is cautious about the results. Continue reading

Sheffield work towards a treatment for SOD1 form of MND

A number of articles were published in various news sources on 11 July 2014, highlighting how scientists in Sheffield are working towards testing a promising treatment for a rare inherited form of MND caused by the SOD1 gene. Here we write about the research and what it means for people living with MND.

The Sheffield Institute for Translational Neuroscience (SITraN) specialises in research into MND and other neurodegenerative diseases. Recently the institute received an anonymous donation of £2.2 million to help translate their research from the lab to the clinic. This is a huge amount of money into MND research and this donation will enable the researchers to further our understanding of the disease.

Laboratory PhotoThe research

We know that approximately 10% of cases of MND are inherited. This means that they are characterised by a strong family history and the disease is caused directly by a mistake in a specific gene. Of these 10% of cases, 2% are caused by the SOD1 gene (meaning that for every 100 cases of MND, 10 cases are inherited and of these, only 2 are directly caused by the faulty SOD1 gene).

Prof Mimoun Azzouz’s research at SITraN was reported in a number of news outlets, highlighting how his research is paving the way to a treatment for a rare form of MND. His research is at a relatively early stage, where he has only just begun investigating the use of a technique known as ‘gene therapy’ in mice affected by the SOD1 inherited form of MND. If the research goes to plan, he will be able to submit a proposal for regulatory approval by August 2015. Continue reading

Early Access to Medicines scheme

Last month the UK Government’s Department of Health announced an Early Access to Medicines Scheme. But, what is this new scheme? and what does it mean for people living with MND?

The drug trial processpipette

The only proven drug to slow progression in MND is riluzole. This is the only drug that has passed all the stages of drug testing – known as clinical trials – and has been shown to be beneficial for people living with MND. Clinical trials are the ‘gold standard’ and are put in place to ensure that a drug is safe and beneficial before it is given to patients.

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