It’s OK to ask about MND research

The National Institute for Health Research (NIHR) has launched their ‘It’s OK to ask campaign’ which encourages patients and the public to ask about clinical research.

The campaign was launched on Monday (20 May 2013), ‘International Clinical Trials Day’ and the NIHR will be promoting this campaign throughout 2013/14.

“Clinical research is the way in which we improve treatments in the NHS. In many cases doctors will tell patients about research but we also need patients to ask about it and keep research at the top of the NHS agenda.” – NIHR website

Get involved in MND research

Mo LeCule the MND meerkat

The NIHR is promoting the fact ‘it’s OK to ask about research’ and encourages patients or the public to ask their doctors about current research opportunities. The MND Association has a section on their website that lists ‘current opportunities to get involved in MND research’ and you can find out more here.

Getting involved in MND research does not only mean taking part in clinical drug trials. There are a number of other ways you can help including; questionnaires, tissue donation and fundraising.

“Last year, more than half a million NHS patients chose to take part in nearly 3,000 clinical research studies. Thanks to those patients, we are learning more all the time about how to deal with a whole range of medical conditions – and make some real breakthroughs that will improve thousands of lives.” – NIHR website

Share your experiences

The ‘It’s OK to ask’ campaign is encouraging patients or the public to share their experiences including what they asked and what response they received, via Facebook, Twitter (@OfficialNIHR #NIHRoktoask), phone: 0300 311 99 66 or email: oktoask@nihr.ac.uk

Adaptive licensing and MND

I have recently updated the clinical trials section of our website with a couple of MND clinical trials that are currently recruiting. This has led me to think about the adaptive licensing discussions that have been taking place recently and how this relates to these MND clinical trials.

Adaptive licensing is an idea. An idea that has seen increasing media attention over recent months and years.  Adaptive licensing aims to see the licensing of drugs somewhat earlier than they currently are at present, particularly with regards to those living with diseases like MND. We, the MND Association, therefore encourage further exploration into the idea of adaptive licensing including as to how it may work.

The current situation

In order for a drug to be licensed in the UK it needs to have been shown to be both safe and beneficial by means of a clinical trial. Clinical trials are considered the ‘Gold standard’ for drug testing in humans and consist of four main parts:

• Phase I Testing the safety of a drug for the first time in healthy people
• Phase II Testing the optimal dose, safety and tolerability of a drug in people living with the disease
• Phase III Testing if a drug is effective (beneficial) at treating a larger group of people living with the disease
• Phase IV Testing and monitoring a drug (including side effects) once it has been licensed for use

After phase III testing the drug, and all of its clinical trials data, is reviewed by the appropriate licensing body before the drug can be licensed for use. If a license is given, then data will be continuously collected over a longer period of time, which is known as phase IV testing.

It is important to know that some drugs, which show promise in the lab, are shown not to be effective in a large phase III clinical trial (particularly with diseases like MND). This is why clinical trials are needed. Drugs, which are not beneficial or may have harmless side effects, need to be fully tested so they are not given to people unnecessarily.

These strict guidelines for clinical trials are in place to protect patients and to ensure that people living with MND are not given treatments that may be harmful or offer no benefit. For more information about clinical trials see our information sheet

The adaptive licensing idea

The European Medicines Agency (the European drug licensing body) describes adaptive licensing as a system that, “seeks to maximise the positive impact of new drugs on public health by balancing timely access for patients with the need to provide adequate evolving information on benefits and harms.”

Clinical trials take time and the aims of adaptive licensing are for ‘more drugs to be available to more people and more quickly’ which we heartily agree with.

But, we do not know how an adaptive licensing approach may work. As it is still currently just an ‘idea’ there are lots of questions that need to be answered. Including; who would administer the drug, and how would their effects be monitored? Who would be responsible – the doctor or the drug company? Would there be a ‘control or placebo group’? What would happen to clinical trials?

This is why the Association encourages answers to these questions by further exploration into the ideas of adaptive licensing including as to how it may work.

Read more:

Our campaigns team have written a series of blog posts, which explain more about adaptive licensing and what it means for people living with MND;

• Adaptive licensing and the MND Association’s position An overview of how a model of adaptive licensing might help to get more drugs to people with serious illnesses like MND more quickly.
• Recent developments in legislation and policy This post explores the various policy initiatives, including adaptive licensing, that have been set up to try to get new medicines to patients earlier.
• Challenges of adaptive licensing, and implications for people with MND This post looks at some of the unresolved issues that must be addressed before we know whether adaptive licensing will provide some of the answers we would like to see.

Progress in MND research

Our understanding of MND has progressed immensely over recent years. Twenty years ago we only knew one of the genes (known as SOD1) behind the rare inherited form of MND. Today, we now know 12 of them. With research into MND growing more and more every year we are hopeful that this research will lead to the likelihood of new drugs and treatments.

While we agree with calls for more drugs to be available to more people and more quickly, achieving this in practice is not easy – if it was, it would have been done by now.

This is why the Association encourages further exploration into the idea of adaptive licensing.

Antisense seems to make sense

Results from a phase I clinical trial of a drug known as ISIS 333611 have been published open-access online in the scientific journal Lancet Neurology on 29 March 2013.

This is the first time researchers have tested the effects of delivering an antisense oligonucleotide directly into the human cerebral spinal fluid (the fluid between the spinal cord) showing that it is both safe and well tolerated in people with the SOD1 form of inherited MND. For information on inherited MND please see our website.

This work suggests that this ‘antisense’ approach may be a good strategy for other neurological disorders.

What is antisense?
Antisense is a type of therapy that causes the ISIS 333611 to directly interfere with the faulty instructions for making a SOD1 protein, thus stopping the production of the disease-causing substance. This is called ‘gene silencing’ as that part of the gene is not ‘heard’ when the final protein is made.

ISIS 333611 works by targeting mRNA, the ‘messenger’ that carries the genetic instructions from the SOD1 gene to the protein-making machinery (for more about mRNA and how proteins are made see our earlier blog post). Instructions in the mRNA for making the SOD1 protein (sometimes called a ‘sense’ sequence) are faulty in people with SOD1 inherited MND, which leads to harmful SOD1 proteins being made.

So if the levels of harmful SOD1 can be reduced, might this be protective? That’s the thinking behind the treatment. By binding to the SOD1 mRNA, ISIS 333611 prevents the production of a harmful SOD1 protein. Indeed, studies in SOD1 positive animal models indicated that reducing the level of SOD1 by antisense therapy increased lifespan. However, targeting the SOD1 gene in this way is a very ‘personalised’ treatment strategy – if it does work it will only work for people who have the SOD1 from of MND.

Results from the trial
Based on the encouraging animal studies, the researchers and ISIS Pharmaceuticals conducted a phase I trial of the antisense oligonucleotide ISIS 333611.

Twenty-one people with SOD1 MND were involved in the study and results from the trial have shown that there were no toxic effects due to increased dosing of the drug and that the drug was safe and well tolerated.

In animal models antisense therapy is found to spread well throughout the central nervous system (brain and spine). However, unlike animal models, the researchers showed that concentrations of ISIS 333611 were lower in the upper end of the spinal cord and brain compared to the injection site. Due to this the delivery site of the drug will probably need to be revisited in future trials.

Dr Pietro Fratta

As this was only a short-term ‘Phase I’ trial it was not designed to test whether this antisense therapy had an effect on MND. This would only be seen with long term treatment and future trials. However, the results are encouraging as they show that this type of therapy is both safe and well tolerated in people with SOD1 MND.

Results make sense

Dr Pietro Fratta (University College London), who is a recipient of a Medical Research Council/MND Association’s Lady Edith Wolfson Clinical Research Fellowship, has written an accompanying commentary on the paper. He said that this study “paves the way for applying antisense oligonucleotides to other forms of genetically determined MND” such as the C9orf72 form of the disease.

However, he stressed that “many hurdles still need to be overcome to bring this treatment to the clinic”.Dr Fratta also cautioned that the longer-term implications of lowering SOD1 protein levels had to be examined. The antisense approach not only targets the harmful mutated SOD1 protein, but will also lower levels of ‘healthy’ normally functioning SOD1, which plays an important role in protecting neurons from damage. So, the antisense treatment approach may be a ‘double-edged sword’ that will require very careful handling.

Reference
Miller, T. M. et al. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurology 2013 DOI: 10.1016/s1474-4422(13)70061-9 Read the full article here.

Fratta P. Antisense makes sense for amyotrophic lateral sclerosis C9orf72 Lancet Neurology 2013 DOI: 10.1016/s1474-4422(13)70059-0

The clinical trials session

A very much ‘must report on’ session of the 23^rd International Symposium on ALS/MND was the clinical trials and trial design session. There are many reasons that make this an interesting session – perhaps the most eagerly anticipated were the presentations on the NP001 study and the results of the stem cell safety trial:

NP001 update

We reported on the blog on 1 November the results of the NP001 study, and these findings were confirmed today by Dr Bob Miller from Forbes Norris Centre in California USA. The trial showed that intra-venous administration of NP001 was found to be generally safe and well tolerated, with a modest clinical benefit seen in the high dose (2mg/kg) group.

As previously reported in their press release, ‘post-hoc analysis’ (meaning literally after the event), showed that some patients in the higher dose group did not have any change of a scale that measures the functional capabilities of people with MND called the ALS-functional rating scale (ALSFRS) over the course of the study. Historical controls were used in the post-hoc analysis – the first time that the US Food and Drugs Administration (FDA) had allowed them to do this.

The room was packed and there were five people queuing to ask questions about this talk. Questions were asked about the use of historical controls; the possibility that patients would identify that they were in the treatment group due to the presence of a ‘burning feeling’ at the injection site; and about other forms or ways of taking NP001. On the last of these points, a question about the chemical structures of NP001 and WF10 went unanswered.

But Dr Miller was categoric about different ways of taking NP001. “Taking NP001 in any other route [than intra-venously] is unsafe and unproductive”.

Results of stem cell safety trial

The first regulatory body (FDA) approved phase I safety trial of a stem cell treatment for MND, conducted in America, is now complete. Dr Johnathan Glass from Emory ALS Center, Georgia USA presented the results of this study.

In the last 5-10 years there has been a huge amount of interest from MND researchers, clinicians and patients alike about the possibility and potential for using stem cells to treat MND. More information about what stem cells are and how they might help is available on the MND Association’s website.

As for any other drug or potentially beneficial intervention, the first part of the assessment should always be to obtain a robust and objective measure on whether such a treatment is safe, and this is what the NeuralStem study was designed to find out.

A team of highly trained specialists, in close consultation with the FDA, designed a study to look at the safety of giving an injection of stem cells directly into the spinal cord of people with MND. Eighteen surgeries were performed on fifteen patients – three of these patients volunteered to have two surgeries (two injections).

The first three people with MND recruited into the study received a single injection of stem cells on one side of the bottom (lumbar) of the spinal cord. The next three received injections on both sides of the lumbar spinal cord. These first six patients were at an advanced stage of MND, where they were unable to walk.

The next six patients, who were able to walk, received injections at one or both sides of the lumbar spinal cord. The last three patients received a single injection higher up the spinal cord (cervical) and finally, the three patients able to walk who received a single lumbar injection underwent a second surgery to receive a single cervical injection.

The results from the first six patients has already been published in a scientific paper:

Stem Cells 2012 30(6) 1144 – 51

Dr Glass concluded that the procedure is well tolerated and safe and that there is no indication that the surgery accelerates the progression of the disease. The next phase of the study, giving injections into the cervical spinal cord at increasing doses (numbers of cells) is funded and is awaiting FDA approval.

Our International Symposium website news stories:

International Symposium closes in Chicago

International Symposium focuses on clinical trials

International Symposium focuses on carer and family support

International Symposium begins in Chicago

Researchers unite at our International Symposium on MND

After you’ve finished reading the symposium articles that interest you, we’d be grateful if you could spare a few minutes to fill in our short online survey on our symposium reporting. Your comments really are useful and allow us to continually improve our symposium reporting. surveymonkey.com/s/alssymp 

Lets talk together

Reblogged from ALS/MND Research and Care Community Blog:

Neurologist and natty dresser Dr Rick Bedlack, from Duke ALS Clinic in North Carolina USA, took on a challenging topic of patient decision making at this afternoon’s session of the 23rd In ternational Symposium on ALS/MND from the perspective of different decision making models.

In quite a philosophical talk, he framed the discussion of the different models of doctor – patient relationships from a discussion that he’d had with one of his patients.

Read more… 442 more words

Dr Rick Bedlack, founder of ALSUntangled speaks at the International Symposium about assisting patient choices. Dr Belinda Cupid, from our Research Development Team explains more:

Of yeast and men: reducing toxic effects of TDP-43 as a potential treatment for MND

A collaborative American research group, led by Prof Aaron Gitler from Stanford University School of Medicine in California, has identified a potential therapeutic target for MND using yeast.

The toxic activity of the MND-linked protein TDP-43 was suppressed when a gene called DBR1 was deleted from yeast and mammal cells.

The study marks the first steps in the identification of a treatment that can target TDP-43, which is found to clump together in over 90% of cases of MND.

The study was published in the prestigious journal Nature Genetics.

Toxic tangle of TDP-43

To develop effective treatments for MND, we need to find ways of targeting the systems that go wrong to cause the disease.

One hallmark of MND is the accumulation of tangled lumps of protein – including TDP-43.

For years, researchers didn’t know whether the clumps of TDP-43 they could see was a by-product of MND, or a cause of the disease. That was of course, until researchers identified that mistakes in the TDP-43 gene can cause inherited MND in 2008. Since then, researchers have been busy creating new disease models to learn more about how TDP-43 can cause MND.

So far, at least 400 studies have been published to better understand TDP-43 in MND (search terms ALS, FTD, variations of TDP-43 on Pubmed).

Yet we still don’t know whether TDP-43 is doing harm by being over active or under active. We do however know that it’s found in the ‘factory floor’ of the cell, called the cytoplasm, when it’s normally found in the control centre. Using this information, it’s possible to focus on therapies that decrease the toxic effect of TDP-43 rather than to increase or decrease the amount of TDP-43.

This is exactly what a collaborative American research group, led by Prof Aaron Gitler has done.

Using yeast, Prof Gitler and colleagues performed two unbiased genetic screens in different laboratories using different techniques. By doing this, they verified a list of genes that can modify the effects of TDP-43 when deleted – by either enhancing the toxic effect or suppressing it.

Out of the list of resulting modifiers, the research group chose to investigate a suppressor of TDP-43 toxicity, a gene called DBR1.

DBR1

Far from a classic Aston Martin sports racing car (also named DBR1), DBR1 in biological terms is an ‘RNA lariat de-branching enzyme’. It plays an important role in recycling genetic ‘junk’.

Our genes are split into segments within our genetic code, separated by what’s often referred to as ‘junk’ DNA. These sections of junk, known as introns, don’t code for anything, but often perform other important roles.

When a gene is copied into its intermediate form of RNA (before these instructions are used to create a functional protein), it needs to be edited to remove the introns, leaving the vital instructions intact. This involves the introns forming loops of RNA – called lariats – which cut away from the rest of the copy. This leaves only the instructions for the gene product. These lariats then move away from the control centre of the cell (the nucleus) to be recycled.

DBR1’s role normally cuts these lariats open into strings, which can then be recycled. When in a lariat form, RNA is resilient to being recycled. DBR1 therefore plays an important role in recycling intronic RNA in the cell.

What happens when DBR1 is deleted?

When the research group deleted DBR1, intronic lariats accumulated in the factory floor of the cell (the cytoplasm). These lariats then competed to bind to TDP-43, acting as a decoy. This stopped TDP-43 from performing its dastardly deeds when faulty – chopping up essential RNAs within the cell –which could be contributing to the cause of MND.

By deleting DBR1 in yeast and in rat neurones grown in a dish, the research group identified that it increased the chance of neurone survival by nearly 20%.

This means that identifying a therapy that can decrease the amount of DBR1 could be a potential treatment for MND.

Reliability

Prof Gitler and colleagues independently verified their results from the genetic screen in yeast using different laboratories and different methods.

This is significant in terms of its reliability, as this often has huge repercussions for future research.

This topic was recently discussed in the popular science magazine New Scientist in an article called ‘Is medical science built on shaky foundations?’ In the article, the writer explains that a number of pharmaceutical companies have recently announced their failure to replicate a large number of promising results of potential drug targets from published studies.

It’s vital that if we are to identify a treatment for MND that works, that the evidence that led it to be tested in humans is solid. Gaining evidence to suggest the effectiveness of a treatment means replicating the results using independent researchers and using different methods to put an idea through its paces. This ensures that the original results aren’t identified as a coincidence and can be relied upon.

The decision by Prof Aaron Gitler’s group to reproduce their genetic screen independently, using different methods should be applauded. It means their findings are unlikely to be added to the heap of potential targets that cannot be reproduced in other studies.

Being thorough to identify potential targets may take more time, but it’s likely to produce more fruitful results in the long haul.

Looking forward

There are many steps left to climb with the development of a treatment that targets TDP-43. For example, the research group will need to determine whether stopping DBR1 could itself be toxic due to side effects. They also need to determine where the ‘therapeutic window’ is with this therapy – where it’s both effective and safe.

This study also identified many other modifying factors for TDP-43, which can begin to be investigated by other research groups for their potential as a therapy for MND.

As this is the beginning of the story of TDP-43 specific treatments for MND, it will inevitably be a long journey to answer these questions and to bring treatments to the doctor’s prescription pad.

Hopefully, the beacon of rigor and scientific righteousness that this study symbolises will continue and we will see the first TDP-43 therapy being developed for MND in the coming years.

References:

Maria Armakola et al Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models. Nature Genetics 2012; doi:10.1038/ng.2434

http://www.newscientist.com/article/mg21528826.000-is-medical-science-built-on-shaky-foundations.html

Encouraging NP001 clinical trial results for MND

Promising results from a Phase II clinical trial for a drug called NP001 have been announced by the biopharmaceutical company Neuraltus.

The trial, conducted in America, suggested that NP001 is safe, well tolerated and could be beneficial for MND.

Following these encouraging results, Neuraltus plan to begin a larger, Phase III trial of NP001 in the second half of 2013. As the Phase III trial is still being planned, we do not have details on American recruitment centres, nor what the eligibility criteria will be.

The trial
The Phase II clinical trial for NP001 was rigorously controlled. This means that it was randomised, double-blinded and placebo controlled. These are important factors in controlling possible bias. We have more information on why these factors are important on our website.

The trial included 136 people living with MND in America across multiple centres.

Participants were randomised into three groups to receive an intravenous infusion of either high dose NP001, low dose NP001 or placebo (inactive substance) treatment for six months. They were then followed for an additional six months. Approximately 45 people were used in each treatment arm.

The results
Results suggest that the treatment was safe and well tolerated. Promising signs of effectiveness were also identified, but were not statistically significant to draw firm conclusions as to whether the treatment could be effective for MND.

The trial organisers state in their press release that 27% of people taking the high-dose NP001 did not progress during the trial period. It’s important to treat these results with a certain degree of caution, as approximately 10% of people taking the inactive placebo also did not progress during the same period as measured by changes in the functional rating scale.

The results provide enough evidence to warrant a larger scale trial to investigate this treatment further.

This finding also importantly identifies the optimum dose that should be used in this larger-scale clinical trial, as their results suggest that a higher dose could be more likely to yield a beneficial effect than the lower dose.

Finding out the optimal dose is an important part of Phase II clinical trials to ‘fine tune’ the details to provide the treatment with the best chances of demonstrating its success at Phase III.

Importance of sharing results via peer-review
These results will need to be published in a peer-reviewed scientific journal. Peer review is an important process to determine whether findings are valid and that appropriate standards have been used in the study. Once published, these findings will also be used by the scientific community to add to their knowledge.

Importance of Phase III planned for 2013
The promising results identified in Phase II will need to be confirmed in the Phase III trial planned for the second half of 2013.

Leading UK clinical trial researcher, Prof Nigel Leigh said, “A larger Phase III randomised placebo-controlled trial is required before we can be confident that these positive trends are consistent and clinically significant.”

Dr Brian Dickie, the MND Association’s Director of Research continues, “We welcome Neuraltus’ plan to initiate a Phase III trial to determine whether NP001 is beneficial for people living with MND.”

Discussing results at the International Symposium on ALS/MND
Results from the Phase II NP001 trial will be discussed in more detail at the 23^rd International Symposium on ALS/MND, to be held on 5-7 December 2012.

The symposium, organised by the MND Association provides a platform for researchers, clinicians and healthcare professionals to discuss the latest developments in research and care, including discussing results from recent clinical drug trials.

We will be reporting live from the symposium via our research blog. To ensure you have daily updates from the symposium, please sign up to our automatic email alerts on the right hand side of the blog.

References:
Our news release
Neuraltus’ press release
International Symposium on ALS/MND
Brian’s NP001 blog article

‘Hothouse’ meeting on drug discovery

Sadie’s recent post on the emerging partnership between Peakdale Molecular and the Sheffield Institute for Translational Neuroscience prompted me to say a little about last month’s Drug Discovery Workshop, held in Washington DC and organised our friends at the ALS Association.

I was fortunate to be invited along to this workshop, which brought together over 100 representatives from industry, academia, drug regulators and government and charitable funding agencies, to share their findings and discuss the future directions and opportunities for MND drug discovery. ‘Hothouse’ meetings like these are vital in giving those working in academic labs an important insight into the complexities of turning new knowledge of disease processes into ‘druggable’ compounds.

Those from industry get to see the new theories that are coming out of the academic labs, while the funders can start to identify where targeted early-stage support may help to encourage industry to follow up with the larger-scale investment needed to take ideas from bench to bedside At a time when some of the biggest drug companies are pulling back from working in neurodegeneration, the mood at the meeting might have been muted, but delegates were positively upbeat. One cause for optimism is that some companies, such as Biogen Idec, have seized the opportunity to fill the gap and increase their investment in this area.

Moreover, universities around the world have benefitted from an influx of new staff with extensive expertise in drug discovery, strengthening one of their historical areas of weaknesses. Universities are generally very good at unpicking the complex biological processes that occur in health and disease, but very poor at turning this knowledge into treatments. Another reason for the optimistic mood at the meeting was the clutch of new gene discoveries that occurred last year, in particular the identification of the chromosome 9 form of MND  which promises to open up many of new secrets of the disease. Researchers have collectively now found about two-thirds of all the causes of familial MND. As we identify more causes, generate better models and home in on the common cellular changes that drive the disease, the opportunities for drug development are going to increase.

Meetings such as this help focus attention on the major challenges – but also the exciting opportunities - that lie ahead.

Cogane produces encouraging results in MND Association-funded study

Prof Linda Greensmith

Thanks to funding and some strategic ‘match-making’ by the MND Association, a new drug may have taken one step closer to beginning clinical trials in MND after producing promising results in an animal model of the disease.

The drug, known as Cogane, was developed by the biotechnology company Phytopharm. It had already demonstrated in laboratory tests that it could help to protect neurones by promoting the production of natural, nerve nourishing substances called neurotrophic factors and early animal testing had hinted at its potential beneficial effects in MND. However, its journey towards clinical testing in MND had hit a road block because it hadn’t been extensively put through its paces in large numbers of the most widely used animal model of the disease, the SOD1 mouse. Without robust data from this model, there would have been little to encourage further investment in Cogane’s development.

So up stepped the Association to introduce Phytopharm to Professor Linda Greensmith at University College London, a leading MND researcher with considerable expertise in SOD1 mouse testing. With funding from the Association, Prof Greensmith and her team were able to conduct a rigorous study of the effects of Cogane, administered to the mice after they had developed MND-like symptoms.

The drug produced some significant improvements in muscle strength and motor neurone survival and managed to produce positive effects even in mice that had reached the later stages of the disease. To give more substance to these preliminary but very encouraging results, the research team will now go on to the painstaking work of examining more closely Cogane’s effects on the motor neurones and other key cells that play a critical role in the progression of MND. 

After the disappointment of the Trophos trial results, it’s great to be able to share some positive news on the drug development front. We know from long experience that it’s wise to limit our excitement over positive results from the mouse model – after all, plenty of drugs have shown promise at this stage and have then gone on to fail in clinical trials. However, Prof Greensmith’s experience and expertise mean that Cogane will have been tested with the utmost rigor. As she herself commented, the results indicate that “Cogane has significant potential as a therapy for ALS and merits further evaluation”.  We don’t yet know what Phytopharm’s next steps will be – these may become clearer once the more detailed data from Prof Greensmith’s work have been published, which could take the best part of a year. Let’s hope that we have a given Cogane enough of a boost to push it out of the drug development ‘doldrums’.

Read the Phytopharm press release.

Clinical trial low down, down under

“After a time where patients and sponsors of trials alike had become disheartened about the lack of positive clinical trials, it is exciting to see so many positives, including the recently approved Neudexta, and the dexpramipexole study”, commented Professor Robert Miller from the Forbes Norris ALS/MDA centre in San Francisco opening the discussions on clinical trials.

Designing a good trial
As MND is a rare disease clinical trials are notoriously difficult to design in order to ensure that they have meaningful results. Designing better and quicker clinical trials will aid us to find the answers as to whether a treatment is beneficial or not, without losing the significance of a study. It is therefore important that clinical trial designers share their methods with one another. In the first presentation of this session Prof Miller gave us some pointers on how this may be done, looking at every aspect from designing shorter trials with fewer participants, to how an effect is measured.

The next few talks were then dedicated to discussing results from recent clinical trials:

Lithium
Prof Leonard van den Berg, from University of Utrecht, The Netherlands presented the results from the Netherlands lithium clinical trial. Unfortunately, although they found the treatment to be safe, no beneficial effects were seen. The results from the UK clinical trial of Lithium Carbonate, which was designed in a different way with more participants will be published early 2012.

Memantine
Dr Ming Chan from University of Alberta, Canada discussed the results of the recent memantine pilot trial for MND. This trial treatment was administered via tablets. Twenty four people took part in this study and were randomly divided into one of three groups who would receive either: high dose memantine; low dose memantine; or a placebo (dummy) drug. Overall, the trial results suggested that the treatment is safe, and at the higher dose a larger, multi-centre clinical trial for memantine may be warranted.

Nogo-A (GSK1223249)
Dr Pierre-Francois Pradat from the Centre for MND in Paris, France presented the very hot-off-the-press results of the Nogo A trial – a drug developed by the pharmaceutical company GlaxoSmithKline, that is delivered directly into the blood stream via an intravenous (IV) drip. This was a Phase I ‘first in man’ study, given to people with MND first. This is different to other Phase I clinical trials, as healthy volunteers are more commonly used for this stage of trial.

The aim of this study was to ensure that the treatment was safe and well tolerated in people with MND. Dr Pradat discussed that the drug was found to enter the body effectively. The investigators saw trends (ie they are not statistically sure) of benefits in slower decline of respiratory function, of a scale that measures the functional capabilities of people with MND called the ALS-functional rating scale (ALSFRS) and muscle strength. Tentative plans are underway for a larger clinical trial next year.

NP001
NP001 is a drug developed by Neuraltus Pharmaceuticals.  This trial treatment is administered directly into the bloodstream via an intravenous (IV) drip.

At present a Phase II clinical trial for NP001 is underway in the USA and we acknowledge that a lot of people living with MND are interested in hearing more about the status of this trial. This talk however, focused on the Phase I trial to tell us the effects of NP001 on potential markers of disease progression in MND (known as biomarkers), identified through the earlier Phase I trial. We can therefore not comment on the current status of the Phase II trial in this blog article.

As discussed by Prof Miller, from Forbes Norris ALS/MDA Research Center in San Francisco USA and principle investigator to the trial, it is thought that NP001 may be beneficial as the levels of proteins which are increased as a result of an inflammation response in MND are decreased by the drug. They also concluded that the levels of these inflammatory response proteins can be related to the rate of progression for people with MND and could potentially be used as a marker.

Read our official press release from day three of the symposium.