Lessons learnt in the past year…update on clinical trials

Looking for a treatment for MND is the ultimate goal of the whole MND community. Unfortunately, as MND is a very complicated disease, it is not as easy as it may sound. Setting aside the sheer cost of running trials, researchers have to look at all the possible causes of MND (the genes, lifestyle and environment) and then target these with specific compounds and hoping that this strategy won’t be halted by a different biological process. This is made even harder by the large number of possible combinations of these causative factors and the many different ways these can interact.

Thankfully, lots of research groups across the world are doing their best to tackle the adverse disease mechanisms, which is why we heard lots of results of early as well as late stage clinical trials, new strategies to design better treatments in the future, and lessons learnt from previous studies.

While there was much more to hear and read at the Symposium, here we summarise the Clinical trials session (4B), where five presenters reported results and analyses of the treatments they have been investigating. Continue reading

Lithium revisited: Is there a baby in the bathwater?

At last year’s Airlie House workshop to develop new ALS/MND Clinical Trial Guidelines the focus was, of course, on MND, but there was also important input and learning from outside the field.

One of the most fascinating presentations was from an oncologist who was explaining how detailed genetic analysis of tumours was leading to an understanding of why some experimental cancer drugs appeared to only work in a small subgroup of patients. The take home message from the cancer field was that there should be more effort made in future MND trials to identify and analyse smaller subgroups of patients, in case a potentially positive effect might be missed.

A new research paper, published in the journal Neurology, raises some intriguing findings from the trials of the drug lithium that were carried out several years ago. Lithium generated a lot of excitement when researchers in Italy reported a positive effect of the drug in the SOD1 mouse model of MND. Almost as an afterthought, their research paper mentioned that they had tested the drug in a small short-term trial in patients and it appeared to have some effect. Continue reading

Disappointing results from UK based lithium clinical trial

Yesterday, we announced on our website the disappointing news that the UK-based lithium clinical trial showed that lithium carbonate is ineffective at treating MND.

Commenting on the lithium clinical trial, Dr Brian Dickie, our Director of Research Development said:

“As many people will know, when lithium was first proposed as having benefit in MND, a couple of small, short-term trials were performed to establish whether the drug had a large and rapid effect on physical changes in disease progression. This trial, by contrast, was developed to ask whether the drug had a more subtle benefit over a longer time course, as is the case with riluzole, using survival times as the primary measure. The only way to answer this question was by performing larger, lengthier and more comprehensive studies.

“While the result is deeply disappointing, we now have a clear answer.

“Lithium can be described as a messy drug. It can act in multiple ways in the body, producing potentially beneficial effects as well as possible unwanted side effects. An overall beneficial effect, even modest, would have refocused scientific interest in the drug to try and separate ‘the good from the bad’ with the longer-term goal of developing more effective compounds. This is a strategy that is presently being pursued with regard to riluzole, in a project co-funded by the ALS Association, the University of Reading and ourselves.

“This trial was the first of its type in the UK, devised and run by clinicians without the need for drug company funding. A number of MND clinics that previously had little or no experience in clinical drug trials for MND have developed vital expertise and confidence in delivering trials to the highest standards. This can only help make the UK a more attractive place in the future for drug companies looking to push potential treatments from lab to clinic.”    

Two hundred and fourteen people with MND took part in this trial, each giving up their time to help find us the answers. We’d like to thank those that have taken part in this trial.

One person who took part in the UK lithium clinical trial was Colin Knight. We spoke to him a few years ago about his views on taking part. Please be aware that in the film clip, Colin speaks frankly about his diagnosis.

Read our official 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:

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.

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 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.