Masitinib, a breakthrough drug shattering neurology boundaries

In the process of writing a blog post on the research findings altering neurological practice, my sight fell on the drug, Masitinib. I was completely unaware of this tyrosine kinase inhibitor, one of the promising drugs in the fight against multiple sclerosis (MS). We are likely to hear a lot more about Masitinib in MS in the coming months.

By Zeldj - Own work, CC BY-SA 4.0, Link
By ZeldjOwn work, CC BY-SA 4.0, Link

Masitinib is however not flexing its muscles just in neuro-inflammation. On the contrary, it is seeking laurels far afield, in the realm of neuro-degeneration. I was indeed pleasantly surprised to find that researchers are studying the impact of Masitinib on two other horrible scourges of neurology. The first report I came across is the favourable outcome of a phase 3 trial of Masitinib in motor neurone disease (MND) or amyotrophic lateral sclerosis (ALS). The drug reportedly ‘reached its primary objectives‘ of efficacy and safety. In this trial, Masitinib was used as an add-on to Riluzole, the established MND drug. It’s all jolly collaborative at this stage, but who knows what threat Masitinib will pose to Riluzole in future! You may read a bit more on Masitinib and MND in this piece from Journal of Neuroinflammation.

By Capilano1 - Own work, CC BY-SA 4.0, Link
By Capilano1Own work, CC BY-SA 4.0, Link

The second report I came across is the potential of Masitinib in the treatment of Alzheimer’s disease (AD). This is at the phase 2 trial stage, and already showing very good outcomes in people with mild to moderate AD. Masitinib was used as an add-on drug to the conventional AD medications Memantine, Donepezil, Galantamine and Rivastigmine. These drugs can therefore rest comfortably on their thrones…at least for now! You can read a bit more on Masitinib and AD in this article from Expert Review of Neurotherapeutics.

Alzheimer's Disease. Hamza Butt on Flikr. https://www.flickr.com/photos/141735806@N08/28007367952
Alzheimer’s Disease. Hamza Butt on Flikr. https://www.flickr.com/photos/141735806@N08/28007367952

The question however remains, why should one drug work well on such disparate diseases? I know, this feels like deja vu coming shortly after my last blog post titled Alzheimers disease and its promising links with diabetes. In that post I looked at the promise of the diabetes drug, Liraglutide, in the treatment of Alzheimers disease. I have however also reviewed this type of cross-boundary activity of drugs in my older posts, Will riluzole really be good for cerebellar ataxia? and old drugs, new roles? Perhaps Masitinib is another pointer that, as we precisely define the cause of diseases, they will turn out to be merely different manifestations of the same pathology. Food for thought.

Benjah-bmm27 assumed. Own work assumed (based on copyright claims). Public Domain, Link
Benjah-bmm27 assumed. Own work assumed (based on copyright claims). Public Domain, Link

 

As I said, this wasn’t the post I set out to write. So watch out for my next blog post, the major research outcomes altering neurological practice.

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Will Riluzole really be good for cerebellar ataxia?

This is just a quick post on a recent paper in Lancet Neurology which looked at the potential benefit of Riluzole in the treatment of cerebellar ataxia.

By Kamil9243 (Own work) [GFDL or CC BY 3.0], via Wikimedia Commons
By Kamil9243 (Own work) [GFDL or CC BY 3.0], via Wikimedia Commons
Neurologist know Riluzole very well. It is the only drug that has even the slightest hint of slowing down the dreadful motor neurone disease (MND). It is however fraught with side effects and demands a strict regime of regular blood tests to monitor for liver toxicity; this puts many people off it. Many neurologists are also sceptical of its reported benefits (in whispering tones of course).

By Images are generated by Life Science Databases(LSDB). - from Anatomography[1] website maintained by Life Science Databases(LSDB).You can get this image through URL below. 次のアドレスからこのファイルで使用している画像を取得できますURL., CC BY-SA 2.1 jp, https://commons.wikimedia.org/w/index.php?curid=7768824
By Images are generated by Life Science Databases(LSDB). – from Anatomography[1] website maintained by Life Science Databases(LSDB).You can get this image through URL below. 次のアドレスからこのファイルで使用している画像を取得できますURL., CC BY-SA 2.1 jp, https://commons.wikimedia.org/w/index.php?curid=7768824

It is therefore with some surprise for me to see a trial of Riluzole in another disease at all. Why Riluzole I wondered? The paper is titled Riluzole in patients with hereditary cerebellar ataxia: a randomised, double-blind, placebo-controlled trial. And it answers my question in the introduction- Riluzole just happened to be one of a bunch of drugs the authors had previously tried at random, and somehow the one that showed any hint of a benefit. Sounds strangely familiar, or is it just déjà vu?

Cerebellum: the brain's locomotion control center. ZEISS Microscopy on Flikr. https://www.flickr.com/photos/zeissmicro/14441559904
Cerebellum: the brain’s locomotion control center. ZEISS Microscopy on Flikr. https://www.flickr.com/photos/zeissmicro/14441559904

 

The authors studied subjects with the genetic conditions spinocerebellar ataxia (SCA) and Friedreich’s ataxia (FA). They used the SARA scoring system to monitor for improvement in the study subjects. And their faith was rewarded; 50% of the subjects on Riluzole improved compared to only 11% of the subjects on placebo. The authors suggest further trials to confirm the benefit. The academically minded will pick apart the methodology and statistical significance; the neurologist on the coal face will hold on to any hope.

 

Is neurology research finally breaking the resolve of MND?

Motor neurone disease (MND) is, to say the least, dreadful. It also doesn’t help that the terminology neurologists use adds to the distress. West of the Atlantic, amyotrophic lateral sclerosis (ALS) means MND but goes eastwards and it is only a subtype of MND. Thankfully, for most Americans at least, there is no confusion; it is simply Lou Gehrig disease.

By Goudey [Public domain], via Wikimedia Commons
By Goudey [Public domain], via Wikimedia Commons

MND however remains a conundrum for neurologists who are struggling to solve its puzzling riddles. MND researchers continue to toil and sweat, but their efforts are bearing fruits. Take for example the great strides that established the link between MND and the C9ORF72 gene. What are the promising prospects in the world of MND? Here are some.

Associations: Thiamine deficiency and Diabetes 

By Jynto [CC0], via Wikimedia Commons
By Jynto [CC0], via Wikimedia Commons
Should we be on the lookout for thiamine deficiency in patients with MND? This question is prompted by an article in the JNNP which shows an unexpectedly high frequency of laboratory, but not clinical, thiamine deficiency. Titled Thiamine deficiency in amyotrophic lateral sclerosis, the paper reported thiamine deficiency in about 28% of subjects with MND. The authors did not impute any causal association, and there is nothing to suggest that replenishing the thiamine improved outcomes. It is still worth thinking about because people with MND, as the paper emphasised, are at risk of thiamine deficiency.

Another reported association, more difficult to fathom, is the one between MND and diabetes mellitus. The report in the European Journal of Neurology is titled Association between diabetes and amyotrophic lateral sclerosis in Sweden. Why am I sceptical?

Risk factor: Human endogenous retrovirus K (HERV K) 

Retrovirus capsid. A J Cann on Flikr. https://www.flickr.com/photos/ajc1/3269017701/in/photostream/
Retrovirus capsid. A J Cann on Flikr. https://www.flickr.com/photos/ajc1/3269017701/in/photostream/

The cause for MND remains unknown. Risk factors however abound such as smoking and other environmental risk factors. You may now add human endogenous retrovirus K (HERV K) to that list. This is according to a recent paper in Science Translational Medicine titled Human endogenous retrovirus-K contributes to motor neuron disease. The authors report that HERV K is activated in some people with MND, and it is the envelope proteins that cause damage to tissues. The US National Institutes of Health (NIH) think this is an important development, and it released a press statement titled Dormant viral genes may awaken to cause ALS. Scary! Is this important, or just another risk factor? Only time will tell.

Pathology: Neuromuscular junction inflammation 

By Elliejellybelly13 - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=40798702
By Elliejellybelly13Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=40798702

This sounds almost sacrilegious- the thought that inflammation may really play a role in MND. And at the neuromuscular junction (NMJ), not the anterior horn cells. Well, some researchers are ready to commit blasphemy; publishing in Experimental Neurology, the authors showed evidence of inflammation in the muscles and NMJs of rat models of MND. They went further to show that injecting a growth factor called GDNF reduced this inflammation. Do I perceive a potential treatment pathway? Read all about it if you dare, its titled Macrophage-mediated inflammation and glial response in the skeletal muscle of a rat model of familial amyotrophic lateral sclerosis (ALS).

Treatment target: TDP-43 protein 

By Emw (Own work) [CC BY-SA 3.0 or GFDL], via Wikimedia Commons
By Emw (Own work) [CC BY-SA 3.0 or GFDL], via Wikimedia Commons
Will MND ever be a curable disease? A big question, but this is the vision of all the hard-working researchers in this field. What are the prospects for a cure? One group of researchers believe the answer is in preventing misfolding of TDP-43, the protein that plays an important role in MND. They set out their case in an article published in Neurotherapeutics titled TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets. And don’t worry, its free access. The bold abstract says it all: “we present the case that preventing the misfolding of TDP-43 and/or enhancing its clearance represents the most important target for effectively treating ALS”. The proof of the pudding….

Diagnostic test: Nerve ultrasound

By Oleg Alexandrov - self-made with MATLAB, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3036844
By Oleg Alexandrov – self-made with MATLAB, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3036844

Making the diagnosis of MND is not always (make that is hardly ever) straightforward. In the early stages, symptoms are vague, and clinical signs are non-specific. MND also has many mimics. One of such mimics is multifocal motor neuropathy (MMN). To distinguish this and other mimics from MND, neurologist rely on a test called nerve conduction study (NCS). Even this however is not always helpful.

Researchers have now reported that ultrasound may be more sensitive in distinguishing MND from MMN. Another sacrilegious thought! They published their paper in Journal of Neurology with a rather long title: Nerve ultrasound in the differentiation of multifocal motor neuropathy (MMN) and amyotrophic lateral sclerosis with predominant lower motor neuron disease (ALS/LMND). Could the diagnosis of MND really be this simple? I am concerned that there were only 16 subjects with MND in the study, all from one centre. Perhaps a randomised, multi-centre, trial will come to the rescue?

Diagnostic biomarker: Brain iron deposition 

By Oleg Alexandrov - self-made with MATLAB, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3036844
By Oleg Alexandrov – self-made with MATLAB, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3036844

Brain magnetic resonance imaging (MRI) is not a test neurologist rely upon to make the diagnosis of MND. Not anymore it seems, going by an article in American Journal of Neuroradiology. The paper is titled A Potential Biomarker in Amyotrophic Lateral Sclerosis. In the article, the authors assessed the amount of iron deposition in the brains of people with MND using the MRI techniques called SWI and DTI. Their findings suggest that the amount of iron in the motor cortex and motor tracts of the brain is a good guide to the presence of MND. If confirmed, this technique will help to reduce the long time it often takes before neurologists confirm their suspicions of MND to patients and their families.

Prognostic biomarker: Neurofilament light chain (NfL) 

Neurofilament and MBP. Dan O'Shea on Flikr. https://www.flickr.com/photos/dan_oshea/4079086197
Neurofilament and MBP. Dan O’Shea on Flikr. https://www.flickr.com/photos/dan_oshea/4079086197

The outcome of MND, poor as it often is, varies quite widely. This is influenced by several factors such as the type of MND, use of the medicine riluzole, and multidisciplinary care. New research suggests that neurofilament light chain (NfL) may be a more sensitive marker of prognosis. This is reported in an article published in Neurology titled Neurofilament light chain: A prognostic biomarker in amyotrophic lateral sclerosis. The authors demonstrated that patients with MND have much higher levels of NfL than those without the disease. Furthermore, subjects with MND who had the highest levels at the onset had a higher mortality hazard ratio. I think I know what that means.

Prognostic scale: ALS-MITOS predictive system

A paper in the JNNP has proposed a new predictive system for MND called ALS-MITOS, reportedly better than the more familiar ALSFRS-R. The report is titled The MITOS system predicts long-term survival in amyotrophic lateral sclerosis. Most practicing neurologists wouldn’t know the difference because they don’t to use such predictive systems. But MND researchers would be licking their lips at the prospect of a better measure of disease progression; it will make it much easier for them to show that their interventions really do work!

Treatment: Copper 

By Native_Copper_Macro_Digon3.jpg: “Jonathan Zander (Digon3)"derivative work: Materialscientist (talk) - Native_Copper_Macro_Digon3.jpg, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=7223304
By Native_Copper_Macro_Digon3.jpg: “Jonathan Zander (Digon3)”derivative work: Materialscientist (talk) – Native_Copper_Macro_Digon3.jpg, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=7223304

There are >100 mutations in the superoxide dismutase 1 (SOD-1), a gene known to cause MND. SOD-1 is an enzyme that binds both copper and zinc, and when defective it results in mutant copper (don’t worry, I’m just finding this out myself). Acting on this hypothesis, researchers came up with a crafty way of delivering normal copper into the central nervous system of  mice modelled with SOD-1 MND. Publishing in Neurobiology of Disease, the authors showed how they achieved this with CuATSM, a chemical that contains copper and currently used for PET scans. CuATSM is readily transported into the nervous system, delivering its copper as it does so.

The paper has a rather cumbersome title: Copper delivery to the CNS by CuATSM effectively treats motor neuron disease in SODG93A mice co-expressing the Copper-Chaperone-for-SOD. The result is however anything but. The technique extended the lives of the mice by an average of 18 months. Unbelievable it seems. Any doubts however vanished when, on stopping the treatment, the mice died within 3 months. The finding is exciting enough for Eureka Alert to run the story with the headline New therapy halts progression of Lou Gehrig’s disease in mice. ‘Halt’ sounds very much like ‘cure’, but lets put the brakes on and wait for confirmation in human trials .

Treatment: Gene therapy

Gene_therapy. 1Droid JamLos on Flikr. https://www.flickr.com/photos/jamlos/2734418031
Gene_therapy. 1Droid JamLos on Flikr. https://www.flickr.com/photos/jamlos/2734418031

Every recalcitrant disease is today threatened with gene therapy. Considering it has a long list of genetic risk factors, why should MND be any different? Research taking steps in this direction is therefore long overdue. One such step was published in Gene Therapy and is titled Healthy and diseased corticospinal motor neurons are selectively transduced upon direct AAV2-2 injection into the motor cortex. The authors report that they successfully transduced motor nerves of mice models of MND. In doing so they have set the stage for gene therapy in MND. I don’t claim to understand it all, but it sounds very much like they have set the ball rolling. Promising.

Treatment: Stem cell therapy

By Ryddragyn at English Wikipedia - Transferred from en.wikipedia to Commons., Public Domain, https://commons.wikimedia.org/w/index.php?curid=2148036
By Ryddragyn at English Wikipedia – Transferred from en.wikipedia to Commons., Public Domain, https://commons.wikimedia.org/w/index.php?curid=2148036

Where gene therapy goes, stem cell therapy seems to follow. And this comes from JAMA Neurology with a classic unwieldy academic title: Safety and Clinical Effects of Mesenchymal Stem Cells Secreting Neurotrophic Factor Transplantation in Patients With Amyotrophic Lateral Sclerosis. The content isn’t any easier to interpret, and I will not pretend I get it at all. I comfort myself that it’s all at the ‘open-label, proof of concept‘ stage, and only the very brainy brains need to delve further. But it seems to offer hope.

By Jim Campbell/Aero-News Network - http://www.flickr.com/photos/39735679@N00/475109138/ / http://mediaarchive.ksc.nasa.gov/detail.cfm?mediaid=31873, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3655144
By Jim Campbell/Aero-News Network – http://www.flickr.com/photos/39735679@N00/475109138/ / http://mediaarchive.ksc.nasa.gov/detail.cfm?mediaid=31873, Public Domain, https://commons.wikimedia.org/w/index.php?curid=3655144

 

The sky is surely the limit. Here are a couple of other headlines if you wish to explore further:

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Old drugs, new roles?

Three recent articles caught my interest because they point to potential new roles for old drugs.

The first paper in the Lancet Neurology  suggests a role for Riluzole in hereditary cerebellar ataxia. With 50% of the treatment arm improving against 11% of the placebo arm, I hope this is not false hope for patients with Friedreich’s ataxia (FA) and spinocerebellar ataxia (SCA).

By Kamil9243 - Own work, CC BY 3.0, Link
By Kamil9243Own work, CC BY 3.0, Link

The second paper in Neurology reports that Statins reduce the risk of post-stroke seizures. You say hmmm, they say more studies needed.

By Solidach - With software of which I am the product manager, CC BY-SA 3.0, Link
By Solidach – With software of which I am the product manager, CC BY-SA 3.0, Link

The third paper in JNNP points to the benefit (or not) of Dantrolene for subarachnoid haemorrhage vasospasm. Feasible, tolearable and safe… but study not powered to detect efficacy!

By Jynto (talk) - Own workThis chemical image was created with Discovery Studio Visualizer., CC0, Link
By Jynto (talk) – Own workThis chemical image was created with Discovery Studio Visualizer., CC0, Link

Keep up with the expanding role of drugs in neurology with my recent blog posts:

 

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