MS-SMART for Progressive MS was it smart…At least it was transparent.

M
Vesterinen HM, Connick P, Irvine CM, Sena ES, Egan KJ, Carmichael GG, Tariq A, Pavitt S, Chataway J, Macleod MR, Chandran S.Drug Repurposing: A Systematic Approach to Evaluate Candidate Oral Neuroprotective Interventions for Secondary Progressive Multiple Sclerosis.  PLoS One. 2015 Apr 9;10(4):e0117705. doi: 10.1371/journal.pone.0117705. eCollection 2015.

OBJECTIVE:To develop and implement an evidence based framework to select, from drugs already licenced, candidate oral neuroprotective drugs to be tested in secondary progressive multiple sclerosis.
DESIGN: Systematic review of clinical studies of oral putative neuroprotective therapies in MS and four other neurodegenerative diseases with shared pathological features, followed by systematic review and meta-analyses of the in vivo experimental data for those interventions. We presented summary data to an international multi-disciplinary committee, which assessed each drug in turn using pre-specified criteria including consideration of mechanism of action.
RESULTS:We identified a short list of fifty-two candidate interventions. After review of all clinical and pre-clinical evidence we identified ibudilast, riluzole, amiloride, pirfenidone, fluoxetine, oxcarbazepine, and the polyunsaturated fatty-acid class (Linoleic Acid, Lipoic acid; Omega-3 fatty acid, Max EPA oil) as lead candidates for clinical evaluation.
CONCLUSIONS:We demonstrate a standardised and systematic approach to candidate identification for drug rescue and repurposing trials that can be applied widely to neurodegenerative disorders.


How did MS-Smart come around and how did they select the drugs. This paper tells you how. 

In this meta analysis, interventions we selected for further investigation if they had either been tested in MS at least once, or had been tested in at least three of the four other neurodegenerative diseases under consideration. From this, two clinicians (SC and JC) independently reviewed all interventions, retaining those with evidence for efficacy or biological plausibility, and excluding those with an immunosuppressant mechanism of action (including corticosteroids and combination interventions, on the basis that this mechanism of action has been adequately evaluated through conventional drug-development programmes in MS), those where the clinical response was likely due to symptomatic relief alone, where another drug of the same class had greater apparent efficacy or safety, and where there were significant adverse effects associated with treatment. Preclinical studies in experimental autoimmune encephalomyelitis (EAE), the dominant experimental model of MS, were also systematically evaluated for candidate interventions.

So a list was made and this here.
The list was whittled it down five


Ibudilast has been a commercial product in Japan for two decades for asthma. It is a non-selective phosphodiesterase (PDE 3,4,10,11) inhibitor and macrophage migration inhibitor factor (MIF) inhibitor with multiple activities relevant to SPMS including: attenuating the pro-inflammatory response of microglia and astrocytes through reducing nitric oxide and reactive oxygen species; promoting secretion of neurotrophins such as glial cell line-derived neurotrophic factor (GDNF) / nerve growth factor (NGF).  Ibudilast has already been tested in RRMS, where it has some effect on MRI outcomes and, possibly, on disease progression.

Riluzole is licensed for MND and has two modes of action of relevance to SPMS: reducing glutamate release and antagonism of voltage dependent sodium channels.

Amiloride, a widely used diuretic and acid sensing ion channel (ASIC) blocker, has recently recognised myelo- and neuroprotective effects in both human and experimental models of progressive MS.

Pirfenidone has been reported to improve neurological function in one small study.

Fluoxetine is a selective serotonin-reuptake inhibitor (SSRI) widely used for depression. However it also has multiple activities relevant to SPMS including: stimulating glycogenolysis and enhancing the production of brain-derived neurotrophic factor (BDNF) in rodent astrocyte cultures. Moreover, after 2 weeks of fluoxetine a significantly improved cerebral white matter NAA/creatine ratio was found on MRI in patients with MS, suggesting an improvement in axonal mitochondrial energy metabolism. It might also suppress the antigen-presenting capacity of glial cells. Furthermore, in a recent Cochrane review in adults with stroke, SSRIs improved measures of dependence. Two trials of fluoxetine have been carried out in MS: in one (mainly RRMS), there was a significant reduction in relapse rate incidence and new inflammatory lesions; whereas in another (progressive cohort) favourable trends emerged such as reduced EDSS scores and improved 9 Hole Peg Test performance.

Oxcarbazepine has been reported to improve paroxysmal pain in MS, but effects on disease progression have not been studied.


According to the authors ” It is therefore possible that we have failed to identify many drugs for which there is good evidence, from various sources, to suggest that they might have efficacy in SPMS. Whether our method to select candidate interventions for rescue and repurposing studies will improve the translational hit-rate remains to be seen. However we believe that combining robust experimental (systematic review / meta-analytic) and ontological selection filters offers a realistic prospect of successful translation into new therapies”.

So the drugs originally selected for the trial are Ibudilast, Riluzole, Amiloride and placebo, based on Clinical Trials.gov. However, Ibudliast was changed to fluoxetine. 

I am happy about this. Whilst an Ibudilast trial in RRMS was uneventful and failed as I would have been predicted from the translatable acute EAE experiments, if we look at what happened with rolipram and anti-TNF, a putative mechanism of action of PDE4 inhibitors, in MS and advanced EAE. It removes a concern.


This approach however probably did miss a few good candidates,eg. agents that have shown promise in EAE and other neurodegenerative conditions but had not been tried in MS. I can think of some. I also know that the authors agree as I had a chat with them.

So if you are an SPMSer consider entering the SM SMART trial

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