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.
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.
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.