Prof Jeremy Chataway

Widely-anticipated trial results for three neuroprotective drugs in secondary progressive multiple sclerosis have been disappointingly negative, researchers told the ECTRIMS meeting in Berlin.

Presented at the 34th Congress of the European Committee for Treatment and Research in MS (ECTRIMS) on 12 October, the findings from the MS-SMART trial of amiloride, riluzole and fluoxetine showed no effect on disability in patients with secondary progressive MS.

Led by Professor Jeremy Chataway of the UCL Institute of Neurology, London, the study investigators in the phase 2b study evaluated outcomes on brain atrophy in 445 patients who were randomised were randomised to 96 weeks of treatment with amiloride (5mg bd), fluoxetine (20mg bd), riluzole (5mg bd) or placebo.

The study found no effect of any of the active treatments on the primary outcome of percentage brain volume change (PBVC) between baseline and 96 weeks, based on structural MR brain imaging data

There were also no apparent neuroprotective effects of the treatments on the numbers of new or enlarging MS brain lesions, cognitive tests or physician and patient perceptions of effectiveness.

However, on a positive note Dr Chataway said the study had shown that a multi-arm trial strategy is an efficient way of screening drugs in SPMS, and that it was possible to evaluate anti-inflammatory drug activity using the count of new and enlarging T2 lesions.

“This is obviously disappointing in its own right, but nonetheless we can learn a great deal from these results,” he said.

“It confirmed that the trial design worked very well … this is a really robust way of working out whether a trial is worth taking onwards

Each of these drugs was chosen very carefully to try and identify and target different pathways that could work in progressive MS and so we’ll learn a great deal about the neurobiology  and the neuropathology from the fact that they didn’t show an effect,  shutting down some pathways and maybe going after others.”

Amiloride is a potassium sparing diuretic that targets the acid-sensing ion channel 1 (ASIC1) gene, which contributes to the excessive intracellular accumulation of injurious calcium and sodium and is over-expressed in acute multiple sclerosis lesions,.

The  SSRI antidepressant fluoxetine shown potential neuroprotective effects in some models, possibly due to stimulating the cAMP-responsive element binding protein; increasing the production of brain-derived neurotrophic factor and the neurotrophic peptide S100beta; enhancing glycogenolysis in astrocytes and blocking voltage-gated calcium and sodium channels and decreasing the conductance of mitochondrial voltage-dependent anion channels.

Riluzole is already used for motor neuron disease/amyotrophic lateral sclerosis and has two potetntially neuroprotective modes of action: reducing glutamate release and antagonism of voltage-dependent sodium channels.