Conference Coverage
INDIANAPOLIS—Although many drugs have failed in clinical trials to provide benefits to patients with progressive multiple sclerosis (MS), neurologists have reason to be optimistic about the quest for effective therapies, according to an overview presented at the 2015 CMSC Annual Meeting. Ongoing studies are investigating agents that appear to offer neuroprotection. An international collaboration is helping to advance research into mesenchymal stem cells (MSCs), which may promote remyelination. “There are lots of things we can look at when we think about how we would approach progressive MS,” said Alan J. Thompson, MD, consultant neurologist at the National Hospital for Neurology and Neurosurgery in London.
Agents That May Offer Neuroprotection
One approach to providing neuroprotection is to block sodium channels on the axon and on the microglia. This technique has proven effective in animal models, but human trials have yielded mixed results. In 2010, Kapoor et al randomized 120 patients with secondary progressive MS to 400 mg of lamotrigine, a sodium-channel blocker, or placebo. At two years, participants who received lamotrigine had greater cerebral volume loss than controls. Brain volume partly recovered when treatment was stopped, however.
When the researchers performed a post hoc analysis of their data, they made two observations that supported a benefit of lamotrigine. The first was that lamotrigine was associated with improvements on the timed 25-foot walk. The other observation was that when patients who stopped taking lamotrigine were excluded from the analysis, lamotrigine reduced serum neurofilament levels, compared with placebo. Serum neurofilament levels were correlated with disability, and the researchers concluded that lamotrigine might protect axons against degeneration. “There’s some indication that this [drug] needs to be pursued a little bit further,” said Dr. Thompson.
Kapoor et al later studied phenytoin, a neuroprotective agent with mechanism of action similar to that of lamotrigine, in a phase II randomized controlled trial of 86 patients with acute optic neuritis. The trial’s primary end point was retinal nerve fiber layer thickness. After six months, participants who received phenytoin had a 30% reduction in atrophy, compared with controls.
Biotin, a coenzyme involved in fatty acid synthesis and energy production, also has shown potential as a neuroprotective agent. In a phase III study of 154 patients with primary and secondary progressive MS, biotin met the primary end point of improvement on EDSS or timed 25-foot walk at nine months that was confirmed at 12 months. The drug’s effect on EDSS score was the greater contributor to the positive result. The data are “exciting,” but should be interpreted cautiously because of the study’s relatively small number of patients, according to Dr. Thompson. The results of a trial of biotin in patients with optic neuritis will be reported later this year, he added.
Ongoing Trials of Neuroprotective Agents
Research into agents that may provide neuroprotection is ongoing. One study, the MS-Secondary Progressive Multi-Arm Randomization Trial (MS-SMART), uses an adaptive trial design that will allow investigators to compare several agents at the same time. In MS-SMART, equal numbers of participants will receive amiloride (5 mg bid), riluzole (50 mg bid), fluoxetine (20 mg bid), or placebo.
Amiloride blocks the neuronal proton-gated acid-sensing ion channel, which is increased within axons and oligodendrocytes in MS lesions. Researchers at the University of Oxford in the United Kingdom found that the drug reduced the rates of atrophy and white and gray matter damage in people with primary progressive MS.
Riluzole is a treatment for motor neuron disease. A Dutch pilot study in 2005 suggested that riluzole reduced the rate of cervical cord atrophy and decreased the development of new T1 hypointense lesions on MRI.
Fluoxetine, a selective serotonin reuptake inhibitor, is an antidepressant. The drug might protect against axonal loss because it stimulates glycogenolysis, which is a necessary energy source for axons, and enhances the production of brain-derived neurotrophic factor in rodent astrocyte cultures. Recruitment into MS-SMART will continue through 2015.
In addition, the Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in MS (SPRINT-MS) will examine the potential neuroprotective effects of ibudilast. The randomized, placebo-controlled study will last for 96 weeks and focus on ibudilast’s effect on whole-brain atrophy. Secondary end points will include diffusion tensor imaging of descending pyramidal tracts, magnetization transfer ratio of the whole brain, and optical coherence tomography of the retinal nerve fiber layer.
Stem Cells Could Promote Remyelination
Neurologists will continue to seek therapies that can stimulate remyelination in patients with progressive MS. Various studies since 2009 have suggested that MSCs could produce this outcome. Despite their small patient populations, these trials can produce meaningful results, said Dr. Thompson.