Assistant Professor of Neurology, Weill Cornell Medical College
Dr. Perumal reports she is a consultant for Genzyme and Biogen.
SYNOPSIS: A Phase II trial of ibudilast in progressive multiple sclerosis demonstrated a decreased rate of brain atrophy when compared to placebo.
SOURCE: Fox RJ, Coffey CS, Conwit R, et al; for the NN102/SPRINT-MS Trial Investigators. Phase 2 trial of ibudilast in progressive multiple sclerosis. N Engl J Med 2018;379:846-855.
Although incredible advancements have been made in the treatment of multiple sclerosis (MS) over the past 30 years, and new therapies have made a significant impact on relapsing-remitting disease (RRMS), the treatment of progressive MS remains challenging. Recent research into the potential underlying pathological processes has shed some light on why medications that predominantly work on the peripheral immune system may not be that effective in progressive MS. Researchers have reported that the inflammatory injury in progressive MS may be caused more by resident immune cells within the central nervous system rather than the influx of immune cells from the periphery, like in RRMS. A better understanding of these mechanisms has helped advance the search for an effective treatment for progressive MS. Given this scenario, the results of the recent Phase II study of ibudilast in progressive MS show promise and are encouraging.
Ibudilast is a phosphodiesterase inhibitor currently available in Japan for the treatment of asthma and post-stroke dizziness. It has inhibitory effects on macrophage migration inhibitory factor and toll-like receptor 4, which have been found to be increased in the cerebrospinal fluid of patients with progressive MS. Ibudilast also can cross the blood-brain barrier. The results of an earlier clinical trial of ibudilast in RRMS showed that it seemed to have a positive effect on the rate of brain atrophy and evolution of T1 hypointensities rather than on the development of new T2 lesions. These observations, along with the known mechanism of action of ibudilast, provided the rationale for exploring this medication in the treatment of progressive MS.
Fox et al conducted this Phase II study of ibudilast in progressive MS through NeuroNEXT, an NIH-sponsored consortium of several neurologic institutions in the United States, with the goal of facilitating faster and more efficient clinical treatment trials in neurology. They randomized 255 patients from 28 U.S. sites in a 1:1 ratio to ibudilast or placebo. The dose of ibudilast was 100 mg/day. Inclusion criteria were progressive (secondary or primary) MS patients between 21 to 65 years of age with an expanded disability status scale (EDSS) range of 3.0-6.5 who demonstrated disease progression in the preceding two years. Disease progression was defined as one of the following: 0.5-point increase in EDSS or a 20% increase in either the 25-foot timed-walk or nine-hole peg test. Concurrent treatment with beta-interferon or glatiramer acetate was allowed. The primary endpoint was the rate of brain atrophy as measured by the brain parenchymal fraction. The main secondary outcomes included change in diffusion tensor imaging in the pyramidal tracts, change in magnetization transfer ratio in normal appearing brain tissue, and thickness of retinal nerve fiber layer as measured by optical coherence tomography. Eight patients in the ibudilast group and three patients in the placebo group withdrew before at least one post-baseline MRI was obtained and were excluded; thus, 244 patients were included in the analysis.
The rate of change in brain volume decreased by 48% in patients taking ibudilast vs. placebo. The rate of change in brain parenchymal fraction was -0.0010 (95% confidence interval [CI], -0.0016 to -0.0004) per year in the ibudilast group and -0.0019 (95% CI, -0.0025 to -0.0013) per year in the placebo group. The secondary outcomes tended to be positive toward ibudilast as well, but there were limitations to their interpretations. There were no opportunistic or serious infections associated with ibudilast. The ibudilast group had a higher incidence of gastrointestinal symptoms (nausea, vomiting, diarrhea, abdominal pain), headache, and depression. There were no other safety concerns during the trial.
The results of this Phase II trial suggest that ibudilast may be effective as a potential treatment for progressive MS. This trial, taken together with an earlier study using ibudilast to treat RRMS, seems to demonstrate that its effect on brain atrophy progression may be separate from any anti-inflammatory effect on new lesion formation. Based on what we now know to be potential disease pathology in progressive MS and the mechanism of action of this medication, ibudilast treatment could have a significant effect on disease processes specific to progressive MS. Further trials are needed to study this drug in progressive MS to examine clinical disability outcomes. A challenge for MS treatment trials is the appropriate endpoints and methods to assess disability, which need to be designed carefully during plans for Phase III trials for ibudilast.