Fox RJ, et al. - Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood–brain barrier, so researchers tested its possible therapeutic impacts in patients with progressive multiple sclerosis in a phase 2 randomized trial. In these patients, they observed a slower progression of brain atrophy in association with ibudilast vs placebo treatment. However, higher rates of gastrointestinal side effects, headache, and depression associated with ibudilast treatment were also documented.

Methods

• Patients with primary or secondary progressive multiple sclerosis received oral ibudilast (≤ 100 mg daily) or placebo for 96 weeks.
• They assessed the rate of brain atrophy (primary efficacy end point), as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain).
• They also evaluated the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis (major secondary end points).

Results

• Randomization involved 255 patients, of those, 129 were assigned to ibudilast and 126 to placebo.
• The primary progressive disease was detected in 53% of the patients in the ibudilast group and 52% of those in the placebo group; the others had secondary progressive disease.
• With ibudilast and with placebo, the rate of change in the brain parenchymal fraction was -0.0010 per year and -0.0019 per year, respectively (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks.
• Gastrointestinal symptoms, headache, and depression were documented as ibudilast-related adverse events.