In the SPRINT-MS phase 2 clinical trial, ibudilast—an anti-inflammatory and neuroprotective oral agent—slowed the rate of brain atrophy by nearly half in patients with progressive multiple sclerosis (MS). Researchers published their results in the New England Journal of Medicine.
“Even though more than a dozen therapies have been approved for the treatment of relapsing forms of multiple sclerosis, only the monoclonal antibody ocrelizumab and the chemotherapy agent mitoxantrone are approved for progressive multiple sclerosis,” wrote the authors, led by Robert J. Fox, MD, the Mellen Center for Multiple Sclerosis, Neurological Institute, Cleveland Clinic, Cleveland, OH.
Ibudilast is able to cross the blood-brain barrier and inhibits various cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4, with possible health benefits to the central nervous system. Macrophage migration inhibitory factor and toll-like receptor 4 are heightened in the cerebrospinal fluid (CSF) of patients with progressive MS, leading to inflammation in the central nervous system.
Specialists aim to slow the clinical course of neurologic impairment that stems from permanent tissue injury and is measured by the degree of brain atrophy in patients with progressive MS.
In this phase 2, multicenter, randomized, double-blind trial, investigators randomized 255 patients to either ibudilast (n=129) or placebo (n=126). In sum, 53% of patients in the ibudilast group and 52% of those in the placebo group manifested primary progressive MS. The remaining patients had secondary progressive disease.
Patients in the ibudilast group were administered up to 100 mg/d of the drug for 96 weeks. The dose was selected based on previous research and data from preclinical trials. Baseline clinical and demographic characteristics in both the ibudilast and placebo groups were similar—except patients in the ibudilast group were younger and displayed lower transverse diffusivity.
The primary outcome was the rate of brain atrophy, indicated by brain parenchymal fraction—the amount of brain tissue relative to the volume of the outer surface contour of the brain, including CSF, as quantified from magnetic resonance imaging data. Secondary outcomes included measures of tissue damage.
The team estimated that the rate of change in the brain parenchymal fraction was -0.0010 per year in patients taking ibudilast and -0.0019 per year in those taking placebo. The absolute difference was 0.0009 per year (P=0.04), which translated to ~2.5 ml less brain-tissue loss with ibudilast during the 96-week study period, and a relative difference of 48%.
Results from prespecified sensitivity analyses, which were adjusted for baseline age and other factors, were in line with differences detected between both groups as measured during primary analysis.
“Although clinical trials in MS use a variety of methods to measure brain atrophy, the 48% difference in atrophy progression favoring ibudilast in the current trial can be broadly compared with results from other trials in progressive multiple sclerosis—for example, 17.5% slowing of brain atrophy with ocrelizumab, 15% slowing with siponimod, and 43% slowing with simvastatin,” the authors wrote.
With respect to secondary outcomes, the team found that disability progression was similar in both the ibudilast and placebo groups. Of note, adverse effects of ibudilast included gastrointestinal complaints, headache, and depression.
“There is a significant need for new treatment options to effectively delay disability progression for patients with progressive MS,” reflected Dr. Fox. “We are hopeful these findings will help us develop more therapies for progressive MS, and do so more rapidly and efficiently.”
“Although a larger study is needed to confirm these findings, this promising study brings people with progressive MS, who currently do not have many treatment options, one step closer to a potential therapy,” said Robin Conwit, MD, program director, National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.
The study was conducted by the Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT), which is sponsored by NINDS. The research was supported by NINDS, National Multiple Sclerosis Society and MediciNova.