Ibudilast Significantly Slows Brain Atrophy for Progressive MS
OCTOBER 28, 2017
Robert J. Fox, MDTreatment with ibudilast (MN-166) slowed the rate of brain atrophy by 48% without inducing significant toxicity compared with placebo for patients with progressive multiple sclerosis (MS), according to findings from the phase II SPRINT-MS trial presented at the 2017 MS Paris Meeting.
In the 255-patient trial, annual change in brain atrophy, as measured by brain parenchymal fraction (BPF), was -0.00105 in the ibudilast group compared with -0.00202 for placebo (P = .040), which remained consistent in a sensitivity analysis (-0.00101 vs -0.00200; P = .045). BPF findings were supported by improvements in magnetization transfer ratio (MTR) for both brain tissue and gray matter with ibudilast versus placebo.
"Compared with placebo, ibudilast treatment was associated with a 48% slowing in the rate of atrophy progression," said Robert J. Fox, MD, from the Mellen Center for MS Treatment and Research, Cleveland Clinic. "No statistically significant difference was seen in tolerability, although there was an absolute difference of about 5% higher discontinuation rate in the ibudilast group."
Ibudilast is an oral inhibitor of macrophage migration inhibitor factor (MIF), PDE-4, PDE-10, and Toll-like receptor 4. This unique profile allows it to be an effective bronchodilator and vasodilator with potential neuroprotective effects. Ibudilast is approved in Japan as a treatment for bronchial asthma and post-stroke dizziness.
In the SPRINT-MS trial, patients with primary or secondary progressive MS were randomized to placebo (n = 126) or ibudilast at escalating doses (60, 80, or 100 mg/day) based on tolerability (n = 129). By week 96 of the study, there were 112 patients in the placebo group and 108 in the ibudilast arm (86% overall retention rate).
Baseline characteristics were balanced across the two groups. Patients were approximately 56 years of age, and two-thirds were female. About 48% of patients in each group had secondary progressive MS. The baseline expanded disability status scale (EDSS) score was near 5.4 and one-third of patients were on a disease-modifying therapy.
Overall, there was a significant difference in MTR measures, Fox noted. Ibudilast was associated with a 77% to 82% slowing in the rate of MTR decline. For normal appearing brain tissue, the MTR per 1 year with ibudilast was -0.00558 versus -0.03064 for placebo (P = .047). For normal-appearing gray matter, there was a 1-year MTR rate change with ibudilast of -0.00753 versus -0.0321 for placebo (P = .054).
There was no significant difference observed in diffusion tensor imaging between the ibudilast and placebo groups, this included for transverse (P = .15) and longitudinal (P = .73) diffusivity. "There was a trend favoring ibudilast, with a decrease in transverse diffusivity in the ibudilast group," said Fox.
An adverse event (AE) of any grade occurred in 88% of those in the placebo group compared with 92% in the ibudilast arm, which was not deemed a statistically significant difference (P = .26). The most common AEs that were higher with ibudilast were gastrointestinal-related, primarily nausea (15% vs 27%) and diarrhea (7% and 16%). Upper respiratory infections were more common with placebo (19% vs 10%). Additionally, 9% of patients treated with ibudilast experienced depression compared with 3% for placebo. There were no reports of suicidality or suicide attempts, Fox noted.
There were 58 total serious AEs in the trial (SAEs), which occurred in 44 patients. The rates of SAEs were similar between the two arms. Overall, twenty-five percent of patients in the placebo group discontinue treatment compared with 30% in the ibudilast arm. Twelve percent and 18% of these discontinuations were due to AEs, in the placebo and ibudilast groups, respectively. Additionally, the rates of early study termination or withdrawal due to AEs were 13% and 20% for placebo and ibudilast, respectively.
"Treatment-related adverse events were mostly gastrointestinal, as well as rash, depression, and fatigue," said Fox. "There was no increased rate of serious adverse events, and importantly no opportunistic infections or cancer signals."
As of the September 2017 data cutoff, findings were still unavailable for optical coherence tomography and cortical atrophy. Fox anticipated these findings would become available soon, along with additional safety and laboratory analyses.
Fox RJ, Coffey CS, Cudkowicz ME, et al. SPRINT-MS/NN 102 phase II trial of ibudilast in progressive MS: top-line results. Presented at: 7th Joint ECTRIMS - ACTRIMS Meeting; October 25-28, 2017, Paris, France. Abstract 278.