Ibudilast Slows Brain Atrophy in Progressive Multiple Sclerosis Trial

August 30, 2018

The small molecule slowed atrophy by roughly 2.5 mL less brain-tissue loss compared to placebo.

Robert J. Fox, MD

Ibudilast has been found to be associated with a slower progression of brain atrophy compared to placebo in a phase II trial of patients with progressive multiple sclerosis (MS).

For those taking the therapy, the rate of change in brain parenchymal function was -0.0010 per year (95% CI, −0.0016 to −0.0004), compared to -0.0019 per year (95% CI, −0.0025 to −0.0013) for those given placebo, for a difference of 0.009 (95% CI, 0.00004 to 0.0017; P = .04). Ultimately, it was equivalent to approximately 2.5 mL less brain-tissue loss over 96 weeks, a relative difference of 48%.

“There were some [adverse] effects—gastrointestinal symptoms, headache, and depression—that were seen more commonly with ibudilast compared to placebo, but the drug discontinuation rate was only 5% different between the ibudilast and placebo, which suggests that, in general, it was quite well tolerated,” Robert J. Fox, MD, a neurologist at the Mellen Center for Multiple Sclerosis at Cleveland Clinic, and lead author of the study, told NeurologyLive.

Ultimately, 16% of patients treated with ibudilast withdrew from the trial, compared to 11% with placebo (P = .24), with 8% and 4%, respectively, withdrawing due to adverse events (AEs; P = .21)).

Overall, the safety profile appeared as expected, Fox noted. The percentage of patients reporting an AE was 92% with the trial therapy and 88% with placebo, with the 2 groups reporting rates of 16% and 19% (P = .46), respectively, for serious AEs.

The multicenter trial randomized 255 patients to ibudilast 100 mg (n = 129) or placebo (n = 126). A total of 53% of those in the ibudilast group and 52% of those in the placebo group had primary progressive MS. Fox and colleagues noted that the per-protocol analysis of the primary endpoint was consistent with the primary analysis (P = .03), as well as a sensitivity analysis when adjusting for age at baseline (P = .03).

Major secondary endpoints that were assessed included transverse diffusivity in the corticospinal tracts (10-3 mm2/sec), longitudinal diffusivity in the corticospinal tracts (10-3 mm2/sec), magnetization transfer ratio in normal-appearing brain tissue, retinal nerve fiber layer (µm), and cortical thickness (mm).

The rate of change in transverse diffusivity in the corticospinal tracts for ibudilast was —0.0015 (95% CI, –0.0043 to 0.0014) compared to 0.0015 (95% CI, –0.0013 to 0.0043) with placebo. Likewise, for longitudinal diffusivity in corticospinal tracts, ibudilast showed a change of 0.0001 (95% CI, –0.0032 to 0.0033) compared to –0.0007 for placebo (95% CI, –0.0039 to 0.0025). The magnetization transfer ratio in normal-appearing brain tissue was shown to be –0.0051 (95% CI, –0.0242 to 0.0139) with ibudilast and –0.0282 (95% CI, –0.0469 to 0.0095) with placebo. Retinal nerve fiber layer and cortical thickness measurements for ibudilast and placebo were 0.0424 (95% CI, –0.3091 to 0.3939) and –0.0019 (95% CI, –0.0061 to 0.0022), and –0.2630 (95% CI,–0.5973 to 0.0714) and –0.0105 (95% CI, –0.0146 to –0.0065), respectively.

“The other thing that this study did was it evaluated 5 different imagining metrics in a multicenter, 28-site, clinical trial to identify which was the best imaging metric for progressive MS,” Fox said. That second part was a little bit beyond the scope of this paper—this paper was just recording the primary outcomes and wasn’t necessarily comparing one imaging modality to another—but we do have that data and it will inform future trials.”

The hazard ratio for 20-week confirmed disability progression with ibudilast as compared with placebo was 0.74 (95% CI, 0.43 to 1.28), as measured by the Expanded Disability Status Scale (EDDS) score. While the most promising of the outcomes, brain atrophy, is not yet a validated biomarker for progressive disability in progressive MS, Fox noted that he still finds the results reassuring.

“What’s encouraging is that the comparison—and it’s hard to do cross-trial comparisons, but we can use it as a little bit of a guidepost—with the only approved therapy for progressive MS, ocrelizumab. It only slowed brain atrophy by 17.5%. There’s another drug that is in development for secondary progressive MS, siponimod, and that slowed brain atrophy by 15%,” Fox explained. “In terms of the magnitude, this is very encouraging that the slowing of brain atrophy was quite robust—almost cut in half. This was not just driven by a couple outliers, this wasn’t driven by a hydration shift in the first few months then everything was the same, it was really an ongoing, continued consistent effect over the course of the entire 96-week study. That’s as encouraging as it can be.”


Fox RJ, Coffey CS, Conwitt R, et al. Phase 2 trial of ibudilast in progressive multiple sclerosis. N Engl J Med. 2018; 379:846-855.


: 10.1056/NEJMoa1803583.