New analyses from the phase 2b SPRINT-MS trial suggest that MediciNova’s ibudilast (also known as MN-166), can lessen retinal thinning as measured by optical coherence tomography.
Robert J. Fox, MD
New optical coherence tomography (OCT) data from analysis of the phase 2b SPRINT-MS trial (NCT01982942) suggest that the ibudilast (MN-166; MediciNova) therapy may attenuate retinal thinning in patients with progressive multiple sclerosis (MS).1
The first-in-class, orally bioavailable, small molecule macrophage migration inhibitory factor (MIF) inhibitor and phosphodiesterase (PDE) -4 and -10 inhibitor reported slowed loss of retinal tissue compared to placebo (n = 123) in measures of peripapillary retinal nerve fiber layer thickness (pRNFL; P = .22), macular volume change, and ganglion cell-inner plexiform (GCIP) layer thickness change (P = .12).
As well, macular volume change in the Zeiss Cirrus SD-OCT site cohort (n = 183) was −0.00040 mm3 per year for the ibudilast group compared to −0.02083 mm3/year for placebo (P = .1734). In the Heidelberg Spectralis cohort (n = 61), the respective changes in macular volume change were −0.00503 mm3 per year versus −0.03659 mm3 per year in the Spectralis cohort (P =.044).
“We are very pleased that the positive OCT data has been published. This data demonstrates that MN-166 can reduce retinal thinning in progressive MS patients and is further evidence of its neuroprotective effect as retinal thinning is associated with brain volume loss and other measures of MS progression,” Yuichi Iwaki, MD, PhD, President and Chief Executive Officer of MediciNova, Inc. said in a statement.2
The change in pRNFL thickness was +0.0424 uM per year for the ibudilast group compared with −0.2630 uM per year for placebo. Likewise, GCIP layer thickness change, available in the Cirrus cohort, was −0.4893 uM per year for the ibudilast group and −0.9587 uM per year for placebo.
When conducting a 3-way interaction model evaluating the differential effect of ibudilast in primary progressive MS versus secondary progressive MS for RNFL was not significant (P = .77).
READ MORE: The Future of Multiple Sclerosis Imaging
Additionally, the sample size of the study (n = 244) suggest that OCT measures can be used as viable outcomes in trials of progressive disease with an appropriate treatment effect, the authors, including Robert J. Fox, MD, neurologist, Mellen Center for Multiple Sclerosis, Cleveland Clinic, suggested. They noted that their trial calculations suggest that pRNFL would require substantially larger sample sizes as the sole OCT outcome, reducing the feasibility of such a measure being used.
“Sample size calculations based off the actual data from SPRINT-MS suggest that a trial in progressive MS with GCIP as outcome measure would have 80% power to detect a 60% treatment effect with n = 264 participants randomized,” Fox et al. wrote. “GCIP, especially if in the future it is able to be combined across more than 1 brand of spectral-domain OCT device, and given it is less susceptible to acute changes in the setting of optic neuritis, may be feasible to serve as an outcome measure in progressive MS trials.”
They also noted that the enrollment and qualification of multiple sites, as well as 2 different spectral-domain scanner brands, and quality control and independent analysis at an OCT reading center were some unique portions of SPRINT-MS. “Many of these are analogous to how MRI is utilized with a reading center in MRI-driven MS clinical trials,” they wrote.
In 2018, ibudilast was shown to be associated with a slower progression of brain atrophy compared to placebo the earlier analysis of SPRINT-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%.3
At the time, Fox told NeurologyLive that “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.”
Additionally, last year, the FDA completed a protocol review and approved a phase 2b/3 clinical trial of ibudilast in amyotrophic lateral sclerosis (ALS). That is a multicenter, 2-arm, randomized, double-blind, placebo-controlled trial, which will compare ibudilast to placebo in a cohort of approximately 150 patients with ALS. Patients will be randomized 1:1 to receive either 100-mg/day ibudilast or placebo for a period of 9 months, with the primary end point measured as the mean change in functional activity at Month 9 as measured by the ALS Functional Rating Scale-revised (ALSFRS-R) score.4