The anti-inflammatory and neuroprotective oral agent MN-166 (ibudilast) shows an excellent safety profile at 60 mg/day and provides significantly prolonged time-to-first relapse and attenuated brain volume shrinkage in patients with relapsing-remitting (RR) and/or secondary progressive (SP) multiple sclerosis (MS).
Sponsor trial coordinator Richard E. Gammans, PhD, Chief Development Officer, MediciNova Inc., San Diego, California, presented the findings from a multicenter, randomised, double-blind, placebo-controlled, phase 2 study here on October 12 at the 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).
"Pharmacologically, MN-166 has mechanisms that include anti-inflammatory effects, such as phosphodiesterase inhibition, and neuroprotective effects, such as inhibition of [nitric oxide] synthesis and reduction in reactive oxygen species," he said. This study was thus designed to evaluate the effects of MN-166 in patients with MS.
The study enrolled patients aged 18 to 55 years who were diagnosed with RRMS or SPMS using McDonald criteria, with continued relapses. They had one or more Gd-enhancing lesion on MRI scan taken 2 weeks before treatment start; and expanded disability status scale (EDSS) no greater than 5.5 at screening. The main exclusion criteria were based around no use of various immunosuppressants within 6 months, or of interferons -- corticosteroids and adrenocorticotropic hormone -- within 45 days of the initial magnetic resonance imaging (MRI) scan.
The primary endpoint was cumulative active lesions on MRI. The secondary endpoints were clinical relapse and other MRI measures.
Of 967 patients screened, 100 were randomized to placebo, 94 were randomized to 30 mg/day of MN-166, and 96 were randomized to 60 mg/day of MN-166 for the first 12 months of treatment, with clinical and MRI evaluations every 2 months. The 12-months extension phase was designed to evaluate the effects of continuation of MN-166 dosing, with placebo patients switched to MN-166 30 mg/day or 60 mg/day.
Baseline clinical characteristics across these three treatment groups were similar for percent RRMS, percent spinal or cerebrum location of lesions, and number of relapses in previous 24 months. There were indications that time since both MS diagnosis and onset of symptoms were longer in the treated groups (39, 50, 60 months; 73, 96, 98 months; respectively).
In terms of primary outcome of cumulative active lesions over the first 12 months, there was no significant difference amongst treatments. However, there was a modest difference between the highest dose of MN-166 and placebo, with an 18% reduction in cumulative active lesions, although this difference was not significant, indicated Dr. Gamman.
Similarly, there were no significant differences between treatment group in the percent of patients with sustained disability progression on EDSS (8.0%, 5.3%, 4.1%).
In contrast, for other MRI assessments over the 12 months, MN-166 at 60 mg/day showed not only a significant improvement in the percentage of brain volume reduction (P =.035), but also a significant increase in the median time to first relapse (P =.04). Thus, the percentage of patients who were relapse-free at year 1 was significantly greater at the higher MN-166 dose (41% vs 41.5% vs 56.0% (P =.03).
Dr. Gammans said that MN-166 was very well tolerated, with 89% of patients completing the first 12 months of treatment. "The side effects were generally mild, and resolved without intervention, and there were no adverse observations on laboratory or [electrocardiographic] findings as well," he added.
When the two MN-166 treatment groups were combined, gastrointestinal side effects were the only adverse events to occur at 2-fold or greater times those of placebo (7.6% vs 14.7% vs 22.2%), although tolerance to these effects occurred rapidly (2-4 days). There were no deaths in the study.
Due to these modest effects of MN-166 on inflammatory lesion counts and based on its pharmacology, Dr. Gamman said that the clinical benefits of MN-166 60 mg/day arise primarily from its actions towards protection of neurons from damage, rather than towards reduction of inflammatory lesions.
At the same time, the excellent safety profile at 60 mg/day and the effects that reached significance in this study suggest that future studies with MN-166 should evaluate higher doses on disease progression and MRI measures of neuroprotection, rather than inflammation.
Funding for this study was provided by MediciNova Inc.
Source: Presentation title: Clinical Effect of the Neuroprotectant MN-166 in Relapsing Forms of MS. Abstract 52 (15/10/07