PARIS — The first-in-its class, small-molecule drug ibudilast (MN-166, MediciNova) is effective and safe for treating progressive multiple sclerosis (MS), new research suggests.
In the multicenter phase 2b Secondary and Primary Progressive Ibudilast NeuroNEXT trial in MS (SPRINT-MS), which included 255 patients, those who received the oral treatment up to 100 mg/day had a 48% reduction in whole-brain atrophy by 96 weeks, the first primary outcome. This reduction was significantly greater than that seen in patients receiving matching placebo.
The study also met its second primary outcome of safety and tolerability for those receiving the active treatment. Adverse events (AEs) that were significantly greater for this group than the placebo group included gastrointestinal events, such as nausea, and depression. Interestingly, the placebo group reported more upper respiratory tract infection and neck pain.
Only two "treatment-related and anticipated" serious AEs occurred: one report of ataxia in the ibudilast group and one report of thrombocytopenia in the placebo group.
Topline results from SPRINT-MS were presented for the first time during a late-breaking news session here at the 7th Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2017 meeting.
"The magnitude of the 48% reduction was quite robust and a little surprising, and the coherence between the atrophy and other imaging metrics was quite encouraging," principal investigator, Robert J. Fox, MD, staff neurologist at the Cleveland Clinic, Ohio, told Medscape Medical News.
After the presentation, chair of the ECTRIMS-ACTRIMS conference, Catherine Lubetzki, MD, PhD, professor of neurology at Pierre and Marie Curie University, Paris, France, called the findings "very impressive" and noted that the next steps will be important.
"Now we have to wait for results in a larger study, but right now this is really interesting," especially for a patient population that hasn't historically had a lot of treatment options, Dr Lubetzki told Medscape Medical News.
Small-Molecule Inhibitory Factor Inhibitor
Ibudilast is a first-in-class, orally bioavailable small-molecule phosphodiesterase-4 and -10 inhibitor and macrophage migration inhibitory factor inhibitor.
Since 1989, the drug has been marketed in Korea and Japan to treat dizziness after stroke and bronchial asthma.
A past phase 2 study suggested that it reduces atrophy progression "and black hole formation" in relapsing-remitting MS, noted Dr Fox. Animal models have also suggested that it provides neuroprotection in Krabbe's disease, spinal cord injury, traumatic brain injury, chronic neuropathic pain, and cerebral aneurysm.
The National Institute of Health's National Institute of Neurological Diseases and Stroke created the Network for Excellence of Neuroscience Clinical Trials, or NeuroNEXT, to test "promising neurological therapies" in phase 2 trials. NeuroNEXT co-sponsored the SPRINT-MS trial.
In the study, 255 patients aged 18 to 65 years were enrolled at 28 sites in the United States. About half had primary progressive MS and half had secondary progressive MS. The disease duration was about 12 years.
All patients had Swanton's criteria–determined MS lesions on brain MRI; a score of 3.0 to 6.5 on the Expanded Disability Status Scale (EDSS); and disability progression shown during the preceding 2 years on the EDSS, 25-foot walk test, or 9-hole peg test.
The participants were randomly assigned to receive oral ibudilast, up to 50 mg twice daily (n = 129; 52% women; 95% white; mean age, 55 years) or matching placebo (n = 126; 55% women; 91% white; mean age, 57 years), and they were followed for at least 96 weeks. Concurrent treatment with interferon β-1a or glatiramer acetate was allowed.
Those receiving ibudilast received total doses of 60, 80, or 100 mg/day, as tolerated.
Slowing in Brain Atrophy Progression
All of the patients underwent MRI using brain parenchymal fraction (BPF) to measure whole-brain atrophy, the study's first primary endpoint. These imaging outcomes, as well as clinical outcomes, were measured every 24 weeks.
Slope of BPF significantly differed between the treatment groups over time, with those receiving the active treatment showing a 48% slowing in the rate of decline over the 2 years of the study. The estimated rate of annual BPF change was –0.00105 for the ibudilast group and –0.00202 for the placebo group (P = .04).
Sensitivity analysis in the per-protocol population showed almost identical findings, with estimate rates of annual changes of –0.00101 vs –0.00200, respectively.
The second primary endpoint was safety, as measured by reports of AEs and serious AEs, and tolerability. The overall retention rate through week 96 was 86%. The rates of treatment discontinuation for any reason were 30% in the ibudilast group and 25% in the placebo group; the rates of discontinuation due to an AE were 18% and 12%, respectively. Neither comparison was significantly different.
Comparisons between rates of early study termination, for any reason or due to an AE, and of "early drug withdrawals" were also not significantly different.
"There was excellent tolerability for ibudilast," noted Dr Fox.
Treatment-emergent AEs that were significantly greater in the ibudilast group included the following:
Nausea (27% vs 15%, respectively, P = .02);
Diarrhea (16% vs 7%, P = .03);
Abdominal pain (5% vs 0%, P = .03); and
Depression (9% vs 3%, P = .048).
Significant differences between the two groups in treatment-related AEs included the following:
Any AE (67% vs 48%, P = .002);
Any gastrointestinal system organ class (SOC) AE (41% vs 20%, P = .0003); and
Nausea (23% vs 9%, P = .004).
There were also more nervous system SOCs in the ibudilast group (16% vs 8%, respectively), such as depression; more skin and subcutaneous tissue SOCs (9% vs 4%), "which were mostly rashes," Dr Fox noted, and of general fatigue (5% vs 1%). None of these comparisons significantly differed between the groups.
Although the independent medical monitor found 58 serious AEs in 44 participants, as mentioned earlier, only two were considered to be treatment-related and anticipated. There were no treatment-related and unanticipated serious AEs.
In addition, 22 nonrelated and unanticipated serious AEs were found: 10 in the ibudilast group and 12 in the placebo group. Among these were 4 cases of cancer in the placebo group and 1 in the active treatment group. No suicidal thoughts or attempts and no opportunistic infections were reported for any of the participants.
Secondary outcome data released at the meeting included magnetization transfer ratio (MTR), as well as diffusion tensor imaging (DTI) for descending pyramidal tracts.
There was a significant difference in slope in MTR measures of normal-appearing brain tissue and of normal-appearing gray matter, and there was a 77% to 82% slowing in the overall rate of MTR decline for patients receiving the active treatment.
No significant between-group differences were seen in DTI measures of transverse and longitudinal diffusivity, "although there was a trend favoring ibudilast," reported Dr Fox.
Still, "these types of advanced imaging measures may point us towards better ways of doing progressive MS trials in the future," he added.
Information on retinal nerve fiber layer with optical coherence tomography and on cortical atrophy will be released later.
"Interesting and Promising"
"There are really two big takeaways from this study," said Dr Fox. "One: Ibudilast looks promising for progressive MS, and what I think is just as important is that the advanced imaging measures look very promising as well."
He noted that the pharmaceutical company is now "looking for opportunities to take this into phase 3."
The National Institutes of Health, which is the funder for the current trial, "is not in the business of doing phase 3 trials. But the hope is, based on these positive results, there will be interest in [other] sponsorship for a phase 3 trial," he said. "I think this is an optimistic time."
Asked for comment, Bernhard Hemmer, MD, head of the Department of Neurology at the Technical University in Munich, Germany, said that this study definitely caught his attention.
"It's nice that this study was done and that it was publicly funded, and the data are interesting," Dr Hemmer told Medscape Medical News. "Of course it's a phase 2 trial, so we have to see how the MRI endpoints really translate into clinical endpoints, but right now, it's both interesting and promising,"
The study was funded by the National Institutes of Health, the National Multiple Sclerosis Society, the National Institute of Neurological Disorders and Stroke for the NeuroNEXT Clinical Coordinating Center and Data Coordinating Center, and MediciNova. Dr Fox has received consulting fees from Biogen Idec, GlaxoSmithKline, Novartis, Questcor, Teva, and Xenoport; and he has received research support from Novartis.
7th Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2017. Late Breaking News session, oral presentation 278. Presented October 28, 2017.
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Cite this: Ibudilast 'Impressive' for Progressive MS in Phase 2 Trial - Medscape - Oct 30, 2017.