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PARIS – An old compound with a novel mechanism of action for a multiple sclerosis drug may diminish brain volume loss in progressive MS, researchers reported here.

In a phase II trial, ibudilast was associated with a 48% relative reduction in the rate of decline in brain atrophy as measured by brain parenchymal fraction (BPF) scanning over 96 weeks (P=0.04), according to Robert Fox, MD, of the Cleveland Clinic, and colleagues.

Ibudilast acts on many pathways. It's a macrophage migration inhibitor factor, a phosphodiesterase-4 (PDE-4) and PDE-10 inhibitor, and it's a toll-like receptor 4 (TLR4) inhibitor.

It was approved in Japan in 1989 for use in bronchial asthma and post-stroke dizziness, and has been shown in recent studies to reduce atrophy in relapsing-remitting MS. Animal models have also suggested that it may be neuroprotective, Fox said in a presentation at the joint ECTRIMS-ACTRIMS meeting.

His group conducted a phase II study in 255 patients with primary or secondary progressive MS, mean age 56, at 28 sites across the U.S. All patients had evidence of disability progression in the previous 2 years.

They were randomized to placebo or to ibudilast at a dose of up to 100 mg/day and followed for 96 weeks. The primary outcome was change in brain atrophy as measured by brain parenchymal fraction, and secondary outcomes included magnetization transfer ratio (MTR) -- a measure of normal tissue -- and diffusion tensor imaging (DTI).

Fox's group also performed optical coherence tomography (OCT) and cortical atrophy assessments, but those results had not been analyzed at the time of the presentation.

A total of 244 patients were included in the modified intention-to-treat population for efficacy analyses, and there was an 86% retention rate through week 96.

In addition to meeting its primary endpoint, the drug was generally safe and well tolerated. Certain treatment-emergent adverse events were more common with ibudilast, including gastrointestinal issues such as nausea, diarrhea, and abdominal pain, as well as a larger proportion of depression (9% versus 3%).

When analyzing treatment-related adverse events, gastrointestinal events driven by nausea remained significant, as did depression. Rash and fatigue were also more common with the drug.

But there were no differences in serious adverse events or in overall tolerability, Fox said.

For the major secondary endpoint of MTR, treatment with ibudilast was associated with a 77% to 82% reduction in the rate of decline, with better outcomes for both normal-appearing overall brain tissue and gray matter.

However, there was no significant difference on DTI results, he noted. Analyses of OCT and cortical atrophy data are under way, as are assessment of clinical outcomes and additional safety and laboratory analyses, Fox stated.