Ibudilast slows growth of chronic brain lesions tied to worsening MS

Use of oral ibudilast — being explored as a treatment for progressive forms of multiple sclerosis (MS) — was found to significantly slow the growth of chronic active lesions in the brains of patients with the neurodegenerative disease, according to MRI data from the SPRINT-MS study.

Such lesions are areas of damage marked by inflammatory cells at their edge, with an inactive core without inflammatory activity. They’re thought to contain compartmentalized regions of inflammation and to grow slowly over time — contributing to a gradual worsening of disability in MS patients.

Treatment with ibudilast “significantly decreased slowly enlarging lesion volume,” by as much as 23%, the researchers noted.

According to the team, these findings “provide further support for the neuroprotective effects of ibudilast in progressive MS.”

The study, titled “Ibudilast reduces slowly enlarging lesions in progressive multiple sclerosis,” was published in the Multiple Sclerosis Journal. The SPRINT-MS trial was funded by grants from the National Institute of Neurologic Disorders and Stroke and the National Multiple Sclerosis Society, and by ibudilast’s developer, MediciNova, through a contract with the National Institutes of Health.

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MS is caused by immune-mediated damage to the myelin sheath, a protective coating around nerve fibers that boosts the speed of electrical impulses. The resulting inflammation, occurring in the brain and spinal cord, also damages nerve cells and the cells that produce myelin.

Such damage can be viewed on MRI scans in the form of lesions, which appear as dark or light spots that are different than normal tissue. Lesions can either be active, with inflammatory cells and ongoing demyelination, chronic inactive, when demyelination stops with no signs of inflammation, or chronic active.

Chronic active lesions, also called smoldering lesions, are thought to increase in size slowly and have been linked to gradual disability worsening.

A recently-developed imaging method now can detect a form of chronic active lesions, called slowly enlarging lesions, or SELs, using standard MRI scans.

Ibudilast is an oral small molecule that lowers the levels of pro-inflammatory signaling molecules that drive inflammation and nerve cell damage in MS. Unlike many approved MS therapies, ibudilast can cross the blood-brain barrier, a tight membrane that regulates the passage of substances from the bloodstream into the brain.

The SPRINT-MS Phase 2b clinical trial (NCT01982942) demonstrated that almost two years of daily ibudilast treatment significantly slowed brain volume loss by 48% compared with a placebo in patients with primary progressive MS (PPMS) or secondary progressive MS (SPMS), with or without relapses.

Because the study’s protocol included MRI scans that can measure SELs, researchers at the Cleveland Clinic, in Ohio, suggested that “SEL volume would be reduced in the ibudilast-treated subjects compared with placebo in SPRINT-MS.”

MRI data from 195 trial participants did, in fact, show a significantly smaller median SEL volume among ibudilast-treated patients compared with those given the placebo (0.50 vs. 0.75 mL). Across all participants, ibudilast was significantly associated with a 23% reduction in SEL volume compared with the placebo. Likewise, SEL volume was significantly reduced by 21% among PPMS patients and by 19% in SPMS patients.

In comparison, treatment did not significantly affect the total lesion volume on MRI scans, the total volume of inflammatory lesions, or the total number of these lesions.

These data suggest that “ibudilast’s mechanism of action is likely to be different from conventional anti-inflammatory therapies in MS,” which normally exert an effect of total new or enlarging lesions and inflammatory lesions, the researchers noted.

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For patients, a larger SEL volume significantly correlated with reduced walking abilities — as indicated by a longer time to walk 25 feet.

Worse manual dexterity, measured by the nine-hole peg test, and impaired cognitive function, assessed using the symbol digit modalities test, also were significantly associated with larger SEL volumes.

The researchers next divided the participants into four groups based on SEL volumes. Consistently, those with the highest SEL volume before treatment had the worst measures across several assessments, including disease severity, cognitive function, walking abilities, and manual dexterity. A higher SEL volume also was tied to a greater brain volume loss, indicating more neurodegeneration.

We found a significant treatment of ibudilast on SELs [slowly enlarging lesions], suggesting ibudilast reduced chronic active lesions and had an effect on compartmentalized inflammation.

No association was found between SEL and confirmed disability progression, as determined by a sustained increase in Expanded Disability Status Scale (EDSS) scores — though the researchers noted that the small number of patients with progression limited this result.

Finally, ibudilast significantly reduced magnetization transfer ratios (MTR) decline in SELs. This measure of myelinated nerve fiber integrity in large brain regions indicated that less myelin was being damaged with treatment. In contrast, MTR changes in other kinds of lesions did not show differences between ibudilast and the placebo.

“We found a significant treatment of ibudilast on SELs, suggesting ibudilast reduced chronic active lesions and had an effect on compartmentalized inflammation,” the researchers wrote.

“The effect of ibudilast on SELs was observed despite there being no effect on new … lesion development and thus reflecting a mechanism outside peripherally [outside the brain] mediated inflammation,” the team added.

The researchers called the measurement of SELs “a relatively straightforward approach” and said it “may be [a] useful marker of chronic active lesions” — one that could be used “as a clinical trial outcome measure in progressive MS.”