Ibudilast Shows Promise for Reducing Lesion Volume in Progressive MS

Ibudilast intervention in patients with progressive multiple sclerosis (MS) can reduce the volume of enlarging lesions, according to a recent study published in Multiple Sclerosis Journal.

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Despite the development of multiple disease-modifying treatments (DMTs) for MS in recent years, many patients still endure clinical progression of their MS, which can culminate in active, chronic lesions with degrees of inflammation. These lesions can be classified as: 1) active lesions, which contain an abundance of inflammatory cells and progressive demyelination; 2) chronic inactive lesions, which are without inflammatory cells or complete demyelination; and 3) smoldering lesions, which resemble inactive lesions at their core, possess inflammatory cells along their edges, and are believed to expand slowly.

Slowly expanding lesions (SELs) are associated with progressive disability in MS. As the authors of the present study note, there are limited approved therapies for progressive forms of MS; however, results from the SPRINT-MS phase 2 clinical trial suggest the prognostic benefits of ibudilast in progressive MS cases. To build on these results, researchers conducted a study to evaluate the impact of ibudilast on SEL volume compared with placebo, the associations of SEL volume in patients with or without disability progression, the clinical characteristics and imaging of patients with smaller and larger SEL volumes, and levels of tissue damage observed in lesions through magnetization transfer imaging. The analysis also including information on patients’ Expanded Disability Status Scale (EDSS), timed 25-foot walk test (T25FTW), symbol digit modalities test (SDMT), and 9-hole peg test (9HPT).

Ibudilast is a selective phosphodiesterase inhibitor that primarily targets phosphodiesterase-3 (PDE-3), PDE-4, PDE-10, PDE-11, and macrophage migration inhibitory factor. “PDEs control the signal of cyclic adenosine monophosphate, which plays an important role in regulation of activated macrophages in inflammatory response. Therefore, ibudilast is expected to have an effect on the activity of microglia and macrophages,” the authors detail. “Ibudilast also crosses the blood–brain barrier and thus is possible to have an effect on the compartmentalized inflammation that is associated with chronic active lesions.”

Data were gathered from the SPRINT-MS trial, in which participants underwent MRI at baseline and weeks 24, 38, 72, and 96. The imaging quantified whole brain atrophy, cortical atrophy, magnetization transfer ratio (MTR), and complete volume of T2 lesions.

There were 195 participants (97 treated with ibudilast, 98 treated with placebo). Patients in the ibudilast group had a median (IQR) SEL volume of 0.5 (0.22-1.22) mL, and the median SEL volume was 0.75 (0.29-1.66) mL for those taking a placebo (P = .03). A patient’s SEL volume was significantly associated with their 9HPT, SDMT, and T25FWT (P < .03), but not with their EDSS.

Ibudilast was significantly linked to smaller SEL volumes, reducing them by 23% (P = .03). Additionally, over time, ibudilast had a significant impact on reducing MTR changes in SLEs by 0.22% per year (P = .04). There was no observed impact of ibudilast on the development of T2 lesions.

Considering these results, the authors conclude, “The measurement of SELs is a relatively straightforward approach and may be a useful marker of chronic active lesions, which could be applied as a clinical trial outcome measure in progressive MS and applied to retrospective data in prior trials or observational studies.”

Reference

Nakamura K, Thoomukuntla B, Bena J, Cohen JA, Fox RJ, Ontaneda D. Ibudilast reduces slowly enlarging lesions in progressive multiple sclerosis. Mult Scler. 2024:13524585231224702. doi:10.1177/13524585231224702