Effects of Ibudilast on MRI Measures in the Phase 2 SPRINT-MS Study

Abstract

OBJECTIVE:For progressive forms of multiple sclerosis, determine whether ibudilast has an effect on brain volume and new lesions.METHODS:A randomized, placebo controlled, blinded study evaluated ibudilast at a dose of up to 100 mg over 96 weeks in primary and secondary progressive multiple sclerosis. In this secondary analysis of a previously reported trial, secondary and tertiary endpoints included gray matter atrophy, new or enlarging T2 lesions as measured every 24 weeks, and new T1 hypointensities at 96 weeks. Whole brain atrophy measured by SIENA was a sensitivity analysis.RESULTS:129 participants were assigned to ibudilast and 126 to placebo. New or enlarging T2 lesions were observed in 37.2% on ibudilast and 29.0% on placebo (p=0.82). New T1 hypointense lesions at 96 weeks were observed in 33.3% on ibudilast and 23.5% on placebo (p=0.11). Gray matter atrophy was reduced by 35% for those on ibudilast vs. placebo (p=0.038). Progression of whole brain atrophy by SIENA was slowed by 20% in the ibudilast group compared with placebo (p=0.08).CONCLUSIONS:Ibudilast treatment was associated with a reduction in gray matter atrophy. Ibudilast treatment was not associated with a reduction in new or enlarging T2 lesions, or new T1 lesions. An effect on brain volume contributes to prior data that ibudilast appears to impact markers associated with neurodegenerative processes, but not inflammatory processes.Classification of Evidence:This study provides Class II evidence that for people with MS, ibudilast does not significantly reduce new or enlarging T2 lesions, or new T1 lesions.

Neurofilament light chain in a phase 2 clinical trial of ibudilast in progressive multiple sclerosis

“…Despite having positive effects on MRI measures of progressive tissue injury, ibudilast did not have a beneficial effect on the development of new or enlarging T2 lesions. 22 This dissociation between measures of neurodegeneration and neuroinflammation, along with our observations that NfL was unchanged by ibudilast, suggests that NfL may be more sensitive to track neuroaxonal injury that is associated with acute focal inflammatory disease activity in MS (i.e. new gadolinium-enhancing lesions and T2 lesions) than other chronic pathologies present in progressive MS (i.e.…”

“…10 One previous study of fingolimod and preliminary reports of several approved MS therapies, including alemtuzumab, natalizumab, pegylated interferon, and ocrelizumab, found that these therapies are associated with lower serum NfL levels. 18–20 Although ibudilast has several anti-inflammatory effects in vitro (described above), it does not reduce the development of new inflammatory brain lesions in either relapsing MS 21 or our trial of progressive MS 22 , and thus does not appear to have clinically relevant anti-inflammatory activity in MS. Rather than acting as an anti-inflammatory in the brain of patients with progressive MS, ibudilast may protect neurons in lesions from continued damage and decline after previous inflammatory injury. 13…”

Ibudilast attenuates alcohol cue–elicited frontostriatal functional connectivity in alcohol use disorder

“…The ongoing trial in treatment-seekers may serve to address this outstanding question as well, as treatment-seeking populations tend to report a greater number of AUD symptoms and consume more drinks per drinking day (Ray et al, 2017b). Severity of AUD and overall brain pathology may be particularly relevant given that ibudilast has been studied for a host of brain-based biomarkers in clinical trials for multiple sclerosis (Fox et al, 2018;Naismith et al, 2021).…”

Response to ibudilast treatment according to progressive multiple sclerosis disease phenotype

“…In addition, the initial trial results showed an overall reduction in the rate of cortical thickness loss, 1 and we again found a similar pattern according to phenotype: this effect was principally driven by the PPMS subjects. Results of conventional imaging outcomes are reported in a separate publication 2 …”

“…We previously reported 1 a significant reduction in the rate of cerebral atrophy progression as determined by brain parenchymal fraction (BPF) assessments in people with progressive multiple sclerosis (MS) in a randomized phase 2 clinical trial, “SPRINT‐MS,” comparing ibudilast to placebo. Detailed results of the MRI outcomes from the SPRINT‐MS trial were recently reported 2 . Despite recognition as different clinical disease phenotypes, 3 primary progressive (PPMS) and secondary progressive (SPMS) are often viewed as being more similar than different pathologically 4 .…”