A Comprehensive Monograph on Ibudilast (DB05266): From Respiratory Agent to Investigational Neuro-Immunomodulator

Executive Summary

Ibudilast is an orally bioavailable, central nervous system (CNS) penetrant small molecule with a multifaceted pharmacological profile. Initially approved in Japan and South Korea in 1989 for the treatment of bronchial asthma and post-stroke cerebrovascular disorders, its clinical application was historically confined to respiratory and circulatory conditions. However, subsequent elucidation of its pleiotropic mechanisms of action—spanning non-selective phosphodiesterase (PDE) inhibition, antagonism of macrophage migration inhibitory factor (MIF), and blockade of toll-like receptor 4 (TLR4)—has catalyzed its repurposing as a promising investigational agent for a range of neuroinflammatory and neurodegenerative diseases.

The most compelling evidence for its neurotherapeutic potential comes from the SPRINT-MS Phase 2b trial, which demonstrated an unprecedented 48% reduction in the rate of whole-brain atrophy in patients with progressive multiple sclerosis (MS). This finding, coupled with a lack of efficacy against acute inflammatory lesions, has shifted the conceptual framework of Ibudilast from a conventional anti-inflammatory to a potential first-in-class glial cell modulator with direct neuroprotective properties. Currently, Ibudilast (under the development code MN-166) is in late-stage clinical trials for amyotrophic lateral sclerosis (ALS) and degenerative cervical myelopathy (DCM). The ongoing COMBAT-ALS trial represents a pivotal milestone in determining its efficacy in this devastating motor neuron disease. While the drug exhibits a favorable safety profile at the lower doses used in Asia, higher doses required for CNS indications have presented tolerability challenges, primarily gastrointestinal adverse events. The future clinical trajectory of Ibudilast hinges on navigating this therapeutic window and vali