Targeting Neuroinflammation and Repair: The Rationale Behind Ibudilast

Treatment for amyotrophic lateral sclerosis (ALS) has historically been limited, with only a handful of therapies approved to modestly slow progression or manage symptoms. In recent years, however, clinical trial designs have become more patient-focused, incorporating survival outcomes alongside measures of quality of life and functional ability. These advances reflect a broader effort to target underlying disease mechanisms and address the complexity of ALS.

MediciNova’s investigational therapy ibudilast (MN-166) builds on this progress, with multimodal anti-inflammatory and neuroprotective activity and the ability to cross the blood–brain barrier. In this interview, MediciNova CEO Yuichi Iwaki, MD, PhD, shares insights into ibudilast’s mechanism of action, the pivotal COMBAT-ALS trial (NCT04057898), and the potential impact across ALS, progressive MS, and other neurodegenerative diseases.

NeurologyLive: What is the mechanism of action of ibudilast, and why do we believe it can have success in treating various conditions like ALS, progressive MS, and neurodegenerative diseases?

Yuichi Iwaki, MD, PhD: Ibudilast (MN-166) was initially recognized as a broad anti-inflammatory agent through its non-selective inhibition of phosphodiesterases (PDEs). Further research has shown that its activity is more targeted, with selectivity for PDE-3, PDE-4, PDE-10, and PDE-11. In addition, studies from MediciNova demonstrated that ibudilast inhibits TLR-4, which also contributes to its anti-inflammatory effects. More recently, it was found to strongly inhibit macrophage migration inhibitory factor (MIF), another key player in neuroinflammation. Beyond its anti-inflammatory properties, ibudilast has also been shown in vitro to stimulate neurons that release neurotrophic factors, which could promote neural repair and survival.

One especially important attribute is that ibudilast can cross the blood–brain barrier (BBB). Overcoming the BBB to deliver sufficient drug concentrations to the brain is a significant challenge for most therapies, and MN-166 is unique in its ability to do so, an essential feature for efficacy in neurodegenerative diseases. Together, these mechanisms support its potential for treating ALS, progressive MS, and other neurodegenerative diseases. We just completed enrollment in our Phase 3 COMBAT ALS trial, and we look forward to analyzing the results.

What will the phase 2 COMBAT-ALS trial look to answer? What are some of the main goals and objectives of this study?

The primary goal of the COMBAT-ALS trial is to evaluate whether ibudilast can provide meaningful benefit to ALS patients by slowing disease progression and improving survival. Key measurements include the rate of decline in ALSFRS-R scores and survival outcomes. In addition to these standard endpoints, the study will assess individual symptoms such as bulbar and speech function, muscle strength, and other aspects of daily life for these patients. A responder analysis will also be conducted to determine how many patients show clinically significant improvements across these measures.

How have ALS trial designs changed over the years? Incorporating more patient-centric ideals

While the fundamental structure of ALS clinical trials has not changed drastically, trial design has evolved to incorporate more comprehensive measures of efficacy beyond ALSFRS-R scores and survival alone. Regulatory agencies, including the EMA, have also mandated longer monitoring periods, such as 12 months of follow-up, to capture a fuller picture of treatment impact. Increasingly, there is also a focus on patient-centered outcomes that reflect quality of life and functional ability.

How has our understanding of progressive MS evolved? While we don’t have a ton of new therapies, what lessons have we learned?

Although the precise causes of both progressive MS and ALS remain unclear, we have learned that they share overlapping mechanisms of neuroinflammation and neurodegeneration. This recognition has reinforced the need to target common biological pathways, such as chronic inflammation and impaired neuronal repair, rather than focusing solely on disease-specific manifestations. These insights are guiding the development of therapies like ibudilast, which may have applications across multiple neurodegenerative conditions.

Transcript edited for clarity.