Ibudilast Phase III Program in ALS Moving Forward

September 27, 2018

The anti-inflammatory agent is also being explored in progressive MS, with phase II results reading out earlier this year.

Yuichi Iwaki, MD, PhD

Thanks to positive feedback from the FDA, MediciNova has announced that a phase III trial of ibudilast (MN-166), an anti-inflammatory and neuroprotective oral agent, in amyotrophic lateral sclerosis (ALS) will be moving forward.1

Notably, MediciNova noted, the agency stated that the if therapy showed a statistically significant benefit compared to placebo in a measure of functional activity, such as the ALS Functional Rating Scale (ALSFRS-R), an additional trial may not be necessary for its approval.

The FDA acknowledged that with ALS’s standing as a rare condition, there may be some flexibility in the marketing application requirements.

“We are excited to receive the green light from FDA to proceed with phase III development of MN-166 for ALS,” Yuichi Iwaki, MD, PhD, the president and chief executive officer of MediciNova. “We will finalize the study design according to FDA’s feedback."

Ibudilast is a first-in-class, oral, small molecule phosphodiesterase-4 and -10 inhibitor, and a macrophage migration inhibitory factor (MIF) inhibitor. The agent suppresses pro-inflammatory cytokines and promotes neurotrophic factors, and additionally attenuates activated glial cells, which have been found to play a major role in certain neurological conditions. The anti-neuroinflammatory and neuroprotective effects of the drug were revealed in preclinical and clinical study results, and, according to MediciNova, “provide the rationale for its therapeutic utility in neurodegenerative diseases, substance abuse/addiction, and chronic neuropathic pain.”

According to the company, in addition to there being no concerns from the US drug approval organization regarding the safety of ibudilast, the FDA also encouraged the clinical development to include a broad spectrum of patients with ALS and randomize them by baseline disease severity, in order to detect the maximal possible benefit of the therapy.

In a phase II double-blind, clinical trial of the therapy in 60 patients with ALS, randomized 2:1 to ibudilast in a dose of 10 mg (maximum 60 mg) 2 to 3 times daily or placebo for 6 months. The trial consisted of 2 stages, a double-blind, 6-month stage, followed by an open-label, 6-month stage for those randomized to placebo (NCT02238626).

Additionally, in July of this year, MediciNova announced subgroup findings from a trial of the therapy.2 Data was included from 70 patients with either bulbar onset or upper limb onset from 2 larger subgroups, the Early ALS subgroup (n = 31) and the Early ALS plus NIV subgroup (n = 39).

For the Early ALS group, data revealed a higher percentage of responders in the ibudilast group compared to the placebo group, with 30.0% (n = 6, of 20) of subjects in the ibudilast group were responders on the ALSFRS-R total score compared to 9.1% ( n = 1, of 11) of those in the placebo group. Additionally, a higher percentage, 25.0% (n = 5) of those who improved in the ibudilast group compared to 0.0% (n = 0) of the placebo group, at the end of the 6-month double-blind period.

Likewise, for the Early ALS plus NIV group, the analysis showed that 26.9% (n = 7, of 26) of those in the ibudilast group were responders on the ALSFRS-R total score compared to 7.7% (n = 1, of 13) of those in the placebo group. At the end of the 6-month double-blind period, 23.1% (n = 6) of the ibudilast group improved in ALSFRS-R score compared to 0% (n = 0) in the placebo group.

Ibudilast has been marketed in Japan and Korea since the late 1980s for the treatment of post-stroke complications, as well as bronchial asthma. It is also currently being tested for the treatment of substance abuse and addiction, as well as progressive multiple sclerosis (MS), having recently completed phase II testing with positive results. In that phase II trial in MS, the therapy showed some adverse effects that occurred more commonly than with placebo, though lead author Robert J. Fox, MD, from Cleveland Clinic, noted that treatment discontinuation was similar between them, and “in general, it was quite well tolerated.”

REFERENCES

1. MediciNova Announces Positive FDA Feedback Regarding Phase 3 Plan for MN-166 (ibudilast) in ALS [press release]. La Jolla, CA: MediciNova Inc; Published September 25, 2018. globenewswire.com/news-release/2018/09/25/1576125/0/en/MediciNova-Announces-Positive-FDA-Feedback-Regarding-Phase-3-Plan-for-MN-166-ibudilast-in-ALS.html. Accessed September 27, 2018.

2. MediciNova Announces Clinical Data from Subgroup Analyses of Completed Clinical Trial of MN-166 (ibudilast) in ALS [press release]. La Jolla, CA: MediciNova Inc; Published July 9, 2018. http://investors.medicinova.com/phoenix.zhtml?c=183833&p=irol-newsArticle&ID=2357510. Accessed September 27, 2018.