Dr Yuichi IwakiYuichi Iwaki, MD, PhD
The FDA has completed its protocol review for a phase 2b/3 clinical trial of ibudilast, also known as MN-166, in amyotrophic lateral sclerosis (ALS) and has decided to allow for its manufacturer MediciNova to move forward with its development.1

If the trial is successful, the company has stated that it will use the data to support a new drug application (NDA) to the agency for ibudilast. The treatment is an anti-inflammatory and neuroprotective oral agent, and a first-in-class, small molecule inhibitor of phosphodiesterase-4 and -10, as well as macrophage migration inhibitory factor (MIF).

“We are very pleased to have successfully completed the FDA review period and look forward to initiating patient enrollment shortly,”  Yuichi Iwaki, MD, PhD, president and chief executive officer of MediciNova, said in a statement. “While we acknowledge this was an important milestone, and we have a clear path forward, this moment is of great importance to the ALS community. We give them our sincerest appreciation for their patience and optimism.”

Iwaka also noted that after completion of the trial’s treatment period, patients will be eligible to receive the study drug from the manufacturer.

The new study’s design was determined based on the review and conversation about ibudilast’s phase 1b/2a trial results with the FDA. It will be a multicenter, 2-arm, randomized, double-blind, placebo-controlled trial, which will compared ibudilast to placebo in a cohort of approximately 150 patients with ALS. Patients will be randomized 1:1 to receive either 100-mg/day ibudilast or placebo for a period of 9 months, with the primary end point measured as the mean change in functional activity at Month 9 as measured by the ALS Functional Rating Scale-revised (ALSFRS-R) score.

Secondary end points are expected to include the mean change from baseline of muscle strength as well as quality of life, the time to and use of a clinically indicated prescription for non-invasive ventilation, and of course, safety and tolerability.

MediciNova indicated that patients will be eligible if their disease onset is no more than 18 months before screening, they have at least 1 documented ALSFRS-R score of at least 35 between 3 and 6 months prior to screening, or if they have used riluzole (Rilutek, Sanofi) for at least 30 days before initiation of study drug. Patients who are on edaravone (Radicava, MT Pharma) or dextromethorphan/quinidine (Nuedexta, Avanir) may also qualify for enrollment, though treatments must be suspended 3 months prior to signing consent.

Ibudilast, which is also being explored in multiple sclerosis, 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.”

In July 2018, MediciNova announced subgroup findings from a trial of the therapy, including data 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 noninvasive ventilation 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% (6 of 20) of subjects in the ibudilast group responders on the ALSFRS-R total score compared to 9.1% (1 of 11) of those in the placebo group. Additionally, 25.0% (n = 5) of patients in the ibudilast group compared to 0.0% (n = 0) in the placebo group showed improvements at the end of the 6-month double-blind period.2

Likewise, for the early ALS plus noninvasive ventilation group, the analysis showed that 26.9% (7 of 26) of those in the ibudilast group were responders on the ALSFRS-R total score compared to 7.7% (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.
REFERENCES
1. MediciNova Announces Plans to Move Forward with a Phase 3 Trial of MN-166 (ibudilast) in ALS [press release]. La Jolla, CA: MediciNova Inc; Published April 16, 2019. apnews.com/Globe%20Newswire/ddcac3daa954a4a2bdc3cb1abdc396f8. Accessed April 16, 2019.
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 April 16, 2019.