Ibudilast (MN-166) is an orally available small molecule that is being developed for the treatment of relapsing and progressive forms of multiple sclerosis (MS).
It works as an anti-inflammatory, reducing damaging immune responses.
The therapy received fast track designation from the U.S. Food and Drug Administration in 2016 for the treatment of progressive forms of MS. This designation is meant to accelerate the development and review in the U.S. of medications with the potential to address unmet medical needs in serious or life-threatening diseases.
MediciNova, the company developing ibudilast, also is testing it for other conditions, such as amyotrophic lateral sclerosis (ALS), COVID-19, and drug and alcohol dependence.
Ibudilast has been marketed in Japan and Korea for more than two decades as a treatment for stroke complications and bronchial asthma. More than 3.2 million people have been prescribed the medication for those indications, and it has shown a good safety profile.
MS is caused by the immune system erroneously launching an inflammatory attack against healthy cells in the brain and spinal cord, which leads to progressive nerve cell death.
Ibudilast is a small molecule designed to reduce MS damage by modulating the levels of certain cytokines, or signaling molecules that coordinate the activity of the immune system.
Cytokines have multiple functions in the immune system. Some are pro-inflammatory, meaning they prompt other immune cells to contribute to ongoing inflammation. Others, meanwhile, are anti-inflammatory, counteracting inflammation and unwanted immune responses.
Ibudilast specifically reduces the production of three pro-inflammatory cytokines: interleukin-1, tumor necrosis factor-alpha, and interleukin-6. It also is thought to increase the levels of an anti-inflammatory cytokine called interleukin-10.
The investigational molecule also inhibits toll-like receptor 4 (TLR4) and macrophage migration inhibitory factor, two molecules increased in the cerebrospinal fluid — the liquid surrounding the brain and spinal cord — of MS patients. These two molecules contribute to inflammation in the central nervous system.
Ibudilast is able to cross the blood-brain barrier, a semi-permeable membrane that regulates which substances in the bloodstream are able to pass into the brain. Crossing this barrier is a major challenge for medications aiming to target the brain.
Ibudilast is an oral medication available in the form of 10 mg capsules. In multiple sclerosis clinical trials, participants were given the medication at doses ranging from 30 to 100 mg. The optimal dose of this medication for Phase 3 trials has not yet been selected. Of note, Phase 3 trials, usually required for a therapy’s approval, are designed to demonstrate a medication’s safety and efficacy in a large group of patients.
Two pilot studies in humans showed ibudilast could reduce markers of inflammation and relapse rates in MS patients. Based on those findings, MediciNova launched a Phase 2 clinical trial testing the molecule in people with relapsing MS.
The trial enrolled 297 patients with relapsing-remitting MS and active secondary progressive MS who had lesions with active inflammation on MRI scans. The participants were randomly assigned to receive one of two doses of ibudilast (30 or 60 mg), or a placebo, daily for one year.
After that period, patients on active treatment continued to receive their assigned dose for one more year, while those on the placebo were reassigned to one of the two doses of the medication.
The trial failed to meet its primary goal of reducing the number of new or enlarging brain lesions after one year. Relapse rates and disability progression also were not significantly different between the groups.
However, the 60 mg dose of ibudilast resulted in significantly smaller changes in brain volume in these patients. It also resulted in a lower number of lesions turning into black holes, which are regions of permanent neuronal damage.
This reduction in brain volume loss continued to be observed in patients who were on the 60 mg dose for the full two years, compared with patients from the other groups. Patients who received ibudilast for two years regardless of dose also were 50% less likely to experience sustained disability worsening, or an increase in Expanded Disability Status Scale (EDSS) scores lasting at least four months, than those initially on a placebo.
The findings suggested that ibudilast could be more effective in progressive forms of MS, in which disease progression is mainly driven by disability worsening in the absence of relapses.
Based on these results, researchers then launched a Phase 2b clinical trial (NCT01982942) called SPRINT-MS. It sought to investigate ibudilast in people with progressive forms of MS, including primary progressive MS (PPMS) and secondary progressive MS (SPMS), with or without relapses.
A total of 255 patients were enrolled and randomly assigned to receive a placebo or ibudilast for 96 weeks. After two weeks on a 60 mg dose (six, 10 mg capsules), participants increased their dose to up to 100 mg, with potential dose adjustments to manage side effects. During the trial, patients either continued on their glatiramer acetate or interferon beta treatment, or received no other MS therapies.
Results showed that ibudilast significantly slowed brain volume loss, by 48%, compared with a placebo. It also exerted neuroprotective effects on the retina, the light-sensitive layer of the eye. The thinning of that layer indicates neurodegeneration in the brain.
Additional analyses showed that the impact of ibudilast was much stronger in PPMS patients compared with those on a placebo. No significant slowing in brain atrophy (shrinkage) was observed in SPMS patients taking ibudilast. According to researchers, this likely was because, in the absence of treatment, brain atrophy progressed more quickly in individuals with PPMS than SPMS.
However, disability progression was significantly reduced, by 46%, in the group of SPMS patients without relapses. Very few treatments are available to modify the disease course in these patients, the scientists noted.
MediciNova announced plans in 2021 for a Phase 3 clinical trial to confirm ibudilast’s benefits in non-active SPMS patients — those who do not experience disease relapses. The trial’s main goal is to determine if the treatment reduces the rates of confirmed disability progression.
The most common adverse events of ibudilast reported in MS clinical trials include:
Multiple Sclerosis News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
Ibudilast is an experimental therapy still in clinical trials for multiple sclerosis (MS). It is designed to reduce inflammation and neurodegeneration by modulating the production and activity of several immune system molecules. In clinical trials, ibudilast reduced disability progression, slowed brain volume loss, and prevented new inflammatory lesions from turning into regions of permanent damage in the brain.
Ibudilast has shown encouraging results in Phase 2 clinical trials, but further Phase 3 studies are still needed to confirm the therapy’s safety and efficacy in multiple sclerosis patients. Even with its fast track designation from the U.S. Food and Drug Administration, which is meant to accelerate its clinical development and regulatory review, it may take several years before the medication can be submitted for regulatory approval. Therefore, there is no specific timeline for when the FDA might approve ibudilast.
Clinical trials of ibudilast have not included people who were pregnant, and all participants who had the ability to reproduce were required to use effective methods of contraception while on treatment, and for one month after their last dose. It is not known if the therapy is safe during pregnancy.
Multiple sclerosis is different in every patient, and responses to treatment also will vary. Still, in multiple sclerosis clinical trials, a significant reduction in the rate of brain atrophy (shrinkage) was evident after one year of ibudilast treatment in both relapsing and progressive forms of the disease.
Neither hair loss nor weight gain have been reported in multiple sclerosis clinical trials as side effects of ibudilast. Patients should talk with their healthcare team if such events occur.
Get regular updates to your inbox.
