Overview:
The MN-166 (ibudilast) portfolio, which includes the Phase 2-staged lead drug compound and proprietary analogs, represents novel, first-in-class, non-opioid drugs for the treatment of drug addiction, progressive multiple sclerosis and pain. MN-166 is a first-in-class, orally bioavailable, small molecule glial attenuator that suppresses pro-inflammatory cytokines IL-1ß, TNF-a, and IL-6, and may upregulate the anti-inflammatory cytokine IL-10. It has additionally been shown to be a toll-like receptor 4 (TLR4) functional antagonist that may contribute to its attenuation of neuroinflammation. While considered a New Molecular Entity, or NME, in the United States and Europe, it involves redirection of an approved drug, ibudilast, which was first approved in Japan more than 20 years ago. Ibudilast has been prescribed to over 3.2 million patients and has a good post-marketing safety profile.
Multiple Sclerosis (MS) is an inflammatory disease of the CNS in which the body’s immune system attacks the protective sheath surrounding nerve fibers. According to the National Multiple Sclerosis Society, MS affects approximately 400,000 people in the U.S. and approximately 2.5 million people worldwide. The most obvious effect of MS is its destruction of nerve fibers leading to the loss of muscle control. However, MS also affects multiple CNS functions. Currently, there is no known cure for the disease. According to the National Multiple Sclerosis Society, relapsing-remitting MS, or RRMS, is the most common type of the disease, and 85% of people with MS are initially diagnosed with RRMS. A majority of RRMS patients progress to secondary progressive MS (SPMS). The most severe type of MS, primary progressive MS (PPMS), represents about 10% of all MS. According to sales data included in most recent annual reports of leading MS drug companies, including Biogen Idec Inc., Merck Serono S.A., Teva Pharmaceutical Industries Ltd., Bayer AG, Novartis AG and Sanofi, worldwide sales of drugs to treat MS exceeded $18 billion in 2014.
Multiple sclerosis (MS) is recognized as a chronic disease in which disability progresses over time. Patients suffering from progressive forms of MS tend to have a poor prognosis and have greater levels of disability. Robert J. Fox, M.D., M.S., FAAN, Medical Director of Mellen Center for MS, Cleveland Clinic, noted that, “Despite recent improvements in pharmacotherapy for relapsing remitting multiple sclerosis, treatment options in progressive multiple sclerosis are extremely limited in the absence of relapses. There is great need for safe, effective, and conveniently-administered therapies for progressive MS.”
In January of 2012 MediciNova was awarded a method of use patent that would expire no earlier than 2029 and covers a method of treating primary progressive multiple sclerosis (PPMS) or secondary progressive MS (SPMS) by administering ibudilast either alone or in combination with other drugs.
Completed Phase 2 Clinical Trial of MN-166 in Relapsing Multiple Sclerosis
We completed a two-year Phase 2 multi-center, randomized, double-blind, placebo-controlled clinical trial of MN-166 for the treatment of patients with relapsing MS in April 2008. This clinical trial involved 297 patients with relapsing MS in several countries in Eastern Europe. Patients received either 30 mg of MN-166 per day, 60 mg of MN-166 per day or a placebo. In the second year of the study, all patients received active drugs. Patients who received 30 or 60 mg of MN-166 per day during the first year of the study remained on the assigned dose for the second 12 months of the study; patients who received placebo during the first 12 months of the study were randomized to receive either 30 or 60 mg of MN-166 per day (double-blind maintained) during the second 12 months of the study. Clinical and radiological outcomes were evaluated.
MN-166 treatment resulted in positive findings on three independent measures indicative of a potential disease-progression modifying effect. First, sustained disability progression was significantly less likely (by approximately 50 percent) in those patients receiving MN-166 at either 30 or 60 mg per day for 24 months than in those patients receiving the drug for 12 months (p=0.026). Sustained disability progression was measured as a greater than or equal to 1.0 point increase from baseline in the EDSS score for four consecutive months. Second, the significant reduction in brain volume loss (p=0.035), as measured by cranial MRI scans, observed after 12 months in patients treated with 60 mg per day of MN-166 compared to placebo was again demonstrated in year two of the study. Brain volume loss was significantly less (p=0.030) in patients receiving 60 mg per day of MN-166 for 24 months compared to the other treatment groups. Third, MN-166 treatment at 60 mg per day significantly reduced the relative risk for conversion of new inflammatory lesions identified at month two to persistent black holes (PBHs) eight months later at month ten by 37 percent (p=0.011); such lesions that remain unchanged for eight months are considered PBHs as compared to transient inflammatory lesions that are more closely associated with relapses. MN-166 was well tolerated at all doses over the two years of this clinical trial. In September 2008, data from this completed two-year clinical trial was presented at the World Congress for Treatment and Research in MS.
Ongoing Phase 2b Clinical Trial of MN-166 in Progressive Multiple Sclerosis
In 2013, MediciNova announced the initiation of a Phase 2b trial of MN-166 (ibudilast) in subjects with progressive multiple sclerosis through an NIH-based grant. The grant is for a funded cooperative effort by the NeuroNEXT clinical trial network within the National Institute of Neurological Disorders and Stroke (NINDS) at the U.S. National Institutes of Health (NIH). The collaboration additionally includes multiple academic centers, MediciNova and advocacy support from the National Multiple Sclerosis Society. The principal investigator is Robert Fox, M.D., M.S., FAAN, Staff Neurologist at the Mellen Center for Multiple Sclerosis at Cleveland Clinic.
The Phase 2 Secondary and Primary Progressive Ibudilast NeuroNEXT trial in Multiple Sclerosis (SPRINT-MS) involves 28 enrolling clinical sites across the U.S. and is designed to evaluate the safety, tolerability and efficacy of MN-166 (ibudilast) administered twice daily to subjects with primary or secondary progressive multiple sclerosis (PPMS or SPMS, respectively). 250 qualifying subjects will be randomly assigned 1:1 to inactive control (placebo) or MN-166 (ibudilast) administered at a dose of 100 mg/day. The progressive MS subjects may be either untreated with long-term disease modifying therapy (DMT) or may continue either glatiramer acetate (GA) or interferon beta (IFNβ-1a or IFNβ-1b) treatment. Hence, randomization will be controlled (stratified) by two factors: therapy status (IFN/GA vs. no DMT) and disease status (PPMS vs. SPMS). The primary objectives of the study are: 1) to evaluate the activity of ibudilast (MN-166) versus placebo at 96 weeks as measured by quantitative magnetic resonance imaging (MRI) analysis for whole brain atrophy using brain parenchymal fraction (BPF), and 2) to evaluate the safety and tolerability of ibudilast (MN-166) (100 mg/day) versus placebo administered orally in subjects with primary or secondary progressive multiple sclerosis. Secondary measures include disability, imaging analyses of brain and retinal tissue integrity, cortical atrophy, cognitive impairment, quality-of-life, and neuropathic pain. Exploratory objectives include pharmacokinetic and biomarker analyses. The trial is expected to require approximately three years for enrollment, treatment, and data analyses.
MediciNova, Inc. was founded in September 2000 with $10 million in Series A seed funding from Tanabe Seiyaku Co., Ltd. (Osaka). MediciNova was established in San Diego as a biopharmaceutical company focused on acquiring and accelerating the global development and commercialization of innovative pharmaceutical products. The Company’s strategy is to build a strong product portfolio through alliances with North American, European and Japanese biotechnology and pharmaceutical companies. MediciNova licensed its first development candidates in 2002
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