The MN-166 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 several pain indications. MN-166 is a first-in-class, orally bioavailable small molecule, a 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 one million patients for a different indication and has a good post-marketing safety profile as reported in nearly 15,000 patients studied at the prescribed doses.
According to the Substance Abuse and Mental Health Services Administration (SAMHSA) and their National Survey on Drug Use and Health, 1.2 million Americans aged 12 years and older abused methamphetamine in the year prior to their 2009 survey. An independent study conducted by the Rand Corporation estimated the overall cost impact of methamphetamine use in the U.S. “reached more than an estimated $23.4 billion in 2005.”
In collaborative studies with NIDA, MN-166 has demonstrated utility in methamphetamine relapse in animals which translated into a NIDA-funded exploratory Phase 1b methamphetamine interaction clinical trial with investigators at the University of California – Los Angeles.
In September of 2012 , UCLA’s Department of Family Medicine/Center for Behavioral and Addiction Medicine, and MediciNova, Inc. announced approval and funding by the National Institutes on Drug Abuse (NIDA), part of the National Institutes of Health, of a Phase 2 clinical trial studying the use of MN-166 (ibudilast) for the treatment of methamphetamine addiction.
"Preclinical studies have shown that MN-166 may prevent the activation of certain cells in the central nervous system, called glial cells, that have been linked to drug dependence. We are very excited to move this promising molecule into a Phase 2 clinical trial in partnership with MediciNova and NIDA,” said UCLA’s Keith Heinzerling, M.D., Assistant Professor, UCLA Department of Family Medicine, Medical Director, UCLA Center for Behavioral and Addiction Medicine, and principle investigator of the trial. “This study has real public health relevance because a medication treatment may improve health outcomes and reduce the public health burden of methamphetamine dependency, especially those with HIV infection, where there is high risk of co-morbidity.”
The Phase 2 trial will study the safety and efficacy of MN-166 (ibudilast) for the treatment of methamphetamine dependence in treatment-seeking volunteers (N = 140) who will be randomly assigned 1:1 to MN-166 at a dose of 100 mg/day or matching placebo. Half of the trial participants in each treatment group will have a co-diagnosis of HIV as methamphetamine addiction in HIV-positive individuals is a growing issue. During the 12-week outpatient study, dependent subjects will participate in thrice-weekly clinic visits for health checkups, counseling, urine drug screens, and medication adherence monitoring. The study is powered to detect a statistically significant benefit of MN-166 over placebo on the primary study outcome of methamphetamine abstinence during the final two weeks of treatment – an outcome favored by regulatory authorities for addiction medication assessment. Additional endpoints include the effect of ibudilast on methamphetamine use and neurocognitive performance as well as regulation of HIV-associated factors such as T-cell counts and sexual behavior.
For more information on the MN-166 Phase 2 clinical trial, please visit http://clinicaltrials.gov.
MN-166 completed a Phase 1b/2a clinical trial in opioid withdrawal and analgesia, or OWA, funded by NIDA and conducted at Columbia University by leading specialists in the study and treatment of substance abuse. MN-166 and analogs have been shown in preclinical models of opioid (morphine or oxycodone) withdrawal to significantly reduce withdrawal symptoms. Moreover, MN-166 attenuates both behavioral and neurochemical markers of opioid reward. MN-166 and analogs are differentiated from other drug candidates in clinical trials that may demonstrate similar effects, in that MN-166 and analogs are not narcotics and do not, themselves, provide reward or “reinforcement” in behavioral models of dependence. Thus, while current therapies involve substitution of one opioid for another (e.g. methadone for heroin), MN-166 represents a novel, non-opioid, approach for the treatment of opioid withdrawal and dependence. Results from the recently-completed OWA trial indicated dose-related attenuation of the opioid withdrawal syndrome (p<0.05 for 80 mg/d treatment arm relative to placebo control on the Subjective Opioid Withdrawal Scale (SOWS) endpoint) and enhanced opioid analgesia (p<0.05 for the McGill Pain Questionnaire endpoint for the 80 mg/d treatment arm vs placebo control). Other measures of withdrawal (Clinicians Opioid Withdrawal Scale) or analgesia (quantitative time endpoints for cold pressor test) were not significantly attenuated.
Currently, investigators at Columbia are moving forward with the next step in clinical development for MN-166 in opioid withdrawl with a Phase 2a outpatient clinical trial.
The aim of treatment is to relieve symptoms of acute attacks by reducing the frequency of relapses and limiting the disabling effects of relapses and to minimize disability caused by disease progression. Steroids are used in treating MS to decrease the severity and shorten the duration of the attacks, but they do not change the course of the disease. Corticosteroid use is normally limited to the short-term treatment of MS, perhaps over a period of one to three weeks, as it generally is believed that the side effects and safety risks of long-term corticosteroid therapy outweigh clinical benefits in extended MS treatment. More recently, immunosuppressive agents and techniques have been introduced for the treatment of MS. However, these treatments are only partially effective and certain side effects may preclude their widespread use. These treatments may slow the course of disease progression and mitigate its effects temporarily, but additional drugs are often required to address the various CNS dysfunctions caused by the disease. We believe drugs for the treatment of MS that can be taken with less discomfort, particularly those that can be taken orally, with efficacy equal or better than the available treatments for MS would have widespread appeal.
According to the National Institute of Neurological Disorders and Stroke, MS is believed to affect approximately 250,000 to 350,000 people in the United States. 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 a Cognos study published by Decision Resources, Inc., relapsing-remitting MS, or RRMS, is the most common type of the disease, accounting for approximately 65% of MS patients, and most patients with RRMS eventually progress to the secondary progressive form of the disease.
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. The patent application is based upon clinical investigations conducted by MediciNova researchers which showed an apparent disease-modifying benefit in which brain volume loss, or brain atrophy, commonly associated with disease progression, was reduced by oral administration of ibudilast to a group of multiple sclerosis patients including some subjects with progressive multiple sclerosis, in a dose-related fashion over at least a 10-month treatment period.
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.”
MediciNova is currently exploring options to commence a Phase 2 trial for MN-166 in Progressive Mutliple Sclerosis patients.
Glial activation in the brain and spinal cord contribute to the establishment and amplification of the chronic pain state. As part of Avigen’s program investigating glial attenuation as a novel approach to the treatment of neuropathic pain, Avigen conceived and demonstrated that MN-166 was efficacious in preclinical models of neuropathic pain and may be effective in a wide range of neuropathic pain syndromes including neuropathy, post-herpetic neuralgia, HIV neuropathy, radiculopathy, spinal cord injury and chemotherapy-induced neuropathy. While ibudilast was initially developed as a non-selective phosphodiesterase (PDE) inhibitor for the treatment of bronchial asthma, its efficacy in some neuropathic pain models appears to be independent of this activity and yet still linked to glial attenuation.
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