Diseases and Products | Multiple Sclerosis
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Disease Overview:
Multiple sclerosis, or MS, is an inflammatory disease of the central nervous system, or CNS, in which the body’s immune system attacks the protective sheath surrounding nerve fibers. 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.
Market Overview:
According to Med Ad News, worldwide sales of drugs to treat MS were approximately $7.2 billion in 2006. According to UBS Warburg, over 20,000 prescriptions are written each week for MS treatments in the United States. This market is forecast to grow due to treatment of patients at earlier stages of the disease and due to new therapies that will allow treatment of patients with progressive forms of the disease as well as for the more common relapsing-remitting form of MS.
The current treatment market is dominated by beta interferon drugs, which include Avonex® (IFN-β1a), Betaseron® (IFN-β1b) and Rebif® (IFN-β2a). They are administered either by intramuscular or subcutaneous injection. These immunomodulators reduce, to some extent, the frequency and severity of attacks, but they do not halt progression of the disease, stop the relapses or heal the damage done to the CNS by the disease.
MN-166 for the Treatment of Multiple Sclerosis:
We licensed MN-166 from Kyorin Pharmaceutical Co., Ltd. MN-166 has been marketed in Japan and Korea since 1989 to treat cerebrovascular disorders and bronchial asthma. In preclinical in vivo and in vitro studies, MN-166 inhibited leukotriene activity, phosphodiesterases and nitric oxide synthase, all of which are inflammatory mechanisms known to be involved in MS. These studies also suggested that MN-166 may suppress the production of pro-inflammatory cytokines (IL-1ß, TNF-µ) and enhance the production of the anti-inflammatory cytokines (IL-4, IL-10). Based on the potential mechanisms of action of MN-166, its clinical safety history in Japan, the results of pilot studies conducted by Kyorin Pharmaceutical in MS patients and the issuance of a U.S. patent covering the method of using MN-166 to treat the disease, we decided to pursue development of MN-166 as a novel, oral agent for the treatment of MS.
Clinical Results:
Based on its anti-inflammatory activity and safety profile, MN-166 was evaluated for potential activity in MS in two pilot clinical trials sponsored by academic investigators in Japan. In one open-label pilot clinical trial, the investigators studied the effects of MN-166 on relapse rates in six MS patients who had a mean of four relapses per year. Following 12 to 20 months of treatment with MN-166, the average relapse rate was reduced. Over this time frame, there was no significant change in the mean Expanded Disability Status Score, or EDSS, a measure of MS drug efficacy and disease progression. No side effects of MN-166 were reported in this clinical trial. In a second pilot trial involving 12 MS patients receiving MN-166 for four weeks, MN-166 tended to normalize the levels of several chemical mediators of inflammation, including tumor necrosis factor alpha and interferon gamma. These two pilot clinical trials in MS were not performed and analyzed in accordance with standards that will allow us to use them to support a marketing application to the FDA.
We obtained authorization from regulatory authorities in several countries in Eastern Europe to initiate a clinical trial and subsequently initiated a two-year Phase II multi-center, randomized, double-blind, placebo-controlled clinical trial of MN-166 involving 297 MS patients with relapsing MS in the third quarter of 2005. The Second year results seen below were announced in April, 2008.
MN-166 treatment resulted in positive findings on three independent measures indicative of a potential disease-progression modifying effect. The findings include:
- 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 Expanded Disability Status Scale (EDSS) score for four consecutive months. This positive clinical finding was corroborated by positive findings on two separate radiologic measures.
- The clinical trial demonstrated that the significant reduction in brain volume loss (p=0.035), as measured by cranial magnetic resonance imaging (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 (for more information on Percent Brain Volume loss for each of the treatment groups in year two of the study, see http://media.primezone.com/cache/7767/file/5480.jpg
- 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 (PBH), an MRI indicator of neuronal loss, 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 treatment at 30 mg per day resulted in a trend toward reducing evolution to PBH (p=0.074). Loss of brain volume and development of PBHs on MRI have been shown to correlate with clinical progression and disability in MS patients.
MN-166 was well tolerated at all doses over the 24 months of this clinical trial. Of the 297 patients enrolled in the study, 82.5 percent, or 245 patients, completed the full 24 months of the study. The most common adverse events possibly related to MN-166 included mild, transient gastrointestinal disturbances and depression.
The two-year randomized, double-blind, placebo-controlled Phase II clinical trial included 297 patients with relapsing MS. In the second year of the study, all patients were on drug. Patients who received 30 or 60 mg of MN-166 per day during the first 12 months 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.
In January 2008, we announced results from a double-blind analysis of the first year of treatment from the two-year Phase II clinical trial of MN-166 for the treatment of MS. The analysis showed that MN-166 decreased the formation of black holes, which are permanent brain lesions believed to indicate the death of nerves in the brain, on MRI scans in patients participating in the clinical trial, thereby adding support to our belief that MN-166 may provide neuroprotection in relapsing MS. The data demonstrated that a 60 mg per day dosing regimen of MN-166 significantly reduced the proportion of new T1 gadolinium-enhancing or new T2 lesions identified at month two of the clinical trial that evolved into persistent black holes at month ten compared to placebo (RR=0.63, p-value=0.011). Treatment with a 30 mg per day dosing regimen of MN-166 showed a trend toward reduced risk of new lesion evolution to persistent black holes compared to placebo (RR=0.735, p-value=0.074). These results were presented at the 18th Meeting of the European Neurological Society to be held in Nice, France from June 7 to 11, 2008. Click here to view presentation slides.
First-year efficacy results of this clinical trial were announced in March 2007 and described more completely at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting in November 2007. Briefly, MN-166 at 60 mg per day significantly reduced brain volume loss by 33 percent and median time to first relapse by 157 days compared to placebo. The median time to first on-study relapse was 244 days for placebo, 255 days on MN-166 at 30 mg per day and 401 days (which could only be calculated after the full study unblinding) on MN-166 at 60 mg per day. MN-166 did not significantly reduce cumulative brain lesion count on MRI in year one of this clinical trial, which was the protocol-defined primary endpoint of the study.
Development Plans:
We have completed the two-year Phase II clinical trial of MN-166. We have also developed prototype once-per-day dosage forms of MN-166 for potential future clinical trials.
At present, we are not planning to undertake any further clinical development of MN-166 beyond completion of the two-year Phase II clinical trial until such time that we are successful in entering into a strategic collaboration to support further clinical development and commercialization of MN-166.
More Information
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