April 11, 2003
Amit Bar-Or, M.D.
Neurologist and Neuroimmunologist, McGill University and the Montreal Neurological Institute
In April, 2003, the American Academy of Neurology (AAN) culminated its annual meeting. Approximately 250 scientific papers were presented on the topic of multiple sclerosis, 75 of which dealt with novel therapeutic approaches. The next three Viewpoints will describe the most exciting of these new approaches to MS therapy. I will try to provide background information on their mode of action, as well as an update on where they are in terms of the drug development process. Readers may wish to refer to earlier Viewpoints describing the modes of action of the immune-modulator drugs that have been approved.
Since the approved immune modulators all require injections (ranging from once-weekly to once-daily), substantial efforts have been focused on the development of drugs that can be taken by mouth. Of particular recent interest are agents that modulate the immune system and have already been approved by the FDA for other conditions. The potential side effects and risks of these agents are better known, and less time is required to have them approved for use in a new condition. Several examples follow.
Gemfibrozil. This oral agent has been used for years to treat high cholesterol, specifically the lipids known as triglycerides. Gemfibrozil belongs to the general class of medications called “PPAR-alpha agonists.” These drugs, in addition to controlling triglyceride levels, appear to have interesting effects on the immune system. A novel report (1) demonstrated that gemfibrozil, ingested by mouth, significantly decreased the severity of a common animal model of MS, experimental autoimmune encephalomyelitis (EAE). The authors further discovered, in animals treated with gemfibrozil, T cells directed against myelin changed their response properties and produced anti-inflammatory, rather than pro-inflammatory, cytokines. This effect, known as immune-deviation, is also thought to be the mechanism by which the drug Copaxone exerts its beneficial effect in MS. Early phase clinical trials with gemfibrozil in MS should follow shortly.
Simvastatin. Surprisingly, this is yet another drug that lowers cholesterol. The ‘statin’ family of medications has been used very successfully to prevent heart disease and stroke. Simvastatin has been shown previously to ameliorate EAE, its mechanism of action is also believed to be ‘immune-deviation’. Dr. Tim Vollmer and colleagues reported on a Phase I study designed to assess the safety of oral simvastatin in patients with MS (2). Twenty-seven patients with relapsing-remitting MS, 18 to 55 years of age, underwent monthly brain MRIs for three months prior to initiation of treatment with simvastatin. Patients then began taking simvastatin daily, and an additional three brain MRIs were obtained while on treatment. Following treatment, the number and volume of new MS lesions identified by MRI were significantly lower. Patients tolerated the medication well. This was considered a successful, albeit small, clinical trial, and a larger multi-center study will start over the next few months.
Minocycline. This oral drug belongs to the tetracycline family of antibiotics. It has been available for over 30 years and, in the United Kingdom alone, more than 6.5 million people have been treated with minocycline for an average of 9 months, mostly for acne. Recent studies have identified that minocycline has many immune-modulating properties. It also crosses the blood-brain-barrier (BBB) efficiently, which many other drugs cannot do.
In laboratory studies, mincocyline suppressed T cell responses as well as the activity of CNS microglia cells that are thought to be important contributors to injury in MS. When used to treat EAE, minocycline was found to be quite effective at delaying and limiting disease activity. Minocycline is widely available as a generic medication and is relatively inexpensive. These features make minocycline an excellent candidate to be evaluated for treatment of MS.
At the AAN meeting, scientists reported on the first clinical trial of minocycline in MS (3). Ten patients with active relapsing-remitting MS were enrolled in the study. After a three-month observation period, treatment was initiated with minocycline by mouth twice daily. Whereas prior to treatment, 80% of patients had active MS by MRI scanning, none of the treated patients have shown subsequent MRI evidence of activity, as much as nine months later. There have been no safety concerns. It is likely that larger MS trials of minocycline will be initiated over the next year.
Gemfibrozil, simvastatin and minocycline are three examples of promising oral agents that may have a therapeutic role in MS. All three represent treatments that are currently approved for other diseases, and are very well tolerated with few side effects. Larger clinical trials with these agents will determine if they indeed have a role in treating MS, either on their own or to supplement immune modulators. Additional types of therapy presented at the 2003 AAN meeting as potential treatments for MS will be examined in my upcoming two Viewpoints.
(1) Michael K. Racke, Rehana Z. Hussain, Sara Northrup, Asim Diab, Amy E. Lovett-Racke. PPAR-alpha Agonists as Therapy for Autoimmune Demyelination. Abstract [P03.104], AAN Annual meeting, 2003.
(2) Timothy Vollmer, Valerie Durkalski, William Tyor, John Corboy, Jana Preiningerova, Silva Markovic-Plese, Marco Rizzo, Lyndon Key, Inderjit Singh. An Open-Label, Single Arm Study of Simvastatin as a Therapy for Multiple Sclerosis (MS). Abstract [S11.004], AAN Annual meeting, 2003.
(3) L. M. Metz, V. W. Yong, M. Yeung, D. G. Patry, R. B. Bell, Y. Zhang,
S. B. Patten, P. Duquette, C. Wallace, R. Sevick, J. Antel, A. Bar-Or,
R. B. Mitchell. Open-Label Trial of Minocycline in Active Relapsing-Remitting
Multiple Sclerosis. Abstract [S31.001], AAN Annual meeting, 2003.
© 2003 Veritas Medicine