HONOLULU - Two drugs - a well-known cholesterol-lowering drug and one approved for leukemia - could one day be standard therapy for treating multiple sclerosis (MS) - but not yet, new research suggests.
In a six-month pilot study, simvastatin (Zocor) reduced the number of MS lesions by 43 percent, researchers reported at the AAN Annual meeting here. However, the results are preliminary, said Aaron Miller, MD, Chief Scientific Officer of the National Multiple Sclerosis Society in New York. The time for using this drug in routine practice for MS has not arrived.
We are only now just beginning to get human data, Dr. Miller said in an interview with Neurology Today. I would caution patients not to take statins for MS. The only exception would be MS patients with high cholesterol. He said, That's okay.
Stephen Reingold, MD, Vice President for Research Programs of the National Multiple Sclerosis Society, said statins have advantages over some drugs traditionally used to treat MS. But, he said, it is a small study, and a clinical trial lasting at least a couple years is needed to see the desired outcomes in clinical management.
REDUCED INFLAMMATION
Lead investigator Timothy Vollmer, MD, Chairman of the Division of Neurology at Barrow Neurological Institute in Phoenix, AZ, said simvastatin was given to 28 patients at 80 mg a day for the six-month study. The drug reduced the volume of inflammation and the number of new areas of inflammation.
The study, supported by an unrestricted educational grant from Merck Inc., was designed to test safety, and did not detect any improvements in disability or number of new attacks.
Figure. Dr. Timothy ...Image Tools
We don't yet know whether this has a benefit for decreasing their attack rate or disability, Dr. Vollmer said at a press briefing. But he added, The patients tolerated it really well. No patient stopped due to side effects. Two of the patients, he said, had mildly elevated liver tests, which resolved after stopping the drug.
ADVANTAGES
He said the study suggested several advantages of statins over the five most commonly used MS drugs: The three interferons, glatiramer acetate, and mitoxantrone cost $10,000 or more a year, compared with $1,000 to $2,000 a year for simvastatin. The current drugs are given by injection, daily or monthly, compared with oral administration of simvastatin.
Four of the drugs have what he termed nuisance adverse effects: pain and swelling at the site of injection and occasionally flu-like symptoms. Mitoxantrone, a chemotherapeutic agent, is associated with infections, secondary neoplasms, and organ damage to the heart and liver. Although it is more effective than the other drugs, its adverse effect profile limits it to 5 to 10 percent of the MS population. The drugs are only partially effective, producing 30 percent fewer attacks and a modest slowing of progression, Dr. Vollmer said.
Study patients were selected on the basis of having at least one gadolinium-enhancing lesion out of a series of three pretreatment monthly MRI scans. Patients were then treated for six months and MRIs were done at months four, five, and six. The primary outcome was a change in the number of enhancing lesions.
HOW THE DRUG WORKS
Dr. Vollmer believes the drug works by suppressing the TH1 CD4 cells and inhibiting their ability to enter the brain. Anything that inhibits these cells seems to be helpful, he said. Research on mice and rats has shown statins are effective at suppressing inflammatory cells from entering the brain.
Other research suggests that statins might enter the brain and work directly on key target sites, suggesting a benefit for the secondary progressive phase of MS, for which, Dr. Vollmer added, other therapies have very little benefit.
Meanwhile, the study indicates there may be a benefit for statins in MS in one way or another. But how it would be used has not been worked out, he said.
In the next year or so, he hopes to conduct a trial on the one or more statins in combination with currently approved therapies. Dr. Vollmer envisions sufficient results in about four years for a consensus to emerge about the role of statins for MS.
ALEMTUZUMAB FOR MS
Researchers reporting on a second drug, alemtuzumab (Campath-1H), said it virtually stopped episodes and decreased the disability of early-stage MS in a small open-label study.
The effect is only seen when the drug, a humanized monoclonal antibody that depletes T cells, is given in the early relapsing-remitting stage of the disease, Alastair Compston, PhD, Chairman of the Department of Neurology at Cambridge University in the UK, said at the meeting. And that is when clinical disease activity is attributable to inflammation, he said.
In the study, supported by Wellcome Trust, the Multiple Sclerosis Society (UK), and Ilex Oncology, Dr. Compston compared the use of alemtuzumab in two groups of patients: 36 patients with the secondary progressive phase of the disease, with a mean of 12 years since onset of disease and four years since onset of progression; and 22 patients who had the disease for a mean of 2.7 years prior to treatment and none of whom were in the progressive phase.
Figure. Dr. Alastair...Image Tools
Both groups of patients had been given 24 mg of the drug per day for five days, for a total dose of 120 mg.
RELAPSE RATE
The relapse rate of the secondary progressive MS group remained suppressed during a mean of seven years of follow-up, but their disability continued to progress. There were no significant infective adverse effects, but one-third of patients developed Graves disease.
In comparison, before treatment, the relapsing-remitting group had a mean of three episodes a year and their Expanded Disability Status Scale (EDSS) had increased by 2.2 points. They have now been followed for up to three years. The mean relapse rate changed after treatment to 0.05 points per year. Whereas disability had been accumulating before treatment, this increase was reversed and EDSS was 1.3 points less disabled for patients followed into the second year.
The main concern, Dr. Compston said, was that 27 percent of the patients developed autoimmune thyroid disease. This resolved in all but one of 15 patients by detecting the disease at a preclinical stage and instituting early treatment. In most patients, it disappeared, but it remains a medical problem for the one patient. No patients experienced any serious infections.
The critical therapeutic issue now is whether this will slow or prevent axonal degeneration and sustained accumulation of disability, Dr. Compston and colleagues said.
HEAD-TO-HEAD TRIAL
Researchers are focusing on that subject in a head-to-head trial comparing two doses of alemtuzumab with a 44 μg of interferon beta-1a (Rebif). This multicenter trial taking place in Europe and the US began in December 2002. The treatment phase will last three years and observations will last five years. Sustained accumulation of disability is the outcome measure.
Dr. Reingold agreed that these results had not been seen with other drugs. But, he said in an interview, it will need rigorous studies to determine if it is real in other patient groups studied at the same stage of the disease, to determine definitively that the effect is a function of the drug rather than the natural course of the disease.
Also, he was concerned about the nearly 30 percent of patients who developed thyroid disease and whether that truly resolves - another question he hopes will be answered by the larger trial.
Alemtuzumab, manufactured by Ilex Pharmaceuticals and distributed by Berlex, is approved by the Food and Drug Administration for treating B-cell chronic lymphocytic leukemia in patients who have been treated with alkylating agents and who have failed fludarabine therapy.
ARTICLE IN BRIEF:
✓ In two separate pilot trials, a well-known cholesterol-lowering drug, simvastatin, and alemtuzumab, approved for leukemia, showed promise for treating multiple sclerosis (MS).
✓ But the investigators and others caution that the data in both studies are preliminary and require further study.
✓ Researchers stress that the drugs are not yet ready for use by MS patients.
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