Even with its on-again, off-again flare-ups of paralysis, blurred vision, impaired balance and incontinence, many of the 333,000 U.S. patients with multiple sclerosis balk at taking their medicine. For one thing, the three types of recombinant interferon that are the drugs of choice must be injected. "They are effective to varying degrees in roughly a third of patients," observed clinical neuroimmunologist Scott Zamvil at University of California at San Francisco, "but are often limited by side effects or toxicities.

"The primary target of an MS attack," explained Zamvil, "is the myelin sheath, which coats the brain's nerve fibers or axons, through which neurons communicate - much like insulation around an electrical wire. The damage to the sheath, demyelination," he continued, "disrupts the ability of neurons to transmit signals swiftly to one another. That destruction causes fatigue, disrupts various motor skills and subtly diminishes cognitive skills.

"Twice as many women as men," Zamvil noted, "incur MS, of which there are several different subtypes. Most common is the relapsing-remitting form, which has an onset of around 30 to 32 years of age. That's the variant most common in women. Then there's later-onset primary progressive MS, which strikes only 10 percent to 15 percent of MS patients, and sets in at around 40 years old."

Zamvil is senior author of a paper in the week's Nature, dated Nov. 7, 2002. Its title: "The HMG-CoA reductase inhibitor, atorvastatin [Lipitor], promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease."

In other words, Zamvil told BioWorld Today, "The major message in our Nature article, "is that statins - the key anticholesterol chemicals - have immuno-modulatory properties. That is, they may regulate the immune system in a manner favorable for potential treatment of organ-specific autoimmune diseases. The broadest application," he went on, "would be the treatment of T-cell Th1 autoimmune diseases, including MS as well as potential therapy for insulin-dependent diabetes and rheumatoid arthritis."

Lipitor Corrected MS In EAE Mouse Models

"What we showed," Zamvil continued, "is that atorvastatin - better known as Pfizer's drug Lipitor - the most widely used and most effective cholesterol-reduction statin currently available, was capable of preventing or reversing chronic or relapsing paralysis in EAE [experimental autoimmune encephalomyelitis], the animal model that mimics MS." (With sales of $7 billion last year, Lipitor is the world's No. 1 drug on the market.)

"The immunological revolt that causes multiple sclerosis," Zamvil explained, "occurs when the roaming CD4-positive T cells, conducting surveillance throughout the body's immune system, receive a molecular miscue. That error recognizes a site known as the major histocompatibility class II on immune-system B cells or macrophages. Recognition of this MHC complex prompts the cells to begin differentiating into a subtype known as the T helper cell. This unleashes destructive cytokines that incite inflammation, leading to events that damage the myelin sheath."

To test Lipitor's apparent leap from controlling cholesterol to preventing or correcting autoimmunity, as in MS, Zamvil and his co-authors recruited several strains of mice and gave some of these cohorts the murine equivalent of multiple sclerosis, namely EAE. "It's the standard model for MS, and not perfect," he noted. "MS is a spontaneous disease, but EAE is an animal model that is induced to present with chronic paralysis.

"In our in vivo experiment," Zamvil recounted, "we induced the animal model of MS to acquire EAE either by immunization with an antigenic myelin protein or by transfer of lymphocytes that had been activated with that myelin antigen. And we showed that we could give Lipitor orally to the mice at the time they were beginning to develop the MS symptoms and protect them from further symptoms. Or we could give them the drug after they had developed signs, namely at onset of second attack, and suppress further flare-ups.

"We waited for them to develop symptoms," Zamvil went on, "and began treatment at onset by giving the drug orally. It suppressed the paralysis. In other trials, we waited for the mice to have a full attack, recover and begin their second flare-up, at which point we started the treatment. It too suppressed the further paralysis. Some experiments we followed for two months and some a month and a half - 42 days to 60 days. Control mice that received vehicle only went on to develop the disease. Those treated with the drug had a much better clinical course."

Contrary to rumor, Zamvil asserted, "There is no ongoing human trial of Lipitor for MS, in Europe or anywhere else. The only human study I'm aware of is a small open-label trial enrolling 30 or 32 patients, at the University of South Carolina. It is testing a different cholesterol-reducing statin, Zocor, in patients who have relapsing-remitting MS. That study is near completion and may be reposted as early as April or May 2003. Our planned Lipitor trial is under review by the Immune Tolerance Network, an agency funded through the NIH and the Juvenile Diabetes Foundation to conduct trials on autoimmune diseases. They've targeted three autoimmune diseases - multiple sclerosis, diabetes and rheumatoid arthritis. If our proposal is approved, we hope to start the trial in 2003."

126 Enrollees Planned; Half On Vehicle Only

"Our protocol," Zamvil continued, "is to test Lipitor patients at the earliest clinical sign of MS symptoms, when they have their first attack. They develop certain neurologic symptoms in the first flare-up, which risks conversion to definite MS. That trial will enroll 126 patents. We propose to give 63 of them Lipitor at 80 mg - the highest approved dose, which is supported by our studies in the EAE animal model. It will be a one-year trial, with the other 63 receiving placebo.

"Our impending trial has certain advantages over combined multiple therapeutics in determining whether it's effective because it will be compared solely to controls. We will be following patients for conversion to definite MS in a second attack," Zamvil concluded, "and also looking for further evidence of MS by frequent MRI brain imaging."