April 4, 2003

MS DRUG SHOWS PROMISE AGAINST ALS

A new study by Israeli scientists shows that the multiple sclerosis drug Copaxone protects mice against amyotrophic lateral sclerosis (ALS), with an effect on survival greater than or equal to that of most other drugs tested in the mice. Though its mechanism of action is unclear, and other labs have seen far less impressive results, researchers are calling for a clinical trial of the drug in people with ALS.

ALS is a paralyzing, often fatal disease, caused by the death of muscle-controlling nerve cells called motor neurons. The disease process is poorly understood, and the only FDA-approved treatment, Rilutek (riluzole), extends life by just a few months.

MS is debilitating but doesn’t affect life span. It’s triggered by autoimmunity, a self-directed attack of the immune system, against myelin, a coating that insulates nerve cells and speeds the signals that flow between them. Copaxone (glatiramer acetate) slows the destruction of myelin and reduces the relapse rate in relapsing-remitting MS.

Although ALS and MS have little in common on the surface, some studies suggest that the immune system might influence the course of ALS. Though controversial, these studies motivated Michal Schwartz and her colleagues at the Weizmann Institute of Science in Rehovot, Israel, to test Copaxone against ALS in mice.

Mice with a genetic form of the disease received a single injection of Copaxone at 60 days of age, and thereafter they received it through their drinking water. (For MS, Copaxone is taken by injection.)

The average life span of the treated mice was 263 days, while that of untreated mice was 211 days — a difference of about 25 percent. The treatment also significantly delayed the onset of motor symptoms.

The mice carry mutations in the SOD1 gene, linked to hereditary ALS in humans in 1993. But since only about 10 percent of human ALS cases are hereditary — and only 3 percent can be traced to mutations in the SOD1 gene — Schwartz and her team also examined Copaxone’s effect on a more general injury to motor neurons. When a nerve is severed, the motor neurons passing through it tend to die back, but in mice given Copaxone, a significant number of motor neurons survived surgical cutting of the facial nerve.

Schwartz’s study, published online by the Proceedings of the National Academy of Sciences on March 31, has generated mixed reactions.

“I am delighted that this [study] is coming out,” said neurologist Benjamin Brooks, who directs the MDA/ALS Clinical Research Center at the University of Wisconsin in Madison. “We have a lot of experience with Copaxone in our MS patients. We need to see if it will synergize with riluzole or other agents in ALS.”

Serge Przedborski, a neurologist at Columbia University in New York and a member of MDA’s Scientific Advisory Committee, is more cautious about the study, but still enthusiastic about a possible trial of Copaxone in people with ALS.

“I think the idea of modulating the immune system [in ALS] is a wonderful strategy, but I’m confused by what they report,” he said. Using a different protocol from the one Schwartz’s group used, he’s also testing Copaxone in mice with SOD1-related ALS, and has seen only modest improvements, if any.

“I’m not saying that I don’t trust their data, but we know that in immunology, a small difference in protocol can make a big difference in results.” He’s planning to retest Schwartz’s regimen in the mice and compare it to his own.

Another problem, he said, is that Schwartz didn’t explore how Copaxone protects against ALS in the mice. On the other hand, Copaxone has become an accepted treatment for MS, and no one is really sure how it works against that disease either. The drug, manufactured by the Israel-based TEVA Pharmaceuticals, is actually a synthetic fragment of a protein found in myelin.

Proneuron, based in Los Angeles, owns the rights to use Copaxone against ALS, and Przedborski has contacted the company about conducting a clinical trial, but hasn’t received a response.

Outside of such a trial, he said, “I would not encourage people [with ALS] to take Copaxone. At the very least, a small safety study should be done.”