April 30, 2009

New Look at Data Polishes Old Principle for ALS Therapy

A sophisticated new look at an old study that investigated an epilepsy drug as a possible ALS (Lou Gehrig's disease) therapy - one that got a "thumbs-down" nearly a decade ago - is now causing researchers to re-think its conclusions.

"This new analysis supports our interest in a potentially good ALS target that surprised us by not appearing to be much good back then," says Jeffrey Rothstein, one of the researchers on the original study. Rothstein, a neurologist/neuroscientist, directs the Packard Center for ALS Research at Johns Hopkins.

The new data review, presented Tuesday in Seattle by Harvard neurologistat the American Academy of Neurology annual meeting, showed survival in some patients lengthened by 25 percent. Cudkowicz was also one of the original study researchers.

In the early 2000s, topiramate, an FDA-approved drug for epilepsy was the tested agent in a clinical trial run by the Northeast ALS Consortium (NEALS) - a nationwide body of academic clinicians dedicated to improving clinical trials for the disease. Nearly 300 people with ALS enrolled in the yearlong test of safety and efficacy, two-thirds of them receiving topiramate.

The idea, says Cudkowicz, who co-directs NEALS, was that topiramate would reduce excitotoxicity, a highly damaging process that occurs in ALS. "The chosen dosage was the maximum that people could be given."

Unfortunately, those in the topiramate group of the study lost more weight than those on a placebo. And though the drug had no apparent effect on survival or breathing ability - lessened breathing ability marks real decline in ALS - the group taking topiramate lost arm strength more quickly than the group on the placebo.

"The trial looked like a failure and that was that," says Rothstein. "Simply having a bad side effect ended any further consideration of topiramate." As important: The result also cast doubts on the underlying rationale for trying the drug.

Earlier, Rothstein had discovered that glutamate, a natural nerve transmitter in the brain and spinal cord, plays a part in the ALS-caused death of motor neurons. He and colleagues later found that motor neurons are especially vulnerable when glutamate acts at specific sites - receptors - in their membranes. A flood of glutamate "docking" with so-called AMPA/kainate receptors trips excitotoxicity, an unfortunate chemical cascade that ends in death.

Rothstein and NEALS colleagues Cudkowicz and Jeremy Shefner, looking for drugs that could block the AMPA/kainate receptors and perhaps rescue motor neurons, hit upon topiramate. The chemical is thought to quell epilepsy's seizures by blocking glutamate receptors.

But, after the "failed" topiramate study, many scientists turned away from AMPA-blocking as a possible route to explore. "That may change," says Cudkowicz.

Recently, neurologist Walter Bradley with the University of Miami queried Cudkowicz and NEALS, asking whether the weight loss might have caused the reported muscle weakness, rather than the topiramate itself. Clinicians have come to believe that weight loss is important in ALS's downward course.

So Cudkowicz pulled the old study data - it's a NEALS policy to purge research results of any patient IDs and thus make completed study data available to any researcher - and she and colleagues began a more sophisticated analysis than was previously possible.

In turning the statistical spotlight on the ALS patients, a comparison of people in the topiramate group and those on placebo with the same weight loss revealed that people on the test drug had a 25 percent longer median survival.

The caution in interpreting this, however, is real, say Cudkowicz and Rothstein: The study is preliminary and needs the peer review that should come with publishing it.

Also, analysis is ongoing, Cudkowicz explains. The researchers are now applying techniques that can answer specifically whether topiramate or weight loss cause the decline in muscle strength.

"This doesn't necessarily prove topiramate is a good therapy for people with ALS," says Rothstein, "but it does bring drugs that work on AMPA receptors back into the picture."

Finding a drug that's like topiramate but that doesn't cause weight loss in ALS patients could be helpful, says Cudkowicz. But because of the weight loss and potential harm from the existing drug, it is not recommended as a treatment for the disease, she adds.

"Also," Cudkowicz says, "it's important in studying possible treatments for people with ALS to test a greater variety of dosages. You don't want to throw out a drug that might be on a good pathway because you lack sufficient data on the best dosage."

The Packard Center contributes financial support to NEALS as well as expertise. NEALS is the largest ALS clinical consortium worldwide, with more than 50 sites in the United States and Canada. It engages patients in clinical trials and improves understanding of clinical aspects of ALS care and management.

Rothstein and Cudkowicz both sit on NEALS' Executive Committee. Packard Center researchers who are also Johns Hopkins clinical faculty frequently conduct NEALS-advised trials at the Johns Hopkins ALS clinic.

The original topiramate study was NIH-sponsored, with additional funding from (the then) Ortho-McNeil Pharmaceuticals and the Muscular Dystrophy Association.

David Schoenfeld of Harvard, collaborated on the new analysis.