NEW LOOK AT DATA POLISHES OLD PRINCIPLE FOR ALS THERAPY
http://www.alscenter.org/news/briefs/090430.cfm

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 neurologist Merit
Cudkowicz at 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.