New ALS Drug Still In The Pipeline After Phase II Trial

A potent new class of drug could have some ability to slow the muscle weakening that comes with ALS, scientists report after completing a Phase II clinical trial - an early, small-scale test to show if the drug works.

In the trial, the drug talampanel showed some potential to slow the loss of major life activities such as speaking, walking and dressing that typically slip away with the disease.

The study by scientists from the Robert Packard Center for ALS Research at Johns Hopkins and Indiana University reveals there's enough benefit from this new use of an existing drug to propel it into much larger trials that will definitively tell its worth.

An account of the work appeared online December 4 in the journal Amyotrophic Lateral Sclerosis.

The trial of 59 volunteers with ALS - also called Lou Gehrig's disease - showed that talampanel can be safe for patients with the disease and that any recorded side effects are tolerable, says Johns Hopkins neurologist/neuroscientist Jeffrey D. Rothstein, M.D., Ph.D., senior scientist on the new study.

Rothstein heads the Robert Packard Center for ALS Research at Johns Hopkins.

Phase II trials are designed to show on a smaller scale if a drug is safe and if it works. So the present trial included ways to measure the drug's benefits, which came across as clear, if not statistically significant. "The research demonstrates that talampanel appears able to slow the progression of disabling ALS symptoms. The effect isn't overwhelming at the dosage of medicine used in this early, very small trial," he says. "Still, having promising human data is reason enough to keep it in the drug pipeline where we can really find out where it stands for patients."

That's especially important in ALS. The always-fatal neurodegenerative disease has foiled therapy for years.

With the exception of riluzole, the single FDA-approved drug for the disease, there's no other treatment to slow or stop it. "Riluzole can extend life only modestly and hasn't been shown to slow ALS symptoms," says Rothstein, "so the need for better therapy is real. Barring a cure, we'd still be glad for agents strong enough - either singly or in combination - to lower ALS to chronic disease status."

In the study carried out at Hopkins and Indiana University, patients in the talampanel-receiving arm were eased, over a month, into the trial-desired dose. Most stayed there for the remaining eight months of the study.

Periodically, clinicians rated the 40 test subjects and 19 controls (the placebo group) on a measure of isometric arm muscle strength. Testing also included the rate of decline in breathing and the ALS Functional Rating Scale (ALSFRS) - a standard measure of ability that includes of speech, swallowing, handwriting, breathing, walking and food-cutting.

To see if the drug was safe for ALS patients, subjects received a variety of laboratory blood tests, an electrocardiogram, neurological exam and other measures.

In most of them, talampanel slowed progression of ALS. Results stood out, especially, in the ALSFRS, where patients' decline in abilities slowed 30 percent.

Several facts about talampanel make it especially attractive to try as a possible therapy, Rothstein says. The drug's talent is its ability to block specific receptors on ALS-vulnerable neurons. These are docking sites for the neurotransmitter glutamate.

An excess of glutamate trips excitotoxicity - a process that can kill the motor neurons that enable movement. Earlier studies by Rothstein and others on cell and animal models of ALS consistently confirm excitotoxicity as a source of damage in the models and ALS patients. Levels of glutamate are elevated in spinal fluid and in the brain in as many as 40 percent of sporadic ALS patients - where disease appears to arise spontaneously.

Talampanel or other molecules that whisk glutamate out of harm's way prolong life in animal models of ALS while they preserve motor neuron life and muscle strength.

Also attractive, Rothstein adds, is that talampanel is a small molecule that can penetrate into the brain and spinal cord where it's needed. The drug is a member of the benzodiazepine family - anti-anxiety and muscle-relaxing agents that work in these areas.

Currently, a larger international trial of talampanel is underway, due to end in 2010. The present trial was funded and organized by Lilly Pharmaceuticals.

The research team also included first author Robert Pascuzzi and Lisa Haas, both with the Indiana University School of Medicine, Jeremy Shefner, with Upstate Medical University, Syracuse, N.Y., Amy Chappell, John Bjerke and Roy Tamura, with Lilly Research Laboratories, Indianapolis, Indiana, and Lora Clawson, with the Johns Hopkins University, Baltimore.