A Tale of Three Drugs:
Where We Stand with Human Trials

With results of last year’s massive screening of existing drugs about to come out, Center scientists are ushering the most promising of the first lot into the testing pipeline. Packard researchers did their share of screening in the government-initiated study of 1,040 agents. Now the top five drugs—ones that target certain known disturbances ALS creates in cells—will enter whole-animal tests this fall.

Simultaneously, planning is going on for human trials of ceftriaxone, the drug at the head of the list (see Speaker's Corner), based on its potent activity in the screening—a tactic that could shave months off the time it takes to get the drug to the bedside. The timing of the trial’s still uncertain; it hinges on getting financial support from the NIH or other sources.

Ceftriaxone combats meningitis. And because of its chemical structure, the antibiotic is able to overstep a traditional hurdle for neurological disease medicines: crossing the blood-brain barrier. “But nobody knows at this point how the drug works,” says Packard Center director Jeffrey Rothstein. “We do know, based on Center tests, that it saves rodent spinal cord models from the toxicity of the neurotransmitter glutamate.” This comes, he explains, by improving the sweep of glutamate from motor neuron synapses.

On another front, human trials of the inflammation-blocker Celebrex are ongoing and now fully enrolled at a consortium of East Coast institutions—including The Johns Hopkins ALS Clinic and its Massachusetts General Hospital counterpart that carries out Packard Center studies. Normally an arthritis drug, Celebrex inhibits an enzyme, called COX-2, that’s pivotal in the body’s inflammatory and other neuro-damage pathways.

Center and Hopkins scientists proved that blocking COX-2 could work, and Celebrex clearly protects motor neurons in mouse spinal cord models. This find moved the drug—already shown in arthritis trials as safe—from lab bench to clinical trials in record time. Results of the human testing should come next summer.

The third drug, talampanol, surfaced in a small study several years ago at Johns Hopkins. Those taking the drug did better than those without it, though its benefits weren’t significant, statistically, to warrant further testing, said a sponsoring pharma company. “But a large enough study can ferret out possible good effects,” says Rothstein.

Like the other two drugs, talampanol quiets activity of the potentially toxic neurotransmitter glutamate. And it’s helped protect ALS model mice in three studies. That’s why Center staff are in the early stages of arranging a proper-sized, “real” trial with patients. “Even though a drug may not be a cure,” Rothstein explains, “it tells us something about ALS and might combine with other drugs for a more powerful effect.”

To speed therapy, the Center collaborates with Project ALS, which is covering the considerable costs of providing and housing ALS mice for testing drug candidates from the NIH Drug Consortium. The Celebrex trials are largely funded by Pfizer Inc, with support from the Muscular Dystrophy Association.

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Why would you study a form of the disease that the vast majority of ALS sufferers don’t have?