By David N. LeffScience Editor

A last-minute symposium spun on to the session on amyotrophiclateral sclerosis (ALS) at the 47th annual Academy of Neurologymeeting in Seattle revealed Wednesday that an experimental drugnamed Rilutek added months to the lives of ALS victims.

The 18-month, double-blind, placebo-controlled trial of thecompound, known chemically as riluzole, tested 959 ALS patients at24 clinical centers in Europe, plus eight U.S. and Canadian sites. Itsresults, compiled too recently for inclusion in the conference programproper, were presented by French investigator Vincent Meininger ofthe Pitie-Salpetriere Hospital in Paris, who conceived and conductedthe record Franco-American study.

Meininger reported that of 236 patients who received the top dailydose of the drug, 100 milligrams, 174 (73.7 percent) were alive afterone year, compared to 152 of 242 (62.8 percent) who got a placebotablet.

Rilutek is a compound under development by Rhone-Poulenc Rorer(RPR) of Antony, France, and Collegeville, Pa.

The company's president of research and development, ManfredKarobath, said that the results of this pivotal Phase III trial "representthe first step in the treatment of ALS." He added: "We believe thistrial is significant for three reasons: First, because we used survival_ a definitive measure of efficacy _ as a primary endpoint. Second,it demonstrated extended survival in both bulbar- and limb-onsetALS. Third, it confirmed the findings of our previous Phase IIclinical trial, which will enable us to file a registration dossier withhealth authorities worldwide, beginning in July 1995."

Pediatric neurologist Larry Powe, who directs central nervous systemclinical research at RPR in Collegeville, explained that registrationdossiers submitted to European health authorities are the equivalentof new drug applications filed with the U.S. Food and DrugAdministration.

First Survival-Extender In 126 Years

A company press statement released to coincide with the symposiumhere, acclaimed Rilutek as "the first compound to prolong ALSsurvival since the disease was first described in 1869" by Frenchneurologist Jean Charcot.

In Europe, in fact, ALS is best known as "maladie de Charcot,"whereas in the U.S. it's eponym is "Lou Gehrig's disease," after thefamed New York Yankee batter who died of it in 1941.

ALS owes its neurological name to its three attributes:"Amyotrophic" signifies loss of muscle mass; "lateral" denotes thenerve tracks coursing down both sides of the spinal cord, where manyALS motor neurons occur; "sclerosis" refers to the scar tissue thatremains after the affected neurons waste away.

Often, the first trivial sign that an imminent ALS victim (or hisfriends and family) notices is a slight slurring of speech, a new nasaltimbre in the voice, perhaps some difficulty in swallowing. Suchnasopharyngeal changes describe the "bulbar" onset of the disease.Alternatively, ALS may telegraph its punch by a nagging muscletwitch, and cramps, in hands or legs _ limb onset. Both bulbar andlimb onset indicate initial degeneration of the relevant motor neuronsthat control voluntary muscles. These annoyances usually prompttheir puzzled subjects to seek medical attention.

Despite every effort of medical science, neurologists cannot evendiagnose ALS (except by excluding other motor neuron diseases thatresemble it), let alone prescribe treatment. Its pitiless progression(usually faster in bulbar than in limb onset) robs its prey of the abilityto dress and feed themselves, sit up, walk or even speak.

Yet, unlike, say, Alzheimer's disease, this bodily disintegrationleaves its victims in full possession of their intellect, and ironically,intact excretory and sexual functions and eye movement.

It may take three to five years for this living death to end in terminaldemise, for which the immediate cause is respiratory failure. Indeed,the final insult inflicted by ALS is surgical insertion of a breathingtube into the airways.

ALS is mercifully rare. It strikes about 25 people per million, usuallyindividuals in their 50s. An estimated 70,000 people worldwide haveALS, close to half of them in the U.S.

Like breast and colon cancer, approximately 10 percent are familialcases _ running in families. Of these, it's known that 20 percenthave a mutated SOD gene in chromosome 21. For the remaining 90percent, cause is unknown.

Unknown, but suspected. At least four plausible but unprovedperpetrators of ALS are under investigation by research neurologists.One implicates those mutant genes that encode defective superoxidedismutase; another blames autoimmune antibodies to calciumchannels; a third impugns overexpression of neurofilaments. (SeeNature, May 4, 1995, pages 62-64.)

Likely ALS Etiology: Glutamate Overdose

The fourth finger points to a hitch in the transport of glutamate, thebrain's main excitatory neurotransmitter.

As Powe told BioWorld Today, although no one knows themechanism that causes ALS, educated speculation says it may wellresult from the toxic buildup of glutamate in nerve-cell synapses. Soit seemed a good bet, Powe said, for RPR to try its drug Rilutek(riluzole), which "may prevent nerve cell degeneration by decreasingglutamate production." (See BioWorld Today, May 2, 1995, p. 4.)

Rilutek belongs to a class of compounds called benzothiazoles, whichare used in industry as rubber accelerators.

"When neurons are exposed to high concentrations of glutamate overa prolonged period of time," Powe explained, "this would lead tochanges in the cell. It would swell, and calcium would flow in,leading to the neuron's death by proteolytic enzymes. That wouldstart a cascade effect," he added. "Other neurons would begin to die,based on the toxic glutamate concentrations."

Powe emphasized: "We're not saying this causes ALS; just that it'sinvolved somehow. At the time we started our Phase II trial inEurope in 1990, we did not have any preclinical evidence to supportthat this antiglutamate compound would work."

The New England Journal of Medicine reported on that Phase IIstudy of 155 ALS outpatients in its issue of March 3, 1994. Theresult: After 12 months, 45 of 78 in the placebo group (58 percent)were still alive, as compared with 57 of 77 patients (74 percent) whoreceived riluzole. These data closely parallel the favorable outcomesreported in Seattle.

But Powe concluded, "While Rilutek appears to show effectivenessas an ALS treatment, it is not a cure for the disease. It just has thepotential to slow the progression of ALS. n

(c) 1997 American Health Consultants. All rights reserved.