CELEBREX SHOWS NO BENEFIT IN ALS
Researchers Want to Know Why
A one-year study of the anti-inflammatory medication celecoxib (Celebrex) in people with amyotrophic lateral sclerosis (ALS) has failed to show benefit, according to the Northeast ALS Consortium, which conducted the trial with support from MDA and Pfizer Inc., makers of Celebrex.
The trial involved 300 people, two-thirds of whom received Celebrex and one-third of whom received a placebo (inactive substance), at 25 medical centers across the United States.
Basing their hypothesis on laboratory studies of cells in culture and in mice with ALS, the researchers had hoped to demonstrate a slower rate of ALS progression with the drug.
Celebrex has been shown to interfere with COX2, part of the chemical pathway that leads to inflammation and to damage from glutamate, a natural central nervous system chemical that is toxic in excess amounts. It has been proposed that elevated levels of prostaglandin E2, one of the chemicals involved in inflammation, may increase secretion of glutamate in the nervous system.
“Celebrex worked in two laboratory models,” said MDA clinic director and research grantee Dan Drachman, a neurologist at Johns Hopkins University Medical Center in Baltimore and a principal investigator on the Celebrex study. “There was more than enough reason to translate the research to humans, and it was a very well done study. It didn’t produce any clinical benefit at the dose used, and our efforts now are to try to figure out why.”
Drachman added that the trial took a “tremendous amount of coordination among the investigators in all 25 institutions” and that “everybody did everything that they should have.”
Celebrex or a substance very similar to it provided significant protection against poisoning of motor neurons (the nerve cells that die in ALS) when rat spinal cords in a culture dish were subjected to glutamate-related toxicity and when mice with genetic ALS were given the drug.
The treated mice developed ALS later, lived longer, lost strength and weight more slowly, and showed less damage in their spinal cord motor neurons, when compared with their untreated counterparts.
The statement from the Northeast ALS Consortium, released yesterday, says: “At 800 milligrams per day, Celebrex was safe and well tolerated. Celebrex did not have any demonstrated beneficial effects on ALS disease course. Studies are under way to assess whether Celebrex as used in this study had the predicted pharmacologic [drug-related] effects in the treated subjects. The study results will be presented at the International Motor Neuron Disease Association meeting on Dec. 3, 2004.”
Drachman said the challenge now will be to see whether the failure of celecoxib in ALS was due to “an inherent flaw in the theory, or to a difference between mice and men, or to a dosage effect, or to lack of penetration of the drug into the nervous system.”
MDA Medical Advisory Committee member Merit Cudkowicz, a neurologist at Massachusetts General Hospital and a principal investigator and coordinator on the Celebrex study, said she and the NEALS group were committed, with MDA, to “understanding why Celebrex at 800 milligrams a day did not work and to finding other therapies.”
