Update - October 25, 2004
The initial analysis of data from the 12-month study of Celebrex failed to show a benefit for people with ALS. Although more analysis of additional study data is continuing, the Northeast ALS Consortium investigators are releasing this key finding to provide timely information to patients. There were no side effects or adverse events from the 800 mg. per day dose. More detailed information will be released when the full data analysis is complete.
The following commentary was taken from The Robert Packard Center for ALS Research at Johns Hopkins www.alscenter.org:
Results of a one-year study of the drug Celebrex, to see if it might be useful against ALS, have just been released. Celebrex is an anti-inflammatory medicine, commonly used to treat arthritis. And the study, which enrolled 300 people with ALS at 25 medical centers across the country, was based on principles brought to light by Packard Center scientists.
"Careful analysis of the data from the Celebrex trials showed no apparent benefit for those who took the drug," says Packard researcher, Daniel Drachman, who initiated the study and was instrumental in getting it underway. "Naturally, we're disappointed."
But both he and Center Director Jeffrey Rothstein, who teamed on preclinical work with Celebrex, say that important questions remain. "We don't know if the lack of a good effect is because the drug itself wasn't helpful or if it wasn't able to reach target tissues," says Rothstein. An announcement put out by the Northeast ALS Consortium, the association of 25 academic medical centers which conducted the trial, says more study is underway to try to explain the results.
Celebrex inhibits a key enzyme, called COX-2, that's on cell pathways leading to inflammation. COX-2 is also involved, though indirectly, in release of the neurotransmitter glutamate from astrocytes, cells in the nervous system that support nerve cell function. In excess, glutamate is toxic to neurons and other cells. Scientists recognize this "excitotoxicity" as a major destructive process in ALS.
Aware of the reported tie between COX-2 and excitotoxicity, Drachman and Rothstein began early experiments to see if blocking COX-2 would be helpful. They saw that inhibiting COX-2 clearly protected motor neurons when rat spinal cords in a culture dish were put in an excitotoxic situation.
They also determined that halting COX-2 action in mouse models of ALS significantly lengthened the animals' lives and slowed onset of their symptoms. "We had strong reasons to carry this research to ALS patients," says Drachman. The subsequent clinical trials were well-designed, he says, and carried out carefully. "Now we hope to find why we got these results."
Background
Celebrex is a cyclooxygenase-2 (COX-2) inhibitor that is FDA approved for the treatment of arthritis. Pre-clinical studies support the hypothesis that drugs that inhibit COX2 activity may be neuroprotective in subjects with ALS. Glutamate-mediated excitotoxicity and oxidative toxicity are possible factors in the pathogeneisis of ALS. Cyclooxygenase-2 may play a key role in these processes by producing prostaglandins, that trigger astrocytic glutamate release and by inducing free radical formation. COX-2 inhibition in an organotypic spinal cord culture model of ALS provided significant protection against loss of spinal motor neurons.1 Preliminary data suggests that COX-2 inhibition prolongs survival in the G93A mutant superoxide dismutase transgenic mouse model of ALS (Rothstein et al, unpublished data). Laboratory findings from the work of Drachman and Rothstein led to this clinical trial of Celebrex.
Study Design
The study is a double-blind placebo controlled study of Celebrex. Enrolled subjects will receive either Celebrex or placebo over a 12 month period. Twice as many people will receive Celebrex than will receive the placebo in this trial. In addition, Celebrex will be provided free of charge, for up to one year, to enrolled subjects regardless of group assignment at the end of the 12 month study period. The total number of subjects to be enrolled is 300 (approximately 12 patients per study site.) Enrollment is expected to take six to tweleve months across all 25 participating sites.
Celebrex is a capsule taken by mouth. In general, Celebrex is well-tolerated. Possible side effects include gastrointestinal disturbances, kidney problems and allergic reactions. People with known allergic sensitivity to sulfa antibiotics should not take Celebrex.
It is hoped that Celebrex will slow the rate of progression of ALS. At this time it is not known if the study medication will provide any benefit. The knowledge gained from this study may be of future benefit to ALS subjects.
Over the course of the 12-month research period, muscle strength, breathing strength, and activities of daily living function will be measured along with estimated counts of functioning motor nerves.
Pharmacia and Pfizer market and sell Celebrex.
CAUTION
Celebrex is an investigational drug for ALS. Unexpected adverse effects can occur. If you are not enrolled in the Celebrex clinical drug trial, do not take Celebrex without consulting with your physician or other health care provider.
Funding
The study is funded by Pharmacia and the Muscular Dystrophy Association.
