24 July 2002. Stockholm. This morning at the 8th International Conference on Alzheimer’s Disease and Related Disorders, Paul Aisen of Georgetown University Medical Center in Washington confirmed the whispers that had been going around among the AD community for a while: The treatment trial of the two NSAIDs naproxen and rofecoxib has not shown any benefit in any of the endpoints measured.
The trial was run by the Alzheimer’s Disease Cooperative Study (ADCS), a multicenter consortium conducting clinical trials of various experimental therapeutics. An ADCS trial of the cholesterol-lowing agent simvastatin, for example, is expected to begin this fall.
The rofecoxib/naproxen trial is the latest in a small number of NSAID trials and followed on the heels of a trial of the steroid drug prednisone, which had also failed. The trial was designed based on evidence that inhibiting the cox 1 and/or 2 enzymes, which are expressed in AD brain, might slow the inflammatory changes that accompany AD. Naproxen is a mixed cox1/2 inhibitor; rofecoxib is one of the newer selective Cox2 inhibitors and was chosen because it promised to be safer for chronic use and because Cox2 is upregulated in AD neurons. Even that did not really pan out, however: 23 percent of the 351 enrolled patients with mild or moderate AD dropped out, mostly because of gastrointestinal side effects.
The trial evaluated success by looking for changes, after one year on drug, in the ADAScog rating scale. It also assessed other cognitive, clinical, and behavioral measures and endpoints such as death, institutionalization. Patients showed no real improvement in any of these measures, those taking rofecoxib even worsened a bit, though that was not statistically significant.
This disheartening result is no surprise to those researchers who believe that only certain NSAIDs, but not rofecoxib and naproxen, inhibit presenilin and that this is a key mechanism of NSAID action in AD. (There are several other proposed mechanisms for how NSAIDs work in AD, however.) The trial failure is also consistent with the reanalysis of the epidemiological data from the Rotterdam study reported here yesterday (see story below).
Finally, ADCS currently conducts a prevention trial for AD using naproxen and celecoxib. Celecoxib is a cox-2 inhibitor much like rofecoxib, raising questions about whether the latest epidemiological and in vitro research still supports this choice of drug.-Gabrielle Strobel.