26 January 2005. Last Friday, the pharmaceutical company Johnson & Johnson announced that health authorities were reviewing safety data on galantamine hydrobromide (trade name Reminyl®), a drug that has been approved to treat symptoms of Alzheimer disease (AD). The concerns arise from clinical trials to test if the drug can slow or prevent decline in patients suffering from mild cognitive impairment (MCI), a condition that often, though not always, precedes AD. During these trials, three times as many people died while on the drug as those on placebo (see statement on Johnson & Johnson website).
Galantamine is approved in almost 70 countries for treatment of mild to moderate AD. By inhibiting the enzyme acetylcholinesterase, the drug slows the breakdown of acetylcholine, making more of the neurotransmitter available in synapses of cholinergic neurons. The basal forebrain cholinergic neurons, critical for memory and other cognitive functions, are among the earliest affected by AD pathology. The clinical trials to evaluate the drug’s potential to treat MCI were conducted on around 2,000 patients in 16 different countries. Fifteen subjects being treated with galantamine died, as opposed to five subjects in the placebo groups.
The scope of the studies was quite limited. “The number of individuals involved is very small and it is very difficult to draw conclusions from such small numbers,” said John Morris, clinician at Washington University School of Medicine, St. Louis. This sentiment was echoed by other clinicians and indeed, at time of writing, the FDA has no new announcements concerning galantamine. For their part, Johnson & Johnson has posted data from the trial to the clinical trials registry.
In other drug news, the fallout from the withdrawal of rofecoxib (Vioxx®), the COX-2 inhibitor that had been widely used to treat arthritis and other inflammatory conditions, continues to grow. In a paper in Monday’s Lancet, David Graham, Office of Drug Safety, USFDA, and colleagues reveal that an estimated 80,000 to 140,000 extra cases of “serious coronary heart disease” could have been caused by the drug in the USA alone, since its launch in 1999.
The numbers are extrapolated from a study that investigated coronary heart disease in some 1.4 million Californians who were taking nonsteroidal antiinflammatories, including rofecoxib, celecoxib, ibuprofen, and naproxen, over the five-year period from 1999 to 2004. Coronary heart disease was 1.6-fold more common in those taking standard doses of rofecoxib as compared to those on celecoxib, while patients taking high doses of rofecoxib were 3.8 times more likely to have heart problems. The study also revealed that naproxen increased the risk for heart disease by a small but significant 14 percent, a finding supported by recent data from the ADAPT trial to evaluate the potential of celecoxib and naproxen to prevent AD (see ARF related news story).
All of these antiinflammatories have been tested at one time or another as treatments for AD because of putative benefits seen in epidemiologic studies and the well-known inflammation component to the disease pathology. In addition, some of them have been shown to modulate the cleavage of amyloid-β precursor protein, an essential step in the release of the amyloid-β peptide that then goes on to form amyloid plaques (see ARF related news story).
“In the future, when trials show that a new treatment confers a greater risk of a serious adverse effect than a standard treatment, we must be much more careful about allowing its unrestrained use," Graham is quoted as saying in a Lancet press release.—Tom Fagan.
Graham DJ, Campen D, Hui R, Spence M, Cheetham C, Levy G, Shoor S, Ray WA. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet. 2005 Feb 5;365(9458):475-81. Abstract