SmithKline Beecham Cancels Trial After High Death Rates Are Found
Anticlotting Drug Failure Dashes Hopes for Preventative Medicine
By RON WINSLOW and RACHEL ZIMMERMAN
Staff Reporters of THE WALL STREET JOURNAL
SmithKline Beecham PLC's halt of a heart-drug clinical trial after an unexpectedly high number of deaths raises fresh concerns about a new class of pills intended to prevent blood clots that could cause heart attacks and strokes.
The once-promising drug, called lotrafiban, is the fourth such agent to fail in late-stage clinical trials because of either mortality concerns or lack of effectiveness. The disappointing performance has dashed hopes, at least so far, for a potential blockbuster medicine that would improve on the benefits that aspirin has demonstrated for heart patients. Two other similar drugs are currently being tested.
The latest findings prompted Eric Topol, chief of cardiology at the Cleveland Clinic and leader of the lotrafiban trial, to call for a "moratorium" on further human studies of the medicines, at least until reasons for the higher number of
deaths can be discerned. Taking tests of the other drugs into account, Dr. Topol said there is cumulative evidence of at least a 33% higher incidence of mortality in patients getting one of the four experimental drugs, compared with
a placebo, in studies involving more than 43,000 patients. "It's hard to imagine that any agent in this class is going to be immune from the problem," Dr. Topol said.
Disheartening Results
The drugs belong to a class of medicines known as oral IIb/IIIa inhibitors, which are intended to prevent blood platelets from clumping together to form clots. Intravenous versions of the medicines have proven effective in preventing heart attacks and other problems in patients who report to the emergency room with unstable chest pain called angina, and in patients undergoing balloon angioplasty and stent procedures to reopen blocked coronary arteries.
Potentially Huge Market
This success persuaded researchers and drug companies to think that a pill form of the anticlotting agents could be developed as a daily, long-term treatment for patients at risk of a heart attack or other cardiovascular problems -- a potential multibillion-dollar market.
But the efforts have proved frustrating. Early last year, Pharmacia Corp.'s Searle unit discontinued development for two such drugs, xemilofiban and orbofiban, after disappointing large-scale studies. Orbofiban was linked to higher-than-expected deaths in one of the studies as well as unimpressive benefit. Roche AG also halted studies last year of a similar drug, sibrafiban. All were successfully tested in smaller pilot studies in advance of the large-scale trials.
In the lotrafiban study, a scheduled safety check by an independent monitoring board done last weekend found that 122, or 2.7%, of the 4,599 patients taking the drug died, compared with 92, or 2.0%, of patients taking a placebo. The drug was also associated with higher bleeding of the gums and nosebleeds as well as a more serious, sharp reduction in white blood cells.
Essentially the Same
Moreover, the incidence of both heart attacks and strokes was essentially the same among both patients treated with the drug and those who got a placebo, indicating the medicine didn't provide any benefit. Cor Therapeutics Inc., South San Francisco, Calif., is developing another oral IIb/IIIa inhibitor, chromofiban. After a successful pilot study, the company said it is nevertheless revising the formulation of its drug in hopes of improving chances it can avoid complications associated with the other compounds. Cor would conduct another small study before launching a large trial, officials said.
DuPont Co. recently launched a large-scale study of its drug roxifiban. The company said it is taking the lotrafiban results into account, but hasn't any plans to halt its trial, which focuses on patients with arterial blockages in their legs.
Dr. Topol said that more than 1,000 patients were already enrolled in the lotrafiban trial when studies of the other compounds raised questions about their safety and efficacy. He said he raised the possibility in August 1999 with SmithKline and other researchers of stopping the trial then, over concerns about how well it would work.
Effective in Smaller Trial
But the drug was especially effective in a smaller trial, and other researchers felt it was premature to stop the larger study. "It was decided this trial should proceed," said Rick Koenig, a spokesman for SmithKline.
Still, Dr. Topol said he and other researchers decided then to increase the number of scheduled safety and efficacy checks of the data to make sure patients weren't put at undue risk for participating in the study. "The hope was that any [lack of benefit] would show up before any excess in mortality," Dr. Topol said. "It all showed up together," in the review that prompted the halt to the study.
Dr. Topol said one reason for higher deaths may be that the drug kills certain heart cells, leaving patients vulnerable to irregular heart beats that can cause sudden death. In the study, there were 28 sudden deaths among patients getting the drug, compared to 18 among those who got placebo.
Another possible reason for the higher deaths is that the drugs at the established doses provoke an inflammatory response that undermines their effect and leads to complications, he said. |
