Discarded Drug May Be First for Gene Therapy


The discovery of a common polymorphism in the gene for β1-adrenergic-receptor blocker that predicts response to the β-blocker bucindolol has resurrected interest in the discarded drug.

Bucindolol could be the first genetically targeted cardiovascular drug, said Dr. Michael Bristow, codirector of the Cardiovascular Institute at the University of Colorado. His company, ARCA Discovery Inc. of Denver, intends to file a new drug and diagnostic test application with the Food and Drug Administration. If approved, the drug would be marketed along with a genetic test to identify potential responders.

Subjects with heart failure who were homozygous for the arginine variant of the β1 AR-389 gene (Arg-389 variant) and who took bucindolol had a 38% reduction in mortality, compared with such patients who were treated with placebo, Dr. Bristow and his colleagues have reported. They also had a 34% reduction in the combined end point of hospitalizations and mortality (PNAS 2006;doi/10.1073/pnas.0509937103).

“This is where the field of pharmacogenetic therapy needs to go in cardiovascular medicine,” Dr. Bristow said in an interview. “Developing therapies that are specifically effective on pharmacogenetic subsets, so patients unlikely to respond to therapy aren't exposed to the risks and costs of treatment.”

The drug could be especially important for blacks, who are twice as likely as whites to develop heart failure, but who also have a poorer response to drugs, he said. The DNA test would target blacks who could benefit from bucindolol. “We wouldn't have to rely on skin color to assign therapy. We could assign therapy based on much better criteria: biology as predicted by a genetic profile.”

The bucindolol study is an exciting one, said Dr. Sidney Goldstein, head, emeritus, of the division of cardiovascular medicine at Henry Ford Hospital in Detroit. “Previous studies trying to link genotypes to β-blocker efficacy have shown some association. This study, which is the largest randomized population that has been looked at, certainly lends further credibility to the thought.”

But it will take more than one DNA study to bring bucindolol to market, he predicted. “It's very intriguing, but in order to get approval we'd need a lot more clinical evidence in this particular population,” said Dr. Goldstein, medical editor of CARDIOLOGY NEWS.

Mainstream research abandoned bucindolol in 1999, when the Beta-Blocker Evaluation of Survival Time study (BEST) was halted for ethical reasons. After a median of 2 years, bucindolol offered no significant survival advantage over placebo, while other β-blockers had long been confirmed as beneficial.

But as the study was further analyzed, substudies using its database emerged, including one using DNA collected from 1,040 BEST subjects. In 1998, Dr. Steve Liggett, BEST's lead investigator, identified several genetic variants of the β1-adrenergic receptor—the target of β-blocker therapy. In a DNA substudy submitted before BEST ended, Dr. Liggett and Dr. Bristow hypothesized that the Arg-389 variant would predict bucindolol response.

Dr. Bristow and his colleagues reexamined the BEST response data, stratifying survival of placebo and bucindolol-treated patients according to genetic type. Only homozygous Arg-389 variant patients treated with bucindolol showed a significant survival advantage: a hazard ratio of 0.62 for mortality, compared with Arg-389 variant placebo-treated patients.

The polymorphism occurred more frequently in whites than in blacks (51% vs. 35%), Dr. Bristow said—an intriguing finding that probably speaks to bucindolol's better performance among whites in the original BEST study (N. Engl. J. Med. 2001;344:1659–67). “We need more research on this point, but it may be possible that this genetic variant has a great deal to do with why black patients have more heart failure, and worse outcomes, than white patients.”

Bucindolol has a unique pharmacologic profile among β-blockers, not only blocking adrenergic receptors but lowering norepinephrine as well. “It appears that those with the Arg/Arg polymorphism can tolerate the loss of norepinephrine signalling better than those who don't have it,” Dr. Bristow said. “In them, the combination of actions produces a supertherapeutic response.”

It's impossible to extrapolate bucindolol's positive effect on patients with the arginine variant to any other β-blocker, however. One study has already addressed this issue, finding no association between β1-AR genetic subtype and survival in patients taking metoprolol (Eur. J. Heart Fail. 2003;5:463–78). There are no data available on carvedilol or bisoprolol.

If bucindolol and its accompanying genetic screen are eventually approved, physicians and patients will have to decide if the additional time and expense of genetic testing will be worth the drug's benefit, Dr. Goldstein said. “Metoprolol and carvedilol will probably both be coming out in generic forms pretty quickly. In all probability they will be substantially less expensive than bucindolol, and it's hard to believe bucindolol would be better than those drugs, although it does appear to be just as good for these particular patients.”

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