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Despite BiDil s Approval in Blacks, Iressa, With Its Asian Benefit, Will Not Follow Tactic

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The approval last week of NitroMed's BiDil, the first drug to be marketed to a specific ethnic group, puts front and center the question of whether other drugs, such as Iressa, will follow in its footsteps and be targeted to specific ethnic groups if they show ethnically variable efficacy.

Earlier this year, AstraZeneca released clinical trial results showing no overall survival benefit for non-small cell lung cancer patients taking Iressa, but two subgroups stood out as exceptions — Asians and nonsmokers. Now that BiDil has been approved for self-identified African-Americans, one might expect that the FDA and pharma would now approach that method as an alternative to using genes and mutations as a guide to drug efficacy. But that doesn't look likely.

"FDA is encouraging the use of genomic biomarkers for either efficacy, safety, or dosing where they add value in terms of improving benefit/risk," Larry Lesko, director of the Office of Clinical Pharmacology and Biopharmaceuticals at the FDA's Center for Drug Evaluation and Research, wrote in an e-mail message to Pharmacogenomics Reporter. "Rather than ethnicity, the scientific community would prefer more precision in molecular biomarkers related to efficacy irrespective of ancestry or declared ethnicity."

Regarding BiDil, Lesko said ethnicity is an imperfect surrogate for efficacy, but is "the best we have." He said he did not know whether to expect more applications along these lines in the future.

Following a December decision by the FDA to restrict marketing of Iressa — which was shown to be particularly efficacious among Asians — the agency announced a revised label for the drug last week that bars new patients from taking the drug.

Patients currently deriving some benefit from Iressa will continue to receive that therapy through a limited distribution program, Mary Lynn Carver, a spokesperson for AstraZeneca, Iressa's manufacturer, told Pharmacogenomics Reporter. "After September 15, when a doctor writes a script, he has to verify that the patient was on it prior to September 15 in order for that script to be filled," she said.


"Rather than ethnicity, the scientific community would prefer more precision in molecular biomarkers related to efficacy irrespective of ancestry or declared ethnicity."

Does AstraZeneca plan to apply Iressa with the FDA as a drug only for Asians and nonsmokers? "No," said Carver. "The drug is approved in 36 markets across the world, openly, and in the US it's a different story," she said. The company markets the drug in Asia, and trials show it seems to stop tumor growth — but the FDA required Iressa's trial to show survival benefit, a much higher endpoint.

Even if AstraZeneca decided to follow the BiDil route to approval with Iressa, the company would need to perform a new clinical trial to support an ethnically based indication, said Carver.

The FDA seems to prefer true genetic markers to associations of ethnicity to efficacy, Carver said. So far, AstraZeneca has identified "some" biomarkers corresponding to response to the drug, but none of these has proven to identify "100 percent" of responders, she said. However, ethnicity can help point to biomarkers, said Carver.

Even people more closely involved with BiDil's trials shy away from portraying the drug's trajectory as an orthodox route to approval. "It is not necessarily correct that race serves as a proxy for genomics, and we all in effect believe that it's a fairly poor proxy for that, and that there are a number of intermediate steps, including environment, other drugs, et cetera," said Clyde Yancy, a professor of medicine and cardiology and medical director of heart failure and transplantation at the University of Texas Southwestern medical center in Dallas. Yancy was one of the principle investigators in NitroMed's BiDil trials, as well as a member of the steering committee with oversight for the A-HeFT trial that proved efficacy in African-American trial subjects.

Yancy said he did not know of other companies considering the BiDil route for their own drugs. "I would say that this is a first of a set of drugs that show unique efficacy in a targeted group, and that at the first outset, this is a fairly crude subdivider for patient populations," Yancy said.

NitroMed will be trying to find biomarkers for efficacy in an ongoing G-HeFt trial. "Our hope is that genomics one day will further sophisticate our decision making," along with information about other biomarkers, said Yancy. In a prospective study parallel with the A-HeFt trial, researchers have already identified "a number of candidate genomic markers," he said.

The search for biomarkers is led by Dennis McNamara at the University of Pittsburgh, Yancy said. "We're all anxious to see how those data will unfold, and whether they will give us a chance to be more sophisticated with regard to who responds best or who doesn't respond, and see if we can find something that more-appropriately defines our patient population," he said.

Yancy shied from saying new response-related biomarker information would definitely change BiDil's market, preferring instead to call the search for biomarkers largely a scientific pursuit.

The BiDil submission for approval used data from the A-HeFT trial and followed two failed attempts, V-HeFT trials I and II, which were unable to show a survival benefit in an ethnically mixed population. An FDA panel in 1997 rejected that data, and the FDA rejected it again in 2001, said Liana Moussatos, who covers NitroMed for investment bank Pacific Growth Equities. A sub-analysis of that earlier data revealed more benefit in African-Americans, she said. Moussatos characterized the A-HeFT data as very strong — it showed a 43-percent survival benefit for African-Americans and a 39-percent decrease in hospitalization compared to placebo.

On June 16, an FDA cardiovascular and renal advisory panel unanimously approved BiDil, with six of the eight voting panel members voting for a label restricted to African-American heart-failure patients, according to a Pacific Growth report by Moussatos.

NitroMed officials said this week in a conference call with investors that BiDil would go on the market within two to four weeks.

BiDil is a combination of isosorbide dinitrate, which is a vasodilator that affects arteries and veins, and hydralazine hydrochloride, a predominantly arterial vasodilator, according to the drug's new label. Although the label says that the precise mechanism of the drug's action is not known, a NitroMed statement cites its ability to enhance blood nitric-oxide levels. African-Americans tend to have lower blood nitric-oxide concentrations.

— Chris Womack ([email protected])

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