Last week at the American Heart Association's annual meeting in Dallas, NitroMed presented data that could strengthen the position of its quasi-personalized antihypertensive drug, BiDil, while the company positions the drug further into larger pharmacogenomics territory.
Approved in June for use in self-identified blacks who have recently had a heart attack, BiDil has survival benefits that are not adversely affected by its blood-pressure lowering effects, NitroMed officers said at the AMA meeting, according to company statements.
But NitroMed also sponsored a symposium in which company officers presented for a second time data from the Genetic Risk Assessment of Heart Failure in blacks study that strongly suggests that it may be possible to identify BiDil responders through the use of a genetic test. If NitroMed decides to market the drug to those patients having a particular genetic profile, the move might increase the size of the drug's market beyond its current size. There are approximately 750,000 black heart-failure patients in the United States for whom BiDil is appropriate, and there are about 5 million heart-failure patients of all ethnicities, without regard to genotype, according to a NitroMed spokesperson.
"Our hypothesis has always been that it doesn't necessarily make sense to base treatment decisions on race. It is truly just a surrogate marker for genetic background, and it makes more sense to find out which specific aspects of the genetic background are different in this [African-American] population, and that may [deliver] genetic clues for where the therapy should be targeted."
"I'm very excited that there is great potential with this particular treatment strategy — a [nitric oxide] donor using isosorbide [BiDil] and hydralazine," said Dennis McNamara, leader of the GRAHF study and director of the Heart Failure/Transplantation Program and an associate professor of medicine at the University of Pittsburgh Medical Center. "We have shown it has a very positive survival effect in a segment of the population, and there's a great motivation for us to see if we can expand this effect."
The GRAHF study identified at least one gene, endothelial nitric oxide synthase, or eNOS, to be important to BiDil response, but there may be more. "We're looking at a dozen variables within the neurohormonal system that may impact on therapy, and what we'll have to decide is which gives us the best clue to efficacy," McNamara said.
But in an uncommon turn of events, should eNOS testing become recommended to identify patients likely to respond to BiDil, rather than relying on patient-reported ethnicity, the drug's market would probably expand. Although the results so far suggest this is the case, "I wish our data clearly suggested it was going to be that simple — I don't know that it is," McNamara said.
Regarding BiDil, ethnicity is an imperfect surrogate for efficacy, but is "the best we have," 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 in June. "FDA is encouraging the use of genomic biomarkers for either efficacy, safety, or dosing where they add value in terms of improving benefit/risk," he wrote. "Rather than ethnicity, the scientific community would prefer more precision in molecular biomarkers related to efficacy irrespective of ancestry or declared ethnicity."
"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," 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, told Pharmacogenomics Reporter in June. Yancy was one of the principle investigators in NitroMed's BiDil trials, and a member of the steering committee that oversees the A-HeFT trial that proved efficacy in black trial subjects. "Our hope is that genomics one day will further sophisticate our decision making," along with information about other biomarkers, said Yancy.
It seems that the GRAHF study was, from the beginning, predicated on the belief that ethnicity would not remain the sole determinant of BiDil efficacy. "Our hypothesis has always been that it doesn't necessarily make sense to base treatment decisions on race," McNamara said. "It is truly just a surrogate marker for genetic background, and it makes more sense to find out which specific aspects of the genetic background are different in this [African-American] population, and that may [deliver] genetic clues for where the therapy should be targeted," he said.
There are marked differences between black and white populations in the prevalence of enzyme variants important in the production of nitric oxide, McNamara said. In particular, the enzyme endothelial nitric oxide synthase, or eNOS, shows "a lot of variability on the genome, and there are, in fact, functional variants which tend to be less active," including Glu298Asp, which has been linked in previous studies to hypertension and coronary artery disease, as well as having an adverse effect on heart failure outcomes, he said.
Endothelial nitric oxide synthase is the primary source of nitric oxide in the cardiovascular system, and it operates generally as a mediator in heart failure with protective effects.
"African Americans tend to have a much higher prevalence of more active enzymes for producing nitric oxide," meaning that they tended to be less likely to carry the Glu298Asp variant, and more likely to carry the Glu298Glu wild-type eNOS gene, McNamara said. Those patients taking part in the A-HeFT trial who were homozygous for the Glu298Asp variant did not show much impact of the drug on their heart failure therapy, he added.
"Alternatively, the 80 percent of patients in the A-HeFT study who were Glu-Glu [homozygotes] had a much more profound effect of therapy," McNamara said. About 20 percent of black individuals are homozygous for Glu298Asp, while around 60 percent of whites carry two copies of the gene variant, he said.
Prospective study still needs to be done before the drug can be applied more widely, perhaps preliminary work employing markers of BiDil's effect, said McNamara. "So what does it mean for the 40 percent of non-African Americans who are Glu-Glu — are we going to see the same enhanced effect of a [nitric oxide] donor?" he asked. "That really remains to be determined."
McNamara said that it is still poorly understood why patients who have a more active NO-producing enzyme should receive disproportionate benefits from an NO-producing drug.
The GRAHF study was not required by the FDA, but pursued by the A-HeFT trial's sponsors, said McNamara. "In the future, I hope we get to the point where the FDA does mandate such substudies, but they haven't yet," he said.
NitroMed previously presented information on the GRAHF study at the Heart Failure Society of America meeting in September, along with data it also issued at the AMA meeting on BiDil's cost effectiveness, its effects on patients' quality of life, and the reduced amount of heart damage found in patients given the drug. The GRAHF study is a sub-analysis of the A-HeFT, which was stopped early after it was clear that the study of 1,050 self-identified blacks received a significant survival benefit when the drug was used in combination with hydralazine.
— Chris Womack ([email protected])