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HHS Draft Report Suggests Genetic Test For BiDil; NitroMed Does Not Rule Out Dx

Racial identifiers alone will not characterize the optimal population for NitroMed’s heart failure drug BiDil, but a genetically based diagnostic may, according to a Health and Human Services draft report on pharmacogenomics.
Separately, a NitroMed spokesperson said that a diagnostic for the drug “is a possibility,” and that the company will address it after completing additional genomic analyses.
The report, written by the HHS Secretary’s Advisory Committee on Genetics, Health, and Society, says that the race-based prescribing information for BiDil is “ambiguous and clinically sub-optimal” and concludes that the US Food and Drug Administration should encourage gene-based studies over race-specific ones.
“Although genetic characteristics may vary according to racial or ethnic origin … these divisions between subpopulations often are determined using ethnic or racial or other demographic information as a proxy for more precise selection criteria,” the report contends. “While [BiDil] may benefit some patients who self-identify as black, it may not benefit others and could be effective for some non-black patients.”
The report, Realizing the Promise of Pharmacogenomics, can be found here. HHS is collecting public comments on the draft report until June 1.
NitroMed has conducted several genomic studies that suggest that a majority of blacks and some white patients with certain polymorphisms may benefit more from BiDil therapy.
In an interview with Pharmacogenomics Reporter this week, Jane Kramer, NitroMed’s vice president of corporate affairs, said there is currently no effort to update BiDil’s label with genomic data.
However, Kramer suggested that data from these genomic studies could eventually lead to the development of a diagnostic for BiDil.  
Linking Genetics and Race
Since its approval in 2005 for the treatment of heart failure in self-identified black patients, BiDil has been a lightening rod for controversy, with some insisting physicians prescribe the drug independent of racial characteristics and others touting the economic and clinical benefits of the targeted therapy.
According to the HHS report, the discussion of racial characteristics in the drug’s labeling is “ambiguous and clinically sub-optimal” and provides “no standard, objective means for identifying a ‘self-identified black’ population.”
However, a genetically based diagnostic “could widen access to a drug that would be effective for those who otherwise would have been excluded and could curtail use of the drug for those who would have been included but who would not have benefited,” the HHS report states.
Kramer said that NitroMed will address the possibility of a diagnostic test for BiDil after completing additional genomic analyses on the drug, which are “going to take awhile,” she said. The development of a diagnostic test “is a possibility. I don’t want to go so far as to say we’re considering it, but it is a possibility.”
On NitroMed’s website, the company acknowledges that it is analyzing genetic data in the hopes that it may lead to a next-generation versions of BiDil targeted to other populations.
As part of this research, the company conducted a prospectively defined genetic analysis from samples collected from the 358 patients who participated in the African American Heart Failure Trial, or A-HeFT – the pivotal study upon which FDA based its approval of the drug.
Then, NitroMed compared the frequency of genotypes in black patients in this sub-study, called the Genetic Risk Assessment in Heart Failure Trial, or GRAHF, to the incidence of the same genotypes in white participants in the University of Pittsburgh’s Genetic Risk Assessment of Cardiac Events, or GRACE, study.
Preliminary results of the study have identified three gene variations – endothelial nitric oxide synthase, aldosterone synthase, and beta-1 adrenergic receptor – as genetic factors that may affect BiDil response. Last year, NitroMed presented data from these ongoing studies at an American College of Cardiology meeting.
According to NitroMed researchers a majority of self-identifying black patients from the A-HeFT trial have endothelial nitric oxide synthase, which fewer than half of the white patients had in the GRACE study.
“The benefit of BiDil therapy on the primary composite score from A-HeFT – combining mortality, first heart failure hospitalization and patient functional status – was seen in those possessing the specific NOS3 gene variation, NitroMed says.  
Additionally, the research identified racial differences in the frequency of -344 C/T variations of the aldosterone synthase gene. In GRAHF, 62 percent of black patients with heart failure possessed the genotype TT, while 38 percent were either TC or CC. In GRACE, about one-third of white patients with heart failure possessed the TT variation. A-HeFT patients participating in GRAHF with the -344 C allele had the greatest event-free survival, while those with the TT variation had the lowest risk for death or hospitalization for heart failure. 
Finally, a third analysis looked at the Gly389Arg polymorphism in the beta-1 adrenergic receptor, which is responsible for the regulation of the heart. In GRAHF, 32 percent of black heart failure patients and 49 percent of white heart-failure patients in GRACE possessed the Arg389Arg variation. According to researchers, black Arg389Arg patients treated with BiDil “experienced significantly better primary composite scores compared to Arg389Arg patients treated with placebo and standard therapy.”
Last year, at the annual meeting of the Heart Failure Society of America, NitroMed also reported data from a study, which found that BiDil therapy in African Americans with the C825T polymorphism in the GNB3 TT gene “had a more pronounced effect” on death, heart failure-related hospitalization, quality of life, and event-free survival. “The mechanism of this effect and the role of GNB3 genotype in targeting therapy deserve further study,” the researchers concluded. 
Adoption Lagging
The HHS notes in its report that BiDil has seen slow penetration in the marketplace. According to the report, only about 1 percent of 750,000 African Americans with heart disease have prescriptions for BiDil.
Deterring patient adoption of the drug — which combines two generic drugs — is “due to health plan resistance to paying the premium price” for the branded product, which costs between $1,382 and $2,765 per year.
This has caused NitroMed’s stock price to plummet from $23 per share to around $3 a share since BiDil launched two years ago.
BiDil combines isosorbide dinitrate and hydralazine hydrochloride. Instead of covering BiDil, health plans are paying for these two inexpensive generic drugs, “even though dosing the generic drugs in a manner that equates with their levels in BiDil poses challenges to patient compliance,” the report says.  
Kramer blamed the slow market growth for the product to disadvantageous timing. The drug was launched a month after its approval in June 2005. A few months later the Medicare Drug Benefit took effect, giving NitroMed little time to negotiate formulary placement with healthcare plans.
“That situation is a lot different now,” Kramer said. “[For] 70 percent of lives that would need BiDil, we have very good insurance coverage.” Currently, patients incur on average a $25 out-of-pocket copayment for a prescription of BiDil, which is a tier 2 drug in most formularies.

The development of a diagnostic test “is a possibility. I don’t want to go so far as to say we’re considering it, but it is a possibility.”

However, the HHS report points out that BiDil’s cost is particularly burdensome to low-income elderly patients, who fall in the “dual eligibles” category since they have been shifted from Medicaid coverage to Medicare Part D plans “that either do not cover BiDil or only offer it with expensive patient copayments.”
According to Kramer, since its genomic studies aren’t in BiDil’s label the company cannot tout the benefits of genetic testing to justify reimbursement. Although NitroMed has not conducted any studies to gauge the economic benefits of incorporating genetic testing into BiDil therapy, the company previously told Pharmacogenomics Reporter that genetic testing could further reduce costs related to hospitalization due to heart failure regardless of race [see PGx Reporter 12-15-2005].
Race-Specific Drugs Bad News?
HHS lays out several socio-economic reasons against developing race-specific drugs. According to the report, the proliferation of drugs such as BiDil could engender a “biologically defined” perception of race, drive research dollars away from making drugs for people in poor countries, and grant companies monopoly over certain ethnic groups.
“Given the considerable genetic variation within conventional or self-identified racial and ethnic groups themselves, attempts to use population categories designated by race or ethnicity as proxies for genetic variation are likely to be scientifically suboptimal and medically impractical,” the report says. “It can result in imprecise prescription guidelines and reinforce a public view of biologically defined race.”
Stratifying patients by race and ethnicity “can have negative effects on uptake of PGx-related diagnosis and treatment,” the report adds.
Furthermore, the promotion of race-based drugs can also contribute to an R&D bias, which shifts the focus on developing drugs for a “racial group in a wealthy country [that] represents a potentially more lucrative market … than patients of other racial backgrounds with the same condition in developing countries.”
Kramer acknowledged that BiDil’s current indication is far from ideal.
“We often say that our indication for self-identified blacks is a very uncomfortable and a very uncertain proxy for patients with heart failure who could benefit from our drug,” Kramer said. “We do hope that further genomic studies are going to help focus that indication much better, but at the moment this is all we have.”
That said, Kramer emphasized that NitroMed can’t ignore the clinical trial experience, which shows that BiDil “works particularly well in African Americans.
“It’s pretty difficult to argue with a 43-percent improvement in mortality.” she said.
“That doesn’t mean that it works in all African-Americans and it doesn’t mean that it doesn’t work in other patients. It just means that we know it clearly works in African Americans.”
According to the HHS report, the BiDil example also illustrates how a company might use race to secure market share and patent exclusivity. With BiDil, NitroMed essentially has monopoly over the African-American heart failure market until 2020, though its exclusivity for the drug in the general population runs out this year.
Citing a five-fold increase in the use of racial categories in gene-related patents since 1976, the SACGHS warns that “this type of intellectual property protection could lay the foundation for commercial ventures in which pharmaceutical companies market products to specific social groups based on the related prevalence of certain genetic variations.”
Recent examples of race-specific marketing of drugs include AstraZeneca’s oncologic Iressa and its statin Crestor. When the epidermal growth factor receptor Iressa failed to show a benefit in the Iressa Survival Evaluation in Lung Cancer trial in the general population, AstraZeneca decided to market the drug in Asians, among whom Iressa has shown a statistically significant survival.
Also, the FDA alerted physicians in 2005 that Asian patients should receive the lowest Crestor doses possible due to their increased risk of adverse effects.
Ultimately, the HHS report recommends that the FDA should encourage gene-based studies over race-specific ones.
“While FDA collects race and ethnicity data for broad group statistical and reporting purposes, collection of such data at the individual and subgroup level may be less apt for scientific and medical research,” the report states. “Gathering more specific genomic data in clinical trials, rather than traditional racial and ethnicity categorization, could lead to a more concrete understanding of the genetic bases of health issues.”

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