FDA approves ‘ethnic’ drug

The US Food and Drug Administration (FDA) has approved the first ever drug marketed for use solely in a specific ethnic group. BiDil, produced by US company NitroMed, has been approved for the treatment of heart failure in self-identified black patients, having been through clinical trials for the treatment of African Americans (see November 2004 newsletter item). This decision has been made amid considerable controversy; critics say that using race or ethnicity as a marker for genetic differences is crude and inaccurate, and fear that approval of BiDil lends weight to notions of race as a distinct biological marker. Others, such as the Association of Black Cardiologists, who sponsored the Nitromed trials, welcomed the decision.
FDA Associate Director of Medical Policy Dr Robert Temple said the drug was "a striking example of how a treatment can benefit some patients even if it does not help all patients”, adding that they hoped in the future “to discover characteristics that identify people of any race who might be helped by Bidil" (see FDA press release). However, some fear that marketing of a race-specific drugs is likely to be driven by financial motives irrespective of the validity of using ethnicity as a marker for genetic variation between individuals; BiDil is a combination of two pre-existing drugs, isosorbide dinitrate硝酸异山梨酯 and hydralazine肼屈嗪, for which the patent covering general use will expire in 2007; patent protection for the use of BiDil in black patients will extend until 2020

GENOMIC ANALYSIS

While BiDil® (isosorbide dinitrate/hydralazine hydrochloride) provides an effective treatment that has been shown in the African American Heart Failure Trial (A-HeFT) to save lives and improve the symptoms of self-identified black patients with heart failure, NitroMed regards this study as a first step in refining the understanding of why these patients may respond differently to BiDil than non-blacks.
Ongoing analysis of the genetic data from A-HeFT may help researchers identify other patient populations in whom BiDil can be studied, potentially leading to a new generation of personalized medicine.
NitroMed has presented preliminary results from ongoing analyses of data collected during A-HeFT that may determine whether specific variations of genes important in cardiovascular diseases can act as genetic markers for heart failure patients who best respond to treatment with BiDil.
NitroMed collected data from 358 patients who participated in A-HeFT in order to conduct the Genetic Risk Assessment in Heart Failure Trial (GRAHF), a prospectively defined genetic analysis of these A-HeFT patients developed to help identify specific, shared biomarkers within patient cohorts to delineate additional subsets where BiDil may also be effective.
In the GRAHF study, the frequency of genotypes important for cardiovascular diseases were determined amongst self-identified black patients who participated in both GRAHF and A-HeFT, and compared with the frequency of those same genotypes amongst white heart failure subjects who participated in the Genetic Risk Assessment of Cardiac Events (GRACE) study at the University of Pittsburgh.
To date, preliminary results from the GRAHF study on three gene variations (endothelial nitric oxide synthase, aldosterone synthase, and beta-1 adrenergic receptor) have been presented, offering the first preliminary data on genetic factors that may affect BiDil response.
Endothelial nitric oxide synthase (NOS3) gene researchers found that a majority of black patients in A-HeFT possess a specific gene variation that was observed in less than half of the white cohort from GRACE. NOS3, which encodes the nitric oxide synthesizing enzyme in the heart and vasculature, is important in hypertension and heart failure. 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.
Aldosterone synthase gene researchers examined a common genetic variation existing in the region of the gene at position -344 (C/T). Abnormally high levels of aldosterone, a hormone important in the control of salt and water balance in the body, can cause sodium retention and high blood pressure. Researchers discovered a racial difference in the frequency of -344 C/T variations. It was found in GRAHF that 62 percent of black patients with heart failure possessed the genotype TT, while 38 percent were either TC or CC. Comparatively, 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, which has been linked to increased aldosterone production, were found to have the greatest event-free survival (risk for death or hospitalization for heart failure). A-HeFT patients, participating GRAHF, with the TT variation were found to have the lowest risk for death or hospitalization for heart failure. In addition, BiDil-treated patients with the TT variation had statistically better primary composite scores compared to patients who received placebo, driven primarily by improvement in functional status. Composite scores include all-cause mortality, first heart failure hospitalization and changes in functional status at six months.
An additional analysis in GRAHF examined variations in the beta-1 adrenergic receptor represented by Gly389Arg polymorphism. The beta-1 adrenergic receptor is involved in the regulation of cardiac rhythm and fluency. The Arg389 gene varation is associated with increased receptor activity and has previously been linked to greater beta-blocker impact. In GRAHF, 32 percent of black heart failure patients, and in GRACE, 49 percent of white heart failure patients, possessed an Arg389Arg variation. The Arg389Arg patients treated with BiDil in A-HeFT experienced significantly better primary composite scores compared to Arg389Arg patients treated with placebo and standard therapy (composite score of 0.40 for BiDil vs. -0.25 for placebo, p=0.047).

BiDil®

In July 2005, NitroMed introduced a prescription medicine named BiDil® (isosorbide dinitrate and hydralazine hydrochloride) to the market. During previous years, BiDil underwent a carefully controlled clinical study referred to as A-HeFT (The African American Heart Failure Trial). A-HeFT demonstrated the drug's effectiveness in improving symptoms in African American patients, when taken as an add-on to their standard heart failure medicines. BiDil was also shown to significantly improve survival and decrease time to first hospitalization for heart failure, compared to patients treated with standard therapy alone. Based on this clinical evidence, BiDil was approved by the U.S. Food and Drug Administration (FDA) in June 2005.
BiDil is indicated for the treatment of heart failure as an adjunct to standard therapy in self-identified black patients to improve survival, to prolong time to hospitalization for heart failure, and to improve patient –reported functional status. There is little experience in patients with NYHA class IV heart failure. Most patients in the clinical trial supporting effectiveness (A-HeFT) received a loop diuretic, an angiotensin converting enzyme inhibitor or an angiotensin II receptor blocker, and a beta blocker, and many also received a cardiac glycoside or an aldosterone antagonist.

What is BiDil?

BiDil is a fixed-dose combination of hydralazine hydrochloride and isosorbide dinitrate (ISDN). Hydralazine is an arterial vasodilator; it relaxes the arteries so the heart doesn’t have to work as hard to push blood through them. Isosorbide dinitrate is also a vasodilator, with effects on both the veins and the arteries. ISDN releases nitric oxide at the blood vessel wall, but its effect wears off rapidly 1. Hydralazine is thought to prevent the loss of ISDN’s effect 2, however the exact mechanism of how the two drugs work together is not fully understood.
1. Preik M, Kelm M, Feelisch M, Strauer BE. Impaired effectiveness of nitric oxide-donors in resistance arteries of patients with arterial hypertension. J Hypertens. 1996;14:903-8.
2. Munzel T, Kurz S, Rajagopalan S, et al. Hydralazine prevents nitroglycerin tolerance by inhibiting activation of a membrane-bound NADH oxidase. A new action for an old drug. J Clin Invest 1996;98:1465-70.

BiDil® PUBLICATIONS

Angus, D.C., Linde-Zwirble, W.C., Tam, S,W., Ghali, J.K, Sabolinski, M.L.,Villagra,V.G., Winkelmayer, W.C., Worcel, M. Cost-Effectiveness of Fixed-Dose Combination of Isosorbide Dinitrate and Hydralazine Therapy for Blacks with Heart Failure. Circulation 112: 3745-3753 (2005)

Taylor, A.L., Ziesche, S., Yancy, C., Carson, P., D’Agostino, R. Jr., , Ferdinand, K, Taylor, M., Adams, K., Sabolinski, M., Worcel, M., Cohn, J.N. and the A-HeFT Investigators. Combination of Isosorbide Dinitrate and Hydralazine in African Americans with Heart Failure. N. Engl. J. Med., 351: 2049-2057 (2004)
Taylor, A.L., Cohn, J.N., Worcel, M., Franciosa, J.A. A-HeFT Investigators, African-American Heart Failure Trial. The African-American Heart Failure Trial: background, rationale and significance. J Natl. Med. Assoc. 94: 762-769 (2002)