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).