Healthcare Industry News:  Bayer HealthCare 

Biopharmaceuticals Cardiology

 News Release - March 13, 2006

Researchers Identify Gene Variations That May Determine Which Heart Failure Patients Are Likely to Benefit from Treatment With BiDil(R)

ATLANTA--(HSMN NewsFeed)--March 13, 2006--Today, NitroMed, Inc. (NASDAQ:NTMD ) announced preliminary results from ongoing analyses of data collected during the African American Heart Failure Trial (A-HeFT), the clinical trial supporting effectiveness of BiDil® (isosorbide dinitrate/hydralazine hydrochloride), that may determine whether specific variations of genes important in cardiovascular diseases can act as genetic markers for heart failure patients who might best respond to treatment with BiDil. The Genetic Risk Assessment in Heart Failure (GRAHF) study was prospectively defined to identify these variations. 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. Results from the GRAHF study on two gene variations in aldosterone synthase and beta-1 adrenergic receptor were presented in Atlanta at the 55th Annual Scientific Session of the American College of Cardiology.

"In GRAHF, we are examining the variation of a number of genes important for cardiovascular diseases, collected from A-HeFT participants to determine a potential correlation between specific biomarkers and the positive A-HeFT results," said Dennis M. McNamara, M.D., director of the Heart Failure/Transplantation Program and associate professor of medicine, University of Pittsburgh Medical Center, Pittsburgh, Penn. "We hope information gathered from GRAHF, as well as other studies of biomarkers, will identify specific genetic variants that will help physicians to determine the best course of treatment for each individual heart failure patient, irrespective of race."

In a recent analysis of the GRAHF study, investigators examined a common genetic variation existing in the region of the aldosterone synthase 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. Patients in A-HeFT with the -344 C allele, which has been linked to increased aldosterone production, were found to have the greatest risk for death or hospitalization for heart failure (event-free survival). A-HeFT patients 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.

A second analysis from 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 allele 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. In A-HeFT, self-identified black patients with the Arg389Arg variation who received standard heart failure therapies (including beta-blockers) were shown to have a greater risk for death or heart failure hospitalization, while the Arg389Arg patients treated with BiDil in addition to their standard therapy 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).

"While BiDil provides an effective treatment that has been shown to save lives and improve the symptoms of self-identified black patients with heart failure, this study is the first step in understanding how these patients may respond differently to BiDil than non-blacks," said Michael L. Sabolinski, M.D., Chief Medical Officer, NitroMed. "Ongoing analysis of the genetic data from A-HeFT may help researchers identify other patient populations in whom BiDil can be studied, potentially leading us to a new generation of personalized medicine."

About BiDil

BiDil was approved in June 2005 by the U.S. Food and Drug Administration and is indicated for the treatment of heart failure as an adjunct to standard therapy in self-identified black patients, to improve survival, prolong time to hospitalization for heart failure and improve patient-reported functional status. There is little experience in patients with New York Heart Association (NYHA) class IV heart failure. Most patients in the clinical trial supporting effectiveness, referred to as A-HeFT, received, in addition to BiDil or placebo, 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.

BiDil is a fixed-dose combination of isosorbide dinitrate and hydralazine hydrochloride. While the mechanism of action underlying the beneficial effects of BiDil in the treatment of heart failure has not been established it is known that isosorbide dinitrate is a vasodilator with effects on both arteries and veins. The dilator properties of nitrates result from the release of nitric oxide that leads to the relaxation of vascular smooth muscle. Hydralazine is an arterial vasodilator. Animal data suggests that hydralazine may also mitigate tolerance to nitrates.

In A-HeFT, self-identified black patients taking BiDil in addition to current standard heart failure therapies (n=518) experienced a significant 43 percent decrease in the risk of mortality (P=.012) (absolute mortality rate: BiDil, 6.2 percent vs. placebo, 10.2 percent), a 39 percent reduction in the risk of first hospitalization for heart failure (P less than .001) (absolute first hospitalization rate: BiDil, 16.4 percent vs. placebo, 24.4 percent) and a statistically significant improvement at most time points in response to the Minnesota Living with Heart Failure Questionnaire, which is a self-report of the patient's functional status, versus patients taking placebo (n=532) in addition to current standard therapies.

Heart Failure Burden in Black Patients

Heart failure, or end-stage cardiovascular disease, affects approximately five million Americans, including an estimated 750,000 African Americans. Each year, over 550,000 people are diagnosed with heart failure for the first time, and there is no cure for this disease - with more than 50 percent of patients dying within five years of diagnosis. With respect to heart failure incidence, blacks are affected at a rate greater than that of the corresponding non-black population, presenting with the disease earlier and dying sooner. According to the Centers for Disease Control and Prevention (CDC), African Americans between the ages of 45 and 64 are 2.5 times more likely to die from heart failure than Caucasians in the same age range.

Important Safety Information

BiDil is contraindicated in patients who are allergic to organic nitrates. Augmentation of the vasodilatory effects of isosorbide dinitrate by phosphodiesterase inhibitors (e.g., Viagra®/Revatio(TM), Levitra®, Cialis®) could result in severe hypotension.

Treatment with hydralazine may produce a clinical picture simulating systemic lupus erythematosus (SLE) including glomerulonephritis. If SLE-like symptoms occur, discontinuation of BiDil should be considered. Residua have been detected many years after discontinuation of hydralazine. Symptomatic hypotension may occur with even small doses of BiDil. BiDil should be used with caution in volume depleted or hypotensive patients. Hydralazine can cause tachycardia potentially leading to myocardial ischemia and anginal attacks. Careful clinical and hemodynamic monitoring is recommended when BiDil is administered to patients with acute myocardial infarction to avoid hypotension and tachycardia. Isosorbide dinitrate therapy may aggravate angina associated with hypertrophic cardiomyopathy.

Hydralazine hydrochloride has been associated with peripheral neuritis, evidenced by paresthesia, numbness and tingling, which may be related to an antipyridoxine effect. Caution should be exercised if BiDil is used with MAO inhibitors, alcohol, sildenafil, vardenafil or tadalafil.

Headache (50 percent) and dizziness (32 percent) were the two most frequent adverse events and were more than twice as frequent in the BiDil group.

Viagra is a registered trademark and Revatio is a trademark of Pfizer, Inc.; Levitra is a registered trademark of Bayer HealthCare, GlaxoSmithKline, and Schering-Plough; Cialis is a registered trademark of Lilly ICOS LLC.

About NitroMed, Inc.

NitroMed of Lexington, Massachusetts is a research-based emerging pharmaceutical company and the maker of BiDil, an orally administered medicine available in the United States for the treatment of heart failure in self-identified black patients. In this population, BiDil is indicated as an adjunct to current standard therapies such as ACE inhibitors and/or beta blockers. BiDil was approved in June 2005 by the U.S. Food and Drug Administration, primarily on the basis of efficacy data from the Company's landmark A-HeFT (African American Heart Failure Trial) clinical trial, and since July 2005, has been marketed by NitroMed through a nationwide, dedicated contract sales force.

The Company is committed to the development of novel pharmaceuticals and safer, more effective versions of existing drugs to treat underserved patient populations. NitroMed's development efforts are primarily directed at expanding its cardiovascular franchise.

Forward Looking Statements

Statements in this press release about future expectations, plans and prospects for the Company, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including risks relating to: the Company's ability to successfully complete current studies, unanticipated outcomes of such studies, and the potential impact of data derived from these studies, if any; unanticipated difficulties in obtaining regulatory approval with regard to new clinical data; patient, physician and third-payer acceptance of BiDil as a safe and effective therapeutic; the Company's ability to obtain the substantial additional funding required to conduct manufacturing, marketing and sales of BiDil and to complete its current research activities; unanticipated difficulties in maintaining regulatory approvals to market and sell BiDil; adverse side effects experienced by patients; the Company's ability to obtain or maintain intellectual property protection and required licenses and other factors discussed in its Annual Report on Form 10-K for the year ended December 31, 2005, which has been filed with the SEC. In addition, the forward-looking statements included in this press release represent the Company's views as of the date of this release. The Company anticipates that subsequent events and developments will cause the Company's views to change. However, while the Company may elect to update these forward-looking statements at some point in the future, the Company specifically disclaims any obligation to do so. These forward-looking statements should not be relied upon as representing the Company's views as of any date subsequent to the date of this release.

Source: NitroMed

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