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Researchers Seek to Determine Whether Genetic Variations May Affect Patients' Response to New Heart Failure Therapy; Data Presented at Heart Failure Society of America Annual Meeting

Posted on: Wednesday, 21 September 2005, 09:00 CDT

NitroMed, Inc. (NASDAQ:NTMD) said today that preliminary results from an ongoing analysis of data collected during the African American Heart Failure Trial (A-HeFT), presented at the annual meeting of the Heart Failure Society of America, may determine that genetic variations influencing cellular levels of nitric oxide (NO) production affect a patient's clinical response to BiDil(R) (isosorbide dinitrate/hydralazine hydrochloride). BiDil was recently approved by the U.S. Food and Drug Administration (FDA) as an adjunct to current standard heart failure therapy in self-identified black patients.

The Genetic Risk Assessment in Heart Failure Trial (GRAHF), a prospectively defined genetic analysis of A-HeFT patients, was developed to help identify specific, shared biomarkers within patient cohorts to delineate additional subsets where BiDil may also be effective. In GRAHF, researchers are examining the genetic variation of a number of genes important for cardiovascular diseases, collected from 358 A-HeFT patients to determine a potential correlation between specific genetic biomarkers and the positive A-HeFT results. African American patients were compared with white heart failure subjects from the Genetic Risk Assessment of Cardiac Events (GRACE) study at the University of Pittsburgh.

"The information gathered from GRAHF, as well as other studies of biomarkers, may assist physicians in determining the best course of treatment for their heart failure patients," 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. "BiDil may benefit other patients, and these patients will be identified by a better understanding of the underlying genetic factors associated with heart failure." Dr. McNamara is performing this genetic analysis of the endothelial nitric oxide synthase (NOS3) gene, which encodes the nitric oxide synthesizing enzyme in the heart and vasculature, and is important in hypertension and heart failure.

Preliminary results from GRAHF indicate that a marked difference exists in the make up of the NOS3 gene in self-identified black patients versus white patients. Researchers found that a majority of black patients possess a specific gene variation that was observed in less than half of the white cohort from GRACE. In the subset of black patients, the benefit of BiDil therapy on the primary composite score from A-HeFT - combining mortality, heart failure hospitalization and patient functional status - was primarily seen in those possessing the specific gene variation observed in GRAHF. Investigators hope the identification of specific genetic variants may help identify other heart failure patients who may receive a greater benefit from BiDil. More comprehensive results from GRAHF are expected to be available in 2006.

"A-HeFT data have not only provided us with a new drug capable of saving and enhancing the lives of self-identified black patients with heart failure, but this study may also help us better understand how blacks with this disease may respond to BiDil," said Manuel Worcel, M.D., chief medical officer for NitroMed. "Although BiDil is currently only approved for use by self-identified black patients, in the future, this ongoing analysis of the genetic data from A-HeFT may help researchers identify other patient populations in whom BiDil can be studied."

According to the Centers for Disease Control and Prevention (CDC), African Americans between the ages of 45 and 64 are 2.5 more likely to die from heart failure than their Caucasians counterparts. The A-HeFT trial was conducted in an all African American heart failure patient population, enrolling 1,050 patients at 169 sites. The study found that black patients taking

BiDil as an adjunct therapy experienced a 43 percent decrease in the risk of mortality, a 39 percent reduction in the risk of first hospitalizations for heart failure and an overall improvement in patient-reported functional status, when compared to patients taking standard heart failure therapy plus placebo.

About BiDil

BiDil is indicated for the treatment of heart failure as an adjunct to current 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 exact mechanism of action underlying the beneficial effects of BiDil in the treatment of heart failure is unknown, 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.

In A-HeFT, self-identified black patients taking BiDil in addition to current standard heart failure therapies experienced a significant 43 percent decrease in the risk of mortality (P=.012) (absolute mortality rate: BiDil, 6.2% vs. placebo, 10.2%), a 39 percent reduction in the risk of first hospitalization for heart failure (P less than .001) (absolute first hospitalization rate: BiDil, 16.4% vs. placebo, 24.4%) 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 in addition to current standard therapies.

BiDil treatment is orally-administered and is initiated at a dose of one tablet, three times per day, and may be increased to a maximum of two tablets, three times per day, based on patient tolerance. Adjustments to maximum dosage may occur in three to five days; however, adverse side effects, which may include headaches and dizziness, may require that some patients take more time to reach their highest tolerated dose.

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, 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(R)/Revatio(TM), Levitra(R), Cialis(R) ) 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. 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%) and dizziness (32%) 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(R) (isosorbide dinitrate/hydralazine hydrochloride), an orally administered medicine that may be prescribed 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 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.

Forward Looking Statements

Statements in this press release about future expectations, plans and prospects for the Company, including statements regarding the Company's expectations about the potential benefits of BiDil in other patient populations , 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: unanticipated difficulties in maintaining regulatory approvals to market and sell BiDil; the Company's ability to develop and maintain the necessary sales, marketing and manufacturing capabilities to launch and commercialize BiDil; patient, physician and third-payer acceptance of BiDil as a safe and effective therapeutic; adverse side effects experienced by patients taking BiDil; the Company's ability to obtain or maintain intellectual property protection and required licenses; the Company's ability to obtain the substantial additional funding required to conduct manufacturing, marketing and sales of BiDil and other factors discussed in its Quarterly Report on Form 10-Q for the Quarter ended June 30, 2005, which is 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.

For full prescribing information, visit: www.BiDil.com.

BiDil is a registered trademark of NitroMed, Inc.

Source: Business Wire

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