The approval of NitroMed's BiDil for treatment of heart failure in self-identified blacks is a step in the direction of drugs based on patient characteristics.

The BiDil approval represents "a step toward the promise of personalized medicine," FDA said in a June 23 "Talk Paper" on the approval.

BiDil's approval "is a striking example of how a treatment can benefit some patients even if it does not help all patients," Office of Medical Policy Director Robert Temple said in the Talk Paper.

"In the future we hope to discover characteristics that identify people of any race who might be helped by BiDil," Temple added.

At its review of BiDil on June 16, FDA's Cardiovascular & Renal Drugs Advisory Committee said that the African-American population served as a surrogate for genomics (¹ [A#00670250001] p. 3).

BiDil, a combination of two older products, isosorbide dinitrate 20 mg and hydralazine 37.5 mg, is an unlikely breakthrough therapy. NitroMed decided to study the product for African-Americans when it failed to show a benefit for whites in two heart failure studies, V-HeFT I & II, but did show efficacy in black patients.

BiDil was approved 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," labeling states. The dual vasodilator had been "approvable" since March 2001.

The African-American indication gives BiDil patent protection until 2020 compared to patent expiration in 2007 if the company had gotten a broader indication.

Approval for BiDil was based on the African-American Heart Failure Trial (A-HeFT) in 1,050 self-identified African-American patients. The trial was halted early, in July 2004, due to the significant survival benefit seen with the drug.

² BiDil labeling notes a 43% reduction in all-cause mortality and a 39% reduction in the risk of first hospitalization for heart failure for the drug compared to placebo. Patients also had a statistically significant improvement in functional status.

The clinical trial primary endpoint, a composite score consisting of all-cause mortality, first hospitalization for heart failure, and quality of life improvement, "was also statistically in favor of BiDil," labeling states.

Labeling does not reflect the advisory committee's concerns about the statistical power of the A-HeFT study or questions about the statistical significance of the results.

The Indications section of labeling makes clear that Bidil should be used on top of other standard cardiovascular therapy.

Most trial patients "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," labeling states.

Labeling also states in several places that the mechanism of action and the basis for the beneficial clinical effects of BiDil are not known, reflecting FDA's discomfort with a lack of information on the contributing effects of the individual components of the product (see ³ Also see "BiDil Survival Benefit Precludes Need For Component Efficacy Evaluation" - Pink Sheet, 27 June, 2005.).

"Whether both hydralazine and isosorbide dinitrate contribute to the overall outcome difference has not been studied in outcome trials. Isosorbide dinitrate and hydralazine have not been systematically studied for the treatment of heart failure as separate agents, and neither drug is indicated for heart failure."

The anti-anginal isosorbide "seems to work by releasing nitric oxide at the blood vessel wall, but its effect usually wears off after half a day. Hydralazine may prevent this loss of effect," FDA explained, "but how the two drugs work together is not fully known."

Isosorbide dinitrate and hydralazine could conceivably be prescribed by physicians since both are available generically. Isosorbide is marketed in 20 mg tablets; hydralazine is available in 10 mg, 25 mg, 50 mg and 100 mg tablets.

Labeling carries a warning about an increase in vasodilatory effects of isosorbide dinitrate by phosphodiesterase inhibitors that could result in severe hypotension; they include the erectile dysfunction drugs Viagra (sildenafil, also for pulmonary arterial hypertension as Revatio ), Levitra (vardenafil) and Cialis (tadalafil).

BiDil Approval In Blacks Is Step Toward Personalized Medicine, FDA Says

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