Tuesday, May 29, 2001
BETHESDA, Md. - Scios Inc. made good on its second trip through the FDA's Cardiovascular and Renal Drugs Advisory Committee on Friday, rectifying the panel's former ambivalence about the effectiveness of Natrecor nesiritide and turning its attention to how the product would fit into clinical practice in terms of dose and management of side effects in the treatment of acute congestive heart failure (CHF).
In 1999, the committee cleared the compound by a 5-3 vote in what chairman Milton Packer said was "an extremely close call" (see BioCentury, Feb. 1, 1999). The FDA then issued a non-approvable letter, citing concerns raised by the panel about Natrecor's slow onset of action, potential to cause hypotension and lack of comparative safety data against existing treatments, such as nitroglycerin.
CHF is a heart condition that results in poor pumping function and lower flow of blood throughout the body. Natrecor is a recombinant form of b-type natriuretic peptide (BNP), a hormone that naturally increases in the ventricle in response to heart failure. It acts to rid the body of salt and water, dilates blood vessels, decreases other hormones that raise blood pressure and acts as a vasodilator to reduce blood pressure in veins and arteries.
"Some of you may wonder why Natrecor is back at this committee, when we already voted for it to be approved," said Packer, who is chief of the division of circulatory physiology at Columbia University in New York. "The purpose is to see whether the new data on Natrecor address the concerns of the previous committee." This time, the vote was unanimous (10-0) in favor of Natrecor's approval.
The new data came from two studies: VMAC and PRECEDENT (see BioCentury Extra, Thursday May 24). The PRECEDENT trial, which was ongoing at the time of the non-approvable letter, compared Natrecor to dobutamine in patients with symptomatic decompensated CHF.
The vast majority of emphasis and discussion on Friday centered on VMAC, which was specifically designed to address the concerns in the non-approvable letter (see BioCentury, Nov. 20, 2000).
VMAC produced statistically significant results in favor of Natrecor versus placebo on both of the two required end points: pulmonary capillary wedge pressure (PCWP), which when elevated can cause fluid to flow into the lungs, and dyspnea (difficulty breathing) at three hours. The trial also included an active control arm, nitroglycerin, and enrolled patients receiving standard care.
Looking for problems
Although VMAC met its end points, panel members expressed concern about potential areas of bias in the trial and the meaning of the dyspnea results.