By Lisa Seachrist
BETHESDA, Md. - An FDA advisory panel Friday endorsed Scios Inc.'s Natrecor (nesiritide) as an intravenous treatment for acute decompensated congestive heart failure (CHF).
Calling it an extremely close call, the Cardiovascular and Renal Drugs Advisory Committee voted 5 to 3 to recommend approval of the new drug application (NDA) for the Mountain View, Calif.-based company's first drug candidate considered by the FDA. Natrecor is the first intravenous therapy for acute CHF that the panel has considered in over a decade.
"I think the committee did a superb job in thoroughly discussing this NDA; everybody benefits from such a discussion," said Richard Brewer, president and CEO of Scios. "Needless to say, we were very happy for the recommendation of the panel and we look forward to working with the FDA."
CHF is a potentially life-threatening disorder that has no cure. It is a chronic pathophysiological condition that results from an inefficiently pumping heart. This causes a reduction in circulation to the body's organs, which results in fluid accumulation in the lungs, hands and feet. The American Heart Association estimates CHF-related costs at $20 billion annually, with more than half of that incurred for hospitalizations related to acute episodes.
Panel Had Concerns About Patient Group
Natrecor is a hormone-based therapy for CHF. First cloned by Scios researchers in 1989, Natrecor's active ingredient is a genetically engineered version of the human b-type natriuretic peptide (BNP), a 32-amino-acid, naturally occurring peptide hormone produced predominantly in the ventricles of the heart. The body secretes BNP, which boosts both sodium and fluid excretion while dilating blood vessels, to combat fluid overload states such as CHF.
Natrecor is considered a "balanced" vasodilator, because it reduces pressure in both veins leading to the heart (known as cardiac preload) and in arteries leading away from the heart (or cardiac afterload.) In addition, the drug doesn't raise heart rate.
The company conducted seven double-blind, placebo-controlled, randomized clinical trials and one trial that pitted two doses of Natrecor against standard therapies for acute CHF. In total, the clinical trials included 721 patients, 505 of whom received Natrecor. The primary endpoint for those studies was reduction of pulmonary capillary wedge pressure (PWPC), a measure of the blood pressure in the heart that, when elevated, results in fluid accumulation in the lungs.
The secondary endpoint was an increased cardiac index (CI), a measure of how much blood the heart is putting into circulation. In addition, the company assessed how well Natrecor alleviated the symptoms of CHF, including dyspnea (difficulty breathing), fatigue, lightheadedness and decreased appetite.
The company tested several dosages, but determined that the 0.015 microgram per kilogram of body weight per minute infusion was the dose that provided the most benefit. The Scios data showed that Natrecor significantly reduced the PWPC of treated patients within an hour, and provided symptom improvement within six hours.
Natrecor produces clinically significant hypotension in some patients. In addition, some patients experienced nausea, bradycardia (slow heartbeat), nervousness, sweating and confusion. Some patients experienced increases in creatine levels, which is an indication of renal problems. However, Natrecor patients were no more likely to die than those treated with standard therapies or receiving placebo.
"Acute CHF is a major public health concern that results in a million hospitalizations annually," said William Abraham, professor at the University of Cincinnati College of Medicine, and an investigator in Natrecor trials. "There is a need for alternative therapies. Natrecor is a balanced vasodilator that improves [heart function measures] as well as symptoms."
The panel, however, had concerns about the patient group that Scios decided to study. The clinical trials prohibited using the drug in patients suffering from an acute myocardial infarction (MI), a sector which represents a significant number of patients likely to suffer from acute CHF.
"There is no representation of patients with acute MI," said panel member and primary reviewer Marvin Konstam, professor of medicine at the New England Medical Center, in Boston. "I think that means we would have to recommend that the label specify there is no information for acute MI. And I think it says what we would like to see the sponsor do in the post-market."
Adverse-Events Worry Cited
However, Milton Packer, panel chair and chief of the division of circulatory physiology at the Columbia University College of Physicians and Surgeons, in New York, had concerns about such an approach.
"Undoubtedly, we will recommend that the agency place such wording on the label," Packer said. "Undoubtedly, the agency will say not to use the drug in the those patients; and, undoubtedly, it won't make a difference - it will be used."
Faced with a recommendation vote, Konstam decided Natrecor didn't meet the standards for approval. Konstam pointed to the bradycardia and renal side effects.
"The standard for approval is safety and efficacy," Konstam said. "I'm confident about the drug's efficacy. There are concerns about the safety. I don't understand some of the adverse events, and I vote no."
Packer cast the final "yes" vote, noting, "I share Marv's concerns, but I'd like to view this drug on its own merits and I think it has a role to play."
Bayer AG, of Leverkusen, Germany, and Scios are worldwide development and marketing partners for Natrecor, whose stock (NASDAQ:SCIO) suspended trading during the panel meeting and ended Friday at $9.875, unchanged. n