Natrecor (nesiritide)

Natrecor has been approved by the FDA for the intravenous treatment of subjects with acutely decompensated congestive heart failure (CHF) who have shortness of breath at rest or with minimal activity.

Natrecor is a recombinant form of human B-type natriuretic peptide (hBNP), a naturally occurring hormone secreted by the ventricles. It is the first of this drug class to be made available as a therapeutic for human disease in the United States. Scios anticipates launching the drug in US hospitals by the end of August.

Congestive heart failure is caused by a reduction in the heart's pumping strength, producing a reduced outflow of blood from the left side of the heart. During acutely decompensated CHF, the heart's already compromised ability to circulate blood throughout the body worsens, causing symptoms to become severe enough to require hospital treatment to stabilize the subject's condition. Events that can precipitate acutely decompensated CHF include a sudden increase in dietary sodium and failure to take chronic oral medications.

Natrecor has been evaluated in 10 trials that included 941 subjects with congestive heart failure.

The randomized, double-blind VMAC (Vasodilation in the Management of Acute Congestive Heart Failure) trial included 489 subjects who required hospitalization for management of shortness of breath at rest due to acutely decompensated CHF. The trial compared the effects of Natrecor, placebo and intravenous nitroglycerin when added to background therapy. Among other measures, the trial was designed to evaluate the change from baseline in pulmonary capillary wedge pressure (PCWP) and the change from baseline in subjects' dyspnea (abnormal breathing), evaluated after three hours.

Results demonstrated that subjects receiving Natrecor reported greater improvement in their dyspnea at three hours than subjects receiving placebo. Additionally, there was a greater reduction in mean PCWP for the Natrecor-treated group compared to placebo- and nitroglycerin-treated subjects.

In a second double-blind trial, 127 subjects requiring hospitalization for symptomatic CHF were randomized to receive placebo or one of two doses of Natrecor. Results demonstrated that subjects receiving both doses of Natrecor reported greater improvement in dyspnea at six hours compared to subjects receiving placebo.

Adverse events that occurred during the first 24 hours of Natrecor infusion in clinical trials include (but are not limited to) the following:

• Hypotension
• Ventricular tachycardia (abnormally fast heart rate)
• Angina pectoris (chest pain)
• Bradycardia (abnormally slow heart rate)
• Headache
• Abdominal pain
• Back pain
• Insomnia
• Dizziness
• Anxiety
• Nausea
• Vomiting

Human BNP binds to the particulate guanylate cyclase receptor of vascular smooth muscle and endothelial cells, leading to increased intracellular concentrations of guanosine 3'5'-cyclic monophosphate (cGMP) and smooth muscle cell relaxation. Cyclic GMP serves as a second messenger to dilate veins and arteries. Nesiritide has been shown to relax isolated human arterial and venous tissue preparations that were precontracted with either endothelin-1 or the alpha-adrenergic agonist, phenylephrine.

In human studies, nesiritide produced dose-dependent reductions in pulmonary capillary wedge pressure (PCWP) and systemic arterial pressure in subjects with heart failure.

In animals, nesiritide had no effects on cardiac contractility or on measures of cardiac electrophysiology such as atrial and ventricular effective refractory times or atrioventricular node conduction.

Naturally occurring atrial natriuretic peptide (ANP), a related peptide, increases vascular permeability in animals and humans and may reduce intravascular volume. The effect of nesiritide on vascular permeability has not been studied. (from Natrecor Prescribing Information)

For additional information on Natrecor, please visit the Scios web site.