Investigators Report New Renal, Mortality And Safety Data; Johnson & Johnson Says Natrecor Meets Goals In Midstage Trial
"Patients with heart failure who require CABG surgery are critically ill and have limited treatment options, as do patients with ADHF, for whom nesiritide is approved for treatment," said John M. Luber, Jr., M.D., one of the NAPA trial primary investigators and cardiothoracic surgeon at the Franciscan Health System Research Center in Tacoma, Wash. "The NAPA trial findings are encouraging because they provide important information about the safety of nesiritide and also suggest the possibility that the drug improves the outcome of these very sick patients."
The prospective, multicenter, double-blind, exploratory NAPA trial included 279 randomized and treated heart failure patients from 54 centers undergoing cardiac surgery with or without mitral valve repair/replacement. Patients with reduced heart pumping function, who were scheduled for CABG surgery utilizing cardiopulmonary bypass, were randomized to an infusion of NATRECOR® or placebo, in addition to usual care, after induction of anesthesia. All patients received an infusion of study drug or placebo for 24 to 96 hours. Investigators evaluated the effect of perioperative administration of NATRECOR® on hemodynamics, renal function, 30-day mortality, hospitalization and adverse events, as well as on 180-day mortality, which was added during the study. Key findings included:
* Hemodynamic parameters: Mean pulmonary artery pressure decreased by -2.8 7.9 mm Hg in the NATRECOR® group versus by -1.9 7.8 mm Hg in the placebo group (p=0.297) 24 hours after surgery. There were no differences between the NATRECOR® and placebo groups in other hemodynamic parameters, including pulmonary capillary wedge pressure, mean arterial pressure, central venous pressure, cardiac index and systemic vascular resistance.
* Postoperative renal function: Urine output in the first 24 hours after surgery was significantly greater in patients treated with NATRECOR® than in those treated with placebo (2,926 mL vs. 2,350 mg/mL, respectively; p<0.001). In addition, significantly fewer patients treated with NATRECOR® had a serum creatinine increase >0.5 mg/dL (7 percent vs. 23 percent, respectively; p<0.001) by hospital discharge or study day 14, whichever came first.
* Mortality: 30-day mortality data were available for 132 patients in the NATRECOR® group and 127 in the placebo group; 180-day mortality data were available for 94 patients treated with NATRECOR® and 95 patients treated with placebo. NATRECOR® treatment was associated with a trend toward decreased mortality at 30 days compared with placebo (2.8 percent vs. 5.9 percent, based on Kaplan-Meier estimates, respectively;
p=0.219). A decrease in mortality at 180 days was observed in the NATRECOR® group compared with placebo (6.7 percent vs. 14.7 percent, based on Kaplan-Meier estimates, respectively; p=0.046).
* Hospitalization: Length of hospital stay was reduced in patients treated with NATRECOR® compared with placebo (9.1 days vs. 11.5 days, respectively; p=0.043).
* Adverse events: The overall frequency of adverse events was similar between NATRECOR® and placebo, with respiratory failure and atrial fibrillation lower in patients treated with NATRECOR®.
"We are encouraged by the mortality and safety results from the NAPA study and by the potential of nesiritide to benefit patients undergoing CABG surgery with cardiopulmonary bypass, and are assessing the design of a Phase 3 trial to further study this investigational use of nesiritide," said Roger Mills, M.D., Vice President, Medical Affairs at Scios. Scios will submit the final data to the FDA once the validation of the data is complete. "We have confidence in the safety profile of nesiritide and are also committed to continuing to further assess its clinical benefits in patients with ADHF, including important clinical outcomes through a robust clinical trials program."
As part of Scios' clinical development program for NATRECOR®, the company recently announced the selection of Duke Clinical Research Institute (DCRI) as the independent academic research organization that will lead the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) trial. This independent, global, multi-center outcomes study will further assess the benefit and safety profile of NATRECOR® in ADHF patients. Robert M. Califf, M.D., Director of DCRI, will serve as chair of the trial. DCRI, the clinical research organization within Duke University Medical Center, will collaborate with the Cleveland Clinic Cardiovascular Coordinating Center (C5) in managing the trial, and other leading medical centers around the world will participate. The randomized, double-blind, placebo-controlled trial will enroll approximately 7,000 patients with ADHF and will be conducted at approximately 600 sites globally. Patient enrollment for ASCEND-HF is expected to begin in the first half of 2007.
About NATRECOR® (nesiritide)
NATRECOR® added to standard therapy is the only approved treatment for ADHF that has shown improvement in difficulty breathing and reduction of elevated wedge pressures in the lungs in controlled clinical trials. NATRECOR® has been studied in 15 clinical trials involving 1,395 patients treated with the drug, and has been used to treat thousands of acutely decompensated heart failure patients.
NATRECOR® is indicated for the intravenous treatment of patients with ADHF who have dyspnea at rest or with minimal activity. In this population, the use of NATRECOR® reduced pulmonary capillary wedge pressure and improved patient reported dyspnea. For full Prescribing Information, visit www.natrecor.com. See Important Safety Information below.
About Scios Inc.
Scios Inc., a Johnson & Johnson company, is a biopharmaceutical company headquartered in Fremont, California. Scios is developing novel treatments for cardiovascular disease, inflammatory disease and cancer. The company's disease-based technology platform integrates expertise in protein biology with computational and medicinal chemistry to identify novel targets and rationally design small molecule compounds and peptides for markets with unmet medical needs. For more information, visit www.sciosinc.com .
IMPORTANT SAFETY INFORMATION
HYPOTENSION
NATRECOR® (nesiritide) may cause hypotension and should be administered only in settings where blood pressure can be monitored closely. If hypotension occurs during administration of NATRECOR® the dose should be reduced or discontinued. At the recommended dose of NATRECOR®, the incidence of symptomatic hypotension (4%) was similar to that of IV nitroglycerin (5%). Asymptomatic hypotension occurred in 8% of patients treated with either drug. In some cases, hypotension that occurs with NATRECOR® may be prolonged. The mean duration of symptomatic hypotension was longer with NATRECOR® than IV nitroglycerin (2.2 versus 0.7 hours, respectively). NATRECOR® should not be used in patients with systolic blood pressure <90 mm Hg or as primary therapy in patients with cardiogenic shock. The rate of symptomatic hypotension may be increased with a baseline blood pressure <100 mm Hg, and NATRECOR® should be used cautiously in these patients. In earlier trials, when NATRECOR® was initiated at doses higher than the 2 mcg/kg bolus followed by a 0.010 mcg/kg/min infusion, the frequency, duration, and intensity of hypotension was increased. The hypotensive episodes were also more often symptomatic and/or more likely to require medical intervention. NATRECOR® is not recommended for patients for whom vasodilating agents are not appropriate and should be avoided in patients with low cardiac filling pressures.
RENAL
NATRECOR® may affect renal function in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with NATRECOR® may be associated with azotemia. In the VMAC trial, through day 30, the incidence of elevations in creatinine to >0.5 mg/dL above baseline was 28% and 21% in the NATRECOR® and nitroglycerin groups, respectively. When NATRECOR® was initiated at doses higher than 0.010 mcg/kg/min, there was an increased rate of elevated serum creatinine over baseline compared with standard therapies, although the rate of acute renal failure and need for dialysis was not increased.
MORTALITY
In seven NATRECOR® clinical trials, through 30 days, 5.3% in the NATRECOR® treatment group died as compared with 4.3% in the group treated with other standard medications. In four clinical trials, through 180 days, 21.7% in the NATRECOR® treatment group died as compared with 21.5% in the group treated with other medications. There is not enough information to know if there is an increased risk of death after treatment with NATRECOR®.
See full Prescribing Information at www.natrecor.com.
This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could vary materially from Johnson & Johnson's expectations and projections. Risks and uncertainties include general industry conditions and competition; economic conditions, such as interest rate and currency exchange rate fluctuations; technological advances and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approvals; domestic and foreign health care reforms and governmental laws and regulations; and trends toward health care cost containment. A further list and description of these risks, uncertainties and other factors can be found in Exhibit 99 of Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended January 1, 2006. Copies of this Form 10-K, as well as subsequent filings, are available online at www.sec.gov or on request from the Johnson & Johnson. Johnson & Johnson assumes no obligation to update any forward- looking statements as a result of new information or future events or developments.
Source: Scios Inc.