FREMONT, Calif., June 13 /PRNewswire/ -- An expert panel of cardiology and
heart failure clinicians chaired by Eugene Braunwald, M.D. met on Wednesday,
June 8th to review and assess important data associated with the acute heart
failure treatment NATRECOR(R) (nesiritide). The panel, which was convened by
Dr. Braunwald at the request of Scios, also provided guidance and counsel on
the ongoing and planned clinical development program for the product as well
as recommendations for use.
The panel's report (see following) consists of three main sections
summarizing the panel discussion: effects on renal function, mortality and
proposed clinical trials. In the area of clinical trials, the panel strongly
encouraged Scios and their clinical investigators to continue enrollment in
ongoing trials of NATRECOR(R). With respect to recent questions raised about
renal function and mortality, the panel endorsed the company's plan to conduct
several trials, including a large trial of clinical outcomes to further assess
the benefits and risks of NATRECOR(R).
In addition, the panel's report includes recommendations to the company
regarding the appropriate clinical use of NATRECOR(R) and the need for related
education for health care providers. The panel described patients for whom it
considers the drug to be appropriate and uses for which the drug should not be
prescribed. The panel also made specific recommendations regarding company
education of physicians about appropriate use.
"We accept the panel's recommendations and are pleased the panel endorsed
our current and planned development programs," said Darlene Horton, M.D.,
Senior Vice President of Clinical Research and Medical Affairs at Scios.
Scios noted that the panel recommended a use for NATRECOR(R) that is
slightly narrower than what is outlined in its approved label. The company is
contacting regulatory agencies to discuss how to best address this
recommendation.
"The panel also described uses for which it believes NATRECOR(R) is
inappropriate," said Dr. Horton. "Scios fully agrees that these are areas for
which there are not sufficient data to support the use of NATRECOR(R). The
company will continue and build upon its efforts to educate physicians
regarding appropriate use."
"Scios appreciates the robust scientific discussion and the thoughtful
guidance provided by the panel. Acutely decompensated heart failure patients
suffer from a debilitating life-threatening condition, for which there are few
good treatment options. The company is committed to the continued study of
these patients to improve their health and well being," added Dr. Horton.
The panel's full report, including its specific recommendations as
outlined above, is attached. Scios has also posted the full report to
http://www.SCIOSINC.com and to http://www.NATRECOR.com.
IMPORTANT SAFETY INFORMATION
NATRECOR(R) (nesiritide) may cause hypotension. If hypotension occurs
during administration of NATRECOR(R), the dose should be reduced or
discontinued, and blood pressure should be monitored closely. At the
recommended dose of NATRECOR(R), 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. The mean duration of
symptomatic hypotension was longer with NATRECOR(R) than IV nitroglycerin (2.2
versus 0.7 hours, respectively).
NATRECOR(R) 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(R) may be associated with azotemia. Other adverse events reported at
a rate of at least 5% during the first 24 hours of infusion with either
NATRECOR(R) plus standard care or IV nitroglycerin plus standard care therapy,
included, respectively: ventricular tachycardia (3%, 5%), nonsustained
ventricular tachycardia (3%, 5%), headache (8%, 20%), abdominal pain (1%, 5%),
and nausea (4%, 6%).
Higher doses of NATRECOR(R) increased the risk of hypotension and elevated
creatinine. NATRECOR(R) should not be used in patients with systolic blood
pressure <90 mm Hg or as primary therapy in patients with cardiogenic shock.
NATRECOR(R) is not recommended for patients for whom vasodilating agents are
not appropriate and should be avoided in patients with low cardiac filling
pressures.
In seven NATRECOR(R) clinical trials, at 30 days, 5.3% in the NATRECOR(R)
treatment group died as compared with 4.3% in the group treated with other
standard medications. In four clinical trials, at 180 days, 21.7% in the
NATRECOR(R) 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(R).
BELOW IS THE PANEL'S REPORT
Nesiritide (Natrecor (R)) is the first member of a new drug class, human
B-type natriuretic peptide (hBNP) and is manufactured from E coli using
recombinant DNA technology. The approval of the drug was based on the
evaluation of 10 completed clinical trials involving 1456 patients with
congestive heart failure. These trials showed that the drug reduced dyspnea
and produced dose-dependent reductions in pulmonary capillary wedge pressure
and systolic arterial pressure when added to standard care. Since approval, 2
additional trials involving 447 patients have been completed.
Nesiritide was approved in 2001 "for the intravenous treatment of patients
with acutely decompensated congestive heart failure who have dyspnea at rest
or with minimal activity" and it has been widely used.
Two recent publications have raised questions about the safety of
nesiritide with respect to worsening renal function and death. The data on
which these analyses were based were available to and known by the FDA. Scios
expanded these analyses to include data from all available trials, and
convened this panel with the following objectives:
1) To review and discuss nesiritide efficacy and safety data;
2) To provide guidance on proposed clinical development strategies for
nesiritide; and
3) To review the current package insert and to provide recommendations on
the use of nesiritide.
The Nesiritide Advisory Panel met in Boston, MA on June 8, 2005. Prior to
the meeting, the panel members reviewed substantial material provided by
Scios, including the original (August 2001) and the current (April 2005)
package inserts, communications sent to physicians by Scios, the recent papers
by Sackner-Bernstein et al, as well as nesiritide publications, including a
submitted paper.
At the meeting, in depth presentations of substantial additional analyses
of existing data were made, plans for future trials were reviewed and
extensive discussions were held with Scios scientific staff. The panel also
held two closed-door executive sessions which were independent of the sponsor
and during which the recommendations were prepared. Our conclusions and
recommendations are based on the data supplied by Scios.
Eugene Braunwald, M.D. (Chairman)
Harvard Medical School
John C. Burnett, Jr., M.D.
Mayo Clinic College of Medicine
Wilson S. Colucci, M.D.
Boston University School of Medicine
Barry M. Massie, M.D.
University of California, San Francisco, School of Medicine
John J.V. McMurray, M.D.
University of Glasgow
Christopher M. O'Connor, M.D.
Duke University Medical Center
Milton Packer, M.D.
University of Texas Southwestern Medical School
Ileana Pina, M.D., FACC
Case-Western Reserve University
Bertram Pitt, M.D.
University of Michigan Health System
James Young, M.D.
Cleveland Clinic Lerner College of Medicine
RENAL DYSFUNCTION
The panel noted that the use of nesiritide was associated with a dose-
dependent increase in serum creatinine indicating renal dysfunction at doses
described in the package insert (0.01 to 0.03 ug/kg/min), including the dose
recommended for initiation of treatment (0.01 ug/kg/min). In the largest
trial that led to the approval of the drug (VMAC), which used a dose of 0.01
ug/kg/min, the serum creatinine rose by more than 0.5 mg/dL above baseline in
at least one blood draw in 7% of patients in the control groups and 8% in the
nesiritide groups by 5 days, and by 21% and 28% respectively, by 30 days.
Most of these increases occurred days after discontinuation of the drug.
The mechanism of these creatinine changes, their duration, implications
for survival, longer term renal function and other clinical consequences is
not clear. There is no evidence, however, that nesiritide results in
improvement in renal function.
Studies to clarify the mechanism and reversibility of the observed changes
in creatinine should be undertaken. These should examine renal function in a
more systematic and comprehensive way and relate changes in renal function to
clinical outcomes. Additional analyses of existing data to identify the
characteristics of patients who experience creatinine elevation should be
conducted.
MORTALITY
The panel noted that completed trials show that the use of nesiritide was
associated with a trend toward an increase in mortality rate at 30 days, with
a hazard ratio of approximately 1.3, a 30% increase. However, the confidence
intervals around this ratio are wide and the number of deaths in a pooled
analysis of all six of the controlled clinical trials (84) is insufficient to
identify or exclude, with confidence, a moderate excess of risk to survival.
Also, there are potentially important imbalances in baseline characteristics
and in other treatments received concomitantly, and the trials differ with
respect to the treatments with which nesiritide was compared. No increased
hazard is observed at 180 days. Because of the small numbers of events in
the current database and the inconclusive nature of these findings, the panel
recommends that additional studies be conducted to assess the effect of
nesiritide on survival.
CLINICAL TRIALS
1) The panel strongly recommends continued enrollment in ongoing trials of
nesiritide, as well as enrollment in trials that are soon to commence.
The panel notes that these trials have been or will be reviewed by
regulatory agencies and that the safety of patients in all of these
trials is carefully monitored by appropriately constituted and
independent Data Safety and Monitoring Committees.
2) The panel endorses Scios' plan to conduct, in a timely manner, a large
(several thousand subjects) trial of clinical outcomes to assess
further the benefits and risks of nesiritide compared to standard
therapy. This trial should be initiated without delay.
The panel recommends that this trial should include patients presenting
to a hospital with acute decompensated heart failure and severe
dyspnea. It should be adequately powered to detect an approximately
15% reduction in the combined risk of mortality and cardiorenal
morbidities at an early time point, e.g. 30-90 days, and mortality at a
later time point, e.g. 180 days. The study design should consider
stratification by important co-variates including the use of inotropic
agents and other previously identified markers of high risk for adverse
outcomes. It should evaluate effects of nesiritide on renal function
e.g. Cystatin C. A pharmaco-economic analysis should be included. The
trial should also evaluate symptomatic changes and ventricular
remodeling in nested substudies. Strong efforts should be made to
harmonize this trial with other global trials so that the results can
be pooled.
3) Additional mechanistic studies, including an examination of the effect
of doses lower than those approved should be considered. Further
exploration of the data from the completed trials should be carried out
to examine the effects of nesiritide in subgroups of patients.
FINAL RECOMMENDATIONS
1) The use of nesiritide should be strictly limited to patients presenting
to the hospital with acutely decompensated congestive heart failure who
have dyspnea at rest, as were the patients in the largest trial that
led to approval of the drug (VMAC). Physicians considering the use of
nesiritide should consider its efficacy in reducing dyspnea, the
possible risks of the drug summarized above, and the availability of
alternate therapies to relieve the symptoms of congestive heart
failure.
2) Nesiritide should not be used to replace diuretics. Furthermore,
because sufficient evidence is not currently available to demonstrate
benefit for the applications listed below, nesiritide should not be
used:
* for intermittent outpatient infusion
* for scheduled repetitive use
* to improve renal function
* to enhance diuresis.
3) Scios should immediately undertake a pro-active educational program to
inform physicians regarding the conditions and circumstances in which
nesiritide should and should not be used, as described above. Sponsor
supported communications, including review articles of nesiritide,
should reflect the above recommendations. Scios should ensure that
current and future marketing and sales activities related to nesiritide
are consistent with this educational program.
SOURCE Scios, Inc.
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Related links:
http://www.sciosinc.com
CONTACT:
Chris B. Ernst of Scios Inc., +1-510-248-2819
- office, or +1-415-710-9445 - cell; or Mark T. Wolfe of Johnson
& Johnson, +1-908-927-2745 - office, or +1-908-672-4988 - cell
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