By David N. Leff
In the next few days, five patients with congestive heart failure (CHF) will enter a controlled clinical trial testing a new drug for treating CHF. The recombinant peptide hormone, nesiritide, was cloned in 1989 by Scios Inc., now of Sunnyvale, Calif., which trade-named the experimental drug Natrecor.
"Those five enrollees," observed Scios' senior manager of industrial relations, Wendy Carhart, "will complete the roster of 480 patients at 62 medical centers across the U.S." The Phase III trial - called "Vasodilation in the management of acute congestive heart failure" (VMAC) - is designed to look into the issues that the FDA had after it did not approve Natrecor in 1999.
"We should have clinical data to announce in October or November, and will submit an amendment to our existing NDA [new drug application] by the end of the year. The FDA has a six-month review period for that amendment - which puts us into mid-2001." (See BioWorld Today, April 29, 1999, p. 1.)
The VMAC's full cohort brings the population participating in the first three clinical trials of Natrecor to 913 CHF patients at 131 centers. Of these, the initial two are reported in today's New England Journal of Medicine (NEJM) under the title: "Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure." Its two leading co-authors are Wilson Colluci and Michael Givertz, clinical cardiologists at Boston University Medical Center.
"Nesiritide, the drug used in these studies," Givertz told BioWorld Today, "is a synthetic recombinant peptide based on an endogenous hormone called brain natriuretic peptide (BNP). It's synthesized predominantly in the ventricles of the heart."
Molecular pharmacologist John Lewicki, vice president of research at Scios, explained: "We make Natrecor recombinantly in E. coli. It's absolutely identical to the native circulating molecule, nesiritide, which is a cardioprotective. When a person has heart failure, that organ increases its production of BNP to protect the heart from the stresses imposed on it by the CHF condition.
"So the heart is trying to compensate," Lewicki went on. "It markedly increases the expression of BNP - upwards of 100- to 1,000-fold. Our studies show that an additional boost to what the heart is already making, by providing additional exogenous hormone, can improve the patient's situation even more."
Syndrome, Not Disease, CHF Portends Fatal Ills
Givertz described that condition: "CHF is a syndrome rather than a specific disease per se. Its primary symptoms, dyspnea - shortness of breath - and progressive fatigue, as well as edema - swelling in legs or abdomen denoting fluid retention - are caused by reduced cardiac output and increased filling pressure. But CHF has many different causes," he continued. "It's a common final pathway for most known cardiovascular disease states, such as coronary artery disease, hypertension and valvular heart disease.
"If the patient has a heart attack," Givertz went on, "and the heart becomes further weakened or enlarged, ultimately he or she will develop this CHF clinical syndrome. Should a leaky or sticky heart valve go uncorrected surgically, or high blood pressure is untreated for years, the increased cardiac stress can lead to heart failure.
"There is a very high morbidity and mortality associated with heart failure," he observed, "worse than many cancers. So although we have treatment that slows the progression of disease, ultimately the majority of patients will die from their heart failure."
Some 5 million Americans suffer from heart failure, but half go undiagnosed because the body compensates for its symptoms. And approximately 2 million hospitalizations a year in the U.S. have a primary diagnosis of CHF. Virtually all of these patients will have at least one acute episode, with symptoms so severe that only intravenous medications administered in the hospital can improve their condition.
The two large-scale clinical trials reported in the NEJM pitted Natrecor against the gamut of traditional remedies in the existing armamentarium. The paper's lead author, Wilson Colucci, pointed out, "The use of dobutamine and milrinone can be limited by the dose-dependent adverse effects they have on heart rate and arrythmias. And patients taking nitroglycerine are susceptible to developing a tolerance of the drug."
Injectable Version Passes Clinical Test
Givertz made the point that "the biggest question the FDA had, and one of the reasons it did not approve Natrecor, was that there wasn't enough comparative data with nitroglycerine - a vasodilator agent that acts similarly to it. So the FDA wanted to know if it's going to approve another such drug, how does it compare to a common remedy long in use, such as nitroglycerine.
"Specifically," he continued, "one of the concerns that came up out of these studies is the incidence of hypotension that occurred in a dose-dependent fashion in both the efficacy and comparative trials. Of patients who received the higher doses of nesiritide, there was a small but significant percentage who had symptomatic hypotension - which occurs with nitroglycerine as well. But since it wasn't compared head-to-head with nitroglycerine in the study, the FDA wanted some better comparative data - and that's being tested right now in the current Phase III VMAC trial. It's basically a large comparative study of nesiritide vs. nitroglycerine."
Givertz made a final observation: "One of the interesting issues is the fact that because this is a recombinant peptide, it's currently available only in an intravenous form, because of the way the peptide is degraded. I know there have been some thoughts as to ways one could make this bioavailable in other formulations, either oral or subcutaneous, as opposed to a drug that has to be infused intravenously. It's my understanding that it hasn't been developed for chronic therapy, but for acute treatment of patients hospitalized for heart failure."
On this score, Scios' Carhart observed, "There's clinical data out there on administration of Natrecor subcutaneously - like insulin. We're looking into it with a partner, but have not investigated an oral formulation." She alluded to an eight-patient trial of injectable brain natriuretic peptide reported by clinicians at the Mayo Clinic in Rochester, Minn., in the Journal of the American College of Cardiology.