Nesiritide

also known as: Natrecor, recombinant human B-type natriuretic peptide, rhBNP, Scios-1

Natrecor — the first recombinant natriuretic peptide drug for acute heart failure. FDA-approved August 2001 based on short-term dyspnea relief, became one of the most controversial drugs of the 2000s after 2005 meta-analyses raised safety concerns; ASCEND-HF (2010, n=7,141) eventually settled the safety debate but demonstrated only marginal clinical benefit. Janssen discontinued manufacturing February 2018; no longer commercially available in the US.

A recombinant form of endogenous human B-type natriuretic peptide (32 residues, disulfide-bridged ring structure) produced in Escherichia coli and marketed as Natrecor® by Scios Inc. (acquired by Johnson & Johnson for $2.4 billion in 2003, later Janssen). Acts via natriuretic peptide receptor A (NPR-A / guanylate cyclase-A) to raise intracellular cGMP, producing arterial and venous vasodilation, natriuresis, diuresis, and suppression of the renin-angiotensin-aldosterone and sympathetic nervous systems. FDA-approved August 2001 for acute decompensated heart failure based on VMAC trial dyspnea relief. Became controversial after 2005 meta-analyses (Sackner-Bernstein, Nissen) suggested increased renal dysfunction and mortality. The definitive ASCEND-HF trial (NEJM 2011, n=7,141) demonstrated no mortality harm or renal harm but only a tiny, statistically non-significant benefit on the primary composite endpoint. Clinical use collapsed; Janssen announced discontinuation of manufacturing in February 2018, and nesiritide is no longer commercially available in the United States.

Mechanism of action

Binds natriuretic peptide receptor A (NPR-A / GC-A / NPR1), a membrane-bound guanylate cyclase, on vascular smooth muscle, renal tubule, and adrenal cortex. Receptor activation raises intracellular cGMP, which activates protein kinase G, phosphorylates IP3 receptor and other targets, and produces: (1) arterial and venous vasodilation with reduction in preload and afterload; (2) natriuresis and diuresis through direct tubular effects on sodium reabsorption; (3) suppression of renin release, aldosterone secretion, and sympathetic nervous system activity. Net hemodynamic effect in acute heart failure is reduced pulmonary capillary wedge pressure and modest rise in cardiac output without positive inotropy. Clearance is via NPR-C-mediated endocytosis and neprilysin cleavage — the latter is the rationale for the sacubitril/valsartan approach, which inhibits neprilysin to augment endogenous BNP and ANP signalling rather than infusing exogenous peptide.

Primary uses

Acute decompensated heart failure with dyspnea at rest or minimal activity (historical; manufacturer-discontinued 2018)

Typical dosing

2 mcg/kg IV bolus followed by 0.01 mcg/kg/min continuous infusion mcg/kg/min continuous infusion 24–168 hours (intravenous)

Historical dosing. Persistent systolic BP <100 mmHg was contraindication because of hypotension risk. Product no longer commercially available in the US as of February 2018.

Regulatory status

FDA-approved August 10, 2001 for IV treatment of acutely decompensated congestive heart failure with dyspnea at rest or minimal activity (Natrecor®, Scios Inc. / Johnson & Johnson / Janssen). Approval based on the VMAC trial (Vasodilation in the Management of Acute Congestive Heart Failure) using dyspnea relief as surrogate endpoint. Peak annual sales ≈$400M (2004). April 2005 FDA required enhanced warnings about death and renal impairment. ASCEND-HF (NEJM 2011) resolved the safety controversy but showed minimal benefit. Janssen Pharmaceuticals announced discontinuation of manufacturing in February 2018; nesiritide has been unavailable in the US since. Label technically remains approved but product is not marketed.

References

[fda-pi] Natrecor® (nesiritide) Prescribing Information. Scios Inc. / Janssen Pharmaceuticals. FDA-approved August 10, 2001.
[clinical-trial] O'Connor CM, Starling RC, Hernandez AF, et al. "Effect of nesiritide in patients with acute decompensated heart failure (ASCEND-HF)." N Engl J Med, 2011;365(1):32-43.
[clinical-trial] Sackner-Bernstein JD, Skopicki HA, Aaronson KD. "Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure." Circulation, 2005;111(12):1487-1491 (key safety-signal meta-analysis).
[news-release] Janssen Pharmaceuticals. "Discontinuation of Natrecor (nesiritide) manufacturing." February 2018.

Related peptides

Carperitide

⚠ Approved in Japan only (1995). The Daiichi Sankyo recombinant hANP has been used in >30,000 pooled patients with acute heart failure in Japanese registries, but its overall mortality effect remains contested — 2024 meta-analyses suggest a possible increase in in-hospital mortality, while other pooled analyses suggest benefit at low doses.

Ularitide

⚠ Phase 3 failure. Cardiorentis's ularitide was the most recent Western attempt to develop an IV natriuretic peptide for acute heart failure. TRUE-AHF (NEJM 2017, n=2,157) failed both the mortality and hemodynamic co-primary endpoints; development was discontinued shortly after. Reinforced a now-consistent pattern of IV natriuretic peptides showing biochemical and hemodynamic effects but failing to improve clinical outcomes.

Disclaimer

This entry is for educational purposes only and does not constitute medical advice. Dosing information reflects published regulatory or research data and is not a recommendation. Many compounds described here are not approved for human use in the United States. Consult a licensed medical professional before considering any peptide therapy.