cenderitide and Heart-Failure

Cenderitide is a novel designer natriuretic peptide (NP) composed of C-type natriuretic peptide (CNP) fused to the C-terminus of Dendroaspis natriuretic peptide (DNP). Cenderitide was engineered to co-activate the two NP receptors, particulate guanylyl cyclase (pGC)-A and pGC-B. The rationale for its design was to achieve the renal-enhancing and anti-fibrotic properties of dual receptor activation, but without clinically significant hypotension. Here, we review the biology of the NPs and the rationale for their use in heart failure. Most importantly, we present the key studies related to the discovery of Cenderitide. Finally, we review the key clinical studies that have advanced this first-in-class dual NP receptor activator for heart failure.

Topics: Drug Design; Drug Development; Heart Failure; Humans; Natriuretic Peptides; Snake Venoms

Heart failure (HF) can rightfully be called the epidemic of the 21(st) century. Historically, the only available medical treatment options for HF have been diuretics and digoxin, but the capacity of these agents to alter outcomes has been brought into question by the scrutiny of modern clinical trials. In the past 4 decades, neurohormonal blockers have been introduced into clinical practice, leading to marked reductions in morbidity and mortality in chronic HF with reduced left ventricular ejection fraction (LVEF). Despite these major advances in pharmacotherapy, our understanding of the underlying disease mechanisms of HF from epidemiological, clinical, pathophysiological, molecular, and genetic standpoints remains incomplete. This knowledge gap is particularly evident with respect to acute decompensated HF and HF with normal (preserved) LVEF. For these clinical phenotypes, no drug has been shown to reduce long-term clinical event rates substantially. Ongoing developments in the pharmacotherapy of HF are likely to challenge our current best-practice algorithms. Novel agents for HF therapy include dual-acting neurohormonal modulators, contractility-enhancing agents, vasoactive and anti-inflammatory peptides, and myocardial protectants. These novel compounds have the potential to enhance our armamentarium of HF therapeutics.

Topics: Amides; Aminobutyrates; Atrial Natriuretic Factor; Biphenyl Compounds; Digoxin; Drug Combinations; Fumarates; Heart Failure; Humans; Natriuretic Peptides; Peptide Fragments; Snake Venoms; Tetrazoles; Valsartan

Acute heart failure is a major cause of emergency hospital admission, with significant impact on health resources and patient outcomes. With no new treatments for over 20 years, the advent of new innovative therapies may facilitate a radical change in our approach to such patients. In this article, we examine the current evidence for the use of current intravenous vasodilators in AHF management, and review the potential of novel therapies currently in development.

Topics: Acute Disease; Administration, Intravenous; Atrial Natriuretic Factor; Benzoates; Heart Failure; Humans; Natriuretic Agents; Natriuretic Peptide, Brain; Natriuretic Peptides; Nitrates; Peptide Fragments; Recombinant Proteins; Relaxin; Snake Venoms; Vasodilator Agents

Topics: Alternative Splicing; Aminobutyrates; Angiotensin Receptor Antagonists; Biphenyl Compounds; Designer Drugs; Drug Combinations; Drug Therapy, Combination; Endothelin-1; Heart Failure; Humans; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Natriuretic Peptides; Neprilysin; Peptidyl-Dipeptidase A; Protease Inhibitors; Receptors, Angiotensin; Renin-Angiotensin System; Snake Venoms; Tetrazoles; Valsartan

Cenderitide is a novel designer natriuretic peptide (NP) composed of C-type natriuretic peptide (CNP) fused to the C-terminus of Dendroaspis natriuretic peptide (DNP). Cenderitide was engineered to coactivate the two NP receptors, particulate guanylyl cyclase (pGC)-A and -B. The rationale for its design was to achieve the renal-enhancing and antifibrotic properties of dual receptor activation, but without clinically significant hypotension. Here we report the first clinical trial on the safety, tolerability, and cyclic guanosine monophosphate (cGMP) activating properties of Cenderitide in subjects with stable heart failure (HF). Four-hour infusion of Cenderitide was safe, well-tolerated, and significantly increased plasma cGMP levels and urinary cGMP excretion without adverse effects with no change in blood pressure. Thus, Cenderitide has a favorable safety profile and expected pharmacological effects in stable human HF. Our results support further investigations of Cenderitide in HF as a potential future cGMP-enhancing therapeutic strategy.

Topics: Aged; Biomarkers; Cardiovascular Agents; Chronic Disease; Cyclic AMP; Double-Blind Method; Drug Administration Schedule; Female; Glomerular Filtration Rate; Heart Failure; Humans; Infusions, Intravenous; Kidney; Male; Middle Aged; Minnesota; Natriuretic Peptides; Prospective Studies; Renal Elimination; Snake Venoms; Time Factors; Treatment Outcome

Topics: Animals; Elapidae; Heart Failure; Humans; Natriuretic Peptides; Snake Venoms