Pharmacodynamics Pharmacodynamics of a Novel Designer Natriuretic Peptide, CD‐NP, in a First‐in‐Human Clinical Trial in Healthy Subjects

Abstract

CD-NP is a novel chimeric natriuretic peptide (NP) consisting of the 22-amino-acid (AA) human C-type natriuretic peptide (CNP), a venodilating peptide with limited renal actions and minimal effects on blood pressure, and the 15-AA C-terminus of Dendroaspis NP (DNP). The rationale for the design of CD-NP was to enhance the renal actions of CNP, the ligand for natriuretic peptide receptor-B, but without inducing excessive hypotension. Here we report the first-in-human studies for CD-NP, which represent the first successful clinical testing of a chimeric NP demonstrating in normal human volunteers that CD-NP possesses cyclic guanosine monophosphate-activating, natriuretic, and aldosterone-suppressing properties without inducing excessive hypotension, laying the foundation for additional studies on this first-in-class new cardiovascular therapeutic in human heart failure, which are now underway worldwide. KeywordsChimeric natriuretic peptide; CD-NP; C-type natriuretic peptide; Dendroaspis natriuretic peptide The design of novel chimeric peptides that are engineered to enhance the favorable properties of native peptides and delete or minimize unfavorable biological actions is an emerging therapeutic strategy in drug discovery.1 , 2 The novel chimeric natriuretic peptide, CD-NP,3 is being developed for the treatment of acute heart failure (AHF); there is a tremendous unmet need for therapy for this rapidly increasing cardiovascular syndrome, which has poor outcomes, and new drugs have repeatedly failed in clinical development.4 CD-NP represents the fusion of the 22-amino-acid (AA) human C-type natriuretic peptide (CNP) with the 15-AA C-terminus of Dendroaspis natriuretic peptide (DNP) (Figure 1).3 The rationale for its design was based on our knowledge that CNP,5 an endothelial6 , 7 cellderived peptide, which mediates favorable cardiovascular hemodynamic effects via the natriuretic peptide receptor (NPR)-B and the second messenger cyclic guanosine monophosphate (cGMP), unloads the heart without inducing excessive hypotension.8 These cardiovascular properties are based on the previous demonstration that CNP primarily

Increased Plasma cGMP in a Family With Autosomal Recessive Retinitis Pigmentosa Due to Homozygous Mutations in the PDE6A Gene

“…Still, at this point we cannot claim that the higher level is a direct consequence of the disease. Differential blood cGMP levels have previously been seen in a variety of situations, for instance, in connection with natriuretic drugs for acute heart failure, 58 blood pressurealtering drugs, 59 preeclampsia, 60 migraine, 61 and in relation to the circadian rhythm, 63 where the cGMP levels may in turn be dependent on melatonin levels. 62 With a possible connection to this, the ROC specificity aspect indicates that some healthy subjects may appear as having the disease.…”

Arg13 of B-Type Natriuretic Peptide Reciprocally Modulates Binding to Guanylyl Cyclase but Not Clearance Receptors

“…1). In a recent clinical trial, CD-NP demonstrated natriuretic and aldosterone-suppressing properties without inducing excessive hypotension (Lee et al, 2009). We found that CD-NP bound GC-A tighter than CNP, which indicates that the carboxyl-terminal extension increases the affinity of CNP to human GC-A.…”

Type 4 Cardiorenal Syndrome: Myocardial Dysfunction, Fibrosis, and Heart Failure in Patients with Chronic Kidney Disease

“…The first chimeric natriuretic peptide (CD-NP) comprised the C-terminus of the dendroaspis peptide (derived from snake venom) and the peptide ring component of the cardiac-type natriuretic (CNP) [119]. CD-NP has been shown to have a potent natriuretic effect, antagonize the RAAS system, inhibit cardiac fibroblast proliferation and collagen synthesis, and importantly not cause significant systemic hypotension [120,121]. BNP and other natriuretic peptide derivatives are now utilized in the diagnosis of acute decompensated HF, chronic compensated HF (including HF with preserved LVEF), prognostication, and treatment.…”