Ularitide for the treatment of acute decompensated heart failure: from preclinical to clinical studies

Abstract

The short- and long-term morbidity and mortality in acute heart failure is still unacceptably high. There is an unmet need for new therapy options with new drugs with a new mode of action. One of the drugs currently in clinical testing in Phase III is ularitide, which is the chemically synthesized form of the human natriuretic peptide urodilatin. Urodilatin is produced in humans by differential processing of pro-atrial natriuretic peptide in distal renal tubule cells. Physiologically, urodilatin appears to be the natriuretic peptide involved in sodium homeostasis. Ularitide exerts its pharmacological actions such as vasodilation, diuresis, and natriuresis through the natriuretic peptide receptor/particulate guanylate cyclase/cyclic guanosine monophosphate pathway. In animal models of heart failure as well as Phase I and II clinical studies in heart failure patients, ularitide demonstrated beneficial effects such as symptom relief and vasodilation, while still preserving renal function. Subsequently, the pivotal acute decompensated heart failure (ADHF) Phase III study, called TRUE-AHF, was started with the objectives to evaluate the effects of ularitide infusion on the clinical status and cardiovascular mortality of patients with ADHF compared with placebo. This review summarizes preclinical and clinical data supporting the potential use of ularitide in the treatment of ADHF.

Keywords: Acute decompensated heart failure; Diuresis; Guanylate cyclase; Natriuresis; Ularitide; Vasodilation.

Figure 1

Schematic drawing of the role of urodilatin under physiological and pathophysiological conditions. (A) Nephron highlighting distal tubule (synthesis site of urodilatin) and collecting duct (binding site of urodilatin). (B) sodium concentration as stimulus for synthesis of urodilatin in distal tubule cells and excretion into the urine, mediated by transduction mechanisms: AC, adenylyl cyclyse; PKC, protein kinase (C) and binding to NPR-A receptor in the inner medullary collecting duct. (C) Processing of urodilatin from pro-ANP. Enzyme responsible not known yet (aa, amino acids).

Figure 2

Schematic drawing of intracellular cyclic guanosine monophosphate signalling induced by nitric oxide and soluble guanylate cyclase and natriuretic peptides via natriuretic peptide receptor A and particulate guanylate cyclase. Cyclic guanosine monophosphate acts through a number of distinct pathways such as cyclic guanosine monophosphate-dependent protein kinases and the cyclic guanosine monophosphate-regulated phosphodiesterase-5 contributing to main effects such as vasodilation through vasorelaxation of smooth muscle cells and natriuresis and diuresis through inhibition of Na⁺-reabsorption in distal tubular cells. NO, nitric oxide; sGC, soluble guanylate cyclase; NP, natriuretic peptide; cGMP, cyclic guanosine monophosphate; NPR-A, natriuretic peptide receptor A; pGC, particulate guanylate cyclase; cGK, cyclic guanosine monophosphate-dependent protein kinases; PDE-5, phosphodiesterase-5.

Figure 3

Radioactive labeled atrial natriuretic peptide and ularitide were infused into the renal artery. Binding sites in the kidney are seen by autoradiography. Atrial natriuretic peptide is not bound to medullary structures while binding of ularitide in medullary stripes indicates that ularitide may not be degraded by neutral endopeptidase in the proximal tubule.

Figure 4

Haemodynamic parameters for placebo (filled circles) and ularitide 7.5 ng/kg/min (diamonds), 15 ng/kg/min (squares), 30 ng/kg/min (triangles) dose groups. (A) Changes from baseline in pulmonary capillary wedge pressure, (B) systemic vascular resistance (SVR), and (C) cardiac index. P values are given (repeated-measures mixed effects analysis of covariance, including baseline as covariate, treatment, and time of assessment as factors as well as treatment-by-assessment interaction). Adapted from Mitrovic et al.

Figure 5

(A) Summarized patients' dyspnoea assessments of ‘moderately improved’ or ‘markedly improved’ at 6 and 24 h. P values of tests vs. placebo, considering all scores (Uleman test). (B) Mean (standard deviation) change from baseline in pulmonary capillary wedge pressure (ΔPCWP) at 6 h in pooled ularitide- and placebo-treated patients who assessed dyspnoea as ‘no change’, ‘minimally improved’, ‘moderately improved’, or ‘markedly improved’.

Figure 6

(A and C) Serum creatinine (SCr) and blood urea nitrogen (BUN) over 72 and 24 h respectively. (B) Percentage patients with BUN elevations and reductions >25% from baseline at 24 h post treatment. (D) Percentage patients with SCr elevations and reductions >25% from baseline at 24, 48 and 72 h post treatment. ^†P< 0.05 vs. placebo (repeated-measures mixed effects analysis of covariance, including baseline as covariate, treatment, and time of assessment as factors as well as treatment-by-assessment interaction). Adapted from Mitrovic et al. and Luss et al.