Palosuran: clinical pharmacology of a urotensin-II receptor antagonist in type 2 diabetes mellitus

Type 2 Diabetes Mellitus (Type 2 DM) is a growing global public health threat, leading to a significant cost burden to society.
Type 2 DM increases the risk of hypertension and associated macro- and microcardiovascular diseases, affecting the eyes, brain, kidneys, and cardiovasculature. Cardiovascular disease accounts for up to 80% of the deaths in individuals with Type 2 DM. The mechanistic background for the disease is an imbalance between increased insulin requirement (insulin resistance) versus insufficient insulin availability (insulin deficiency) resulting in hyperglycemia and increased circulatory fatty acids. Treatment of Type 2 DM is aimed at increasing pancreatic ß-cell function and lowering insulin resistance in order to lower blood glucose levels. While in first line life style changes such as weight loss and exercise should be implemented, various antidiabetic drugs are available that are can be used either as mono- or combination therapy. Overall, these agents are well tolerated. However, some risks remain which could affect patient's compliance and safety. Therefore, there is a need for better and safer antidiabetic drugs.
Urotensin-II (U-II) has been described as one of the most potent vasoconstrictors up to date, though its function in humans is not fully understood.
In humans, U-II receptors (UT receptor) have been identified in various tissues; amongst others the kidney and pancreas. These organs have a crucial role in glucose regulation and cardiovascular homeostasis, mechanisms which are disrupted in diabetic patients. Increases in U-II concentrations have also been observed in diabetic patients. Therefore, antagonism of U-II could be beneficial in treatment of this disease. Palosuran is a potent, selective, oral antagonist of the human UT receptor. In healthy subjects, palosuran was well tolerated after single- and multiple-dose administration over a wide dose range. The pharmacokinetics were indicative of a twice daily dosing regimen. Two absorption peaks could be detected at approximately 1 and 4 h after drug administration. Following peak plasma concentrations, elimination was biphasic with a faster and slower elimination phase resulting in low plasma concentrations at 12 h after drug administration. The intake of food had a minor effect on drug exposure when expressed in area under the curve, but is not considered to be of clinical relevance. Therefore palosuran can be administered with and without food.
In an open-label study in patients with Type 2 diabetic nephropathy, 2-week treatment with palosuran significantly reduced the 24-hour urinary albumin excretion rate, an accepted clinical marker for cardiorenal disease progression. Surprisingly, in this study, no effects on other renal hemodynamic parameters (i.e., glomerular filtration rate, renal blood flow, filtration fraction) were observed, which hampered the understanding of the mechanism underlying the reduction of 24-h UAER. In a proof-of-concept, randomized, double-blind, placebo-controlled study, 4-week treatment with palosuran did not show any effect on insulin secretion or blood glucose levels in diet-treated patients with Type 2 DM.
These studies suggest that palosuran is not efficacious in subjects with diabetic nephropathy and Type 2 DM. However, based on the expression of UT receptors in humans, there is enough reason to believe that UT receptor antagonists can have therapeutic value in various other cardiovascular, pulmonary, renal, and oncologic indications.