LUCASSIN® (terlipressin) is a synthetic 12-amino acid vasopressin analogue that acts via the vasopressin V1 receptor as a systemic vasoconstrictor. In Hepatorenal Syndrome (HRS) patients, the V1 mediated vasoconstriction particularly in the splanchnic area, results in an increase in effective arterial volume, an increase in mean arterial pressure, normalization of endogenous vasoconstrictor systems, and improved renal blood flow. These effects are thought to lead to improved renal function, thereby providing the therapeutic rationale for treatment of HRS. Terlipressin is the most widely-studied agent for HRS treatment with 19 clinical investigations in HRS patients published to-date (May 2008).
Terlipressin is not approved by the FDA for use in the U.S. Outside the U.S., terlipressin has been approved for esophageal variceal hemorrhage in patients with liver cirrhosis for over two decades. It was also recently approved in France, Ireland and South Korea for the treatment of patients with HRS type 1.
Orphan Therapeutics has recently begun its rolling NDA submission for LUCASSIN® for the treatment of patients with HRS type 1 to the U.S. Food and Drug Administration (FDA) and is seeking regulatory approval to add this product to the armamentarium of physicians in the US. The LUCASSIN® rolling NDA submission is based on the results from OT-0401 a randomized, double-blind, multi-center, placebo-controlled Phase III study in 112 patients with HRS type 1, conducted by Orphan Therapeutics, and is independently supported by TAHRS, a second randomized, multi-center, controlled study in 46 patients coordinated by the Hospital Clinic (University of Barcelona). Orphan Therapeutics holds exclusive rights to the TAHRS data for the NDA submission. Both of these studies were published in the May 2008 issue of Gastroenterology (1, 2).
Hepatorenal Syndrome (HRS) is the development of renal dysfunction in patients with late stage liver cirrhosis in the absence of any other renal pathology. The likely pathogenic mechanism leading to HRS is a vasoconstriction of the renal circulation secondary to a marked arterial vasodilation in the splanchnic vascular bed leading to reduction in effective arterial blood volume with subsequent homoeostatic activation of vasoconstricitor systems.
Two types have been described. HRS type 1 is characterized by rapid renal failure with a high mortality rate that exceeds 80% within 3 months. The estimated United States (US) prevalence for HRS type 1 ranges between 9,000 to 20,000 patients. HRS type 2 is a more stable form with less severe renal failure and longer survival.
Confirmation of HRS is based on exclusion of other precipitating factors for renal failure.
No parenchymal renal disease
No shock
No uncontrolled infection
No dehydration
No nephrotoxic drug
The only potentially curative treatment for HRS and its underlying end-stage liver disease is liver transplantation, provided that the patient is a suitable candidate for transplantation and survives until a transplant is available. However, many patients may not receive a new liver, further supporting the need for alternate therapy options to improve renal function. Thus, patients with HRS type 1 are in dire need of a pharmacological agent to reverse the functional renal failure.
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1 Sanyal 2008: Sanyal AJ, Boyer TD, Garcia-Tsao G, Regenstein F, Rossaro L, Appenrodt B, Blei A, Gülberg V, Sigal S, Teuber P and the Terlipressin Study Group. A randomized, prospective, double-blind, placebo controlled trial of terlipressin for type 1 hepatorenal syndrome. Gastroenterology. 2008;134:1360-1368.
2 Martín-Llahí 2008: Martín-Llahí M, Pépin M-N, Guevara M, Díaz, F, Torre A, Monescillo A, et al. Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study. Gastroenterology. 2008;134:1352-1359
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