Portal Hypertension and Liver Cirrhosis

Portal Hypertension is the result of an increased resistance to blood flow in the liver. Ascites and variceal bleeding are direct consequences of Portal Hypertension and their presence marks the transition from a compensated (no variceal bleeding or ascites) to a decompensated stage of cirrhosis (variceal bleeding or ascites). Decompensated cirrhosis has a mortality rate of up to 57% per year. In the United States, there are 5M people living with cirrhosis.

Economic Burden of Portal Hypertension

Although patients with Portal Hypertension represent only a fraction of all patients with cirrhosis, the cost of treating the direct complications of Portal Hypertension are very high. The key cost driver is the frequent hospitalization of patients with ascites, renal complications (such as Acute Kidney Injury and Hepatorenal Syndrome), infections, hepatic encephalopathy and variceal bleeding.

Current Standard of Care for Portal Hypertension

The current standard-of-care includes interventions that reduce blood flow to the liver through the portal vein. Drugs such as terlipressin, midodrine, somatostatin analogues and β-blockers are used but are not FDA-approved for this purpose, and benefit only a fraction of patients. As of today, there is significant interest in developing treatments for chronic liver disease (such as NASH and Viral Hepatitis). However, the medical need is the most pressing in patients with Portal Hypertension, but this indication remains neglected.

Endothelin: an Important Regulator of Intra-hepatic Resistance

Portal Hypertension is the result of increased vascular resistance in the liver through the contraction of the sinusoidal space. There is evidence that endothelin is a significant contributor to this abnormality. Recent experimental and clinical data in patients with decompensated cirrhosis have shown that blockade of the effects of Endothelin reduces intra-hepatic resistance, reduces portal pressure and increases liver blood flow (Link).

Micro-dose Ambrisentan in Portal Hypertension

Experimental and clinical data have shown that endothelin antagonism rapidly and significantly reduces portal pressure, possibly by reversing Endothelin-induced intra-hepatic vasoconstriction, a key component of Portal Hypertension (Link). Endothelin antagonism is mechanistically different from current therapies such as terlipressin, midodrine and β-blockers which work by lowering blood flow to the liver. Endothelin antagonism reduces portal pressure by decreasing intra-hepatic resistance and increasing liver blood flow by decreasing hepatic sinusoidal resistance (Link).

Noorik is currently performing a study in patients with advanced liver cirrhosis, in order to determine whether micro-dose Ambrisentan is safe and of clinical benefit in reducing Portal Hypertension in this patient population.