N-003 (ambrisentan) is not approved for commercialisation
© — Noorik Biopharmaceuticals, Switzerland
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, but less than 200'000 are in the decompensated stage.
Although decompensated patients represent only a fraction of all patients with cirrhosis, the cost of treating the 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.
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.
Portal Hypertension is the result of increased vascular resistance in the liver through the contraction of the sinusoidal space. There is significant 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 endothelin reduces intra-hepatic resistance, reduces portal pressure and increases liver blood flow (Link).
To determine the benefit of any intervention in Portal Hypertension, portal pressure is frequently estimated by measuring the Hepatic Vein Pressure Gradient (HVPG), an invasive procedure accepted as accurate, reliable, safe and reproducible. HVPG is the current gold standard for determining portal pressure. As portal pressure changes with the stage of cirrhosis and is a good predictor of morbidity and mortality, HVPG may be considered an acceptable surrogate marker of clinical benefit. This may represent a regulatory opportunity to accelerate the approval of drugs developed for Portal Hypertension and its complications.
Development of a new drug for Portal Hypertension may qualify for accelerated approval, as: