Our initial disease target is ascites due to advanced liver cirrhosis resulting from NASH (non-alcoholic steatohepatitis), hepatitis B & C, alcoholism, or other causes. Ascites is the most common complication of advanced (“decompensated”) liver cirrhosis. It involves the excessive accumulation of fluid in the abdomen, and complications of ascites are often life-threatening. Patients with ascites suffer a miserable quality of life with frequent infections and other serious health problems requiring hospitalization.
Chronic liver disease (CLD) including cirrhosis is the 12th leading cause of death due to disease in the US, killing an estimated 38,000 people annually. Liver cirrhosis is responsible for an estimated 326,000 hospitalizations each year and generates over $4 billion in annual patient treatment costs.
There are 3 major causes of liver cirrhosis. Alcoholism accounts for about 25% and is slowly rising. Hepatitis C is another leading cause, but the new antiviral therapies will eventually reduce the number of these patients. Unfortunately they arrived too late for many hepatitis C patients whose livers have already been destroyed by the virus. The fastest-growing cause of liver cirrhosis is NASH, which comes from fatty-liver disease due to obesity, and is now at epidemic proportions. NASH is now the leading driver for liver transplants.
It takes decades for the cirrhosis damage to accumulate and destroy the liver. At first the liver is “compensated” meaning that it’s still cleansing the blood and doing other important jobs. Once it reaches the “decompensation” stage it’s no longer functional, and ascites and other deadly complications start to occur.
How Ascites Develops
(the expert consensus in plain language)
In advanced liver cirrhosis, the liver becomes “clogged” and the blood pools in the region below the liver, called the splanchnic bed, because it can’t flow through. This increases pressure in the portal vein which supplies blood to the liver.
With blood pooling below the liver, the blood volume in the arteries decreases and the patient experiences “low effective blood volume.” In an effort to correct this situation, the brain send signal via the renin-angiotensin-aldosterone system(“RAAS”) to the kidneys to retain extreme amounts of water and salt. The excess liquid weeps from the lymphatic system and collects in the abdomen – which is when ascites appears.
Anticipated Mechanism of Action
Investigative studies conducted overseas have shown that terlipressin, the active agent in BIV201, has the potential to correct this problem by vasoconstricting the blood vessels where the blood is pooling and restoring blood flow through the kidneys and liver. This reduces portal vein pressure and increases blood volume in the arteries. Consequently, the body may respond by shutting down the RAAS system which has been generating the ascites.
Terlipressin has been available for decades outside the US (it is not available in the US or Japan). It is approved in more than 40 countries for treating two deadly conditions related to ascites called bleeding esophageal varices (BEV) and hepatorenal syndrome (HRS) in hospitals. The drug has been studied extensively overseas and its efficacy and safety profiles in BEV and HRS have been elucidated by hundreds of scientific publications.
BIV201 Potential Future Disease Targets
BIV201 is being developed for treating refractory ascites patients, who no longer respond to diuretic drugs and required repeated paracentesis procedures (the physical withdrawal of large amounts of ascites fluid from the abdomen with a large-bore needle). Eventually the Company may pursue FDA approvals to market BIV201 for two related conditions due to advanced liver cirrhosis: bleeding esophageal varices (BEV) and hepatorenal syndrome (HRS). All of these conditions are very deadly as shown in the table.
|Refractory Ascites||50% within 6-12 months1|
|Bleeding esophageal varices (BEV)||15 – 25% mortality at 6 weeks after bleeding episode2|
|Hepatorenal syndrome type 1 (HRS-1)||Median survival of 1.7 to 4 weeks3|
No medications have ever been approved by the FDA specifically to treat ascites and the prognosis for these patients is very poor. Certain drugs which have been approved for other medical conditions (such as diuretics) combined with a salt-restricted diet may provide symptomatic relief in the initial stages of the disease. But as the ascites worsens they typically become ineffective.
1.D’Amico 2014; Gines 2004
2.La Jolla Pharmaceuticals market assessment, published 2015
3.US Patient Hospital Discharge Data, 2005
4.Ascites & BEV: Assumes three 21-day treatment regimens annually; CRH: Assumes 3 days of therapy (Auchet, 2017) & HRS: Assumes 10 days of therapy; $400 per day WAC pricing assumption