Ascites / Cirrhosis Innovations
Ascites / Cirrhosis Research
BioVie is especially focused on exploring the treatment of ascites (the excessive accumulation of fluid in the abdomen). Ascites often occurs in the presence of advanced liver cirrhosis, which can be caused by the progression of NASH (non-alcoholic steatohepatitis), infection with Hepatitis B & C, alcoholism, and other causes. Ascites is, indeed, the most common complication of advanced (“decompensated”) liver cirrhosis. Complications of ascites can be life-threatening.
Current clinical outcomes are generally not optimistic. For some individuals diagnosed with cirrhosis and ascites, a path towards liver transplant may be a positive and available option.
Targeting Ascites
We are targeting the disease pathway of ascites and have received both Orphan and Fast Track Status from FDA. Taking a new look at the biology and physiology of ascites, we are exploring a potential new solution to ascites that combines existing technology and an innovative application.
We are conducting clinical trials in this orphan condition, which, if successful, could produce an important new therapy for the treatment Ascites.
Ascites / Cirrhosis Research Sites
Chronic Liver Disease
Chronic liver disease (CLD), including cirrhosis, is responsible for the death of 42,000 Americans each year. As a population, people diagnosed with both liver cirrhosis and ascites are hospitalized 116,000 times each year, incurring an estimated $5 billion in annual treatment costs.
There are 3 major causes of liver cirrhosis. The fastest-growing cause of liver cirrhosis is NASH, which can develop from fatty-liver disease due to obesity, and whose diagnosis has reached epidemic rates. NASH progression to fibrosis and cirrhosis is now the leading reason for liver transplant. Alcoholism accounts for about 25% of all causes of cirrhosis, and is rising. Hepatitis C is another leading cause of liver cirrhosis and ascites. Although the new antiviral therapies will eventually reduce the number of people affected by viral hepatitis, these life-saving therapies have not arrived in time for many people whose livers have already been irreversibly damaged by Hepatitis C.
It may take decades for damage to accumulate and for cirrhosis to destroy the liver. At first, the liver may be in a “compensated” state, meaning that the liver is still cleansing the blood and performing other important functions. Once the liver reaches the “decompensation” stage it is 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 blood pools in the region below the liver, called the splanchnic bed, because it can’t flow through the liver. 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 person with cirrhosis experiences “low effective blood volume.” In an effort to correct this situation, the brain sends signals via the renin-angiotensin-aldosterone system (“RAAS”) to the kidneys to retain extreme amounts of water and salt to attempt to reflexively increase the blood volume in the arteries. 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 BIV-201, has the potential to reduce the presence of ascites in the abdomen through vasoconstricting the blood vessels where the blood is pooling, hence 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 in hospital use for the treatment of two deadly conditions related to ascites called bleeding esophageal varices (BEV) and hepatorenal syndrome (HRS). The drug has been studied extensively overseas.
1. Varies by ethnicity – Setiawan, 2016 (link)
2. CDC National Vital Statistics Report, 2017 Data (link)
3. HCUP Nationwide Readmissions Database 2016 Links to our poster on the Investors page (link)
BIV-201 Potential Future Disease Targets
BIV-201 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 BIV-201 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.
Orphan and Fast Track Status for BIV-201
(FDA) has also granted Fast Track status for BIV-201. The Company is applying for patent coverage of its novel liquid formulation of terlipressin around the world. This unique formulation has demonstrated stability at room temperature for at least 12 months, which BioVie believes will be an important advantage for treating people with ascites in the home care setting.
Future Possibilities
Based on terlipressin drug approvals around the world, BIV-201 has the potential for future uses to treat other life-threatening conditions resulting from advanced liver cirrhosis, including HRS-AKI and BEV as described below. Securing marketing approvals for any of these new uses will require well-controlled clinical trials to satisfy the FDA and/or other countries’ regulatory requirements, none of which have commenced at this time.
Bleeding Esophageal Varices (BEV): The bursting of blood vessels lining the Esophagus as a consequence of very high blood pressure (“portal hypertension”) in the portal vein which supplies blood to the liver. This situation requires emergency treatment to avoid extensive blood loss and death.
Hepatorenal Syndrome–Acute Kidney Injury(HRS-AKI): As liver cirrhosis and ascites progresses over time, patients’ kidneys may begin to fail, and this life-threatening condition may set in. It often occurs once a patient no longer responds to diuretic drugs that are used initially to help control ascites. The more advanced stage is called “type 1 HRS” and requires hospitalization as kidney failure, multiple organ failure (MOF), and death may occur within days if liver transplantation is not feasible.
Anticipated Mechanism of Action
Publications / Bibliography:
The Pharmacokinetics of Terlipressin Administered as a Continuous Infusion in Six Cirrhotic Patients with Refractory Ascites
U.S. HOSPITALIZATION CHARACTERISTICS OF CIRRHOTIC PATIENTS WITH ASCITES RECEIVING PARACENTESIS
