PPAR/FXR agonists for NASH

Therapies for NASH (Non-Alcoholic Steatohepatitis) have the potential to reduce the build up of fat in the liver, which could avoid up to 12,000 transplants in Europe each year

PPAR and FXR agonists are the first therapies in development for NASH and are expected to reduce liver fat build up, inflammation and fibrosis. These new treatments promise to reverse disease progression resulting in a significant improvement in patient prognosis and reducing the need to undergo liver transplantation.

What is the potential breakthrough for patients with NASH?

NASH – or Non-Alcoholic Steatohepatitis – is the accumulation of fat in the liver, resulting in inflammation – after years of inflammation and fibrosis, NASH will develop into full cirrhosis of the liver. There are currently no therapies indicated for treatment or prevention of NASH. Two new agonists in development could provide novel treatment options in NASH, enabling disease reversal and reduction in transplants.

These are:

• Peroxisome proliferator-activated receptors (PPARs): when activated, PPAR subunits suppress fat metabolism, reduce lipid production and suppress inflammation.

• Farnesoid X receptors (FXRs): when activated, FXRs suppress carbohydrate and lipid metabolism, and activates liver growth and regeneration following liver injury.

How will it help patients?

NASH patients are typically asymptomatic, meaning they often do not feel pain even during advanced cirrhosis. However, patients who reach the final stages of NASH have poorer prognoses (1-year survival of decompensated liver disease is lower than 50%) and are likely to require a liver transplant. These two new therapies may be able to reverse the progression of the disease, lower associated risks with late-stage NASH, ultimately reducing the need for liver transplants.

How many patients could it help?

About 15% of the general European population suffers from NASH. The number of liver transplants due to NASH has grown in the region of 500% in the last 10 years, driven in part by the obesity epidemic. Simply put, there are not enough livers available to provide a transplant for every patient on the waiting list. These new therapies may help patients avoid liver transplants by reversing the disease’s pathology, translating to approximately 12,000 fewer transplants per year.

What might this mean for patients awaiting liver transplants?

Severe NASH accounts for between 4 – 10% of liver transplants in Europe. Reducing the number of transplants would reduce the number of surgery-related complications that patients suffer. They could spend less time in hospital and return home to their families faster. Fewer patients will be required to take immunosuppression therapy – reducing this life-long drug burden. In turn, a greater proportion of patients may receive transplants in a timely manner.

What is the potential impact on Europe’s healthcare systems?

The ability to reverse disease progression would see fewer patients requiring costly liver transplants and treatment associated with liver failure complications. The use of PPAR and FXR agonists could reduce the number of late-stage NASH patients by more than 120,000 in Europe per year, which could lead to cost savings of about €1bn over the course of one year.