Contributed Commentary by Dr. Pol F. Boudes

June 28, 2021 | Along with the worldwide rise of obesity comes a rise in people diagnosed with nonalcoholic Steatohepatitis (NASH), where fat stored in the liver causes inflammation, tissue damage, and eventually cirrhosis. Because it remains asymptomatic for many years, NASH has been called a hidden epidemic. As with any chronic liver disease, NASH can progress to liver cirrhosis and is fast becoming the most frequent cause of liver cirrhosis. Many patients first learn of their NASH disease only when it has already advanced to the cirrhotic stage.

NASH represents a major opportunity to find new treatments, as none has been approved specifically for this disease. There are hundreds of clinical trials in progress targeting this indication. Most of these drug development efforts target early-stage disease and primarily use liver biopsies as a means to evaluate efficacy. This is challenging, as studies show lifestyle changes like diet and exercise can often help resolve early-stage NASH. Such lifestyle intervention strategies are less effective for late-stage NASH, particularly when the disease has progressed to liver cirrhosis.

Relying on a liver biopsy as a way to monitor the progression of NASH or the efficacy of any potential NASH treatment is also problematic. In their practice, physicians—including hepatologists—don’t perform liver biopsy as a diagnosis method or a surveillance tool to manage NASH or NASH cirrhosis. So, biopsies should not be recommended for the so-called pragmatic clinical trials, the ones that form the basis of a drug registration. Instead, a more appropriate measure would be to focus on clinically relevant outcomes: Are our efforts improving the lives of patients? Are we preventing the development of the more serious complications of NASH and NASH cirrhosis?

The Problems with Liver Biopsies

There are numerous problems with liver biopsies. For one, liver biopsies are invasive and not without risk. The biopsy procedure can be painful, but the main problem is bleeding induced by the biopsy needle. This is particularly true in patients with cirrhosis, as they frequently have a dysfunctional coagulation system, and their bleeding risk is higher. In the worst case, this may require emergency surgery.

Secondly, there are also potential problems in the accuracy of the findings, making it difficult to monitor the progression of the disease. The damage in liver disease is seldom spread uniformly throughout the liver—the liver is our largest organ and the biopsy tests only 1/50,000th of the liver. There is no certainty that such a small sample is representative of the overall health of the liver. In NASH, the interpretation of the biopsy relies on a semi-quantitative system that is also subjective, varying from one reader to the other and, sometimes, even when the same reader re-reads the same biopsy.

Using Clinically Relevant Endpoints

Clinical trials, especially late-stage clinical trials that form the basis of drug registration, should consider using the established, clinically relevant outcome of efficacy. Particularly in patients with cirrhosis of the liver, clinical outcomes used by hepatologists and gastroenterologists in treating cirrhosis are immediately clinically relevant. They are measures of efficacy that tie to Standard of Care for NASH cirrhosis and have an impact on the health outcomes or the quality of life of the patients.

One such approach is to focus on the potential complications of cirrhosis, many of which can be serious and potentially life-threatening.

The presence of these complications defines two stages of cirrhosis: The compensated, when no complications have yet occurred, and the decompensated stages, when one or more of these complications are present. These include esophageal varices (that can lead to internal hemorrhage), ascites (fluid in the abdomen), hepatic encephalopathy (an altered mental state), or liver failure.

Patients at the decompensated stage have a strikingly reduced life expectancy. One study found that patients with compensated cirrhosis had a one-year mortality rate of 5.4%, while in decompensated cirrhosis, this rate was 20%.

The goal in treating NASH cirrhosis, therefore, is to prevent the patient from further progression of cirrhosis. This, then, could serve a meaningful, clinically relevant endpoint for any potential clinical trial.

The development of small esophageal varices is a harbinger of more serious complications to come; it is clinical evidence that a patient is on the verge of decompensating. Such varices are not a trivial development, as bleeding varices are immediately life-threatening and a cause of death in about one-third of cirrhotic patients.

The prevention of esophageal varices, therefore, offers a clinically meaningful NASH cirrhosis trial measure of efficacy (also called an “endpoint” in drug development jargon). The progression of varices is easily observed via an esophago-gastro endoscopy, and this exam, contrary to a liver biopsy, is part of the Standard of Care of a cirrhotic patient.

NASH truly is a hidden epidemic, with fatty liver disease and NASH affecting tens of millions around the world. NASH is a progressive disease, and many of those affected will eventually progress to the liver cirrhosis stage. It is certainly appropriate to focus on NASH and the prevention of NASH cirrhosis as a therapeutic target, but we should not ignore patients with NASH cirrhosis, as the medical need here is even more urgent. Likewise, drug developers and regulators should also focus on studying, beyond liver biopsies, clinically relevant endpoints linked to better outcomes for patients.

Dr. Pol F. Boudes has more than 25 years of experience in clinical drug development in immunology, endocrine, metabolic, orphan, and liver-related diseases. He is currently Chief Medical Officer of Galectin Therapeutics (NASDAQ: GALT), the leading developer of therapeutics that target galectin proteins to treat NASH cirrhosis and cancer. He can be reached at boudes@galectintherapeutics.com.