Obesity News Today recently interviewed Dr. Peter Traber, Chief Executive Officer and Chief Medical Officer at Galectin Therapeutics. Here are some of his insights on non-alcoholic fatty liver disease (NAFLD), a prevalent but often unrecognized medical condition that is on the rise. For more insights on Galectin’s GR-MD-02 and NASH, visit Dr. Traber’s blog CEO Perspectives.
Dr. Alisa Woods: Can you elaborate on the unmet need for treatments of fatty liver disease?
Dr. Peter Traber: Obesity and related disorders, such as diabetes, have been increasing for decades. In parallel, fatty liver disease has likewise been increasing. While some lean individuals can develop NASH, the overwhelming preponderance is associated with obesity. Non-alcoholic fatty liver disease, or NAFLD, consists of simple fatty liver. NASH (non-alcoholic steatohepatitis), which is when fat [is] in the liver, is associated with inflammation and cell death, and NASH with various stages of liver fibrosis, which are scored from 0-4. Stage 4 liver fibrosis is the most advanced form, called cirrhosis.
Among asymptomatic adults in the U.S., as many as 50% have fatty liver and 12% have NASH. Information like this has led analysts (Deutsche Bank) to estimate that there may be as many as 30 million people with NASH in the U.S. Of those, up to 9 million have NASH with stage 2,3 fibrosis and 1-2 million have the most advanced form of NASH cirrhosis. The end stage of this disease, cirrhosis, is a severe condition which leads to complications and death. As an indication of this, it is projected that NASH patients will make up the majority of patients who receive liver transplants in the coming years. However, since there are only just over 6,000 liver transplants per year in the U.S., many patients with NASH cirrhosis may die of their disease. There are no therapies currently approved for NASH or for the fibrosis associated with NASH, so the unmet medical need is enormous.
AW: Why does NASH frequently go undetected?
PT: NASH is asymptomatic. Patients will not know that they have the disease. The disease is most often identified in patients when their physician gets a blood test of liver enzymes (AST and ALT), which may be elevated, or an imaging test of the liver (ultrasound, CT, MRI), which will show fat. The only way to confirm the diagnosis and determine the amount of fibrosis is a liver biopsy. Research is underway to identify non-invasive methods for evaluating what a liver biopsy can reveal.
AW: What is the plan for Phase III studies of GR-MD-02 or the clinical development plan in general?
PT: We are now studying two indications for NASH with GR-MD-02 in phase 2 clinical trials. One trial, NASH-CX, is enrolling patients with NASH cirrhosis, with the goal of one year of therapy to reverse or partially reverse fibrosis. The second trial, NASH-FX, is enrolling patients with NASH with stage 3 fibrosis, but not cirrhosis, with the goal of 4 months of therapy to reverse or partially reverse fibrosis. Phase 3 trials in either indication will be guided by the results of these trials, and the design for the phase 3 clinical trials will be different for each indication.
AW: Can fatty liver disease be detected earlier?
PT: Yes, it can be detected earlier at this time. This requires an awareness program for physicians and patients, evaluation of serum liver enzymes, which are a common part of general medical visits, and imaging tests for liver fat. One of the barriers to detection programs is that there is no therapy. However, detection programs may lead to weight loss, better diabetes care and exercise, which can reverse the early stages of NASH. The later stages of fibrosis and cirrhosis are not reversible by lifestyle changes. There are emerging tests available that can distinguish early from late stage disease. However, once again, there is no therapy.
AW: Could GR-MD-02 be used as a preventative for fatty liver disease?
PT: Preventative approaches need to be carefully considered for such a large problem. Even if you focus preventative care on those patients with simple fatty liver disease, that includes nearly 50% of the adult population! It is impractical to think of drug treatment prevention for such a large group of people. A focus on lifestyle changes, while challenging, makes more sense. In any event, GR-MD-02 is an intravenous drug given once every two weeks which could not be used as a preventative, but only in the advanced patients that we are focusing on in our clinical trials.
AW: Do you have plans for other galectin-3 inhibitors?
PT: Yes, we have a discovery program for synthetic carbohydrate molecules and small organic molecules that inhibit galectin-3 to identify even more potent inhibitors and compounds that will allow subcutaneous and oral administration.
AW: Is there additional information that you would like to discuss?
PT: I want to make three additional points. First, NASH is a chronic disease that takes decades to progress to cirrhosis in most people. We cannot predict early which patients will progress to the end stage. There was a study done in Scandinavia that followed patients with NASH for up to 33 years. Those with early disease (stage 1 and 2 fibrosis) at the beginning of the study had no increase in mortality compared to a reference group. Whereas those with late disease (stage 3 and 4 fibrosis) had a marked increase in mortality. This is a disease where we need to think carefully about where therapy is targeted, and that’s why we are focused on advanced fibrosis.
Second, NASH is a growing problem in children and adolescents. In a recent analysis of liver transplants for NASH cirrhosis in young patients, a review of the transplant registry (1987-2012) found that 14 subjects were less than 18 years of age at the time of liver transplant and 20 subjects were between the ages of 18 and 25. Even though this covers a long period of time, the data are rather shocking to me. With the increasing problem of childhood obesity, we will certainly see many more young people requiring liver transplant, highlighting the need for effective therapies. These data also show that NASH can progress rapidly, but we cannot identify as of yet who are the rapid progressors.
And finally, should GR-MD-02 reverse fibrosis in advanced NASH, it will be a huge breakthrough. With such a large problem, there will be NASH cirrhosis for many decades to come and prevention will not make a meaningful impact for a long time. A drug that can reduce fibrosis and thereby reduce symptoms, complications, transplants, and death from this disease is greatly needed. Additionally, should GR-MD-02 work in NASH cirrhosis, it should also work in other fibrotic liver diseases and fibrosis of other organs such as lung, kidney, heart and vessels.