1. Can you tell us about yourself and your experience in the field of hepatology and in particular, NASH and NAFLD?
I am a transplant hepatologist and the director of the Metabolic Liver Disease Center at the Texas Liver Institute in San Antonio, Texas. After completing a combined residency in internal medicine and pediatrics, I completed a combined fellowship in adult and pediatric hepatology. I have a busy clinical practice where I see both adults and children with NAFLD/NASH and I am principal investigator on multiple clinical trials for NASH therapeutic agents.
2. Can you explain how the problem of NAFLD and NASH has developed and how quickly it is escalating globally?
The epidemic of NAFLD parallels the rise of obesity and type 2 diabetes epidemics in the western world and globally. We estimate that 25% of adults globally have NAFLD and these rates are higher in South America and the Middle-East. The awareness of NAFLD as a complication of obesity and diabetes has increased over the past decade and more patients are being referred to our clinics for suspected NAFLD.
3. Is there an increased incidence in children in the same way that type-2 diabetes (T2D) has increased?
Unfortunately, NAFLD affects children and adolescents with a marked increase in prevalence over the past 3 decades. NAFLD now affects 5–10% of children in the United States and has a strong association with obesity and metabolic syndrome.
4. How do co-morbidities complicate the clinical trials of NASH?
Co-morbidities such as uncontrolled diabetes and significant cardiovascular disease are typically considered as exclusion criteria for NASH clinical trials. Medications used to treat these co-morbidities including GLP-1 agonists, pioglitazone, and statins may affect the course of NAFLD.
5. Can you briefly discuss some leading pharmacological approaches tested in phase II and III clinical trials in 2019 and expectations for 2020/21?
Several medications are being developed to treat NASH with significant fibrosis; some have advanced to phase 3 trials. These medications can be divided into three major categories based on their mechanism of action including (1) Medications that target the gut-liver axis and bile acid enterohepatic circulation, (2) Medications that target lipids and metabolism, and (3). Medications that target Liver injury including hepatocyte death, inflammation, and fibrosis.
An example of a medication that targets the gut-liver axis is obeticholic acid (OCA) which is the most advanced drug in development. OCA is an agonist for the farnesoid X receptor (FXR), a nuclear receptor that senses bile acids and regulates their synthesis.
In the phase 3 REGENERATE trial, patients who received OCA at 25 mg daily had significant improvement in fibrosis by 1 stage at 18 months compared to those in the placebo arm. In an updated analysis that was presented at the Liver Meeting in Boston, OCA demonstrated efficacy in terms of NASH resolution in patients with stage 1–3 fibrosis and active NASH. OCA’s consistent efficacy on fibrosis regression in phase 2 and 3 trials in patients with NASH and significant fibrosis is paving the way for potential FDA approval by 2020.
6. What are the challenges for clinical endpoints in phase II/III NASH trials?
Patient enrollment due to strict inclusion/exclusion criteria.
The reliance on liver biopsy and histologic improvement as the primary endpoint for phase 3 NASH trial and as a pathway for FDA-approval of drugs.
The need for noninvasive tests to assess the response to treatment and futility of treatment.
7. What in your view are the key challenges and considerations with NASH clinical trials and how can researchers address these challenges during trial design or study execution?
Intensive research is taking place to find a reliable replacement for liver biopsy as a method for identifying patients that will benefit from pharmacologic treatment and monitoring the response to treatment.
8. What are the key advancements made in diagnostics and how important is noninvasive testing?
Several noninvasive tests (NITs) have been developed to predict the presence of advanced liver fibrosis in patients with NASH. These can be divided into serologic tests such as the FIB4 index and the ELF score OR imaging tests such as transient elastography measurements with Fibroscan or MRI.
9. Finally, what are your hopes for the prevention and treatment of patients with this disease over the next decade?
My hopes are as follows:
Widespread screening programs for NAFLD/NASH in high-risk populations such as those with type 2 diabetes and metabolic syndrome.
Validation of NITs to classify patients into low-risk and high-risk without the need for liver biopsy.
The availability of several pharmacologic agents with great efficacy and excellent safety profiles to treat patients with NASH as mono- and combination-therapies.
Disclaimer
The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Taylor & Francis.
Declaration of interest
N. Alkhouri has received research funding from Gilead, Intercept, Allergan, Cirius, Madrigal, and Genfit. The interviewee has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.