Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome (MetS) and defined as the accumulation of fat in the liver in patients who do not consume significant amounts of alcohol.1 NAFLD encompasses a wide spectrum of conditions, from simple fat accumulation (fatty liver) to steatohepatitis (NASH) with or without fibrosis up to the stage of cirrhosis.1 Features of MetS are highly prevalent in patients with NAFLD and the risk of developing NAFLD increases with the number of components of MetS. As a consequence, the increasing prevalence of MetS and NAFLD go hand in hand, and NAFLD is strongly associated with insulin resistance, type 2 diabetes, central adiposity, dyslipidemia, and hypertension.1,2
NAFLD affects an estimated 20-30% of people in the United States and is the leading cause of chronic liver disease in the Western World.2,3 NASH, the most aggressive form of the disease, when accumulation of liver fat is accompanied by cellular injury and inflammation, is estimated to affect 2-5% of Americans; however, the actual prevalence of NASH may be considerably higher due to the challenge of identifying patients with the disease, which remains largely symptomless until well advanced.3-5 The disease can progress to fibrosis, cirrhosis, and/or hepatocellular carcinoma (HCC) 2,4 making these the second leading cause of liver transplants in the United States and poised to become the leading cause of transplants by 2020.6 Several clinician specialties are involved in the management of this disease, and the role of the endocrinologists, diabetologists, and primary care clinicians is crucial in the early recognition, diagnosis, and overall management of NAFLD and NASH.7
Despite these impacts, NASH frequently goes undiagnosed.5,8-11 In addition, its management is challenging since there are no current FDA-approved agents for this condition. However, many agents are being evaluated in clinical trials for the treatment of NASH. To explore some of the challenges and considerations with NASH clinical trials, we spoke with Andrew Roche, PhD, Senior Director, Scientific Affairs at ICON, one of the largest international clinical research organizations with expertise in running NASH studies.
Cardiometabolic Chronicle: Currently, a big part of the problem with NASH is delayed diagnosis or underdiagnosis. How is this affecting NASH clinical trials?
Dr. Roche: Without a doubt, diagnosis remains a challenge on multiple levels, including obtaining and assessing the liver biopsy, which remains the gold standard for diagnosing and staging of NASH12. It’s also believed that a high proportion of NASH patients are undiagnosed because the disease is largely symptomless or causes non-specific symptoms until well advanced. Also, patients and their physicians may prefer to sidestep diagnosis, knowing that the recommended treatment for most patients, improved diet and more exercise, is anyway within their grasp.
From a clinical trials perspective, studies from phase 2b and on need to have a liver biopsy per the FDA guidance.12 Prior to phase 2b, other less invasive assessments can be performed (e.g., imaging), although the different clinical accuracies of the respective processes can be expected to lead to differences in the characteristics of the populations studied pre and post phase 2b. The risk of performing a liver biopsy is a hurdle for enrollment in many studies. Increasing awareness about the implications and complications of NASH is important, but at this time, NASH is still an underappreciated disease for which many people do not want to get tested. This is compounded by the current absence of approved therapies and thus the enticements to encourage patients to undergo a liver biopsy are currently comparatively limited. It is expected that this will be partially alleviated by providing a better understanding of the exciting new therapies for NASH that are currently in development
Another challenge that impacts site engagement and, consequently, enrollment rates is the analysis of the liver biopsy and the differences in assessments performed by the local pathologist and the central specialist pathologist. A diagnosis of NASH by a local pathologist may lead to the conclusion that the patient is suitable to be enrolled in the trial. However, it is not uncommon that the central specialist pathologist deem the patient to be unsuitable for the study when the NAFLD Activity Score (NAS)13 criteria are used to assess suitability of the subject against the enrollment criteria of the clinical study protocol. The NAS scoring system is designed to allow for assessment of changes with therapy during the course of a clinical trial and is not commonly utilized at local level. Such situations of discordance can demotivate sites if they are unable to enroll subjects who, they feel, are appropriate for the study. Improving communication between the local pathologist, investigator and the central pathologists is crucial to ensure understanding of the role of the central pathologist, i.e., to ensure uniformity of the study population and the consistency of assessment throughout the study.
It is also important to note that a liver biopsy will not represent the whole liver and it is critical to obtain as sizeable a specimen as possible. The impact of sampling quantity and variability can significantly affect the assessment, e.g., Ratizu et al. 14 illustrated how often a diagnosis can be missed if you have too little specimen. In 24% and 35% of cases hepatocyte ballooning and bridging fibrosis, respectively, were missed as a result of insufficient sample.
Cardiometabolic Chronicle: What is being done to better identify patients and overcome challenges associated with liver biopsies?
Dr. Roche: Several groups are trying to address this by creating clinical diagnostic tools, including imaging solutions, that are less invasive and of comparable clinical accuracy thus eliminating the need for liver biopsy. While there are promising candidates on the horizon such a tool does not yet exist. As such, liver biopsies for phase 2b trials and up are still required as these remain to be the gold standard method of NASH diagnosis.12
Other strategies include use of non-invasive tools to pre-screen subjects to better predict those that are least likely to be suitable for the enrollment requirements of a clinical study and therefore should not proceed to a biopsy. There are a number of imaging tools and laboratory biomarkers that have a strong ability to predict steatosis and fibrosis, e.g., ultrasound in the case of the former and the Fibrosis-4 (FIB-4) score 15 in the case of the latter. The European Medicines Agency (EMA) has approved the ELF test for assessment of fibrosis. Both are based on multiple blood-borne biomarkers and work very well in identifying subjects who have cirrhosis (F4) and those who have no fibrosis (F0) but are not optimal for differentiating between intermediate stages of fibrosis e.g. F2 vs F3. While strong options exist to identify levels of steatosis and fibrosis, the same is currently not true for biomarkers that can accurately distinguish, with high accuracy, presence of NASH from absence. Some biomarkers, like cytokeratin-18 (CK-18) fragments, have reported levels of clinical accuracy of up to 80% which, while promising, is still not ideal. Noninvasive NASH biomarkers are an area of continued focus for the industry and an area of considerable unmet need.
Cardiometabolic Chronicle: What are the important NASH endpoints that are being evaluated in clinical trials? Dr. Roche: The current prevailing opinion is that a NASH therapy must demonstrate ability to prevent a liver transplantation in order to ensure reimbursement. As such, a key component that a candidate drug must address is fibrosis. NASH also includes other manifestations in addition to fibrosis, such as steatosis, inflammation, and ballooning, but ultimately it is fibrosis that determines the need for a liver transplant.
This focus on recruiting NASH patients with moderate fibrosis (F2-F3) creates one of the key challenges of NASH studies - enrolling subjects at a suitable rate, 25-45% of NAFLD patients typically have no fibrosis, approximately 30% have fibrosis stage F1, 5-10% have cirrhosis (F4), leaving only ~25% with fibrosis stage F2 to F3.
Cardiometabolic Chronicle: Based on your experience with NASH trials, is there any outreach to other physician specialties that are in the forefront the NASH epidemic to better identify patients who can be candidates for these trials?
Dr. Roche: This is a very important point. Historically, NASH clinical trials have been supported primarily by hepatologists or gastroenterologists. However, the field needs to involve those physicians who see the majority of diagnosed and undiagnosed NASH patients, i.e., primary care physicians and endocrinologists. This can be achieved by increasing general awareness of NASH amongst these physicians and their patients. ICON is working to expand our network of NASH qualified clinicians and sites by helping them link up with specialists with the appropriate skills and equipment (e.g., MR imaging, radiologist for biopsies and Fibroscan to measure liver stiffness) as a means of optimizing enrollment.