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The Future of Fatty Liver: From Education to Anticipated Approvals
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The increasing prevalence of nonalcoholic fatty liver disease and its progressive form, nonalcoholic steatohepatitis, presents a significant need for therapeutic options. While no specific therapy or medication has yet received approval for treating NAFLD and NASH, several therapeutics are under clinical evaluation, some of which have already reached phase 3 testing. These therapeutic regimens, once approved, along with improved diagnostics and screening, and increased education and awareness of these diseases, will lead the way to better patient outcomes.
Most experts agree that the future of NAFLD and NASH treatment with new therapeutics will require combination therapy and long-term application, due to the metabolic aspect of fatty liver disease.
“Given the complexity of this disease, you will ultimately need more than one drug to treat patients, and the combination of what you would need to treat these patients will probably depend on the phenotype of the patient,” Zobair M. Younossi, MD, chairman of the department of medicine at Inova Fairfax Hospital, told Healio Gastroenterology and Liver Disease. “This is similar to diabetes, how we use different regimens and combine different drugs for a single patient.”
In his comparative example of patients with diabetes, Younossi explained that NAFLD and NASH are not diseases that can be treated for a short period and cured; rather, they will require ongoing treatment or else the process will begin again and not much will be gained in the end.
“In the initial treatment, which I call induction treatment, you can treat patients with significant fibrosis to reduce the fibrosis, to reduce the steatohepatitis or resolve it,” he said. “Following this, you will use a number of different regimens that could get the patient to a stage that is manageable, to a lower stage of fibrosis and less steatohepatitis, and then maintain that for life. That sort of paradigm shift from a viral hepatitis C scenario to NASH is what we need to get used to.”
Promising Pipeline
According to Younossi, as well as much of the recent data presented at this year’s meetings, there are four therapeutics currently in advanced phases of testing. These four show some of the most significant promise for safety and efficacy, providing a path to potential approval.
The first of these is Ocaliva (obeticholic acid, Intercept), a farnesoid X receptor (FXR) agonist that is approved by the FDA for treating primary biliary cholangitis in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in adults unable to tolerate UDCA.
In August 2017, Intercept initiated a randomized control phase 3 study of obeticholic acid for patients with NASH and compensated cirrhosis, including 540 participants. The company estimates that completed results for the primary outcome — significant improvement in fibrosis by at least 1 stage with no worsening of NASH — will be available by July 2020.
At the International Liver Congress in 2018, Vlad Ratziu, MD, PhD, from the Université Pierre et Marie Curie, Paris, presented updated information on cenicriviroc (Allergan) for patients with NASH and fibrosis.
Cenicriviroc, an oral C-C chemokine receptor type 2 and type 5 antagonist also known as CVC, demonstrated safety and provided antifibrotic activity in adult patients with NASH and fibrosis in a phase 2b clinical study. These data support previously reported 1-year outcomes that showed a significant decrease in Hb1Ac after 12 weeks. Ratziu noted in his presentation that an upcoming trial will look at CVC in combination therapy to evaluate NASH resolution.
Gilead currently has three therapeutics under investigation for advanced NASH-related fibrosis, including the acetyl-CoA carboxylase inhibitor GS-0976; the selective, nonsteroidal FXR agonist GS-9674; and an apoptosis-signal regulating kinase inhibitor known as selonsertib, which is being evaluated in combination with either GS-0976 or GS-9674.
A recent study published in Hepatology explored the safety and efficacy of selonsertib in patients with NASH and stage 2 or stage 3 fibrosis in a phase 2 trial. Rohit Loomba, MD, from the University of California in San Diego, and colleagues found that 18 mg of selonsertib with or without simtuzumab reduced fibrosis by at least one stage in 43% of patients and 6 mg of selonsertib with or without simtuzumab reduced fibrosis in 30% of patients after 24 weeks, compared with 20% of patients who received simtuzumab alone.
“These findings suggest that selonsertib may reduce liver fibrosis in patients with NASH and moderate to severe fibrosis,” Loomba and colleagues wrote. “The novelty of this proof-of-concept trial includes its use of standardized assessments of treatment response using magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF) and MRE with central reading of the images in a co-localized manner.”
Loomba and colleagues noted that a phase 3 trial of selonsertib for patients with NASH and bridging fibrosis and a phase 3 trial for those with compensated cirrhosis are currently underway.
Finally, Younossi pointed toward elafibranor (Genfit), an agonist of the peroxisome proliferator-activated receptor-alpha and peroxisome proliferator-activated receptor-delta. Previous studies have shown that elafibranor improved insulin sensitivity, glucose homeostasis and lipid metabolism, and reduced inflammation.
Results from a phase 2 study published in Gastroenterology showed that 120 mg of elafibranor per day for 1 year resolved NASH without worsening of fibrosis in patients with moderate to severe NASH. Elafibranor was also well tolerated and improved cardiometabolic risk profiles.
Genfit initiated a randomized control phase 3 trial of 120 mg elafibranor in February 2016 and estimates that completed primary results will be available by December 2021. The study includes approximately 2,000 patients with NASH and fibrosis.
First-line Therapy
News from recent phase 2 and phase 3 trials of NAFLD and NASH therapeutics indicate that it is only a matter of time before at least some of these medications receive approval. However, many hepatology experts advise that first-line therapy should be lifestyle intervention. Even once approved, fatty liver medications should be administered alongside dietary and physical activity guidance.
“The way we are trying to pose therapy is that it should be used as a complement to what patients are already working on — similar to a statin — this medication can be prescribed, but it should be used in combination with first-line therapy, optimization of healthy eating behaviors and maintaining physical activity,” Monica A. Konerman, MD, MSc, director of the Michigan Medicine NAFLD Clinic, told Healio Gastroenterology and Liver Disease. “Definitely the way providers should be presenting these medications to patients is that it will have to be in combination with first-line intervention therapy for these disorders.”
Konerman has led the discussion on lifestyle intervention for patients with fatty liver previously, including a presentation at Digestive Disease Week 2018 with a “call to action” imperative.
In her presentation, Konerman highlighted that 54% to 64% of patients with NAFLD or NASH reported minimal physical activity, less than the recommended 150 minutes or more per week of moderate intensity exercise or 75 minutes or more per week of vigorous intensity exercise. In contrast, a meta-analysis showed that exercise led to a 20% to 30% relative risk reduction in intrahepatic content among patients with fatty liver, regardless of weight loss.
Weight reduction has also aided in improving NAFLD outcomes. A study published in Journal of Hepatology showed that lifestyle intervention, including a regulated diet and moderate exercise with weight loss outcomes, significantly improved the likelihood of NAFLD remission and decline of intrahepatic triglyceride regardless of obesity.
“Lifestyle intervention is central in the management of NAFLD,” Vincent Wai-Sun Wong, MD, from the Chinese University of Hong Kong, and colleagues wrote in their study. “A number of diets including low-carbohydrate diet, low-fat diet, low-glycemic index diet and the Mediterranean diet have been shown to improve liver enzyme levels, liver fat, and histology of NAFLD patients. Likewise, beneficial effects have been observed for both aerobic exercise and resistance training.”
Arun Sanyal, MD, of Virginia Commonwealth University, echoed these sentiments during the Leon Schiff State-of-the-Art Lecture at the Liver Meeting 2018, stating that, as exciting as the current pharmacology pipeline is, it is critical that treating physicians remember to fight the root cause of fatty liver disease.
“While progress is being made to control liver outcomes, this is only a band aid,” Sanyal said during his lecture. “We face a moral, ethical and medical imperative to tackle the root cause of diabetes, cardiovascular disease and NASH — ie, diet-induced obesity. Weight loss, in general, is linked to improvement in histology but weight loss is not a resolution of NASH. Furthermore, fibrosis improvement can occur with less than 10% weight loss. There is biology there that we have left behind on the table.”
Noninvasive Diagnostics
Part of the effort to improve NAFLD and NASH outcomes is to diagnose fatty liver and steatosis early. However, general screening is not currently recommended, and certain noninvasive tests can be complicated, time-consuming, and expensive.
According to Younossi, there are three different kinds of diagnostic tools: those that can diagnose fat, those that can diagnose steatohepatitis, and those that can stage fibrosis. While MRI-estimated PDFF is a reasonable option for quantifying fat, he said, it is more important to establish a diagnosis of NASH and then stage fibrosis.
“Most of the effort to develop a noninvasive test for nonalcoholic steatohepatitis or steatohepatitis has failed so far and is not really a target of most diagnostic companies,” he said. “It’s really about stage of fibrosis.”
Regarding tests for fibrosis, the options include radiology, such as transient elastography with FibroScan (Echosens); serum-based testing, such as the Enhanced Liver Fibrosis (ELF) test; and those based on clinical algorithms of available data.
“From the noninvasive serum-based tests that we have available, the most promising in my view is a test called ELF — that has not been approved in the United States, but is available in Europe,” he explained.
Maja Thiele, PhD, from the Odense University Hospital of Southern Denmark, and colleagues published results of a study that evaluated the accuracy of ELF for the detection of advanced fibrosis in patients with a history of excessive alcohol use compared with other noninvasive diagnostic tools.
The ELF cut-off value of 10.5 correctly diagnosed advanced fibrosis in 79% of patients and the absence of advanced fibrosis in 91%. The 10.5 cut-off ruled out advanced fibrosis with a negative predictive value of 98% but could not affirm diagnosis of advanced fibrosis as the positive predictive value was 60%.
ELF outperformed the aspartate aminotransferase-to-platelet-ratio index, age-platelet index, Fibrosis-4 index (FIB-4), Forns index, aspartate aminotransferase-to-alanine aminotransferase ratio, and gamma-glutamyltransferase-to-platelet ratio.
Younossi explained that algorithms such as the FIB-4 and NAFLD fibrosis score are usually available in clinical settings and tend to give a good idea of what is going on with a patient in terms of risk.
“These tests, in my view of what we have available, are not diagnostic tests. They’re actually what I call enrichment tests,” he said. “By enrichment, I mean, if you take three tests in a row ... if you look at say a FIB-4, followed by an ELF test when it becomes available, followed by a FibroScan, the likelihood of having indeterminant cases of significant fibrosis would become very small. If you use these tests individually, the indeterminant area is about 20% to 40%. So, these tests will enrich the population that is at high risk, but then you ultimately still need a liver biopsy.”
Konerman highlighted multiparametric MRI as a leading option for imaging.
“Multi-parametric MRI and 3D MRE is where there’s a lot of the promising data in terms of noninvasive diagnosing for NASH, because that’s where we are in the most need,” Konerman said. “Between FibroScan and MRI-PDFF we have a pretty good ability to assess amount of steatosis and fibrosis in many cases. The difficulty is in getting at that inflammatory and primary hepatocyte injury piece that we’re not that great at. There are also multiple confounding processes that can impact fibrosis assessment using these noninvasive modalities, so the data on these new protocols of mutliparametric MRI and 3D MRE are exciting.”
Stephen A. Harrison, MD, medical director of Pinnacle Clinical Research, San Antonio, presented data at Digestive Disease Week 2018 showing that multiparametric MRI identified and stratified patients with NAFLD and NASH at a population level.
The study presented included 3,227 participants from the U.S. and U.K. who received multiparametric MRI to estimate liver fat fraction. Nearly all the participants (99%) with PDFF of 5% or higher and a Liver Inflammation and Fibrosis score of 2 or higher had NAFLD and 56% had NASH. After projecting their estimates on the U.K. portion of the cohort, the researchers found an estimated NASH prevalence of 11.8% in the general population.
Harrison concluded his presentation stating that multiparametric MRI using LiverMultiscan (Perspectum Diagnostics) can accurately identify histological hallmarks of NASH, specifically fatty liver disease.
Raising Awareness
Younossi and Konerman both stressed the “next steps” toward improving NAFLD and NASH outcomes and prevention of these diseases involves raising awareness among physicians and patients.
“There is not enough knowledge about this disease among the lay public, by the policymaker standpoint, and by the provider standpoint,” Younossi said. “You leave the hepatology side and find that very few in primary care and some subspecialties that are important for this disease such as endocrinology have a good understanding of what this disease is.”
The problem, he continued, is that these treating physicians in primary care of other subspecialties will be first to see these patients for other problems like hypertension or diabetes but might not think to investigate their liver function.
“The most important thing between now and the time when we will have an accurate diagnostic test and an effective treatment is to raise awareness that there is a subgroup of their patients with certain characteristics that can actually experience bad outcomes from a liver standpoint,” he said. “That awareness needs to be raised.”
According to Konerman, one barrier is that the current guidelines, including those by the AASLD in 2018, do not support general screening even among high-risk populations.
“When you talk to primary care physicians or other referring providers that see a lot of patients that likely have NASH, they’re frustrated and not sure what they should be doing in terms of evaluating and risk stratifying these patients,” Konerman said. “Anecdotally, many primary care and referring providers I have discussed this issue with have stated they don’t use the clinical decision aides suggested by the guidelines including FIB-4 and NAFLD fibrosis score, and among those who have used them, they often find the information difficult to interpret or not helpful for identifying patients who need specialist evaluation. In addition, many referring providers do not have access to directly order a FibroScan. As a result, in clinical practice, these recommendations are not panning out to be very helpful for many referring providers.”
Younossi pointed toward societies as a first-line bridge to improving awareness and education.
“I think societies have to take a lead on that,” he said. “Most of the time, societies are at the basic science and clinical level. We don’t really have effective educational programs for the lay public or other subspecialties. Number one, there has to be a cross-fertilization of societies.”
In those terms, he said that while obviously AASLD could work closely with ACG and AGA, they could extend their connections to the American Diabetes Association, American Family Practice, and the American College of Physicians, as these patients are rarely only the concern of hepatologists and gastroenterologists.
“Number two, there are programs like Chronic Liver Disease Foundation, that can actually provide the opportunity to spread the word out,” he continued. “I think these efforts need to be supported. None of these will work if there is not enough support. I think both private industry as well as the government should provide funding to raise awareness, because at the end of the day, you can have very good drugs, and very good diagnostics tests, but if there is not awareness, you’re not going to have the patients.” – by Talitha Bennett
- References:
- Konerman M, et al. Abstract Sp87. Presented at: Digestive Disease Week; June 2-5, 2018; Washington, D.C.
- Lawitz E, et al. PS-105. Presented at: International Liver Congress; Apr. 11-15, 2018; Paris, France.
- Loomba R, et al. Am J Gastroenterol; 2016;doi:10.1038/ajg.2016.6.
- Loomba R, et al. Hepatol. 2018;doi:10.1002/hep.29514.
- Mantry P, et al. FRI-488. Presented at: International Liver Congress; Apr. 11-15, 2018; Paris, France.
- Ocaliva (obeticholic acid) label. FDA. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/207999s003lbl.pdf.
- Phase 3 Study to Evaluate the Efficacy and Safety of Elafibranor Versus Placebo in Patients with Nonalcoholic Steatohepatitis (NASH) (RESOLVE-IT). U.S. National Library of Medicine. Posted: Mar. 10, 2016. Updated: Sept. 25, 2018. https://clinicaltrials.gov/ct2/show/NCT02704403.
- Ratziu V, et al. GS-002. Presented at: International Liver Congress; Apr. 11-15, 2018; Paris, France.
- Ratziu V, et al. Gastroenterol. 2018;doi:10.1053/j.gastro.2016.01.038.
- Sanyal A, et al. Leon Schiff State-of-the-Art Lecture. Presented at: The Liver Meeting 2018; Nov. 9-13, 2018; San Francisco.
- Schwabi P, et al. FRI-248. Presented at: International Liver Congress; Apr. 11-15, 2018; Paris, France.
- Study Evaluating the Efficacy and Safety of Obeticholic Acid in Subjects with Compensated Cirrhosis Due to Nonalcoholic Steatohepatitis (REVERSE). U.S. National Library of Medicine. Posted: Feb. 20, 2018. Updated: May 24, 2018. https://clinicaltrials.gov/ct2/show/NCT03439254.
- Thiele M, et al. Gastroenterol. 2017;doi:10.1053/j.gastro.2018.01.005.
- Wong VW, et al. J Hepatol. 2018;doi:10.1016/j.jhep.2018.08.011.
- For more information:
- Monica Konerman, MD, MSc, can be reached at konerman@med.umich.edu.
- Zobair M. Younossi, MD, can be reached at zobair.younossi@inova.org.
Disclosures: Younossi reports he is a consultant to or has received research funds from AbbVie, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Intercept, NovoNordisk and Shinogi. Konerman reports no relevant financial disclosures.