January 15, 2021
11 min read
Goulden reports no relevant financial disclosures. Loomba reports consulting for Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse bio, Inipharm, Intercept, Ionis, Janssen Inc., Madrigal, Metacrine Inc., NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, Sagimet, 89 Bio, and Viking Therapeutics; his institution has received grant support from Allergan, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, Genfit, Gilead, Intercept, Inventiva, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, Pfizer and Siemens; is co-founder of Liponexus Inc., and receives funding support from NIEHS (5P42ES010337), NCATS (5UL1TR001442), DOD PRCRP (W81XWH-18-2-0026), NIDDK (U01DK061734, R01DK106419, R01DK121378, R01DK124318, P30DK120515), NHLBI (P01HL147835), and NIAAA (U01AA029019). Younossi reports receiving research funding and/or is a consultant for Abbott, AbbVie, Bristol Myers Squibb, Gilead Sciences, Intercept, Madridgal, Merck, Novartis, Novo Nordisk, Quest, Siemens, Terns, and Viking. Fried is chief medical officer and stockholder in Target RWE and Friedman reports consulting for 89 Bio, Amgen, Axcella Health, Blade Therapeutics, Bristol Myers Squibb, Can-Fite Biopharma, ChemonAb, Escient Pharmaceuticals, Forbion, Forsite laboratories, Galmed, Gordan Biotechnology, Glycotest, Glympse Bio, Hepgene, In sitro, Morhpic Therapeutics, North Sea Therapeutics, Novartis, Ono Pharmaceuticals, Pfizer Pharmaceuticals, Scholar Rock and Surrozen; has stock options in Blade Therapeutics, Escient, Galectin, Galmed, Genfit, Glympse, Hepgene, Lifemax, Metacrine, Morphic Therapeutics, Nimbus, North Sea Therapeutics, Scholar Rock and stock ownership in Group K, Intercept and Madrigal.
Nonalcoholic steatohepatitis is the second leading indication for liver transplantation in the United States but there are currently no FDA-approved treatments available.
Rohit Loomba, MD, MHSc, director of the NAFLD Research Center and director of hepatology, professor of medicine at the University of California, San Diego, told Healio Gastroenterology that in the next decade NASH will likely become the No. 1 indication for liver transplantation. The increase in the prevalence and incidence of obesity and type 2 diabetes will increase the burden of liver disease in the coming decades.
In an interview, Zobair M. Younossi, MD, MPH, FACP, FACG, AGAF, FAASLD, president of Inova medicine, at the Inova Health System and professor and chairman of the department of medicine at Inova Fairfax Medical Campus, said the most challenging part is the lack of awareness about this liver disease.
“There is a tremendous lack of awareness about NAFLD and NASH amongst all stakeholders. That includes patients and providers,” Younossi said. “So there has to be a great deal of focus on understanding this important liver disease that impacts not only clinical outcomes, but also quality of life and we need to make sure that we address that.”
Younossi said there needs to be a better way to identify patients at risk for significant liver disease to give them proper care.
“We have recently completed a global survey of over 3,000 providers like primary care, endocrinologists, gastroenterologists and hepatologists. The data suggested a lack of awareness among front line providers who see most of these patients and a lot of these patients are not getting identified in clinical practices,” Younossi said.
He also said another challenge is conducting risk stratification using noninvasive tests and linking patients at high risk to gastrointestinal and hepatology care.
COVID-19 seems more aggressive in patients with visceral obesity, especially morbid obesity, Younossi said, and these poor outcomes may be seen in patients with NAFLD and NASH.
“[The] pandemic had slowed down enrollment of NASH patients in clinical trials of new drugs, initially, but people have actually gone into alternative ways of collecting data, including virtual visits and other novel approaches to clinical trials so it’s not as bad as we initially thought it could be,” he said.
“When I talk to companies, there has obviously been some delays in enrollment [in trials], but I wouldn’t say it’s been catastrophic at all; in fact, for the most part, it’s better than what one might have expected,” Scott Friedman, MD, dean for therapeutic discovery and chief of the division of liver disease at the Icahn School of Medicine at Mount Sinai, told Healio Gastroenterology.
Noninvasive Diagnostics for NAFLD, NASH
Michael W. Fried, MD, FAASLD, chief medical officer of TARGET RWE, told Healio Gastroenterology, liver biopsy was relied on the most for diagnosing and staging NASH; however, he said in usual practice it is not practical to perform biopsy on every patient. Biopsies may be expensive, have modest risk and patients may not accept them. Therefore, it is not the ideal way to diagnose patients, according to Fried.
Fried said many tests rely on algorithms using clinical markers routinely obtained during care of patients with NASH such as the NAFLD fibrosis score, which includes age, diabetes, aspartate aminotransferase, alanine aminotransferase platelet count and albumin to create a risk score for likelihood of advanced fibrosis.
Fried said there are some blood tests, but many were not recognized as being the most accurate way to diagnose to NASH.
Friedman told Healio Gastroenterologythe NAFLD fibrosis score uses measurements in blood as well as another blood test from OWL metabolomics that measures lipid components in blood and is undergoing validation.
Fried said his group from TARGET-NASH presented information regarding a few initiatives in which non-invasive markers were associated with long-term outcomes related to liver disease, cardiovascular disease, liver cancer and mortality at the recent AASLD meeting.
“We’re also working to validate a simple clinical algorithm that we use as a pragmatic definition for NASH and compare the results from liver biopsies that have been reviewed by a central pathologist,” Fried said.
Friedman said there is also growing interest in detecting new proteins that may reflect the disease state. Technology that measures many proteins in blood at once like the SomaLogic platform, a newer entry in the NASH diagnostic space, may help.
Friedman also mentioned magnetic resonance elastography, the stiffness test for measuring potential correlation with fibrosis. A related technology, corrected T1 weighted imaging, is being evaluated by Perspectum Diagnostics, a company in the U.K.
“I work with Glympse Bio, and they use a test that administers nanoparticles that are cleaved in a very selective way and excreted in the urine where they can be measured, and the pattern of the particles’ breakdown products in the urine may reflect the stage of disease – this is also nearing clinical testing,” Friedman said.
He also said there are at least four companies using artificial intelligence-based digital pathology methods to quantify the different features of a liver biopsy. These methods do not rely upon the evaluation of pathologists or may complement them, since a pathologist’s evaluation is more subjective. Among these companies are Histo Index, Pharma Net, Path AI and Revealbio.
“As an endocrinologist, I see patients with obesity in combination with type 2 diabetes, so you know one of the things I’m always looking for is whether those patients have evidence of NASH,” Peter Goulden, MD, FRCP, medical director, endocrinology, Mount Sinai, told Healio. “So, one of the noninvasive measures that I will look at to determine that is if they had a recent liver enzyme test. You may see elevation on some of the liver enzymes, particularly the AST, ALT, gamma-GT, three of the enzymes we see. But that’s not always the case in NASH.”
He said liver ultrasounds can indicate if there is NAFLD (NASH is only diagnosed by biopsy). Additionally, transient elastography equipment such as FibroScan (Echosens) and MR elastography can assess liver elasticity as well as fatty liver disease.
Radiologic tests are based on measurement of liver stiffness, but they can also assess the amount of fat in the liver. The most common one used in clinical practices is transient elastography (TE), which is a point of care test that can be used in a clinical setting. According to Younossi, TE is much more practical in the clinical setting. Although MR elastography is the most accurate technology, it is less available and more expensive than TE.
These radiologic tests are used in conjunction with other non-invasive clinical tools for fibrosis such as FIB-4. If the FIB-4 is less than 1.3, it suggests a low risk for significant liver disease or fibrosis. However, if the FIB-4 is more than 1.3, then a second line of noninvasive testing such as TE should be done, according to Younossi.
Loomba and colleagues published study results in Gut that showed MR elastography 3.3 or greater Kpa with FIB-4 1.6 or more had a high positive predictive value of over 90%, which can eliminate the need for liver biopsy in those who are positive in the screen.
Younossi said there are currently no serum biomarkers approved for fibrosis in the U.S.; however, in Europe there is the alpha test or enhanced liver fibrosis test that determines the stage of liver disease.
“In the future, there’s going to be much better use of these algorithms that risk stratify patients. Probably in the medium term, we will have additional algorithms that will be much more accurate to not only rule out significant liver fibrosis, but also rule in presence of advanced fibrosis,” Younossi said.
“In the future, there’s going to be much better use of these algorithms that risk stratify patients. Probably in the medium term, we will have additional algorithms that will be much more accurate to not only rule out significant fibrosis, which each can be pretty good, but also rule in significant fibrosis, which is what we are hoping that the future noninvasive tests will optimized,” Younossi said.
“We are moving toward a future where we will not need a liver biopsy,” Loomba said. “Currently, for treatment trials, we are using some of these tests to [identify] who should get a biopsy rather than everybody coming in getting a biopsy.”
“Everybody recognizes that right now the lack of good noninvasive markers, certainly markers that can be used for drug approval in the phase 3 trial, is a huge handicap to progress in drug approval,” Friedman said.
Pipeline of Treatments
“The NASH therapeutic pipeline is really robust and, truly there are probably dozens of medications with different mechanisms that are being investigated in various phases of drug development,” Fried said. “But, while there have been some setbacks, there are also numerous drugs, particularly some presented at the Liver Meeting Digital Experience just a few weeks ago, that are showing great promise for the potential to treat NASH. Most of these drugs are going to be approved on the basis of relatively short-term studies demonstrating histological improvement and ameliorating histological changes in NASH.”
Younossi said right now lifestyle modification is the best treatment option available for NAFLD and NASH. However, he said to get the benefit of the weight loss and lifestyle modification, patients would have to lose 10% of their baseline weight, which is both difficult to achieve and maintain in the long term.
Younossi said vitamin E is not FDA approved but is recommended by AASLD guidance for non-diabetic patients with NASH and no cirrhosis.
“The first thing I really want to emphasize before I even talk about medication is lifestyle, right at the start with these cases,” Goulden said. “We know that actually that’s probably one of the most effective ways of treating this, so actually it may be somewhere between 5% and 10% weight loss, emphasizing dietary changes, steady weight loss, physical activity; there’s good evidence around that.”
Goulden said as an endocrinologist he tends to look for treatments that he may use in patients with type 2 diabetes. He said he has used a glucagon-like peptide-1 (GLP-1) receptor antagonist that produces weight loss and there are improvements in liver enzymes. He also uses metformin and sodium-glucose cotransporter-2 inhibitors in patients with type 2 diabetes.
Loomba said we have FXRs such as obeticholic acid (Intercept Therapeutics Inc). Intercept showed positive data, Friedman said. However, the FDA cancelled the advisory board to consider approving the drug because of safety concerns that are being addressed by the company. Agonists may also be effective.
“We also have therapies that lower liver fat and could reduce lipotoxicity. Among those, we have [acetyl-CoA carboxylase (ACC)] inhibitor, and I have designed and published several of those trials,” Loomba said.
Loomba said he and his colleagues combined a low-dose FXR with a full-dose ACC inhibitor and showed that it can improve liver histology in patients with stage 3 and stage 4 cirrhosis.
Friedman also pointed out that there are other FXR agonists such as tropifexor (Novartis) and cilofexor (Gilead).
Thyroid hormone beta receptor agonists – which increase fatty acid oxidation in the liver, reduce liver fat and improve liver disease – can improve NASH resolution. Among these, resmetirom from Madrigal is the most advanced of these agents. Further, researchers are conducting clinical trials of BK2809 from Viking Therapeutics in patients with biopsy-proven NASH. Loomba said there are robust data from these trials showing liver fat reduction.
Loomba noted there are a few therapies in the fibroblast growth factors (FGF) family such as FGF21 that can reduce liver fat and improve lipotoxicity. It may also improve insulin resistance at the level of the liver and thus improve NASH. Additionally, FGF19 may inhibit bile acid synthesis, decrease lipotoxicity, increase beta oxidation and decrease fatty acid synthesis.
“There’s a study that GLP-1 with ACC inhibitor achieves better reduction in liver fat and you could see greater reduction in ALT and AST, a biomarker based study, so I expect in the future there will be combination therapy trial,” Loomba said.
TVB-2640 from Sagimet Biosciences is a fatty acid synthase inhibitor that can lead to reduction in de novo lipogenesis, reduction in liver fat, improvement in ALT and AST and other biomarkers of fibrosis and leads to significant reduction in liver fat with an oral dose of 50 mg daily. These promising data provide proof-of-concept data to move to assess the efficacy of TVB-2640 in patients with biopsy-proven NASH with fibrosis.
“Semaglutide, which is a GLP-1 agonist from Novo Nordisk, yielded a dramatic improvement in the resolution of NASH, however the drug did not improve fibrosis and there was a very high placebo response rate, so it looked encouraging but not definitive and it was a phase 2 not a phase 3 trial,” Friedman said.
“[This is] just the tip of the iceberg, there are so many other things going on in NASH that to me it’s just a matter of time before we break through with the clinical drugs and some hope for patients,” Friedman said.
During the Liver Meeting Digital Experience, Phillip N. Newsome, PhD, from the Birmingham Biomedical Research Centre in the United Kingdom, said semaglutide produces NASH resolution without worsening fibrosis.
Fried said with the TARGET-NASH longitudinal study, patients once treated with new, approved medications in the future are going to be observed to assess long-term safety and effectiveness over multiple years.
“Demonstrating the impact of these medicines over the long term will be really important for the field,” Fried said. “So, we’re very excited by the potential for all these new drugs.”
“We have several classes of agents that are becoming available and moving on to phase 2b and phase 3 trials that show promise, and so the future seems really bright for both monotherapy and then moving on to combination therapy for treatment of NASH and NASH-related fibrosis,” Loomba said.
Younossi said in the future he believes there will be a combination of two or three drugs that will improve fibrosis stage of patients with NASH. Once the initial improvement is documented, patients may be managed with a maintenance regimen to continue to experience the benefits, according to Younossi.
What to Expect in 2021
“In my estimation, hopefully we’ll have a drug approved in 2021, hopefully we’ll have at least one additional serum biomarker available for approval in 2021, but a number of output protocols for new research would be also up and running,” Younossi said.
Friedman said there may not be an approval seen for a NAFLD or NASH treatment in 2021. He said the treatment closest to getting approval may be Intercept’s obeticholic acid, which is working with the FDA to address its concerns.
Loomba said, “Next year in 2021, we’ll have a lot of activity. There will be two or three programs that will get to combination and then we might see some additional results that might show promise and drugs might have a chance for approval.”
Goulden said for now there are currently some treatments for type 2 diabetes and weight loss also helps in combination with physical therapy and diet.
“Actually, there’s some studies showing that resistance exercising [helps] as well,” Goulden said. “There’s some studies that show patients who do regular resistance exercise also can see improvement in their liver function.”
“For the foreseeable future, the treatment of NASH is still going to be focused on maintaining ideal body weight, improved management of underlying metabolic diseases such as diabetes, hyperlipidemia, trying to minimize cardiovascular risk,” Fried said. “It’s a little unclear exactly when these new approved therapeutics will be routinely available for clinical use. But I do expect that the results from these more advanced phase 2 and phase 3 trials that we’re going to start seeing more and more that will provide a lot of insights into the best ways to treat NASH and I’m confident there will be multiple drugs available, ultimately to treat this disease.”
Fried said NASH is a complex, multiorgan disease that may involve different mechanisms of action, so it may be beneficial to have several approved drugs. This way the therapy can be tailored to the individual patient because some patients may respond better to a certain mechanism than others.
“Real world evidence will certainly contribute to the potential to help tailor these medications better as they get out into the marketplace,” Fried said. “Once we start having drugs available in the marketplace is again going to help refine how these medications are used similar to how real-world evidence really helped inform the way we treated hepatitis C in the past.”
“So, there’s a lot of exciting things going on and these kinds of real-world data are going to be very important for many years to come,” Fried said.
“It’s a marathon, not a sprint,” Friedman said. “There’s interest, there’s a rising unmet need, and despite a couple of setbacks in drug approvals, no one is giving up on the space, although investors are getting a little twitchy. But from the point of view of somebody who’s been in the field for a while, I’m still very optimistic in the long term.”
“We’re really starting to wrap our arms around the understanding of the disease in a new way,” Friedman said. “So, while there will not be any overnight success stories, progress will be incremental but meaningful.”
- Jung J, et al. Gut. 2020;doi:10.1136/gutjnl-2020-322976.
- Semaglutide produces NASH resolution without worsening fibrosis. Available at: www.healio.com. Accessed on: Dec. 20, 2020.