Finally!

In March 2020, India’s Zydus Cadila received local regulatory approval for Lipaglyn (saroglitazar) for the treatment of non-alcoholic steatohepatitis (NASH) without cirrhosis. In December 2020, Lipaglyn received approval for the treatment of non-alcoholic fatty liver disease (NAFLD).

This way, Lipaglyn became the first drug in the world officially approved for the treatment of NASH and NAFLD.

Oral Lipaglyn debuted in India in June 2013, oriented toward the therapy of dyslipidemia and hypertriglyceridemia in patients with type 2 diabetes mellitus in whom the lipid profile is not adequately controlled with statins. In January 2020, Lipaglyn expanded its indication range by adding therapy for type 2 diabetes on metformin.

In November 2017, Lipaglyn received regulatory approval in Mexico for the treatment of hypertriglyceridemia and diabetic dyslipidemia. Lipaglyn then appeared in Kenya, Burundi, and Myanmar.

Lipaglyn is claimed to have been used by more than one and half million patients in the past over 7 years that it has been on the market.

What’s notable is that Zydus Cadila sent an application to the regulator for saroglitazar to connect patients with NASH in early December 2019. And the green light was on almost instantly — three months later. This is understandable: first of all, the debut in the path of NASH is more than promising, and secondly, saroglitazar is a molecule entirely created and developed in India.

Lipaglyn (saroglitazar).

 

What Is Non-Alcoholic Steatohepatitis?

Non-alcoholic steatohepatitis (NASH) is a slowly progressive liver disease caused by excessive fat accumulation in the liver, resulting in chronic inflammation, fibrosis, cirrhosis, and cardiovascular disease. If NASH is left untreated, it can result in liver failure, hepatocellular carcinoma, and death. There are currently no approved therapies for NASH. Preventive and therapeutic recommendations are limited to lifestyle change and control of body weight and related disorders such as obesity, diabetes mellitus, and hyperlipidemia.

NASH is a serious advanced form of non-alcoholic fatty liver disease (NAFLD), also known as metabolic (dysfunction) associated fatty liver disease (MAFLD), a complex clinical and histopathologic condition. And while NAFLD is characterized by hepatic steatosis (and iron deposition), the histological diagnosis of NASH requires the simultaneous presence of two additional major features: ballooning degeneration of hepatocytes and lobular inflammation.

The primary medical problem of non-alcoholic steatohepatitis is its asymptomatic course, and therefore the disease is rarely diagnosed. Meanwhile, approximately 1 billion people are thought to have NAFLD which advances to the NASH stage in a quarter of cases. A more pessimistic estimate is that one in four could be diagnosed with NAFLD or NASH. Silence on the need for proper prevention as well as the lack of both non-invasive diagnostic methods (now examined with liver biopsy specimens) and effective treatment of NASH will lead to the fact that in the foreseeable future non-alcoholic steatohepatitis, bypassing chronic viral hepatitis C and alcoholism, will be the leading cause of liver transplantation.

The development of therapy for non-alcoholic steatohepatitis, like any other disease affecting the liver, is fraught with significant challenges since its pathophysiology involves many diverse pathways.

The global market for NASH is seen as extremely lucrative, estimated at a peak of $35–40 billion per year due to the continuing total obesity of the world’s population.

As for the United States, the situation with NASH is as follows. Presumably, NAFLD can be found in at least 25% of Americans (~95 million people) of whom 20% have progressed to NASH (~20 million). Given that approximately 40% of NASH cases reach the advanced fibrosis stage requiring mandatory treatment, the patient pool for saroglitazar and similar drugs is approximately 8–9 million people. Let’s assume that 30–40% of patients will be treated and the cost of therapy will be $9000 (at the average cost of treating diabetes and hypertension). The bottom line is that the US market for NASH is at least $25 billion.

 

Lipaglyn: Efficacy and Safety of Saroglitazar Treatment for Non-Alcoholic Steatohepatitis

The positive verdict of the Indian regulator for Lipaglyn was based on the safety and efficacy results collected in the EVIDENCES II phase 3 clinical trial which compared daily administration of 4 mg of saroglitazar or placebo to Indian patients with NASH.

Clinical outcomes were assessed by changes in NASH status, consistent with histological studies of liver biopsy specimens, after 52 weeks of experimental therapy. It is stated that the saroglitazar group demonstrated a statistically significant reduction of fat fraction in the liver, improvement of its enzyme profile, and decrease of NASH activity.

Alas, Zydus Cadila has not yet provided any details on the efficacy of saroglitazar treatment for NASH, on the basis of which it was approved. And therefore, it is appropriate to cite the data that have been disclosed and that have been taken into account by the regulator.

In fairness, we strongly do not understand Zydus Cadila’s mysteriousness and secretiveness. If Lipaglyn really is such a worthy and effective cure for NASH and NAFLD, why not trumpet it everywhere?

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So, the EVIDENCES IV (NCT03061721) phase 2 clinical trial (randomized, double-blind, placebo-controlled, multicenter) enrolled US adult patients (n=106) with a body mass index (BMI) ≥25 kg/m2 and serum alanine aminotransferase (ALT) level ≥50 units/l.

Inclusion criteria for participants: diagnosis of NAFLD confirmed by ultrasound, CT, MRI, or liver biopsy suggestive of NASH or steatosis.

Experimental 16-week therapy with saroglitazar (at a dose of 1, 2, or 4 mg) or placebo provided the following outcomes (for a maximum 4-mg dose):

  • ALT
  • ALT level, indicative of liver damage, decreased by 44.4% in the saroglitazar group — versus an increase of 4.2% in the placebo group (p<0.001)
  • 51.8% of patients recording its drop of 50% or more (p<0.0001) — vs. 3.5%.
  • Liver fat fraction
  • the absolute decrease in liver fat, as assessed by changes in the magnetic resonance imaging proton density fat fraction (MRI-PDFF), was 4.21% — vs. 0.31% (p=0.01)
  • liver fat reduction of at least 10% and 30% was observed in 55.6% and 40.7% of patients — vs. 28.0% and 8.0% (p=0.04 and p=0.007).
  • Glycemic parameters
  • fasting insulin levels decreased by 13.8 μU/mL — vs. 6.1 (p=0.027)
  • fasting glucose levels decreased by 8.96 mg/dL — vs. 4.39 (p=0.21)
  • Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) decreased by 5.2 points — vs. 2.5 (p=0.024)
  • glycated hemoglobin (HbA1c) decreased by 0.20% — vs. 0.05% (p=0.3).
  • Lipid profile
  • triglyceride levels decreased by 29.6% —vs. an increase of 1.9% (p=0.0003)
  • total cholesterol levels fell 9.5% — vs. 1.8% (p=0.08)
  • high-density lipoprotein (HDL) cholesterol levels increased by 10.9% — vs. a decrease of 0.3% (p=0.03)
  • low-density lipoprotein (LDL) cholesterol levels decreased 20.4% — vs. 3.9% (p=0.057).
  • Specific biomarkers and noninvasive diagnostic tests
  • plasma levels of cytokeratin 18 (CK-18) fragments, indicating the extent of hepatocyte apoptosis, decreased by 14.2% — vs. an increase of 41.2% (p=0.07)
  • aspartate aminotransferase (AST) to platelet count index (APRI), indicating the likelihood of liver fibrosis and cirrhosis, decreased by 27.6% — vs. an increase of 22.0% (p<0.0001)
  • FibroScan (transient elastography) test, which assessed liver elasticity to determine the stage of fibrosis in this case, showed a 5.5% improvement — vs. a 20.0% worsening (p=0.10)
  • Enhanced Liver Fibrosis (ELF) test, which performed quantitative analysis of circulating extracellular matrix components such as hyaluronic acid, N-terminal propeptide of type III procollagen (PIIINP), and tissue inhibitor of metalloproteinases TIMP-1 to establish liver fibrosis stage, showed a 2.5% improvement — vs. a 3.9% deterioration (p=0.02).
  • Other measures
  • serum creatinine levels, which provide an indication of the risks of adverse effects of saroglitazar on renal function, increased by a small 3.72% — vs. a decrease of 1.55% (p=0.07)
  • Body Mass Index (BMI) increased by 0.510 kg/m2 — vs. 0.095 kg/m2 (p=0.31).

The administration of saroglitazar has not been associated with any of the common serious adverse effects or events for PPARα/γ dual agonists, including cardiovascular complications. And this is more than surprising. But in fact, saroglitazar necessarily needs to go through long-term clinical trials that would clearly define its safety profile. Again, saroglitazar has not been studied in patients at high risk of cardiovascular complications, and therefore should be considered somewhat cautiously. The prescribing information for Lipaglyn suggests the possibility of congestive heart failure in patients with a history of it.

Once again: the rich dismal history of related molecules, the weak evidence base for saroglitazar, the clearly established molecular basis for cardiac dysfunction when certain glitazars are prescribed (due to suppression of the SIRT1–PGC1α axis) all prompt Zydus Cadila to collect more reliable and valid safety data for Lipaglyn.

 

Lipaglyn: Efficacy and Safety of Saroglitazar Treatment for Non-Alcoholic Fatty Liver Disease

As with non-alcoholic steatohepatitis, Zydus Cadila has not yet provided full data on which basis the Indian regulator has approved saroglitazar for the treatment of non-alcoholic fatty liver disease.

Zydus Cadila only reported that Lipaglyn has successfully completed a number of clinical trials. Thus, it achieved positive results in the 52-weeks EVIDENCES III (PRESS XI, CTRI/2015/10/006236) phase 3 liver biopsy trial (randomized, double-blind, placebo-controlled, multicenter) of saroglitazar 4 mg versus placebo in Indian patients with NASH. Lipaglyn demonstrated a significant reduction in liver fat, liver enzymes, and disease activity.

In the 24-weeks EVIDENCES VIII (CTRI/2017/11/010511) phase 3 clinical trial (randomized, double-blind, placebo-controlled, multicenter) of saroglitazar 4 mg versus placebo in Indian patients with NAFLD, Lipaglyn provided an improvement in the liver fat content measured by MRI-PDFF and an improvement in the liver enzymes and liver stiffness measured by FibroScan.

 

Update #1

The EVIDENCES III clinical trial recruited adult patients (n=102) with biopsy proven NASH without cirrhosis (fibrosis stage 1, 2, or 3) with a NAFLD activity score (NAS) of ≥ 4 with a score of at least 1 in each component (steatosis, hepatocyte ballooning, lobular inflammation).

Administration of 4 mg of saroglitazar daily for 52 weeks resulted in the following outcomes:

  • to the primary endpoint, set by the proportion of patients whose NAS score decreased by at least 2 points (among at least two NAS components ) and without worsening fibrosis stage, came out 52.3% of subjects in the saroglitazar group — versus 23.5% in the placebo group (p=0.0427)
  • saroglitazar group reached all secondary endpoints related to NASH and NAFLD (p<0.0001), except that saroglitazar did not succeed in dealing with lobular inflammation in a statistically significant way (p=0.0526).

 

Lipaglyn: What’s Next

Zydus Cadila intends to launch registration clinical trials in the United States for saroglitazar for the treatment of non-alcoholic steatohepatitis. This is necessary for submission to the U.S. Food and Drug Administration (FDA) of an application to approve Lipaglyn for this indication.

Zydus Cadila is not opposed to entering into a partnership or granting a license to sell saroglitazar in markets where its presence is limited.

The EVIDENCES VII (NCT03617263) phase 2a clinical trial (randomized, double-blind, placebo-controlled, multicenter) in adult women (n=90) living in the United States or Mexico diagnosed with polycystic ovary syndrome (PCOS) is underway. It tests whether saroglitazar (4 mg daily for 24 weeks) is effective in eliminating concomitant NAFLD.

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The NCT04193982 (CTRI/2019/12/022339) phase 3 clinical trial (randomized) has been initiated in India that will compare outcomes after 24 weeks among four parallel groups of adult patients (n=250) with NAFLD who will be given either saroglitazar (4 mg daily) or vitamin E (400 mg twice daily) or a combination of the two or only diet and lifestyle recommendations with a weight loss target of 7–10%.

Patients (n=270) are being recruited into the 52-week CTRI/2019/06/019592 phase 4 (randomized, open-label) clinical trial that will compare two experimental groups (saroglitazar or antianginal ranolazine) with a control group (metformin + atorvastatin) in the treatment of NAFLD with diabetic dyslipidemia.

In December 2020, the FDA has granted Fast Track Designation to saroglitazar for the treatment of patients with primary biliary cholangitis (primary biliary cirrhosis, PBC) after it passed the appropriate clinical trial.

As Zydus Cadila suggests, given the high prevalence of NASH and NAFLD among people in India, saroglitazar will become the top-selling molecule in the company’s portfolio in the next 3–5 years. Nevertheless, Zydus Cadila aims to capture the US pharmaceutical market as the most lucrative on the planet. And the plans here are that saroglitazar for PBC treatment could be on the US market in 2023 and for NASH treatment by 2025. Nevertheless, it will take a lot of effort to convince the FDA that saroglitazar is safe and effective.

 

Lipaglyn: Mechanism of Action of Saroglitazar

Saroglitazar is an oral low-molecular-weight agonist of peroxisome proliferator-activated receptors (PPARs), a group of nuclear protein receptors that function as transcription factors regulating the expression of genes involved in cell differentiation, development, metabolism (carbohydrates, fats, proteins), oncogenesis. Saroglitazar, first, predominantly affects the PPAR-alpha (PPARα), which is translated into increased hepatic fatty acid oxidation and decreased hepatic triglyceride synthesis and secretion, and, second, shows a moderate affinity for the PPAR-gamma(PPARγ), which leads to improved insulin sensitivity and glucose metabolism.

PPARα is a key regulator of fat metabolism in the liver. PPARα is activated under conditions of energy deprivation when ketogenesis, the body’s adaptive response to prolonged starvation, becomes necessary. PPARα activation promotes fatty acid uptake, utilization, and catabolism by increasing expression of genes involved in transport, binding, activation, peroxisomal and mitochondrial beta oxidation of fatty acid.

PPARα activation induced by saroglitazar leads to increased fatty acid oxidation in the liver and inhibition of triglycerides synthesis and secretion therein. This, in turn, causes fatty acids to migrate from peripheral tissues (skeletal muscle and adipose tissue) to the liver, where they undergo breakdown. There is an increase in lipolysis and elimination of triglyceride-rich particles from blood plasma — through activation of lipoprotein lipase (LPL) and reduction of apolipoprotein C3 (APOC3) production, which inhibits it. There is a decrease in plasma levels of low-density lipoprotein (LDL) cholesterol. The synthesis of apolipoprotein A1 (APOA1) and A2 (APOA1) as well as high-density lipoprotein (HDL) cholesterol is induced.

Mechanism of action of saroglitazar in NASH. J Clin Transl Hepatol. 2021 Feb 28; 9(1): 40–50.

PPARγ, also known as the glitazone receptor, regulates fatty acid accumulation and glucose metabolism. Through PPARγ-activated genes, it stimulates small lipophilic compounds uptake and adipogenesis, mediates adipocyte differentiation, promotes fat accumulation, indirectly increases insulin sensitivity, and enhances glucose release in adipose tissue and skeletal muscle.

PPARγ activation induced by saroglitazar is mirrored by increased expression of multiple genes involved in carbohydrate and fat metabolism, including adiponectin (ADIPOQ), fatty acid binding adipocyte protein 4 (FABP4, aP2), LPL, long-chain fatty acid transport protein 1 (FATP1), fatty acid translocase (FAT, CD36). Among the outcomes: inhibition of postprandial increase of free fatty acid in plasma, improvement of postabsorptive insulin-mediated suppression of hepatic glucose output, reduction of metabolic load on liver and muscle, promotion of glucose utilization. In preclinical models characterized by hyperglycemia and/or impaired glucose tolerance due to insulin resistance in the target tissues, strong antidiabetic and insulin-sensitizing effects of saroglitazar were observed.

 

PPAR modulation

It should be understood that despite the therapeutic promise of PPAR modulation, the situation with PPAR agonists is not entirely serene due to the number of, often very serious, adverse effects they cause. It is appropriate to provide a more detailed view of this situation.

Physiological and/or pharmacological role of peroxisome proliferator-activated receptors (PPARs) in energy metabolism. Cell Res. 2010 Feb; 20(2): 124-137.

 

PPAR-alpha (PPARα) agonists

PPARα is the main target of fibrates, a class of amphiphatic carboxylic acids that originally focused on combating different types of hypercholesterolemia and then connected therapies for different types of hyperlipidemia. Most fibrates cause mild stomach upset and myopathy, carry the risk of cholelithiasis, and when combined with statins increase the risk of rhabdomyolysis, idiosyncratic muscle destruction, and renal failure.

In addition to the well-known fenofibrate, fibrates as a class of drugs include: bezafibrate, gemfibrozil, clinofibrate, clofibrate, ronifibrate, simfibrate, ciprofibrate.

Parmodia (pemafibrate), a highly selective PPARα agonist developed by Kowa Pharmaceuticals and approved in July 2017 in Japan for therapy of hyperlipidemia (including familial type), is considered to have a significantly improved safety profile and clearly reduced frequency and severity of adverse side effects compared to the fenofibrate.

 

PPAR-gamma (PPARγ) agonists

PPARγ is the main target of thiazolidinediones (TZDs), a class of drugs used in the therapy of type 2 diabetes as insulin sensitizers. The main side effect of all thiazolidinediones is fluid retention leading to peripheral edema and, if the retention is significant, decompensation of previously undetected congestive heart failure. Thiazolidinediones reduce bone mineral density and increase the risk of overweight in women.

Thiazolidinediones (glitazones) include troglitazone, pioglitazone, rosiglitazone, and lobeglitazone.

In March 2000, the U.S. Food and Drug Administration (FDA) was ordered to halt sales of troglitazone because of its hepatotoxicity.

Long-term prescribing of pioglitazone has been found to be associated with an increased risk of bladder cancer.

In September 2010, the European Medicines Agency (EMA) demanded that all drugs containing rosiglitazone be discontinued: the risk of cardiovascular complications outweighed its therapeutic benefits.

 

PPAR-delta (PPARδ) agonists

PPARδ is involved in energy metabolism, controlling not only fatty acid and glucose oxidation, but also redox homeostasis, mitochondrial biogenesis, inflammation, and cardiomyocyte proliferation.

GlaxoSmithKline and Ligand Pharmaceuticals tried to bring GW501516, a selective PPARδ agonist for therapy of metabolic disorders and cardiovascular disease, to fruition. But the research was curtailed due to the evidence of rapid oncogenesis in animals. GW501516, known as endurobol or cardarine, can be obtained on the black market; it is popular with bodybuilders because it shifts the body’s energy preferences from glucose to fat effectively serving as a strength-training mimetic.

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CymaBay Therapeutics had to stop research on seladelpar, a selective PPARδ agonist against NASH, because of unexpected cases of interface hepatitis (piecemeal necrosis). Efforts in the development of seladelpar were shifted to primary biliary cholangitis (PBC).

 

Dual-acting PPAR agonists

Drug compounds targeting PPARα and PPARγ simultaneously are called glitazars. Saroglitazar is the world’s first approved dual PPAR agonist. Previous but unsuccessful attempts to give commercial life to molecules of this class have been made by many pharma manufacturers:

  • farglitazar (GW-409544): GlaxoSmithKline (research stopped in 2001)
  • reglitazar (JTT-501): Japan Tobacco (2002)
  • ragaglitazar (DRF-2725, NN-622): Novo Nordisk/Dr. Reddy’s Laboratories (2003)
  • MK-767 (KRP-297, L-410198): Merck & Co./Kyorin Pharmaceutical (2004)
  • imiglitazar (TAK-559): Takeda Pharmaceutical (2005)
  • naveglitazar (LY519818): Eli Lilly/Ligand Pharmaceuticals (2006)
  • cevoglitazar (LBM642): Novartis (2007).

Some dual PPARα/γ agonists even got on the track of phase 3 clinical trials although they were not helped by the results. In May 2006, for example, AstraZeneca discontinued the Galida (tesaglitazar) clinical program due to a rise in serum creatinine and an associated decrease in glomerular filtration rate. It was further shown that tesaglitazar (AZ-242) was definitely cardiotoxic.

At the same time, Bristol-Myers Squibb rejected Pargluva (muraglitazar) which, already in a pending regulatory approval status, had an increased incidence of death, edema, heart failure, and weight gain compared to pioglitazone. A meta-analysis found that muraglitazar (BMS-298585) increased the likelihood of encountering myocardial infarction, stroke, transient ischemic attack, and congestive heart failure.

In July 2013, Roche discontinued aleglitazar (R-1439) because of safety concerns (bone fractures, heart failure, gastrointestinal bleeding) and for lack of effectiveness.

The favorable, as stated, safety profile of saroglitazar is probably due to a different activity (absolute and relative) than that of other glitazars in application to PPARα and PPARγ agonism.

The pharmaceutical industry is also working its way through dual PPAR agonists affecting other pairs. For example, the Genfit (France) tried very hard to defeat NASH with elafibranor, a PPARα/δ agonist, but in the RESOLVE-IT phase 3 clinical trial the battle was lost and it had to switch to the war against primary biliary cholangitis (PBC).

Meanwhile, T3D Therapeutics is counting on the success of T3D-959 (DB959), a PPARγ/δ agonist, in the treatment of Alzheimer’s disease. An ongoing phase 2 clinical trial, PIONEER (NCT04251182), will look at the impact of T3D-959 on cognitive and functional ability in patients (n=256) with mild-to-moderate Alzheimer’s disease.

 

Pan-PPAR agonists

China’s Shenzhen Chipscreen Biosciences is awaiting the verdict of the local regulator on its Bilessglu (chiglitazar; also known as carfloglitazar), a PPARα/γ/δ agonist that has successfully passed registration clinical trials in the therapy of type 2 diabetes. Yes, a dose-dependent increase in the incidence of side effects (weight gain and edema) has been observed in the chiglitazar (CS-038) groups, but no serious cardiac problems have been reported.

The French company Inventiva successfully guided lanifibranor, a pan-PPAR agonist, through the NATIVE (NCT03008070) phase 2b clinical trial in patients with NASH without cirrhosis. Scheduled for the first half of 2021, the 72-week NATIVE3 phase 3 clinical trial should definitively confirm the efficacy of lanifibranor.

 

Extras

Lipaglyn (saroglitazar). Prescribing information. India. [PDF]

Lipaglyn (saroglitazar). Product monograph. [PDF]

Cadila Healthcare Limited. Q3 FY ’21 earnings conference call. February 05, 2021. [PDF]

Effectiveness of the PPAR agonist saroglitazar in nonalcoholic steatohepatitis: positive data from preclinical & clinical studies. Preprint. [source]

Saroglitazar, a PPAR-α/γ agonist, for treatment of nonalcoholic fatty liver disease: a randomized controlled double-blind phase 2 trial. Hepatology. 2021 Apr 2. [source]

Saroglitazar in patients with non-alcoholic fatty liver disease and diabetic dyslipidemia: a prospective, observational, real world study. Sci Rep. 2020 Dec 3;10(1):21117. [source]

A phase 2 double blinded, randomized controlled trial of saroglitazar in patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2020 Nov 2;S1542-3565(20)31509-3. [source]

An observational study of reduction in glycemic parameters and liver stiffness by saroglitazar 4 mg in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Cureus. 2020 Jul 8;12(7):e9065. [source]

Clinical case series of decrease in shear wave elastography values in ten diabetic dyslipidemia patients having NAFLD with saroglitazar 4 mg: an Indian experience. Case Rep Med. 2020 Mar 27;2020:4287075. [source]

Saroglitazar improves transaminases and elastography in patients with diabetic dyslipidemia and non-alcoholic fatty liver disease. J Assoc Physicians India. 2020 Jan;68(1):97. [source]

New dual peroxisome proliferator activated receptor agonist — saroglitazar in diabetic dyslipidemia and non-alcoholic fatty liver disease: integrated analysis of the real world evidence. Cardiovasc Diabetol. 2019 Jun 17;18(1):80. [source]

A multicenter, open-label, single-arm study to evaluate the efficacy and safety of saroglitazar in patients with primary biliary cholangitis. Clin Transl Gastroenterol. 2021 Mar 26;12(4):e00327. [source]

Drugs for non-alcoholic steatohepatitis (NASH): quest for the Holy Grail. J Clin Transl Hepatol. 2021 Feb 28;9(1):40-50. [source]

Peroxisome proliferator-activated receptors and their agonists in nonalcoholic fatty liver disease. J Clin Exp Hepatol. Nov-Dec 2019;9(6):731-739. [source]

Anti-NASH drug development hitches a lift on PPAR agonism. Cells. 2019 Dec 21;9(1):37. [source]

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