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Combination for Therapy Non-Alcoholic Steatohepatitis: Rationale, Opportunities and Challenges

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Recent advances in clinical practice Combination for therapy non- alcoholic steatohepatitis: rationale, opportunities Gut: first published as 10.1136/gutjnl-2019-319104 on 7 May 2020. Downloaded from and challenges Jean- François Dufour ,1,2 Cyrielle Caussy,3,4 Rohit Loomba5 1Hepatology, Department of ABStract for clinical approval of new drugs for the treat- Clinical Research, University of Non-alcoholic steatohepatitis (NASH) is becoming a ment of NASH, trials should include patients who Bern, Bern, Switzerland 2University Clinic for Visceral leading cause of cirrhosis with the burden of NASH- have significantly higher risk of progression to Surgery and Medicine, related complications projected to increase massively cirrhosis and hepatic decompensation, as defined as Inselspital, Bern, Switzerland over the coming years. Several molecules with different those who have biopsy-proven NASH with stage 2 3 Centre Hospitalier Lyon Sud, mechanisms of action are currently in development to fibrosis or higher. The regulatory approval pathway Endocrinologie Diabète et treat NASH, although reported efficacy to date has been for pharmacological therapies for NASH requires Nutrition, University Lyon 1, Hospices Civils de Lyon, Lyon, limited. Given the complexity of the pathophysiology therapies to show clinical benefit in improving France of NASH, it will take the engagement of several targets liver- related outcomes for full regulatory approval, 4 NAFLD Research Center, and pathways to improve the results of pharmacological which may take several years due to low event rates. University of California at San intervention, which provides a rationale for combination To expedite drug development, liver histological Diego, La Jolla, California, USA 5Division of Gastroenterology therapies in the treatment of NASH. As the field is improvements have been accepted as a surrogate and Hepatology, Department moving towards combination therapy, this article reviews for clinical improvements for a subpart H approval of Medicine, NAFLD Research the rationale for such combination therapies to treat process. The subpart H approval endpoints include Center, University of California NASH based on the current therapeutic landscape as either one- stage improvement in liver fibrosis or at San Diego, La Jolla, well as the advantages and limitations of this approach. California, USA resolution of NASH. This approval is contingent on showing clinical benefits over long- term follow- up Correspondence to for full approval. Professor Jean- François Dufour, INTRODUCTION Several therapies have been investigated for the Hepatology, Department of In the context of therapies for liver diseases, the treatment of NASH- related fibrosis using liver Clinical Research, University of histology improvement as an endpoint. It has been Bern, Bern 3010, Switzerland; treatment of non- alcoholic steatohepatitis (NASH) jean- francois. dufour@ dbmr. represents a major unmet need. Therefore, treat- observed that the difference in treatment effect unibe. ch relative to placebo has been relatively small. The ment of NASH is a major focus of drug develop- http://gut.bmj.com/ ment worldwide. Currently, there are no Food and percentage of patients with histological resolution Received 13 January 2020 of NASH in completed trials of a drug as mono- Revised 8 April 2020 Drug Administration (FDA)-approved or European Accepted 21 April 2020 Medicines Agency (EMA)-approved therapies for therapy does not exceed 32% over placebo and this NASH. As of December 2019, 84 interventional holds true across drugs with different mechanisms studies were ongoing and had enrolled patients to of action (figure 1). This underlies the complexity evaluate the therapeutic efficacy of treatments for of the pathophysiology of NASH, which is driven NASH ( www. clinicaltrial.gov). Most of these trials by a metabolic overload that places stress on on October 2, 2021 by guest. Protected copyright. are testing new drugs as monotherapy with some hepatocytes, leading to cell damage, inflammation trials investigating combination therapy for the and fibrosis. Metabolic overload impacts not only treatment of NASH. the liver, but also adipose tissue, the endocrine It is now well accepted that fibrosis stage is a major pancreas, the immune system and the gut. This predictor of liver-related morbidity and mortality. complex pathogenesis explains why several classes FDA and EMA guidance documents indicate that of drug are in development for the treatment of © Author(s) (or their employer(s)) 2020. Re- use permitted under CC BY- NC. No commercial re-use . See rights and permissions. Published by BMJ. Figure 1 (A) Percentage of patients with resolution of non- alcoholic steatohepatitis (NASH) defined as ballooning To cite: Dufour J- F, Caussy C, Loomba R. Gut Epub ahead 0 and inflammation 0–1, without worsening fibrosis in placebo and intervention arms of randomised clinical trials of print: [please include Day showing an effect. (B) Percentage of patients with more than one-stage improvement in fibrosis without worsening of Month Year]. doi:10.1136/ NASH in placebo and intervention arms of randomised clinical trials showing an effect. The references are provided in gutjnl-2019-319104 the text, the data for the obeticholic acid phase 3 are based on study by Sanyal et al.2 Dufour J- F, et al. Gut 2020;0:1–8. doi:10.1136/gutjnl-2019-319104 1 Recent advances in clinical practice NASH, although one therapeutic target is unlikely to be suffi- Norursodeoxycholic acid, a bile acid derivative like many cient when treating patients with NASH. As the success of drugs FXR agonists, but which is not an FXR agonist showed in a as monotherapy appears limited, combination of agents might double- blind randomised, placebo-controlled phase 2 trial seem a logical approach to increase efficacy, with numerous without histology a dose- dependent reduction in serum ALT Gut: first published as 10.1136/gutjnl-2019-319104 on 7 May 2020. Downloaded from combinations possible. Logical combinations might see a drug (NCT03872921).5 with a metabolic mechanism of action combined with a drug with an anti-inflammatory or an antifibrotic mechanism of PPAR agonists action. Some combinations might be selected based on specific Peroxisone proliferator- activated receptors (PPARs) comprise patient characteristics, whereby patients are identified as poten- a family of three transcription factors—PPAR-α, PPAR-δ and tial responders to a combination. Except for patients with type 2 PPAR-γ—which are involved in lipid and glucose metabolism, diabetes mellitus (T2DM), specific NASH subpopulations have and have anti- inflammatory effects. Schematically, PPAR-α not yet been well enough defined to become a selection or a plays a key role in fatty acid metabolism including absorp- stratification criterion in clinical trials precluding prespecified tion, transport and β-oxidation, PPAR-δ inhibits inflammatory comparisons. The field investigating the role of combination macrophage phenotypes contributing to its anti-inflammatory therapy in the treatment of NASH is moving at a fast pace. In effects, regulates the β-oxidation of free fatty acids and improves the current review, we discuss the rationale for such combination glucose homeostasis, and PPAR-γ regulates fatty acid storage and therapies to treat NASH based on the current therapeutic land- adipogenesis and improves insulin sensitivity in adipose tissue, scape as well as the advantages and limitations of this approach. liver and skeletal muscle. The PPAR-γ agonist pioglitazone at the dose of 30 mg failed to demonstrate an improvement of NASH 6 DRUG CLASSES SUitaBLE FOR COMBINatiON THERAPY compared with placebo in the PIVENS trial (NCT00063622). FXR agonists However, at a dose of 45 mg, pioglitazone resolved NASH in a significantly greater proportion of patients with pre-diabetes or Farnesoid X receptor (FXR) is a transcription factor activated 7 by bile acids. As such FXR regulates bile-acid metabolism, but T2DM compared with placebo (51% vs 19%; NCT00994682). Pioglitazone’s favourable effect was confirmed in a recent meta- since bile-acid biology is paced by food intake, FXR also controls 8 hepatic metabolism. Drugs-activating FXR have demonstrated analysis. Although the American Association for the Study of Liver Diseases9 and European Association for the Study of effects in cholestatic liver disease and are in advanced clinical 10 development for NASH. In phase 2 clinical trials, FXR agonists Liver guidelines recommend pioglitazone for use in patients have shown an improvement of hepatic histology. The front with biopsy-proven NASH, there are several side effects associ- runner—obeticholic acid, which is a bile-acid derivative—has ated with this drug, including weight gain and fluid retention, shown efficacy on liver fibrosis and significantly more patients and the increased risk of bone fracture, which limits its poten- receiving obeticholic acid 25 mg daily had resolution of NASH tial for combination with anti-NASH treatments. A second- without worsening of fibrosis at 18 months when patients with generation PPAR-γ agonist designed to selectively modulate the F1 fibrosis were also included in the analysis in an interim anal- entry of pyruvate into the mitochondria is currently being inves- ysis of a phase 3 trial (NCT02548351).1 2 In the FLIGHT.-FXR tigated in a phase 2b clinical trial (NCT02784444). http://gut.bmj.com/ phase 2 study, tropifexor showed a decrease in steatosis, and Several dual PPAR agonists are
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  • Peroxisome Proliferator-Activated Receptors and Their Novel Ligands As Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease

    Peroxisome Proliferator-Activated Receptors and Their Novel Ligands As Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease

    cells Review Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease Anne Fougerat 1,*, Alexandra Montagner 1,2,3, Nicolas Loiseau 1 , Hervé Guillou 1 and Walter Wahli 1,4,5,* 1 Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; [email protected] (A.M.); [email protected] (N.L.); [email protected] (H.G.) 2 Institut National de la Santé et de la Recherche Médicale (Inserm), Institute of Metabolic and Cardiovascular Diseases, UMR1048 Toulouse, France 3 Institute of Metabolic and Cardiovascular Diseases, University of Toulouse, UMR1048 Toulouse, France 4 Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Clinical Sciences Building, 11 Mandalay Road, Singapore 308232, Singapore 5 Center for Integrative Genomics, Université de Lausanne, Le Génopode, CH-1015 Lausanne, Switzerland * Correspondence: [email protected] (A.F.); [email protected] (W.W.); Tel.: +33-582066376 (A.F.); +41-79-6016832 (W.W.) Received: 29 May 2020; Accepted: 4 July 2020; Published: 8 July 2020 Abstract: Non-alcoholic fatty liver disease (NAFLD) is a major health issue worldwide, frequently associated with obesity and type 2 diabetes. Steatosis is the initial stage of the disease, which is characterized by lipid accumulation in hepatocytes, which can progress to non-alcoholic steatohepatitis (NASH) with inflammation and various levels of fibrosis that further increase the risk of developing cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is influenced by interactions between genetic and environmental factors and involves several biological processes in multiple organs. No effective therapy is currently available for the treatment of NAFLD.