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  • Mini Review
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NASH Drug Development: Seeing the Light at the End of the Tunnel?

  • Yong Q. Chen* 
 Author information
Journal of Clinical and Translational Hepatology   2023;11(6):1397-1403

doi: 10.14218/JCTH.2023.00058

Abstract

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease affecting a large population worldwide. No clinically approved drugs are available. In this minireview, we discuss the heterogeneous nature of NASH and lack of consensus in outcome measures among clinical trials. We summarize NASH therapeutic targets and candidate drugs. We compare the efficacy of 33 published clinical trials that evaluated noninvasive biomarkers and liver biopsy. Currently, phase II trial results of fibroblast growth factor 21 (FGF21) and phase III trial results of resmetirom and pioglitazone are encouraging.

Keywords

Nonalcoholic fatty liver disease, Nonalcoholic steatohepatitis, Fibroblast growth factor 21

Introduction

Nonalcoholic fatty liver disease (NAFLD) describes a collection of steatotic liver conditions. Nonalcoholic steatohepatitis (NASH), first coined by Ludwig et al.1 in 1980 is the inflammatory subtype of NAFLD involving liver steatosis, inflammation, and hepatocyte ballooning often along with fibrosis.2 Even though NASH has become a global epidemic,3 it receives much less attention from the public, healthcare professionals, and policymakers than other metabolic diseases such as diabetes and cancer. Recent consensus and recommendations from a Delphi study may raise public awareness of the disease and provide a solid foundation for a comprehensive public health response to NAFLD.4 Nevertheless, there is no approved drug for NASH treatment in the clinic. Considerable efforts have been vested in NASH drug development; the arduous road continues.

Heterogeneous nature of NASH

Approximately 25% of the world population develops NAFLD, and 20% progress to NASH (Fig. 1). NASH is a heterogeneous disease, and its phenotypic manifestation likely reflects the interactions of different primary drivers and coexisting disease modifiers. Environmental factors such as diet and microbiota, genetic determinants such as PNPLA3 and TM6SF2 mutations as well as epigenetic modifications such as methylation and acetylation can all contribute to NASH. Comorbidities, e.g., type 2 diabetes, dyslipidemia, and gout may exacerbate the disease and thus should be evaluated in NASH patients. Other types of liver conditions such as autoimmune hepatitis, HBV/HCV infection, and Wilson’s disease differ from NASH and should be excluded from NASH clinical trials. Unfortunately, present trial recruitment is mainly based on histologic grading and staging, and the response rates to investigational agents are often low.5

Heterogeneity of nonalcoholic fatty liver disease.
Fig. 1  Heterogeneity of nonalcoholic fatty liver disease.

Disease progression from fatty liver to cirrhosis is illustrated. Possible major anthropometric, environmental, genetic, and epigenetic factors are listed. Important comorbidities associated with nonalcoholic steatohepatitis (NASH) are shown. Other types of liver disease that should be excluded from NASH are suggested. PNPLA3 I148M, patatin-like phospholipase domain containing three amino acids 148 I to M mutation; TM6SF2 E167K, transmembrane 6 superfamily member two amino acid 167 E to K mutation; ENPP1 K121Q, ectonucleotide pyrophosphatase one amino acid 121 K to Q mutation; IRS1 Q972R, insulin receptor substrate one amino acid 972 Q to R mutation; GCKR P446L, glucokinase regulator amino acid 446 P to L mutation; HFE C282Y, homeostatic iron regulator amino acid 282 C to Y mutation; MBOAT7, membrane bound O-acyltransferase domain containing 7; HSD17B13, hydroxysteroid 17-beta dehydrogenase 13; Lnc18q22.2, liver cell viability associated long noncoding RNA; Blnc1, brown fat long noncoding RNA 1; MHO, metabolically healthy obesity; MUO, metabolically unhealthy obesity.

Clinical trials

Currently, 1282 NASH-related trials are registered at the ClinicalTrials.gov website (https://clinicaltrials.gov ), 537 are drug intervention trials including 289 phase II trials, 75 phase III trials, and 67 phase IV trials. Of all registered trials, 68 (5.6%) have published results in peer-reviewed journals (Supplementary Table 1). This percentage is significantly lower than those of type 2 diabetes (18%) and obesity trials (89%). The vast majority (94%) of NASH trials are in the adult population (Supplementary Table 1), and most involve Caucasians (66%) followed by Hispanics (43%), Asians (22%), and Africans (21%).

Trials using surrogate biomarkers or histological outcome endpoints can lead to regulatory agency conditional or full approval of drugs. Some investigators argue whether a biopsy-based evaluation is an appropriate efficacy endpoint because imprecise histological staging may disproportionally impact the active arm relative to the placebo. Many clinicians and investigators do consider liver biopsy and histological evaluation as the reference standard for NASH. Thirty-three of 68 trials (49%) have histological outcome measures (Supplementary Table 1). Thirty-nine trials evaluate drug effects on noncirrhotic NASH (F1-F3), four trials are on cirrhotic NASH (F4) and four trials include both (F1–F4). Of three known histological assessment systems, the National Institute of Diabetes and Digestive and Kidney Diseases NASH Clinical Research Network (commonly referred to as CRN) system, the Steatosis-Activity-Fibrosis system, and the Goodman classification, the CRN system have been unanimously adopted in all 33 publications. Frequently used noninvasive measures (Supplementary Table 1) include biometric markers (body weight, body mass index, and hepatic fat), liver function markers (alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase), lipid markers (plasma cholesterol, triacylglycerol, high-density lipid cholesterol, and low-density lipid cholesterol), glycemic markers (fasting plasma glucose, insulin, homeostatic model assessment for insulin resistance and glycated hemoglobin). However, common sets of noninvasive clinical measures for steatosis, inflammation, and fibrosis remain to be established, and biomarkers for hepatocyte ballooning are absent.

Therapeutic drugs and targets

Approximately 216 drugs are being or have been evaluated for the treatment of NASH (Fig. 2 and Table 1). Most drugs target metabolic pathways; some aim at inflammation or fibrosis. The vast majority (>80%) are small-molecule drugs. Biological drugs include fibroblast growth factor 21 (FGF21), FGF19, glucagon-like peptide 1 (GLP-1), glucagon, glucose-dependent insulinotropic polypeptide (GIP or gastric inhibitory polypeptide), or a combination thereof (Fig. 2).

Major targets and drugs in NASH.
Fig. 2  Major targets and drugs in NASH.

Names and producers of drugs are listed. Drugs in gray letters failed in clinical trials. Drugs are classified as antisteatosis, anti-inflammatory, antifibrosis, and anti-apoptotic agents. ACC, acetyl-CoA carboxylase; FASN, fatty acid synthase; DGAT, diacylglycerol O-acyltransferase; ANGPTL3, angiopoietin-like 3; HSD17B13, hydroxysteroid 17-beta dehydrogenase 13; HSD11B1, hydroxysteroid 11-beta dehydrogenase 1; PNPLA3. patatin-like phospholipase domain containing 3; CCR2/5, chemokine (C-C motif) ligand 2 and 5; AOC3, amine oxidase copper containing 3; FXR, farnesoid x receptor; SGLT2, sodium-glucose cotransporter-2; AMPK, adenosine 5′ monophosphate-activated protein kinase; FFAR1/4, free fatty acid receptor 1/4; ASK1, apoptotic signal-regulating kinase 1; LOXL2, lysyl oxidase-like 2; THRb, thyroid hormone receptor beta; NR3C2, nuclear receptor subfamily 3 group C member 2; PPAR, peroxisome proliferator-activated receptor; FGFR, fibroblast growth factor receptor; KLB, beta klotho; GLP1R, glucagon-like peptide 1 receptor; DPP4, dipeptidyl peptidase-4; GIPR, glucose-dependent insulinotropic polypeptide receptor; GCGR, glucagon receptor.

Table 1

Additional targets and drugs

DrugTargetCompany
Cysteamine/Raptor Pharma
FIA586/Novartis
LY3849891/Eli Lilly
MG-1//
NC101 (undefined)//
NRL972 (cholyl lysyl fluorescein)/Norgine
TRO19622 (Olesoxime)/Hoffmann-La Roche
XZP-5610/Xuanzhu Biotech
XZP-6019/Xuanzhu Biotech
ZSP0678/Raynovent
TEV-45478/Teva Pharma
FM101A3ARFuture Medicine
NamodenosonA3ARCan-Fite BioPharma
PBF-1650A3ARPalobiopharma
Aceon (Perindopril)ACE/
CF102ADORA3Can-Fite BioPharma
WY-8678 (Guanabenz acetate)ADRA2APfizer
Cozaar (Losartan)AGTROrganon
NitazoxanideAntiparasiticGenfit
LPCN 1144 (testosterone)ARLipocine
SHP626 (Volixibat)ASBTShire
BLD-0409 (Cudetaxestat)ATXBlade Therapeutics
PLN-1474avb1Pilant
IDL2965avb3Indalo
Dasatinib (Sprycel)BCR-ABLBMS
CP-945598CB1RSTEMCELL Technologies
JNJ-2463 (Nimacimab)CB1RBird Rock Bio
ProglumideCCKA/BRAdvaCare Pharma
CM-101CCL24Chemomab
RYI-018CNR1Bird Rock Bio
SNP-630CYP450Sinew Pharma
Singulair (Montelukast)CYSLTRMerck
MN-001 (Tipelukast)CYSLTR/PDE/5-LOXMediciNova
DUR-928EpigeneticDurect
EstradiolER/
NGM282 (Aldafermin)FGFR4-KLBNGM
GB1211Galectin-3Galecto Biotech
GR-MD-02 (Belapectin)Galectin-3Galectin Therapeutics
NGM395GFRALNGM
Tesamorelin (GHRH)GHTheratechnologies
LUM-201 (Ibutamoren)GHSRLumos Pharma
Crestor (Rosuvastatin)HMGCRAstra Zeneca
BMS-986263HSP47BMS
GM-60106HTR2AJD Bioscience
ElobixibatIBATAlbireo
HPN-01IKKHepanova
CC-90001JNKCelgene
PF-06835919KHKPfizer
MetreleptinLEPRAmylin Pharma
IMM-124ELPSImmuron
Oltipraz (Dithiolethiones)LXRaPharmaKing
BMS-963272MGAT2BMS
MetforminmGPD/
LB-P6MicrobiomeLISCure Biosciences
RG-125 (AZD4076)miR-103/107Regulus
MSDC-0602KMPCCirius Therapeutics
IdB 1016 (Siliphos)NF-κBIndena
GRI0621NK cellGRI Bio
DFV890NLPR3Novartis
SGM-1019P2X7RSecond Genome
CER209P2Y13RAbionyx
ZSP1601PDERaynovent
ASP9831PDE4Astellas Pharma
CRV-431 (Rencofilstat)PPIHepion Pharma
RifampicinPXR/
DenosumabRANKLAmgen
TB-840RORaTherasid Bioscience
HydroxytyrosolROS/
IDDF2019-ABS-0026 (Metadoxine)ROSMicro Labs
Vitamin EROS/
AGN-242266RXRAbbvie
AramcholSCD1Galmed
BI 685509sGCBoehringer Ingelheim
Idebex (Idebenone)ShcABCO Lab
NS-0200SIRT1/AMPKNuSirt Biopharma
AmlexanoxTBK1/IKKε/
ZED1227TG2Zedira
Pradaxa (Dabigatran)ThrombinBoehringer Ingelheim
JKB-122TLR4TaiwanJ Pharma
Trental (Pentoxifylline)TNFα/
Vitamin DVDR/
Uloric (Febuxostat)XDHTakeda

/, unknown. Italic font indicates drugs that failed clinically.

Major therapeutic targets include lipid metabolic enzymes acetyl-CoA carboxylase (ACC)6 and fatty acid synthase (FASN),7 which affect liver steatosis; farnesoid X receptor (FXR)8 which interferes with bile acid signaling; nuclear receptors peroxisome proliferator-activated receptor (PPAR),9 and thyroid hormone receptor beta (THRb)10 as well as antidiabetic-peptide receptors GLP-1 receptor (GLP1R),11 glucagon receptor (GCGR)12 and GIP receptor (GIPR),13 which alter glucose and lipid metabolism; FGF21 and FGF19 receptors, which have pleiotropic effects on liver steatosis, inflammation and fibrosis;14 chemokine (C-C motif) ligand 2 and 5 (CCL2/5)15 and amine oxidase copper containing 3 (AOC3),16 which influence inflammation; lysyl oxidase-like 2 (LOXL2),17 which involves in fibrosis; and caspases, which are key players in apoptosis (Fig. 2). Despite hundreds of potential drugs and a plethora of targets, there is no clear winner.

Seeking alpha

Although no consensus on noninvasive measures for NASH has been reached, histological evaluations of steatosis, inflammation, hepatocyte morphology, and fibrosis are well accepted. We have appraised treatment efficacy in the 33 trials with histological outcome measures (Supplementary Table 1, trials labeled in red) from seven perspectives, i.e. effects on liver steatosis, hepatocyte ballooning, inflammation, fibrosis (F1-F3), cirrhosis (F4), treatment duration, and safety (treatment-emergent adverse events). The first five parameters are NASH-specific and the last two are important clinical considerations for all medications.

FGF21 (NCT03976401), FGF19 (NCT03912532), obeticholic acid (NCT01265498, T02548351), pioglitazone (NCT00994682, NCT00063622, NCT00062764, CT00227110), semaglutide (NCT02970942), and resmetirom (NCT02912260) had significant effects on NASH patients (Table 2). It seems that FGF21 was the most efficacious, followed by resmetirom, pioglitazone, FGF19, semaglutide, and obeticholic acid (Table 2 and Fig. 3). FGF21 had a greater antifibrosis activity and shorter treatment duration than other drugs.

Table 2

Outcomes of major clinical trials

TrialPhaseDrugSteatosis (Score)Ballooning (Score)Inflammation (Score)Fibrosis F1-F3 (Score)Cirrhosis (Score)Tx Duration (Score)Safety (Score)Total score
NCT03976401IIFGF2117/17 (1)13/14 (0.93)13/14 (0.93)10/13 (0.77)7/12 (0.58)12 (1)No increase (1)6.21
NCT03912532IIFGF1934/43 (0.79)21/43 (0.49)0/43 (0)7/43 (0.16)ND (0)24 (0.8)Grade 1 (0.8)3.04
NCT01265498IIIObeticholic acid62/102 (0.61)47/102 (0.46)54/102 (0.53)36/102 (0.35)ND (0)72 (0.4)Grade 3 (0.4)2.75
NCT02548351III127/308 (0.41)108/308 (0.35)136/308 (0.44)84/308 (0.27)ND (0)72 (0.4)Grade 3 (0.4)2.27
2.51
NCT00994682IVPioglitazone35/50 (0.70)25/50 (0.50)25/50 (0.50)20/50 (0.40)NC (0)72 (0.4)No increase (1)3.10
NCT00063622III55/80 (0.69)35/80 (0.44)48/60 (0.6)35/80 (0.44)ND (0)96 (0.2)Weight gain (0.8)3.17
NCT00062764II6/18 (0.33)6/18 (0.33)6/18 (0.33)6/18 (0.33)ND (0)48 (0.6)Weight gain (0.8)2.72
NCT00227110IV17/26 (0.65)14/26 (0.54)17/26 (0.65)12/26 (0.46)ND (0)24 (0.8)No increase (1)4.10
3.27
NCT02970942IISemaglutide33/56 (0.59)33/56 (0.59)33/56 (0.59)0/56 (0)ND (0)72 (0.4)Grade 2 (0.6)2.77
NCT02912260IIResmetirom41/73 (0.60)41/73 (0.60)41/73 (0.60)21/73 (0.29)ND (0)12 (1)Grade 2 (0.6)3.69

Steatosis, ballooning, inflammation, fibrosis and cirrhosis score: number of responders/total number of patients; Treatment duration score: weeks 1–12=score 1, 13–24=score 0.8, 25–48=score 0.6, 49–72=score 0.4, >72=score 0.2; no effect=score 0; Safety (TEAE) score: no increase in TEAE over placebo=score 1, increase in Grade 1=score 0.8, Grade 2=score 0.6, Grade 3=score 0.4, Grade 4=score 0.2, Grade 5=score 0, no result=score 0; Average score in case of having multiple trials. N, no change; ND, not determined.

Efficacy of various treatments.
Fig. 3  Efficacy of various treatments.

Efficacy is evaluated from perspectives of steatosis, hepatocyte ballooning, lobular inflammation, fibrosis, cirrhosis, treatment duration, and safety (treatment-emergent adverse events). Steatosis, ballooning, inflammation, fibrosis, and cirrhosis score: responders/patients; duration score: weeks 1–12=1, 13–24=0.8, 25–48=0.6, 49–72=0.4, >72=0.2; no effect=0; safety score: no increase in TEAE over placebo=1, increase in Grade 1=0.8, Grade 2=0.6, Grade 3=0.4, Grade 4=0.2, Grade 5=0, no result=0; average score in case of having multiple trials.

Obeticholic acid improved steatosis, ballooning, inflammation, and fibrosis but had significant side effects, i.e. pruritus (aka itching).18,19 The FXR agonist cilofexor20,21 and EDP-30522 treatment were also associated with pruritus. It is unclear whether the itching side effect is obeticholic acid-specific or associated with bile acid metabolism in general. Compared with other PPAR agonists lanifibranor, rosiglitazone,and elafibranor, pioglitazone had a greater effect on steatosis, hepatocyte ballooning, inflammation, and fibrosis.23–26 Glitazones for type 2 diabetes therapy have been linked to serious side effects such as fluid retention, congestive heart failure, weight gain, bone loss, and increased risk of bladder cancer.27–29 Interestingly, pioglitazone had a safe profile in all four trials (NCT00994682, NCT00063622, NCT00062764, CT00227110). Side effects of longer treatment duration remain unclear. GLP-1 analog semaglutide30 and exenatide31 reduced liver steatosis, ballooning, and inflammation, but not fibrosis. It is noteworthy that obeticholic acid and pioglitazone data are from phase III trials and other drug results are from phase II trials. Resmetirom was effective in a phase II trial32 and positive phase III results have recently been announced by Madrigal (https://www.madrigalpharma.com/ ).

FGF21 phase II trial results are encouraging. AKERO-001 (an FGF21 analog) had excellent effectiveness on liver steatosis, ballooning, inflammation, and fibrosis with a short duration and mild adverse drug reactions.33 It was also effective in patients with cirrhosis (https://ir.akerotx.com/news-releases/news-release-details/akero-announces-positive-histological-improvements-cirrhotic ). Among patients with PNPLA3I148M mutation, 8/18 (44% I/M carriers) and 5/9 (56% M/M carriers) achieved a ≥ 4-point improvement in NAS and 10/18 (56% I/M carriers) and 7/9 (78% M/M carriers) had a ≥ 1 stage improvement in fibrosis ([email protected]). FGF19, a close relative, was less effective than FGF21, possibly owing to a significant elevation of total plasma cholesterol and low-density lipid cholesterol.34 Therefore, the FGF21 analog appears to be a strong therapeutic candidate for NASH.

There may still be room for improvement of FGF21 analogs. Pegbelfermin and BIO89-100 are FGF21 peptides stabilized by polyethylene glycol modification, whereas AKERO-001 is stabilized by FGF21-IgG1 Fc fusion. FGF21-Fc fusion protein seems to be more stable and thus more effective than PEG-modified ones. However, AKERO-001 is expressed in prokaryotic cells, and our experiment suggests that eukaryotic-expressed FGF21-Fc is significantly more stable and consequently more efficacious than the prokaryotic-expressed proteins. In addition, multitarget fusion peptides are emerging; for example, GLP1-FGF21 (DDKJ Biomedicals, HEC Pharm), GLP1-GCG-FGF21 (Doer Biologics), and GLP1-GIP-FGF21 (DDKJ Biomedicals). Preclinical evidence indicated that dual targeting molecule GLP1-FGF21 was more effective than FGF21 alone.35 GLP1-GIP combination has been reported to reduce GLP-1-caused gastrointestinal problems,36 therefore, the combination of GLP1-GIP-FGF21 may have a significant effect on both glucose and lipid metabolism while minimizing gastrointestinal discomfort. Are we seeing the light at the end of the tunnel? One should cautiously wait for the outcome of the FGF21 Phase III clinical trial.

Supporting information

Supplementary Table 1

Clinical outcome measures.

(XLSX)

Click here for additional data file.

Abbreviations

FGF21: 

fibroblast growth factor 21

NASH: 

nonalcoholic steatohepatitis

Declarations

Funding

None to declare.

Conflict of interest

YQC holds shares of DDKJ Biomedicals.

References

  1. Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980;55(7):434-438 PubMed/NCBI
  2. Sheka AC, Adeyi O, Thompson J, Hameed B, Crawford PA, Ikramuddin S. Nonalcoholic Steatohepatitis: A Review. JAMA 2020;323(12):1175-1183 View Article PubMed/NCBI
  3. Younossi ZM, Golabi P, de Avila L, Paik JM, Srishord M, Fukui N, et al. The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis. J Hepatol 2019;71(4):793-801 View Article PubMed/NCBI
  4. Lazarus JV, Mark HE, Anstee QM, Arab JP, Batterham RL, Castera L, et al. Advancing the global public health agenda for NAFLD: a consensus statement. Nat Rev Gastroenterol Hepatol 2022;19(1):60-78 View Article PubMed/NCBI
  5. Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of NAFLD development and therapeutic strategies. Nat Med 2018;24(7):908-922 View Article PubMed/NCBI
  6. Paul B, Lewinska M, Andersen JB. Lipid alterations in chronic liver disease and liver cancer. JHEP Rep 2022;4(6):100479 View Article PubMed/NCBI
  7. Angeles TS, Hudkins RL. Recent advances in targeting the fatty acid biosynthetic pathway using fatty acid synthase inhibitors. Expert Opin Drug Discov 2016;11(12):1187-1199 View Article PubMed/NCBI
  8. Rausch M, Samodelov SL, Visentin M, Kullak-Ublick GA. The Farnesoid X Receptor as a Master Regulator of Hepatotoxicity. Int J Mol Sci 2022;23(22):13967 View Article PubMed/NCBI
  9. Zhou S, You H, Qiu S, Yu D, Bai Y, He J, et al. A new perspective on NAFLD: Focusing on the crosstalk between peroxisome proliferator-activated receptor alpha (PPARα) and farnesoid X receptor (FXR). Biomed Pharmacother 2022;154:113577 View Article PubMed/NCBI
  10. Kowalik MA, Columbano A, Perra A. Thyroid Hormones, Thyromimetics and Their Metabolites in the Treatment of Liver Disease. Front Endocrinol (Lausanne) 2018;9:382 View Article PubMed/NCBI
  11. Nevola R, Epifani R, Imbriani S, Tortorella G, Aprea C, Galiero R, et al. GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives. Int J Mol Sci 2023;24(2):1703 View Article PubMed/NCBI
  12. Patil M, Deshmukh NJ, Patel M, Sangle GV. Glucagon-based therapy: Past, present and future. Peptides 2020;127:170296 View Article PubMed/NCBI
  13. Seino Y, Yabe D. Glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1: Incretin actions beyond the pancreas. J Diabetes Investig 2013;4(2):108-130 View Article PubMed/NCBI
  14. Tian H, Zhang S, Liu Y, Wu Y, Zhang D. Fibroblast Growth Factors for Nonalcoholic Fatty Liver Disease: Opportunities and Challenges. Int J Mol Sci 2023;24(5):4583 View Article PubMed/NCBI
  15. Roh YS, Seki E. Chemokines and Chemokine Receptors in the Development of NAFLD. Adv Exp Med Biol 2018;1061:45-53 View Article PubMed/NCBI
  16. Weston CJ, Shepherd EL, Claridge LC, Rantakari P, Curbishley SM, Tomlinson JW, et al. Vascular adhesion protein-1 promotes liver inflammation and drives hepatic fibrosis. J Clin Invest 2015;125(2):501-520 View Article PubMed/NCBI
  17. Dongiovanni P, Meroni M, Baselli GA, Bassani GA, Rametta R, Pietrelli A, et al. Insulin resistance promotes Lysyl Oxidase Like 2 induction and fibrosis accumulation in non-alcoholic fatty liver disease. Clin Sci (Lond) 2017;131(12):1301-1315 View Article PubMed/NCBI
  18. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 2015;385(9972):956-965 View Article PubMed/NCBI
  19. Younossi ZM, Ratziu V, Loomba R, Rinella M, Anstee QM, Goodman Z, et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2019;394(10215):2184-2196 View Article PubMed/NCBI
  20. Loomba R, Noureddin M, Kowdley KV, Kohli A, Sheikh A, Neff G, et al. Combination Therapies Including Cilofexor and Firsocostat for Bridging Fibrosis and Cirrhosis Attributable to NASH. Hepatology 2021;73(2):625-643 View Article PubMed/NCBI
  21. Patel K, Harrison SA, Elkhashab M, Trotter JF, Herring R, Rojter SE, et al. Cilofexor, a Nonsteroidal FXR Agonist, in Patients With Noncirrhotic NASH: A Phase 2 Randomized Controlled Trial. Hepatology 2020;72(1):58-71 View Article PubMed/NCBI
  22. Ratziu V, Rinella ME, Neuschwander-Tetri BA, Lawitz E, Denham D, Kayali Z, et al. EDP-305 in patients with NASH: A phase II double-blind placebo-controlled dose-ranging study. J Hepatol 2022;76(3):506-517 View Article PubMed/NCBI
  23. Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, et al. Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial. Ann Intern Med 2016;165(5):305-315 View Article PubMed/NCBI
  24. Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362(18):1675-1685 View Article PubMed/NCBI
  25. Promrat K, Lutchman G, Uwaifo GI, Freedman RJ, Soza A, Heller T, et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology 2004;39(1):188-196 View Article PubMed/NCBI
  26. Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 2006;355(22):2297-2307 View Article PubMed/NCBI
  27. Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM, Horton ES, et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. October 7, 2003. Circulation 2003;108(23):2941-2948 View Article PubMed/NCBI
  28. Korhonen P, Heintjes EM, Williams R, Hoti F, Christopher S, Majak M, et al. Pioglitazone use and risk of bladder cancer in patients with type 2 diabetes: retrospective cohort study using datasets from four European countries. BMJ 2016;354:i3903 View Article PubMed/NCBI
  29. Aubert RE, Herrera V, Chen W, Haffner SM, Pendergrass M. Rosiglitazone and pioglitazone increase fracture risk in women and men with type 2 diabetes. Diabetes Obes Metab 2010;12(8):716-721 View Article PubMed/NCBI
  30. Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V, et al. A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis. N Engl J Med 2021;384(12):1113-1124 View Article PubMed/NCBI
  31. Kenny PR, Brady DE, Torres DM, Ragozzino L, Chalasani N, Harrison SA. Exenatide in the treatment of diabetic patients with non-alcoholic steatohepatitis: a case series. Am J Gastroenterol 2010;105(12):2707-2709 View Article PubMed/NCBI
  32. Harrison SA, Bashir MR, Guy CD, Zhou R, Moylan CA, Frias JP, et al. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2019;394(10213):2012-2024 View Article PubMed/NCBI
  33. Harrison SA, Ruane PJ, Freilich BL, Neff G, Patil R, Behling CA, et al. Efruxifermin in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a trial. Nat Med 2021;27(7):1262-1271 View Article PubMed/NCBI
  34. Harrison SA, Rinella ME, Abdelmalek MF, Trotter JF, Paredes AH, Arnold HL, et al. NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2018;391(10126):1174-1185 View Article PubMed/NCBI
  35. Pan Q, Lin S, Li Y, Liu L, Li X, Gao X, et al. A novel GLP-1 and FGF21 dual agonist has therapeutic potential for diabetes and non-alcoholic steatohepatitis. EBioMedicine 2021;63:103202 View Article PubMed/NCBI
  36. Borner T, Tinsley IC, Doyle RP, Hayes MR, De Jonghe BC. Glucagon-like peptide-1 in diabetes care: Can glycaemic control be achieved without nausea and vomiting?. Br J Pharmacol 2022;179(4):542-556 View Article PubMed/NCBI
Copyright © 2023 Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial 4.0 License (CC BY-NC 4.0), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
  • Journal of Clinical and Translational Hepatology
  • pISSN 2225-0719
  • eISSN 2310-8819

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NASH Drug Development: Seeing the Light at the End of the Tunnel?

Yong Q. Chen
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