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. 2021 Aug 23;12(1):155–173. doi: 10.1016/j.jceh.2021.08.017

Table 1.

Summary of Studies Evaluating Therapeutics in NAFLD and NASH.

Author Drug and dose Inclusion criteria, stage of fibrosis Type of study Duration of therapy Outcome
Ongoing Elobixibat (IBAT inhibitor) 5 mg once daily NAFLD, NASH Randomized double-blind, placebo-controlled Phase 2 study 16 weeks Change in serum LDL cholesterol
Nadinskaia et al. WJG 2021101 N = 174; 15 mg/kg/d UDCA
121 (69.5%) men and 53 (30.5%) women
Men significantly younger than women
Ultrasound-diagnosed NAFLD; FLI >60 Open-label, multicenter, international uncontrolled trial 6 months Δ decrease in ALT, AST, and GGT during 0–3 m > 3–6 m.
↔ in NFS, FIB-4.
Significant ↑ in HDL, ↓ in LDL-C, TC, TG
Sex differences in response observed
Traussnigg et al, Wien Klin Wochenschr, 2021102 5 mg PX-104 (nonsteroidal FXR agonist) once daily Nondiabetic NAFLD (n = 12) Open-label Phase 2a study 4 weeks ↑ IS
↓ ALT and GGT
↔ ALP or serum lipids.
↔Hepatic steatosis: MRI-PDFF, 1H-MRS, and CAP
↔ Serum BAs Cardiac arrhythmia in two patients led to the termination of the study.
Newsome et al. Journal of hepatology 2020103 N = 197 were randomized to receive Volixibat 5 mg (n = 49), Volixibat 10 mg (n = 50), Volixibat 20 mg (n = 49), or placebo (n = 49) once daily Adults, ≥5% steatosis, and NASH without cirrhosis Phase 2 randomized, double-blind, Phase II, placebo-controlled study 48 weeks Volixibat did not meet interim endpoints (24 weeks), i.e., ≥5% reduction in MRI-PDFF and ≥20% reduction in serum ALT.
The study was terminated owing to a lack of efficacy
Pockros et al. Liver international, 2019104 5 mg, 10 mg, 25 mg OCA once daily Biopsy-confirmed NASH without hepatic decompensation Randomized, double-blind, placebo-controlled, Phase 2 study 16 weeks ↓ LDL-C with OCA + statin
Palmer et al. BMC pharmacology and toxicology 2018105 20, 40, or 80 mg Volixibat (n = 63); placebo (n = 21) once daily Overweight and obese adults Phase 1 study 12 days Volixibat (≥20 mg/day): maximal fecal BA excretion in obese and overweight adults
Harrison et al Hepatology 2020106 Subcutaneous NGM282 1 mg (n = 24) NGM282 3 mg (n = 19) once daily Paired biopsies, NASH as per NASH CRN criteria; F1-F3; liver fat ≥8%; ↑ ALT Open-label, multicenter trial 12 weeks 50% and 68% in the 1 mg and 3 mg treatment arms, respectively, achieved significant histological improvement.
12% and 10% in the 1 mg and 3 mg groups, respectively, achieved NASH resolution without fibrosis worsening at 12 weeks
Younossi et al. Lancet 201981 N = 931; placebo (n = 311) OCA 10 mg (n = 312); or OCA 25 mg (n = 308) Stage F2-F3 fibrosis Phase 3 multicenter, randomized, placebo-controlled trial Interim analysis at 18 months (total study period = 4 years) OCA 25 mg significantly improved fibrosis without worsening of NASH by 1.9 times (95% CI 1·4–2·8) c/w placebo.
Greater proportion of patients receiving 25 mg OCA showed improvement in liver histology and in serum ALT and AST
Harrison et al. Lancet 201891 Subcutaneous NGM282 (FGF-19 analog) 3 mg (n = 27), NGM282 6 mg (n = 28), or placebo (n = 27) once daily Biopsy-confirmed NASH; Stage 1–3 fibrosis; liver fat ≥8%; ↑ ALT Multicenter international randomized, double-blind, placebo-controlled, Phase 2 trial 12 weeks NGM282: ↓ ALT/AST, ↓ liver fat
↓ TGs seen only in 6 mg group and ↑ total and LDL cholesterol in both groups
Neuschwander-Tetri et al (FLINT trial) Lancet 201580NCT01265498 OCA 25 mg (n = 141) or Placebo (n = 142) once daily Histologically proven NASH or borderline NASH Phase 3 Randomized double-blind, placebo-controlled trial 72 weeks OCA: improved liver histology (≥2-point NAS without worsening of fibrosis).
Mean change in NAS: OCA > placebo.
OCA: ↓ ALT and AST.
↑ ALP, ↓ GGT which reversed after stopping OCA.
NASH resolution (OCA = placebo).
OCA (ADE): ↑ LDL-C, Pruritis: 23% vs. 6% in placebo
Siddiqui et al Journal of Hepatology. 2020107 Serum and biopsy samples of 196 patients who were enrolled in the FLINT trial; OCA group (n = 99), placebo group (n = 97) once daily Histologically proven NASH or borderline NASH 72 weeks OCA: ↑ increase in lipoprotein levels, which improves after drug discontinuation
Mueller et al. Journal of hepatology 2015108 20 mg/kg/day
UDCA (n = 19) in two daily doses; Controls (n = 18)
Morbidly obese (BMI >35 kg/m2)
NAFLD scheduled for laparoscopic Roux-en-Y gastric bypass
Randomized open-label study 3 weeks UDCA: ↓ AST, GGT, free FA, total and LDL-C, and ↑ TGs
Mudaliar et al. Gastroenterology 2013109
NCT00501592
Placebo (n = 23), 25 mg OCA (n = 20), or 50 mg OCA (n = 21) once daily Patients with type 2 diabetes mellitus and NAFLD Phase 2
Multicenter, randomized, double-blind, placebo-controlled study
6 weeks OCA: ↑ IS by 28% as c/w placebo
OCA: ↓ GGT, ALT, and dose-related weight loss.
↑ LDL-C and FGF-19, a/w ↓ 7ɑ-hydroxy-4-cholesten-3-one and endogenous BAs
Ratziu et al J Hepatol. 2011110 N = 126; high-dose UDCA (HD-UDCA; 28–35 mg/kg per day) Biopsy-proven NASH and elevated ALT Phase 2 randomized, double-blind, placebo-controlled multicenter trial 12 months HD-UDCA: ↓ ALT
Leuschner UF, Hepatology. 2010111 N = 185; UDCA 23–28 mg/kg (n = 94) or placebo (n = 91) daily in three divided doses NASH (per NAS and modified brunt score) Randomized, double-blind, placebo-controlled study 18 months No difference in histology c/w placebo
Lindor et al. Hepatology 2004112 N = 166; 13–15 mg/kg/day of oral UDCA (n = 80) or placebo (n = 86) four divided doses daily Patients with biopsy-proven NASH Prospective, randomized, double-blind, placebo-controlled trial 24 months UDCA (13–15 mg/kg/d): not effective in patients with NASH
Laurin et al. Hepatology 1996113 13–15 mg/kg/day of oral UDCA in divided doses with meals (n = 24); 2 g/day Clofibrate in two divided doses (n = 16 with NASH + hypertriglyceridemia) Biopsy-proven NASH Open-label study 12 months UDCA: ↓ ALP, ALT, GGT, and hepatic steatosis

IS, insulin sensitivity; IBAT, ileal bile acid transporter; LDL-C, low-density lipoprotein cholesterol; OCA, obeticholic acid; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; LDL, low-density lipoprotein; FXR, Farnesoid X receptor; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, γ-glutamyltransferase; ALP, alkaline phosphatase; MRI-PDFF, magnetic resonance imaging–proton density fat fraction; 1H-MRS, proton magnetic resonance spectroscopy; CAP, controlled attenuation Parameter; BA, bile acid; NASH CRN, nonalcoholic steatohepatitis clinical research network; FGF-19, fibroblast growth factor 19; PSC, primary sclerosing cholangitis; NAS, NAFLD activity score; TG, triglycerides; BMI, body mass index; UDCA, ursodeoxycholic acid; ADE, adverse drug events; FA, fatty acids; CI, confidence interval; NFS, NAFLD fibrosis score; FLI, Fatty Liver Index; FIB-4, Fibrosis-4 Index; TC, total cholesterol.