Table 1.
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.