| Thiazolidinediones |
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Modulate adipose tissue distribution, decreasing visceral fat;
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Regulate insulin sensitivity by the activation of peroxisome proliferator-activated receptor-γ
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| Vitamin E |
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Vitamin E use was associated with improved clinical outcomes in patients with histological proven NASH and bridging fibrosis or cirrhosis [13].
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Vitamin E treatment, as compared with placebo, was associated with a significantly higher rate of improvement in NASH (43% vs. 19%, p = 0.001), but not significant if pioglitazone as compared with placebo (34% and 19%, p = 0.04) [14].
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Vitamin E and pioglitazone were associated with reductions in hepatic steatosis (p = 0.005 and p < 0.001, respectively) and lobular inflammation (p = 0.02 and p = 0.004, respectively) but not with improvement in fibrosis scores (p = 0.24 and p = 0.12 respectively) [14].
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| Silymarin |
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| Obeticholic acid |
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45% patients in the obeticholic acid group had improved liver histology (2 point or greater improvement in NAFLD activity score without worsening of fibrosis) compared with 21% of patients in the placebo group (p = 0.0002) [35];
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Improvement of NASH without worsening of fibrosis was not statistically significant. Itch was the most common adverse event and forced the discontinuation especially in obeticholic acid 25 mg arm. Increases in LDL were also observed by week 4 [37].
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| NGM282 |
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Induced marked relative reduction from baseline in steatosis with a 57% and 45% (p < 0.0001) at the 6- and 3-mg doses, respectively. Improvements in ALT (p < 0.0001), AST (p < 0.0001) were also observed, but not in glycemic control. Injection site reactions were reported in 54% and 41% of subjects in the 6- and 3-mg dose groups relative to 7% in the PBO group [40].
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| Cilofexor |
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Phase II study with 140 NASH patients, treated with cilofexor at 100 or 30 mg or placebo orally, once daily for 24 weeks. A significant decrease in hepatic steatosis of at least 30% assessed by MRI-PDFF was observed in 38.9% of patients treated with cilofexor 100 mg (p = 0.011), 14% treated with cilofexor 30 mg (p = 0.87), and 12.5% treated with placebo. Further significant observations in the cilofexor-treated patients were improvements in serum GGT and serum 7α-hydroxy-4-cholesten-3-one (C4) [42].
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| Tropifexor |
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At 12 weeks, a significant decrease in hepatic steatosis of at least 5% assessed by MRI-PDFF was observed in 33.3% of patients treated with Tropifexor 90 μg, 27.8% treated with Tropifexor 60 μg, and 14.6% treated with PBO. Furthermore, a dose–response decrease in GGT levels was observed as well as increases in FGF19. Adverse events, especially pruritus and increase in LDLc and HDLc, were reported in 90 μg Tropifexor arm [45].
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| Elafibranor |
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With the intention to treat analysis, 92 patients received placebo and 93 and 89 patients received Elafibranor 80 and 120 mg, respectively. Outcome: a score of 0 of at least 1 between steatosis, ballooning and inflammation (reversal of NASH) without worsening of fibrosis (progression of patients with fibrosis stage ≤ 2 to F3-F4 or from F3 to F4). no differences were observed between patients treated with Elafibranor and placebo (OR 1.53, 95% CI 0.70−3.34, p = 0.280); conversely, using the modified definition, the response rate was significantly higher in those who received Elafibranor 120 mg in comparison with placebo (OR 2.31, 95% CI 1.02−5.24, p = 0.045), with a lower placebo effect [67];
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Post-hoc analysis restricted to 234 patients with NAS score ≥ 4 at baseline showed that treatment with Elafibranor 120 mg (n = 75) was significantly associated with higher response rate in comparison with placebo (n = 76), using both definitions of response, although it should be considered that no stratification according this covariate was performed at randomization [67].
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| Lanifibranor |
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| GS-0976 |
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A group of 93 patients with NASH (diagnosed with magnetic resonance elastography or with histology) were assigned to GS-0976 (46 patients to 20 mg dosage and 47 to 5 mg), while 26 patients received placebo for 12 weeks. In comparison with placebo, GS-0976 20 mg was significantly associated with a relative reduction of at least 30% from baseline in magnetic resonance imaging-estimated MRI-PDFF (48% vs. 15%, p = 0.004), as well as median relative decreases in MRI-PDFF were more pronounced for GS-0976 20 mg in comparison with placebo [72,73].
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| Aramchol |
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A group of 247 patients with histologically proven NASH, NAS ≥ 4 without cirrhosis and type 2 diabetes/prediabetes were randomized to receive Aramchol 400 mg (n = 101), Aramchol 600 mg (n = 98) and placebo (n = 48). Primary endpoint was the decrease from baseline in steatosis assessed by MRS; secondary endpoints were fibrosis score improvement without worsening of NASH and NASH resolution without worsening of fibrosis. Treatment with Aramchol 600 mg was associated with reduction of at least 5% in liver fat from baseline in 47% of patients (versus 24% in placebo, p = 0.0279, OR 2.77 (95% CI 1.12–6.89) and with NASH resolution alone in 19% of patients (versus 7.5% in placebo, p = 0.046) [77].
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| Resmetirom |
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Dosage of 80 mg once daily was assigned to 78 patients and 38 patients received placebo for 36 weeks. Primary endpoint at 12 weeks (relative reduction in MRI-PDFF) was met (−36% in treated arm versus −9% in placebo arm). Conversely, histological endpoint at 36 weeks (2-points NAS reduction with ≥ 1-point decrease in ballooning or inflammation) was not met (51% in treated arm vs. 32% in placebo arm, p = 0.09). However, limiting the analysis to patients treated with Resmetirom who obtained a reduction of at least 30% in MRI-PDFF, response rate was significantly higher (65%, p = 0.006) in comparison with placebo, suggesting a relationship between early reduction in liver fat at 12 weeks and NASH histological improvement at 36 weeks [85].
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| VK-2809 |
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A 12-week phase II RCT, in whom 16 patients received VK-2809 10 mg once a day, 16 patients received 10 mg every other day and 15 patients were assigned to placebo. Daily dose administration was associated with a median reduction of 60% (p < 0.01) at 12 weeks of liver fat content in comparison with placebo, although an increase in ALT levels was observed, especially during early treatment. However, after 12 weeks of treatment, ALT levels were similar between VK-2809 and placebo [86].
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| Liraglutide |
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It was associated with a significant improvement in liver enzymes and with a good safety profile in an individual patient data meta-analysis of six randomized controlled trials, concerning more than 4000 diabetic patients [91];
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A treatment of 48 weeks of subcutaneous liraglutide (1.8 mg/day) were compared with placebo and primary endpoint was NASH resolution without impairment of fibrosis. Thirty-nine percent of patients treated with liraglutide compared to 9% placebo group patient (p = 0.019) met the primary endpoint, whereas no significant differences were observed in progression of fibrosis between two groups [92].
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| Ipraglifozin |
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| Pegbelfermin |
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Although no histological outcome was assessed, pegbelfermin showed to be safe and well tolerate and an absolute decrease of 6.8% in MRI-PDFF from baseline was observed in the arm treated with 10 mg once a day, that was significantly higher if compared to placebo (−1.3%. p = 0004), regardless of the presence of type 2 diabetes. Although mean reduction in liver stiffness (assessed with MR elastography) was higher in patients who received placebo, the prevalence of patients who obtained a reduction of at least 15% in liver stiffness was significantly higher in patients treated with pegbelfermin 10 mg in comparison with placebo (36% vs. 7%, respectively) [112].
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| Emricasan |
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Treatment with emricasan resulted associated with a significant reduction of ALT and cytokeratin-18 levels, a well-known marker of apoptosis, although no histological outcomes were assessed [116].
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No significant change in HVPG after emricasan treatment, although a significant HVPG decrease was observed only in patients with severe portal hypertension [117].
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| Cenicriviroc |
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Dosage of 150 mg per os once daily. After 1 year the primary endpoint of NAS improvement in the intent-to-treat population was achieved in a similar proportion of subjects on CVC (N = 145) and placebo (N = 144; 16% vs. 19% respectively; odds ratio (OR), 0.82 (95% confidence interval, 0.44–1.52); p = 0.52). Resolution of steatohepatitis and no worsening of fibrosis, a key secondary outcome, was also observed in similar rates in the 2 groups (8% vs. 6%, respectively; OR, 1.40 (95% CI, 0.54–3.63); p = 0.49). The improvement in fibrosis by ≥1 stage and no worsening of steatohepatitis, another key secondary outcome, was observed in more patients on CVC if compared to placebo (20% vs. 10%, respectively; OR 2.20 (95% CI, 1.11–4.35); p = 0.02) [130].
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| Selonsertinib |
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NASH patients, with presence of stage F2-F3 fibrosis and NAS ≥ 5. 72 patients were randomly assigned in a 2:2:1:1:1 ratio to receive 24 weeks of treatment with 6 mg or 18 mg of selonsertib alone, 6 mg or 18 mg of selonsertib with 125 mg of simtuzumab, or 125 mg of simtuzumab alone. Because of the lack of effect of simtuzumab on histology or selonsertib pharmacokinetics, selonsertib groups with and without simtuzumab were pooled. Selonsertib is better than placebo in achieving the primary efficacy endpoint of fibrosis improvement of one stage or greater after 24 weeks of treatment [136].
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| Simtuzumab |
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