Antioxidants
Vitamin E
Vitamin E has been studied in the landmark PIVENS (adult patients) and TONIC trials (pediatric population), where the antioxidative and free radical scavenging property of vitamin E has been hypothesized to improve NASH.6,8 Indeed, there was a significant improvement in steatosis and inflammation in patients treated with vitamin E for 96 weeks compared to placebo.6 However, there was no improvement in fibrosis.6 There have been conflicting reports on the rise in all-cause mortality in patients receiving vitamin E.32,33 However, a small increase in prostatic cancer due to long term administration of vitamin E is known.34 Though the drug is well tolerated, the current guidelines recommend vitamin E (rrr-α-tocopherol) at a daily dose of 800 IU/day in non-diabetic adults with biopsy-proven NASH, weighing the risk-benefit ratio before initiation of treatment.24 The long-term safety of administration of vitamin E for more than 6 months is unclear.
Pioglitazone
Pioglitazone, an agonist of peroxisome proliferator-activated receptor (PPAR) γ, was evaluated in the same PIVENS study. Pioglitazone has been hypothesized to increase the adipocyte uptake of fatty acids, thereby potentially drawing fat away from the hepatocytes.6 The use of 30 mg of pioglitazone for 96 weeks in non-diabetic patients showed a significant improvement in NASH compared to placebo. However, there was no improvement in fibrosis.6 The major drawback of vitamin E and pioglitazone is the lack of improvement in fibrosis, which is an important determinant of outcomes in NASH.35 Thus, the clinical relevance of the results from the PIVENS study is limited. Further, weight gain, bladder cancer, and bone loss are major concerns associated with pioglitazone.24 Of note, pioglitazone may be used for both diabetic and non-diabetic patients with biopsy-proven NASH only after explaining the risks and benefits in detail.24,31
Ursodeoxycholic acid (UDCA)
UDCA at a dose of 13–15 mg/kg body weight in patients with biopsy-proven NASH has not shown any benefit when compared with placebo and is not recommended for NASH.7 Animal studies on a side-chain-shortened homologue of UDCA, nor- (n)UDCA, can attenuate the progression of NASH.36 A recent human study (phase 2 trial) reported significant improvement in serum ALT levels at 12 weeks with the use of nUDCA at 1,500 mg per day compared to placebo.37 Further phase III studies are required to confirm if the drug can meet the recommended endpoints.
Omega-3 fatty acids
Omega-3 fatty acids can reduce oxidative stress, lipotoxicity, and inflammation in patients with NASH.38 There have been conflicting reports about efficacy of omega-3 fatty acids in NAFLD.10,39 The optimum dose has not yet been determined. However, the benefits of omega-3 fatty acid supplementation have been noted with a dose of ≥0.83 g/day.40 Currently, they can be used to treat hypertriglyceridemia in NASH but not for the treatment of NAFLD or NASH.24
Metformin
Early studies with metformin showed improvement of insulin resistance, liver chemistries, and a modest reduction in hepatic steatosis.41 Subsequently, two meta-analyses with the use of metformin in NASH showed no benefit and are currently not recommended for the treatment of NASH.42,43
Pentoxifylline (PTX)
PTX inhibits several pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α.44 PTX increases hepatic glutathione levels in mice with steatohepatitis induced by a methionine choline-deficient diet and reduces the production of oxygen radicals induced by prolonged ischemia time in rat livers.44,45 PTX down-regulates profibrogenic cytokines and procollagen I expression in a rat model of biliary duct occlusion.46 Although preclinical studies have demonstrated the efficacy of PTX in NASH, there are conflicting reports in human trials of PTX.45,47 PTX is currently not recommended for NASH, due to insufficient evidence.
Drugs in the pipeline for NASH
The increasing burden of NASH worldwide has kept researchers astute to discover a new drug. NASH is associated with a high lifetime economic burden. In the absence of treatment, the total direct cost of illness for these patients will continue to grow.48 Several drugs are in the pipeline for the treatment of NASH. Although none of these drugs appear as ideal, many of them seem promising. Some of these drugs are detailed in Table 1.
Table 1Mechanism of novel therapies for NASH
Name of drug | Mechanism of action | Phase of study | Comments |
---|
OCA | FXR agonist | 3 | Review with FDA for approval likely in June 2020 |
Elafibranor | PPARαδ agonist | 3 | Missed primary endpoints in 2015 and 2020 |
Aramchol | Stearoyl Co-A desaturase 1 inhibitor and prevents de novo lipogenesis | 3 | Results of the ARMOR study are awaited |
Saroglitazar | Dual PPARαγ agonist | Phase 2 studies in USA and phase 3 studies in India | Currently approved by the DCGI. Abstracts have shown more effect on steatohepatitis. |
Cenicriviroc | CCR2 and CCR5 chemokine receptor antagonist | CENTAUR study has shown improvement | Data from AURORA study are expected by September 2020 |
Emricasan | Pan-caspase inhibitor | Phase 2 | Did not meet the primary endpoint |
Belapectin | Galectin-3 inhibitor | Phase 2 study on effect in NASH and fibrosis and reduction of portal pressure | No improvement in fibrosis or portal hypertension |
GLP-1 agonists: liraglutide and semaglutide | GLP-1 hormone | 3 | Studies with semaglutide hold promise and have shown fibrosis improvement |
Obeticholic acid (OCA)
Bile acid signal receptors are abundant in the liver, kidney, adipose tissue, small intestine, and immune cells.49 OCA, 6α-ethyl chenodeoxycholic acid (INT 747), is a semi-synthetic derivative of chenodeoxycholic acid. It is a 100-times more potent agonist of FXR than chenodeoxycholic acid.50,51 OCA is rapidly absorbed orally and reaches a peak plasma concentration in approximately 1.5 hours after intake and has a steady-state half-life of 4 days. The drug is not affected by food intake. The mean volume distribution of OCA is 618 L and is about 99% protein bound. The liver extensively metabolizes it into glycine and taurine conjugates. OCA undergoes extensive entero-hepatic circulation, and >85% of metabolites are excreted in feces. FXR activation is mediated by binding of OCA to FXR receptors, which leads to increased secretion of FGF19 from the ileum. This results in formation of the β-klotho-FGF4-FGF19 complex, which inhibits CYP7A1 expression and bile acid synthesis. Besides, there is an increase in bile salt exporter protein (known as BSEP) and multidrug resistance 3 (known as MDR3) protein, promoting efflux of bile from hepatocytes. Further, OCA has a mild suppressive effect on the transforming growth factor-beta gene and extracellular matrix reorganization and stellate cell activation. The mechanism of action of OCA is summarized in Fig. 2.
The phase 2b study of OCA in NASH, called the ‘FLINT’ study, showed a significant improvement of NAS score by ≥2 points, without worsening of fibrosis, in 45% of patients receiving OCA at 25 mg, as compared with 21% in placebo (p=0.0002). Thirty-five percent in the OCA group also showed improvement in fibrosis compared to 19% in the placebo group (p=0.004).52 However, this study was terminated early due to administrative reasons. This was followed by a subsequent phase 3 study (the REGENERATE trial) involving 2,400 NASH patients with F2-3 fibrosis. They were randomized in 1:1:1 ratio to receive either placebo or OCA at 10 mg or OCA at 25 mg per day for 48 weeks.53 An interim analysis at 18 months on 931 patients showed improvement in fibrosis by ≥1 stage, with no worsening of NASH in 23% of patients receiving OCA at 25 mg, when compared with 12% in the placebo arm (p=0.0002) and 18% in the OCA 10 mg group (p=0.04 for placebo).11 A dose-dependent decrease in liver chemistries was observed from 3 months to 18 months. Similarly, improvement in NAS score by 2 points without worsening of fibrosis was significantly higher in the OCA 25 mg group when compared to placebo (36% vs. 24%; p=0.0012), with no such difference between the OCA 10 mg and placebo groups (30% vs. 24%; p=0.11).11 Considering the vast number of NASH patients worldwide, this promising data would help to avoid many of the liver transplants attributable to NASH. Recent studies have shown that underlying genetic abnormalities may identify a cohort of patients who would respond to OCA.54
Pruritis and a rise in low-density lipoprotein cholesterol (LDL) are the two major concerns with the use of OCA. The most common side effect reported with OCA is pruritus. Pruritus on treatment was reported in 19% of patients on placebo compared to 28% with OCA at 10 mg and 51% with OCA at 25 mg.11 Nearly 10% had to discontinue OCA (25 mg) due to pruritis compared to 1% each in the OCA 10 mg and placebo arms.11,55 The general concern for a physician is introducing pruritis in an asymptomatic disease. However, in a recent abstract, the interim analysis of the REGENERATE trial showed lower patient-reported outcomes than the general population on a specific questionnaire (the chronic liver disease questionnaire-NASH), and the patient-reported outcomes improved with OCA treatment.56 The authors further argued that pruritis is present in 21% of individuals at baseline, which is also unclear. Female gender, gastrointestinal comorbidity, and psychiatric comorbidity were associated with clinically important low itch score. However, data suggested that OCA-related pruritus occurs early in the treatment, without any subsequent worsening or negative impact on patient-reported outcomes. Importantly, thus far, OCA is the only drug to have met the endpoint of fibrosis improvement.
Besides, OCA therapy increases small very low-density lipoprotein (VLDL) particles, large and small LDL particles, and reduces high-density lipoprotein particles at 12 weeks, which reverses after drug discontinuation.57 Whether this leads to an increased risk of cardiovascular mortality in NASH patients is not yet known. Concurrent use of statins (in the CONTROL trial) lowered the LDL cholesterol to below baseline as early as 4 weeks after initiation and has an acceptable tolerability profile.57 The FDA approved OCA in 2016 for use in primary biliary cholangitis at a dose of 5–10 mg/day for non-responders in Child A cirrhotics and non-cirrhotics. While the recommended dose for Child B/C cirrhotics is 5 mg/weekly, to a maximum dose of 10 mg twice weekly.58
PPAR agonists
These are a group of nuclear receptor proteins that act as modulators of gene expression by functioning as transcription factors.59 They have a role in lipid, protein and carbohydrate metabolism, as well as in cellular differentiation. Fibrates consist of fenofibrate, clofibrate, gemfibrozil, are PPARα agonists. They help in breakdown and transport of fatty acid and are found in abundance in the liver, skeletal muscle, and endothelial cells.60 Studies with fibrates in NASH did not show any difference in the improvement in either steatosis or fibrosis.61,62 A possible reason for their ineffectiveness in humans is because of the lower expression of PPARα in humans when compared to mouse models.
Thiazolidinediones (TZD), pioglitazone, and rosiglitazone are PPARγ agonists. PPARγ, which is mainly located in the adipose tissue, plays a vital role in the regulation of adipocyte differentiation, adipogenesis, and lipid metabolism.63 They have shown to improve glucose uptake and increase fatty acid oxidation, and insulin secretion, leading to improvement in insulin sensitivity.64 Pioglitazone, a weak PPARγ agonist, showed a significant decrease in serum ALT and total hepatic lipid content and an increase in adiponectin expression in mouse models.65 In a trial of 55 patients with impaired glucose tolerance (or T2DM), pioglitazone administered with a hypocaloric diet improved steatosis and inflammation but not fibrosis.66 Even in the PIVENS trial, there was no improvement in fibrosis.6 (Pioglitazone has been discussed in the previous paragraph). Rosiglitazone, a potent PPARγ agonist, on the other hand, has shown some beneficial effects in rodent models.67 Rosiglitazone improved steatosis and transaminase levels, despite significant weight gain.64 Even prolonged therapy of rosiglitazone had no substantial improvement in NAS score.68 A meta-analysis of four trials did not show improvement in fibrosis with the use of TZD therapy; although, there was a significant improvement in steatosis and inflammation.69 Weight gain remains the major concern associated with the use of TZD.6,64,70
PPARβ/δ agonists, are universally present in all cells of the body and are involved in regulating mitochondrial metabolism and fatty acid beta-oxidation.71 The data regarding the effectiveness of PPARδ agonists for the treatment of NAFLD are limited, precluding formulation of any conclusions.72
Dual agonists
Glitazars are a group of drugs that have PPARα/γ agonism and can improve dyslipidemia and insulin resistance.73 Muraglitazar and aleglitazar posed severe safety concerns for cardiovascular events and weight gain and were withdrawn.74,75 Saroglitazar, a dual PPARα/γ agonist, was recently approved by the Drugs Controller General of India (known as the DCGI) for the treatment of NASH. Saroglitazar has promising results in the treatment of NASH. Elafibranor, a PPARα/δ agonist, also had favorable results in preclinical trials. Bezafibrate is also a dual PPARα/δ agonist and has some in vitro studies supporting its use in NASH, but there are no clinical studies on its efficacy in NASH.76
Saroglitazar
PPARα agonism is thought to affect fatty acid catabolism/dyslipidemia, while PPARγ has an impact on glycemic control and insulin sensitization. A combination of fenofibrate (PPARα) and rosiglitazone (PPARγ) improved diabetic dyslipidemia and glycemic control.77 Saroglitazar is a dominant PPARα agonist and is effective in improving insulin sensitivity.78,79 Saroglitazar in mice has shown to ameliorate NASH through down-regulation of the hepatic lipopolysaccharide/toll-like receptor-4 pathway and inhibition of adipocyte dysfunction.80 Saroglitazar prevents weight gain, normalizes liver enzymes, improves insulin resistance, dyslipidemia, and hepatic inflammation in NASH mice.80 Saroglitazar also led to a significant change in adipokine levels, resulting in a substantial decrease in serum leptin and TNF-α level.80 In NASH models, saroglitazar reduced hepatic steatosis, inflammation, ballooning, and fibrosis.81 It also reduced liver enzymes and the expression of inflammatory and fibrosis biomarkers. Saroglitazar led to a significant reduction in the NAS score, better than that achieved with pioglitazone and fenofibrate.81,82 The mechanism of action of saroglitazar is shown in Fig. 3. A recent randomized multicenter placebo-controlled trial using different doses of saroglitazar (the EVIDENCE IV trial) was presented as an abstract at the annual meeting of the American Association for the Study of Liver Diseases (AASLD). Saroglitazar at 4 mg improved dyslipidemia, hepatic steatosis, and insulin resistance, when compared to placebo (L010 AASLD 2019).83 Another phase 3 multicenter, double-blind, randomized study concluded that saroglitazar at 4 mg for 52 weeks improved NAS score, transaminitis, and lipid profile without fibrosis worsening [Abstract 1427, APASL liver meet 2020 Hepatol Int (2020) 14 (Suppl 1): S326].
Elafibranor
Elafibranor (GFT505) is a PPARα/δ agonist under evaluation for the treatment of NASH. It has been shown in in vivo studies on Western diet-fed, human apolipoprotein E2 transgenic mice to improve steatosis, inflammation, and fibrosis.84 The study also demonstrated that the drug decreased hepatic lipid accumulation and inhibited pro-inflammatory and profibrotic gene expression. In the initial multicenter, double-blind placebo-controlled randomized trial (the GOLDEN-505 trial), elafibranor at 80 mg and 120 mg were compared against placebo for treatment of NASH for 52 weeks.85 In the intention-to-treat (ITT) analysis, no difference was noted in the protocol-defined primary outcome, which was NASH resolution without fibrosis worsening. However, in a post ad hoc modified endpoint, NASH resolution without fibrosis worsening was higher with elafibranor at 120 mg compared to placebo (19% vs. 12%; p=0.045). Improvement in NAS score was seen in 20% of patients with elafibranor at 120 mg compared to only 11% in the placebo group (p=0.018).85 Elafibranor was associated with a mild reversible rise in serum creatinine but had no adverse effects on cardiac profile or body weight. Recently, the disappointing results of the phase 3 trial on elafibranor (the RESOLVE-IT trial) were announced. In the ITT analysis of 1,070 patients, the response rate (NASH resolution without fibrosis worsening) was 19.2% for patients who received elafibranor at 120 mg compared to 14.7% for the placebo arm. Twenty-five percent of patients who received elafibranor at 120 mg achieved fibrosis improvement compared to 22.4% in the placebo arm. There was also no significant improvement in other biochemical parameters.
Lanifibranor (IVA337) is a pan-PPAR agonist, which has been shown to improve all the histological factors of NASH, including fibrosis, in experimental mouse models.86 A phase 2 randomized placebo-controlled trial is under evaluation for assessing the safety and efficacy of lanifibranor in patients with T2DM and NAFLD (NCT03459079).
Arachidyl-amido cholanoic acid (aramchol)
Aramchol is an inhibitor of stearoyl-Co-A desaturase 1 (known as SCD1), which is an enzyme located in the endoplasmic reticulum and catalyzes the rate-limiting step of monounsaturated fatty acid formation and prevents de novo lipogenesis.87 Initial studies on the methionine and choline-deficient diet model of NASH showed down-regulation of SCD1, along with increasing flux through the trans-sulphuration pathway, thereby maintaining cellular redox homeostasis.88
A double-blind, multicenter placebo-controlled trial on biopsy-proven NASH comparing aramchol at 100 mg or 300 mg against placebo for 3 months concluded that there was significant reduction in hepatic fat content with aramchol at 300 mg.89 An open-labeled safety study was conducted on 16 healthy volunteers (Abstract #2326 Liver meeting AASLD 2019). Twice-daily dosing with aramchol at 300 mg resulted in significantly higher exposures than once-daily dosing of aramchol at 600 mg. Both dosing regimens were safe and tolerable, without any adverse effects. Currently, a double-blind, placebo-controlled randomized phase 3 study with aramchol at 300 mg in subjects with NASH and F2-3 who are overweight (or obese) and have prediabetes or adequately controlled T2DM (the ARMOR study) is underway (NCT04104321).
Cenicriviroc (CVC)
CVC is a dual human C-C motif chemokine receptor type 2 and 5 (CCR2/CCR5 chemokine) antagonist. CVC-mediated antagonism of CCR2 reduces the recruitment, migration, and infiltration of pro-inflammatory monocytes and macrophages at the site of liver injury.90,91 CCR5 antagonism by CVC is expected to additionally impair the migration, activation, and proliferation of collagen-producing activated hepatic stellate cells/myofibroblasts.91,92 The CENTAUR phase 2b study included patients with NAS score ≥4 and NASH-CRN fibrosis stage 1–3. The study concluded that CVC improved fibrosis in patients with NASH, and most of these improvements occur at year 1 and are maintained until the end of the 2nd year.93,94 Phase 3 (the AURORA study) trial is designed to strengthen the findings of this drug further.95 In this multicenter, randomized, double-blind, placebo-controlled study (NCT030328740) of approximately 2,000 adults with histological evidence of NASH and F2-3 fibrosis will be randomized in 2:1 ratio to oral CVC 150 mg or placebo once daily. The primary efficacy endpoint includes the proportion of subjects with ≥1-stage improvement in liver fibrosis and no worsening of steatohepatitis at 1 year. The results are expected by September 2020.
Glucagon-like peptide-1 (GLP-1) inhibitors
Liraglutide is a human incretin (GLP-1) agonist. Liraglutide alleviated the features of metabolic syndrome in rats fed with a high-fat diet.96 Liraglutide improved glucose tolerance, reduced weight gain, triglyceride levels, and liver fat accumulation.96 The initial randomized study compared liraglutide at 1.8 mg against placebo for 12 weeks. Liraglutide reduced the body mass index, improved hepatic and adipose tissue insulin sensitivity, and also improved glycemic control, all of which form the major component in NASH pathogenesis.97 A subsequent multicenter randomized phase 2 placebo-controlled trial (the LEAN trial) found that liraglutide is safe, well-tolerated, and leads to histological resolution of NASH (39% vs. 9% in placebo; p=0.019).98 The progression of fibrosis was also more significant in the placebo arm (36% vs. 9%; p=0.04). Common side effects with liraglutide were gastrointestinal in 81% of patients, and the most common were nausea and diarrhea.98 There are conflicting reports of increased incidence of pancreatic cancer and acute pancreatitis with this incretin analogue.99,100 However, further studies are ongoing comparing liraglutide and bariatric surgery in obese Asian NASH patients, and results are awaited (NCT02654665).
Semaglutide is another GLP-1 agonist discovered in 2012 and approved for the treatment of T2DM since 2017. It is currently being investigated for NASH. A double-blind placebo-controlled trial for 52 weeks with semaglutide and lifestyle modification has shown significant weight loss compared to liraglutide and placebo.101 The cardiovascular outcomes of 104 subjects with dose of semaglutide at 0.5 or 1.0 mg/week in T2DM (the SUSTAIN-6 trial; NCT01720446) and a 52-week weight management trial with a dose of semaglutide at 0.05-0.4 mg/day (NCT02453711) were analyzed. Semaglutide had cardioprotective effects in T2DM patients. Among subjects treated with semaglutide (especially at 0.4 mg/day), the proportion of patients with metabolic syndrome approximately halved during the trial compared with the baseline.102 Semaglutide also reduced inflammatory markers and aminotransferases.102 The investigation of semaglutide at 0.1, 0.2 and 0.4 mg/day for NASH resolution without fibrosis worsening after 72 weeks of therapy has recently been completed, and the results are expected (NCT02970942).
Galectin-3 inhibitors (GT-MD-02)
Galectins are conserved proteins with the ability to bind β-galactosides through carbohydrate-recognition domains.103 Galectin-3 contains a C-terminal carbohydrate-recognition domain linked to an N-terminal protein-binding domain and is a unique chimeric galectin.103 In the cytoplasm, galectin-3 is vital for cell survival due to its interaction with specific survival-associated proteins. In the nucleus, galectin-3 promotes pre-mRNA splicing and regulates gene transcription, whereas extracellular galectin-3 modulates cell-cell interactions. Thus, it is involved in cell differentiation, inflammation, fibrogenesis, and the host defense.104
Galactoarabino-rhamnogalacturonan, belapectin (GR-MD-02), binds mostly to galectin-3 receptors and has been hypothesized to manipulate the upstream events in the pathogenesis of NASH, which leads to substrate overload.105 The sequential dose-ranging, placebo-controlled, double-blinded safety study in biopsy-proven NASH patients with advanced fibrosis (Brunt stage 3) revealed no difference in adverse effects when GR-MD-02 single or three weekly repeated doses of 2, 4 or 8 mg/kg was used.106 Galectin-3 ablation protects from diet-induced NASH by decreasing hepatic advanced lipoxidation end products’ accumulation, with attenuation of inflammation, hepatocyte injury, and fibrosis.107 A multicenter phase 2b, randomized trial has enrolled patients with NASH, cirrhosis, and portal hypertension to randomly receive biweekly infusions of belapectin at a dose of 2 mg/kg or 8 mg/kg or placebo for 52 weeks. Although belapectin was safe, it was not associated with a significant reduction in hepatic venous pressure gradient (HVPG) or fibrosis compared to placebo. In the subgroup analysis of patients without esophageal varices, 2 mg/kg belapectin did reduce HVPG and development of varices.108
Emricasan
Emricasan is a pan-caspase inhibitor that acts on the final apoptotic pathway involved in the pathogenesis of NASH. In a murine model of NASH, hepatocyte apoptosis was attenuated by emricasan, which led to an improvement in fibrosis, bringing forth the use of emricasan as an antifibrotic agent in NASH.109 A subsequent multicenter study involving cirrhotic patients (etiology: alcohol, hepatitis C virus, and NASH) demonstrated a significant reduction in model for end-stage liver disease (MELD score), Child-Pugh scores, international normalized ratio, and total bilirubin in patients with MELD scores ≥15 following emricasan 25 mg.110 A multicenter, double-blind, randomized trial recruited 263 patients with NASH-related cirrhosis and baseline HVPG of ≥12 mmHg. These patients were treated with twice-daily with oral emricasan at 5 mg, 25 mg or 50 mg, or placebo in a 1:1:1:1 ratio for up to 48 weeks. The primary endpoint was change in HVPG (ΔHVPG) at week 24. Secondary endpoints were changes in biomarkers (aminotransferases, caspases, cytokeratins) and development of liver-related outcomes. Although emricasan was safe, there was no reduction in HVPG or biomarkers.111 Similarly, another randomized placebo-controlled trial with NASH patients with F1-F3 fibrosis with emricasan (5 mg or 50 mg) for 72 weeks did not improve liver histology in patients with NASH fibrosis and showed a trend towards worsening of fibrosis and ballooning.112 This drug is unlikely to hold promise.
Selonsertib
Selonsertib is an inhibitor of apoptosis signal-regulating kinase 1 (ASK1), with potential anti-inflammatory and antifibrotic properties. A preliminary study of NASH was conducted with F2-3 fibrosis patients treated with selonsertib at 6 mg or 18 mg orally alone or in combination with simtuzumab (125 mg subcutaneously weekly) or simtuzumab alone for 24 weeks. The study demonstrated a decrease in hepatic collagen with the use of selonsertib.113 A follow-up study that used magnetic resonance imaging (MRI)-based evaluation of fibrosis assessment in patients receiving selonsertib showed a positive trend warranting further investigations.114 Two subsequent randomized, double-blind, placebo-controlled, phase 3 trials of selonsertib in patients with NASH and bridging fibrosis F3 (STELLAR-3 trial) or compensated cirrhosis (STELLAR-4 trial) were conducted, wherein patients were randomized 2:2:1 to receive selonsertib at 18 mg, selonsertib at 6 mg, or placebo once daily for 48 weeks.115 Neither of these trials met the primary endpoint, and no improvement in fibrosis was noted.
Tipelukast
MN-001 is an antifibrotic and anti-inflammatory molecule that acts by antagonizing leukotriene receptors (referred to here as LT), phosphodiesterases, and 5-lipoxygenase (referred to here as 5-LO).116 The inhibitory effect of tipelukast on the 5-LO/LT pathway may contribute to its antifibrotic effects. In an interim report of nine NASH/NAFLD patients with hypertriglyceridemia who completed tipelukast (MN-001) at 250 mg qd for the first 4 weeks, tipelukast significantly reduced triglycerides.117 The complete results are awaited (NCT02681055).
Volixibat
Volixibat (SHP626) is a potent inhibitor of the apical sodium-dependent bile acid transporter (ASBT). In the initial phase 1 study, the absorption of the drug was found to be very low after oral ingestion.118 The drug was reviewed based on the hypothesis that ASBT inhibition in the terminal ileum would facilitate the removal of free cholesterol in the liver by reducing the recirculation of bile acids to the liver and promoting new bile acid synthesis. A randomized controlled trial comparing volixibat at 0.5 mg, 1 mg, 5 mg, or 10 mg against placebo for 28 days in healthy volunteers and T2DM patients showed increased fecal excretion of bile acids with an elevation of serum C4 levels in both groups.119 A recent randomized, double-blind trial recruited steatosis and non-cirrhotic NASH patients treated with volixibat at 5 mg, 10 mg, or 20 mg or placebo once daily for 48 weeks.120 The study failed to reach the primary endpoint, which was defined as a ≥5% reduction in MRI-proton density fat fraction (PDFF) and ≥20% reduction in serum ALT level at interim analysis at 24 weeks, and the study was terminated.
NS-0200
The 5′ adenosine monophosphate-activated protein kinase (AMPK)/Sirtuin 1 (Sirt1) pathway is a crucial regulator of mitochondrial biogenesis, energy, and lipid metabolism.121 Activation of this pathway may reverse or at least prevent excess hepatic lipid accumulation and inflammation. L-leucine is an activator of the SIRT1/AMPK pathway, serving as a partial mimetic of calorie restriction in preclinical models, and thereby modulates lipid and energy metabolism and increases insulin sensitivity.122 The combination of leucine with low-dose metformin reversed hepatic steatosis in preclinical studies in murine models of T2DM and NASH. Adding low-dose sildenafil enhances this effect by stimulating endothelial nitric oxide synthase activity, leading to exacerbated stimulation of Sirt1 and thereby attenuating inflammation and fibrosis.123,124 NS-0200 is a leucine-metformin-sildenafil fixed-dose combination that may reduce hepatic steatosis and improve metabolic parameters. The study revealed that high-dose NS-0200 relatively reduced hepatic fat by 15.7% from baseline in the high ALT group (p<0.005), while no such benefit was seen at lower doses.125 Further studies are underway for this combination. The effect of high- and low-dose NS-0200 on the fat content (MRI-PDFF) is being assessed in a randomized, 16-week, placebo-controlled, double-blind study in NAFLD patients (NCT02546609).