Summary
Background
Non‐alcoholic steatohepatitis (NASH) and resultant liver fibrosis is a major health problem without approved pharmacotherapy. Pre‐clinical results of GR‐MD‐02, a galectin‐3 ...inhibitor, suggested potential efficacy in NASH with advanced fibrosis/cirrhosis and prompted initiation of a clinical development programme in NASH with advanced fibrosis.
Aim
To evaluate the safety, pharmacokinetics and exploratory pharmacodynamic markers of GR‐MD‐02 in subjects having NASH with bridging fibrosis.
Methods
The GT‐020 study was a first‐in‐human, sequential dose‐ranging, placebo controlled, double‐blinded study with the primary objective to assess the safety, tolerability and dose limiting toxicity of GR‐MD‐02, in subjects with biopsy‐proven NASH with advanced fibrosis (Brunt stage 3). The secondary objectives were to characterise first‐dose and multiple‐dose pharmacokinetic profiles and to evaluate changes in potential serum biomarkers and liver stiffness as assessed by FibroScan.
Results
GR‐MD‐02 single and three weekly repeated of 2, 4 and 8 mg/kg revealed no meaningful clinical differences in treatment emergent adverse events, vital signs, electrocardiographic findings or laboratory tests. Pharmokinetic parameters showed a dose‐dependent relationship with evidence of drug accumulation following 8 mg/kg (~twofold).
Conclusions
GR‐MD‐02 doses were in the upper range of the targeted therapeutic dose determined from pre‐clinical data and were safe and well tolerated with evidence of a pharmacodynamic effect. These results provide support for a Phase 2 development programme in advanced fibrosis due to NASH.
Summary
Background
Nonalcoholic steatohepatitis (NASH) is associated with dyslipidemia and cardiovascular disease (CVD).
Aim
To determine the relationship between resolution of NASH and dyslipidemia.
...Methods
Individuals in the Pioglitazone vs. Vitamin E vs. Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) trial with paired liver biopsies and fasting lipid levels were included (N = 222). In the PIVENS trial individuals were randomised to pioglitazone 30 mg, vitamin E 800 IU or placebo for 96 weeks. Change in lipid levels at 96 weeks was compared between those with and without NASH resolution.
Results
Dyslipidemia at baseline was frequent, with low high‐density lipoprotein (HDL) (<40 mg/dL in men or <50 mg/dL in women) in 63%, hypertriglyceridaemia (≥150 mg/dL) in 46%, hypercholesterolaemia (≥200 mg/dL) in 47% and triglycerides (TG)/HDL >5.0 in 25%. Low‐density lipoprotein (LD) ≥160 mg/dL was found in 16% and elevated non‐HDL cholesterol (non‐HDL‐C) (≥130 mg/dL) in 73%. HDL increased with NASH resolution but decreased in those without resolution (2.9 mg/dL vs. −2.5 mg/dL, P < 0.001). NASH resolution was associated with significant decreases in TG and TG/HDL ratio compared to those without resolution (TG: −21.1 vs. −2.3 mg/dL, P = 0.03 and TG/HDL: −0.7 vs. 0.1, P = 0.003). Non‐HDL‐C, LDL and cholesterol decreased over 96 weeks in both groups, but there was no significant difference between groups. Treatment group did not impact lipids.
Conclusions
NASH resolution is associated with improvements in TG and HDL but not in other cardiovascular disease risk factors including LDL and non‐HDL‐C levels. Individuals with resolution of NASH may still be at increased risk of cardiovascular disease. ClinicalTrials.gov identifier: NCT00063622.
Summary
Drug‐induced liver injury (DILI) is often caused by innate and adaptive host immune responses. Characterization of inflammatory infiltrates in the liver may improve understanding of the ...underlying pathogenesis of DILI. This study aimed to enumerate and characterize leucocytes infiltrating liver tissue from subjects with acute DILI (n = 32) versus non‐DILI causes of acute liver injury (n = 25). Immunostains for CD11b/CD4 (Kupffer and T helper cells), CD3/CD20 (T and B cells) and CD8/CD56 T cytotoxic and natural killer (NK) cells were evaluated in biopsies from subjects with acute DILI, either immunoallergic (IAD) or autoimmune (AID) and idiopathic autoimmune (AIH) and viral hepatitis (VH) and correlated with clinical and pathological features. All biopsies showed numerous CD8+ T cells and macrophages. DILI cases had significantly fewer B lymphocytes than AIH and VH and significantly fewer NK cells than VH. Prominent plasma cells were unusual in IAD (three of 10 cases), but were associated strongly with AIH (eight of nine) and also observed in most with AID (six of nine). They were also found in five of 10 cases with VH. Liver biopsies from subjects with DILI were characterized by low counts of mature B cells and NK cells in portal triads in contrast to VH. NK cells were found only in cases of VH, whereas AIH and VH both showed higher counts of B cells than DILI. Plasma cells were associated most strongly with AIH and less so with AID, but were uncommon in IAD.
Summary
Background
Sirtuin 1 (Sirt1) is suppressed in non‐alcoholic fatty liver disease (NAFLD), while its’ stimulation or overexpression results in reduced disease severity in pre‐clinical NAFLD ...models. Leucine allosterically activates Sirt1 and synergise with other Sirt/AMPK/NO pathway activators. We developed a triple combination of leucine, metformin and sildenafil (NS‐0200), which was effective in a mouse model of non‐alcoholic steatohepatitis (NASH).
Aim
To report the results from a Phase 2, randomised clinical trial of of NS‐0200 in 91 subjects with NAFLD (liver fat ≥15% by magnetic resonance imaging‐proton‐density fat fraction (MRI‐PDFF)).
Methods
Subjects were randomised to placebo, low‐dose (1.1 g leucine/0.5 g metformin/0.5 mg sildenafil) or high‐dose NS‐0200 (1.1 g leucine/0.5 g metformin/1.0 mg sildenafil) b.d. for 16 weeks; change in hepatic fat was assessed via MRI‐PDFF, and lipid metabolism was assessed via changes in the lipidomic signature. Seventy subjects completed the trial and met a priori compliance criteria. Analyses were conducted on the full cohort and on those with alanine aminotransferase (ALT) values above median (50 U/L; n = 35).
Results
In the full cohort, active treatments did not separate from placebo. High dose NS‐0200 reduced hepatic fat by 15.7% (relative change from baseline) in the high ALT group (P < 0.005) while low dose NS‐0200 and placebo did not significantly change hepatic fat. Lipidomic analysis showed dose‐responsive treatment effects in both overall and high ALT cohorts, with significant decreases in metabolically active lipids and up‐regulation of fatty acid oxidation.
Conclusion
These data support further evaluation of high‐dose NS‐0200 for treating NASH, especially in those with elevated ALT (NCT 02546609).
Linked ContentThis article is linked to Noureddin and Loomba paper. To view this article visit https://doi.org/10.1111/apt.14819.
Linked ContentThis article is linked to Vilar‐Gomez et al, and Gifford and Dhaun papers. To view this article visit https://doi.org/10.1111/apt.13860 and https://doi.org/10.1111/apt.13901.
Summary
Background
Several recent studies have shown a strong association between non‐alcoholic steatohepatitis (NASH) and chronic kidney disease.
Aim
To examine the relationship between changes in ...liver histology and renal function in patients with NASH.
Methods
The present analysis represents a post hoc analysis of a recently published trial that included 261 patients with NASH who were treated with lifestyle modifications during 52 weeks. Kidney function was evaluated through Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rates (eGFR, mL/min/1.73 m2) overtime. We explored correlations between the kidney function and improvement in histological outcomes at 52 weeks.
Results
Interestingly, a one‐stage reduction in fibrosis (r = 0.20, P < 0.01) and resolution of NASH (r = 0.17, P < 0.01) were significantly correlated with an improvement in the kidney function. The eGFR values significantly increased in patients with fibrosis improvement (+7.6 ± 6.5 mL/min/1.73 m2), compared to those without fibrosis improvement (−1.98 ± 6.4 mL/min/1.73 m2) (P < 0.01) at end of treatment (EOT). Likewise, NASH resolution was associated with an increase in eGFR compared with patients without NASH resolution (2.32 ± 7.8 mL/min/1.73 m2 vs. −1.04 ± 5.9 mL/min/1.73 m2, P = 0.04) at EOT. After controlling for the confounders, the association between fibrosis improvement, NASH resolution and eGFR change remained significant (P < 0.05 for both).
Conclusions
Improvement in liver histology due to lifestyle modification is independently associated with improved kidney function in NASH. As new drugs for NASH emerge, studies should address whether improvement in histology in response to pharmacotherapies yield the same improvement in kidney function as weight loss.
Linked Content
This article is linked to Vilar‐Gomez and Chalasani, and Gifford and Dhaun papers. To view this article visit https://doi.org/10.1111/apt.14915 and https://doi.org/10.1111/apt.13901.
Summary
Background
Idiosyncratic drug‐induced liver injury (DILI) is a complex disorder that is difficult to predict, diagnose and treat.
Aim
To describe the global serum proteome of patients with ...DILI and controls.
Methods
A label‐free, mass spectrometry‐based quantitative proteomic approach was used to explore protein expression in serum samples from 74 DILI patients (collected within 14 days of DILI onset) and 40 controls. A longitudinal analysis was conducted in a subset of 21 DILI patients with available 6‐month follow‐up serum samples.
Results
Comparison of DILI patients based on pattern, severity and causality assessment of liver injury revealed many differentially expressed priority 1 proteins among groups. Expression of fumarylacetoacetase was correlated with alanine aminotransferase (ALT; r = 0.237; P = 0.047), aspartate aminotransferase (AST; r = 0.389; P = 0.001) and alkaline phosphatase (r = −0.240; P = 0.043), and this was the only protein with significant differential expression when comparing patients with hepatocellular vs. cholestatic or mixed injury. In the longitudinal analysis, expression of 53 priority 1 proteins changed significantly from onset of DILI to 6‐month follow‐up, and nearly all proteins returned to expression levels comparable to control subjects. Ninety‐two serum priority 1 proteins with significant differential expression were identified when comparing the DILI and control groups. Pattern analysis revealed proteins that are components of inflammation, immune system activation and several hepatotoxicity‐specific pathways. Apolipoprotein E expression had the greatest power to differentiate DILI patients from controls (89% correct classification; AUROC = 0.97).
Conclusion
This proteomic analysis identified differentially expressed proteins that are components of pathways previously implicated in the pathogenesis of idiosyncratic drug‐induced liver injury.
Summary
Background
The relationships between primary sclerosing cholangitis (PSC) and the environment are largely unknown.
Aim
To validate associations reported in previous studies and to identify ...novel environmental exposures among PSC patients.
Methods
We performed a multicenter, case–control analysis utilising self‐administered questionnaires. Responses between cases (n = 1000) and controls (n = 663) were compared using multivariable logistic regression adjusted for age and gender. The model was further stratified based on inflammatory bowel disease (IBD) status (with IBD n = 741 without IBD n = 259).
Results
Smoking was associated with PSC only when IBD was present (OR, 0.5; 95% CI 0.4–0.7) but not among those PSC patients without IBD (OR, 0.9; 95% CI 0.7–1.2). Compared to controls, women with PSC (irrespective of the presence of IBD) were less likely to have received hormone replacement therapy (HRT; OR, 0.5; 95% CI 0.4–0.7) and were more likely to have recurrent urinary tract infections (OR, 1.6; 95% CI 1.2–2.3). PSC patients regardless of gender or IBD status were less likely to eat fish (OR, 0.4; 95% CI 0.3–0.6) and grilled/barbecued meat (OR, 0.8; 95% CI 0.7–0.9). In contrast, PSC patients with and without IBD were more likely to consume steak/burgers that were more well done (OR, 1.3; 95% CI 1.2–1.5).
Conclusions
IBD (rather than PSC) is associated with smoking. Women with PSC are more likely to have recurrent urinary tract infections and less likely to receive HRT. Dietary intake and methods of food preparation differ in PSC patients when compared to controls.
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