Hepatic and renal improvements with FXR agonist vonafexor in individuals with suspected fibrotic NASH.

BACKGROUND & AIMS: The LIVIFY trial investigated the safety, tolerability, and efficacy, of Vonafexor, a second-generation, non-bile acid farnesoid X receptor agonist in patients with suspected fibrotic non-alcoholic steatohepatitis (NASH). METHODS: This double-blind phase 2a study was conducted in two parts. Patients were randomised (1:1:1:1) to receive placebo, Vonafexor 100 mg twice daily (VONA-100BID), Vonafexor 200 mg once daily (VONA-200QD), or 400 mg Vonafexor QD (VONA-400QD) in Part A (safety run-in, pharmacokinetics/pharmacodynamics) or placebo, Vonafexor 100 mg QD (VONA-100QD), or VONA-200QD (1:1:1) in Part B. Efficacy endpoints were reduction in liver fat content (LFC) from baseline to Week 12 by magnetic resonance imaging proton density fat fraction (MRI-PDFF, primary), imaging biomarker of fibrotic steatohepatitis (corrected T1 signal), and liver enzymes. RESULTS: One hundred and twenty patients were randomised (Part A, n=24; Part B, n=96). In Part B, there was a significant reduction in least-square mean (SE) absolute change in LFC from baseline to Week 12 for VONA-100QD, (-6.3% [0.9]), VONA-200QD (-5.4% [0.9]), versus placebo (-2.3% [0.9], p=0.002 and 0.012, respectively). A >30% relative LFC reduction was achieved by 50.0% and 39.3% of patients in the VONA-100QD and VONA-200QD arms, respectively, but only in 12.5% in the placebo arm. Reductions in body weight, liver enzymes, and corrected T1 were also observed with Vonafexor. Creatinine based glomerular filtration rate (eGFR) improved in the active arms but not the placebo arm. Mild to moderate generalised pruritus was reported in 6.3%, 9.7%, and 18.2% of subjects in the placebo, VONA-100QD, and VONA-200QD arms, respectively. CONCLUSIONS: In patients with suspected fibrotic NASH, Vonafexor was safe and induced potent liver fat reduction, improvement in liver enzymes, weight loss, and a possible renal benefit. CLINICAL TRIAL NUMBER (EUDRACT): 2018-003119-22. GOV IDENTIFIER: NCT03812029. IMPACT AND IMPLICATIONS: NASH has become a leading cause for chronic liver disease and patients are also at higher risk for the development of chronic kidney disease. There are no approved therapies and only few options to treat this population. LIVIFY Phase 2a trial results show that single daily administration of oral Vonafexor, a FXR agonist, leads in the short term to a reduction in liver fat, liver enzymes, fibrosis biomarkers, body weight and abdominal circumference, and a possible improvement in kidney function, while possible mild moderate pruritus (a peripheral FXR class effect) and an LDL-Cholesterol increase are manageable with lower doses and statins. These results support exploration in longer and larger trials to ultimately provide therapies for the unmet medical need in NASH.

Designing an exploratory phase 2b platform trial in NASH with correlated, co-primary binary endpoints.

Non-alcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease (NAFLD) and a disease with high unmet medical need. Platform trials provide great benefits for sponsors and trial participants in terms of accelerating drug development programs. In this article, we describe some of the activities of the EU-PEARL consortium (EU Patient-cEntric clinicAl tRial pLatforms) regarding the use of platform trials in NASH, in particular the proposed trial design, decision rules and simulation results. For a set of assumptions, we present the results of a simulation study recently discussed with two health authorities and the learnings from these meetings from a trial design perspective. Since the proposed design uses co-primary binary endpoints, we furthermore discuss the different options and practical considerations for simulating correlated binary endpoints.

From the Editor’s Desk…Immunogenicity of COVID-19 vaccination in patients with NAFLD and in liver transplant recipients

Despite the large number of clinical trials on COVID-19 vaccines, only a few participants with pre-existing liver diseases were included. In this issue of the Journal, 2 separate studies analyse the safety and efficacy of COVID-19 vaccines in patients with non-alcoholic fatty liver disease (NAFLD) and in liver transplant recipients.

Clinical Interest of Serum Alpha-2 Macroglobulin, Apolipoprotein A1, and Haptoglobin in Patients with Non-Alcoholic Fatty Liver Disease, with and without Type 2 Diabetes, before or during COVID-19.

In patients with non-alcoholic fatty liver disease (NAFLD) with or without type 2 diabetes mellitus (T2DM), alpha-2 macroglobulin (A2M), apolipoprotein A1 (ApoA1), and haptoglobin are associated with the risk of liver fibrosis, inflammation (NASH), and COVID-19. We assessed if these associations were worsened by T2DM after adjustment by age, sex, obesity, and COVID-19. Three datasets were used: the "Control Population", which enabled standardization of protein serum levels according to age and sex (N = 27,382); the "NAFLD-Biopsy" cohort for associations with liver features (N = 926); and the USA "NAFLD-Serum" cohort for protein kinetics before and during COVID-19 (N = 421,021). The impact of T2DM was assessed by comparing regression curves adjusted by age, sex, and obesity for the liver features in "NAFLD-Biopsy", and before and during COVID-19 pandemic peaks in "NAFLD-Serum". Patients with NAFLD without T2DM, compared with the values of controls, had increased A2M, decreased ApoA1, and increased haptoglobin serum levels. In patients with both NAFLD and T2DM, these significant mean differences were magnified, and even more during the COVID-19 pandemic in comparison with the year 2019 (all p < 0.001), with a maximum ApoA1 decrease of 0.21 g/L in women, and a maximum haptoglobin increase of 0.17 g/L in men. In conclusion, T2DM is associated with abnormal levels of A2M, ApoA1, and haptoglobin independently of NAFLD, age, sex, obesity, and COVID-19.

Efficacy and safety of PXL770, a direct AMP kinase activator, for the treatment of non-alcoholic fatty liver disease (STAMP-NAFLD): a randomised, double-blind, placebo-controlled, phase 2a study.

BACKGROUND: AMP kinase (AMPK) is an energy sensor implicated in regulation of lipid metabolism, inflammation, and insulin sensitivity. We aimed to assess efficacy and safety of PXL770, a novel direct AMPK activator, in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: STAMP-NAFLD, a randomised, double-blind, placebo-controlled phase 2a study, was done across 15 US clinical sites. Patients aged 18-75 years with liver fat content of at least 10% at baseline when assessed by MRI-proton density fat fraction (MRI-PDFF) were eligible. Patients were randomly assigned (1:1:1:1), via an interactive web response system, to receive oral PXL770 250 mg once daily, 250 mg twice daily, or 500 mg once daily, or matched placebo. Patients were stratified according to type 2 diabetes status and study site. The primary endpoint was relative change in liver fat content from baseline compared with placebo at week 12, assessed by MRI-PDFF. The primary endpoint was analysed in an ANCOVA model with treatment and stratification criteria as factors and baseline liver fat content as a covariate in the modified intention-to-treat population, defined as all as-randomised patients who received at least one dose of study treatment. Safety was analysed in the safety population, defined as all as-treated patients receiving at least one dose of the study treatment. The trial has been completed and the final results are reported. The trial is registered with ClinicalTrials.gov, NCT03763877. FINDINGS: Between March 29, 2019, and March 13, 2020, 387 patients were screened, of whom 120 were included in the modified intention-to-treat and safety analyses (30 in the 250 mg once daily group, 30 in the 250 mg twice daily group, 29 in the 500 mg once daily group, and 31 in the placebo group). The mean relative change from baseline in liver fat content at week 12 was -1·1% in the placebo group, -1·0% in the 250 mg once daily group (mean difference versus placebo 0·1% [95% CI -15·4 to 15·7], p=0·99), -14·3% in the 250 mg twice daily group (-13·1% [-28·1 to 1·8], p=0·084), and -14·7% in the 500 mg once daily group (-13·5% [-28·5 to 1·4], p=0·076). At least one treatment-emergent adverse event occurred in 23 (77%) of 30 patients in the 250 mg once daily group, 20 (67%) of 30 patients in the 250 mg twice daily group, 21 (72%) of 29 patients in the 500 mg once daily group, and 21 (68%) of 31 patients in the placebo group. The most common treatment-emergent adverse event was diarrhoea (five [17%] of patients in the 250 mg once daily group, seven [23%] in the 250 mg twice daily group, six [21%] in the 500 mg once daily group, and none in the placebo group). No life-threatening events or treatment-related deaths occurred. INTERPRETATION: PXL770 treatment did not meet the primary outcome of liver fat improvement compared with placebo. Treatment was well tolerated. Given indications that metabolic features improved with PXL770 treatment, AMPK activation might be a promising pharmacological target for patients with type 2 diabetes and NAFLD, and could also be considered for further assessment in patients with non-alcoholic steatohepatitis. FUNDING: Poxel.

Performance of serum apolipoprotein-A1 as a sentinel of Covid-19.

BACKGROUND: Since 1920, a decrease in serum cholesterol has been identified as a marker of severe pneumonia. We have assessed the performance of serum apolipoprotein-A1, the main transporter of HDL-cholesterol, to identify the early spread of coronavirus disease 2019 (Covid-19) in the general population and its diagnostic performance for the Covid-19. METHODS: We compared the daily mean serum apolipoprotein-A1 during the first 34 weeks of 2020 in a population that is routinely followed for a risk of liver fibrosis risk in the USA (212,297 serum) and in France (20,652 serum) in relation to a local increase in confirmed cases, and in comparison to the same period in 2019 (266,976 and 28,452 serum, respectively). We prospectively assessed the sensitivity of this marker in an observational study of 136 consecutive hospitalized cases and retrospectively evaluated its specificity in 7,481 controls representing the general population. RESULTS: The mean serum apolipoprotein-A1 levels in the survey populations began decreasing in January 2020, compared to the same period in 2019. This decrease was highly correlated with the daily increase in confirmed Covid-19 cases in the following 34 weeks, both in France and USA, including the June and mid-July recovery periods in France. Apolipoprotein-A1 at the 1.25 g/L cutoff had a sensitivity of 90.6% (95%CI84.2-95.1) and a specificity of 96.1% (95.7-96.6%) for the diagnosis of Covid-19. The area under the characteristics curve was 0.978 (0.957-0.988), and outperformed haptoglobin and liver function tests. The adjusted risk ratio of apolipoprotein-A1 for survival without transfer to intensive care unit was 5.61 (95%CI 1.02-31.0; P = 0.04). CONCLUSION: Apolipoprotein-A1 could be a sentinel of the pandemic in existing routine surveillance of the general population. NCT01927133, CER-2020-14.