Liver biopsy evaluation in MASH drug development: Think thrice, act wise.

During recent decades, the metabolic dysfunction-associated steatohepatitis (MASH) field has witnessed several paradigm shifts, including the recognition of liver fibrosis as the main predictor of major adverse liver outcomes. Throughout this evolution, liver histology has been recognised as one of the main hurdles in MASH drug development due to its invasive nature, associated cost, and high inter- and intra-reader variability. Collective experience demonstrates the importance of consistency in the central reading process, where consensus methods have emerged as appropriate ways to mitigate against well-known challenges.

FGF21 agonists: An emerging therapeutic for metabolic dysfunction-associated steatohepatitis and beyond.

The worldwide epidemics of obesity, hypertriglyceridemia, dyslipidaemia, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH) represent a major economic burden on healthcare systems. Patients with at-risk MASH, defined as MASH with moderate or significant fibrosis, are at higher risk of comorbidity/mortality, with a significant risk of cardiovascular diseases and/or major adverse liver outcomes. Despite a high unmet medical need, there is only one drug approved for MASH.

NIS2+ as a screening tool to optimize patient selection in metabolic dysfunction-associated steatohepatitis clinical trials.

Background & Aims: Strategies to reduce liver biopsy (LB) screen failures through better patient selection are needed for clinical trials. Standard fibrosis biomarkers were not derived to detect "at-risk" metabolic dysfunction-associated steatohepatitis (MASH; MASH with metabolic dysfunction-associated steatotic liver disease score ≥4 and fibrosis stage ≥2). We compared the performance of screening pathways that incorporate NIS2+™, an optimized version of the blood-based NIS4® technology designed to identify at-risk MASH, with those incorporating fibrosis (FIB)-4 within the RESOLVE-IT clinical trial (NCT02704403), aiming for optimized selection of patients for LB.

Hyperinsulinemia, an overlooked clue and potential way forward in metabolic dysfunction-associated steatotic liver disease.

Metabolic dysfunction-associated steatotic liver disease is closely associated with other features of the metabolic syndrome such as type 2 diabetes. The progression of the disease may lead to liver fibrosis, which is the main predictor of major adverse liver outcomes. Insulin resistance plays a major role in the pathogenesis of the disease.

NIS2+™, an optimisation of the blood-based biomarker NIS4® technology for the detection of at-risk NASH: A prospective derivation and validation study.

Background & Aims: NIS4® is a blood-based non-invasive test designed to effectively rule in/rule out at-risk non-alcoholic steatohepatitis (NASH), defined as non-alcoholic fatty liver disease activity score ≥4 and significant fibrosis (stage ≥2), among patients with metabolic risk factors. Robustness of non-invasive test scores across characteristics of interest including age, type 2 diabetes mellitus, and sex, and optimised analytical aspects are critical for large-scale implementation in clinical practice. We developed and validated NIS2+™, an optimisation of NIS4®, specifically designed to improve score robustness.

Clinical Trial Landscape in NASH.

Nonalcoholic fatty liver disease consists of a spectrum starting from nonalcoholic fatty liver disease that may progress to nonalcoholic steatohepatitis (NASH), which can lead to fibrosis, cirrhosis, hepatocellular carcinoma, or even liver failure. The prevalence of NASH has increased in parallel with the rising rate of obesity and type 2 diabetes. Given the high prevalence and deadly complications of NASH, there have been significant efforts to develop effective treatments.

Challenges and opportunities in NASH drug development.

Nonalcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH), represent a growing worldwide epidemic and a high unmet medical need, as no licensed drugs have been approved thus far. Currently, histopathological assessment of liver biopsies is mandatory as a primary endpoint for conditional drug approval. This requirement represents one of the main challenges in the field, as there is substantial variability in this invasive histopathological assessment, which leads to dramatically high screen-failure rates in clinical trials.

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.

A phase 1, open-label, drug-drug interaction study of rucaparib with rosuvastatin and oral contraceptives in patients with advanced solid tumors.

Purpose: This study aimed at evaluating the effect of rucaparib on the pharmacokinetics of rosuvastatin and oral contraceptives in patients with advanced solid tumors and the safety of rucaparib with and without coadministration of rosuvastatin or oral contraceptives.

Methods: Patients received single doses of oral rosuvastatin 20 mg (Arm A) or oral contraceptives ethinylestradiol 30 µg + levonorgestrel 150 µg (Arm B) on days 1 and 19 and continuous doses of rucaparib 600 mg BID from day 5 to 23. Serial blood samples were collected with and without rucaparib for pharmacokinetic analysis.

Pharmacokinetics and safety of rucaparib in patients with advanced solid tumors and hepatic impairment.

Purpose: The poly(ADP-ribose) polymerase inhibitor rucaparib is approved for the treatment of patients with recurrent ovarian and metastatic castration-resistant prostate cancer; however, limited data are available on its use in patients with hepatic dysfunction. This study investigated whether hepatic impairment affects the pharmacokinetics, safety, and tolerability of rucaparib in patients with advanced solid tumors.

Methods: Patients with normal hepatic function or moderate hepatic impairment according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria were enrolled and received a single oral dose of rucaparib 600 mg.

The pharmacokinetics of pamiparib in the presence of a strong CYP3A inhibitor (itraconazole) and strong CYP3A inducer (rifampin) in patients with solid tumors: an open-label, parallel-group phase 1 study.

Purpose: Pamiparib is an investigational, selective, oral poly(ADP-ribose) polymerase 1/2 (PARP1/2) inhibitor that has demonstrated PARP-DNA complex trapping and CNS penetration in preclinical models, as well as preliminary anti-tumor activity in early-phase clinical studies. We investigated whether the single-dose pharmacokinetic (PK) profile of pamiparib is altered by coadministration of a strong CYP3A inducer (rifampin) or a strong CYP3A inhibitor (itraconazole) in patients with solid tumors.

Methods: In this open-label, phase 1 study, adults with advanced solid tumors received either oral pamiparib 60 mg (days 1 and 10) and once-daily oral rifampin 600 mg (days 3-11) or oral pamiparib 20 mg (days 1 and 7) and once-daily oral itraconazole 200 mg (days 3-8).

A structurally optimized FXR agonist, MET409, reduced liver fat content over 12 weeks in patients with non-alcoholic steatohepatitis.

Background & Aims: The benefits of farnesoid X receptor (FXR) agonists in patients with non-alcoholic steatohepatitis (NASH) have been validated, although improvements in efficacy and/or tolerability remain elusive. Herein, we aimed to assess the performance of a structurally optimized FXR agonist in patients with NASH.

Methods: In this 12-week, randomized, placebo-controlled study, we evaluated MET409 - a non-bile acid agonist with a unique chemical scaffold - in patients with NASH.

A blood-based biomarker panel (NIS4) for non-invasive diagnosis of non-alcoholic steatohepatitis and liver fibrosis: a prospective derivation and global validation study.

Background: Non-invasive tests that can identify patients with non-alcoholic steatohepatitis (NASH) at higher risk of disease progression are lacking. We report the development and validation of a blood-based diagnostic test to non-invasively rule in and rule out at-risk NASH (defined as non-alcoholic fatty liver disease [NAFLD] activity score [NAS] ≥4 and fibrosis stage ≥2).

Methods: In this prospective derivation and global validation study, blood samples, clinical data, and liver biopsy results from three independent cohorts with suspected NAFLD were used to develop and validate a non-invasive blood-based diagnostic test, called NIS4.

Defining Improvement in Nonalcoholic Steatohepatitis for Treatment Trial Endpoints: Recommendations From the Liver Forum.

Identifying effective therapies for nonalcoholic steatohepatitis (NASH) with fibrosis is a pressing challenge, with 1%-2% of the population in developed nations at risk of developing NASH cirrhosis and its complications. The design of NASH clinical therapeutic trials is hampered by the long period of minimally symptomatic disease that typically precedes the development of decompensated cirrhosis and the accompanying uncertainties regarding the best precirrhotic trial endpoints that reliably reflect a subsequent reduction in liver-related morbidity and mortality. The Liver Forum is a multistakeholder organization comprised of academic, industry, and regulatory experts working from a regulatory science perspective to identify barriers, prioritize research, and identify solutions to accelerate therapeutic development for NASH.