Efruxifermin in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a trial

Nature Medicine, Journal Year: 2021, Volume and Issue: 27(7), P. 1262 - 1271

Published: July 1, 2021

Language: Английский

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TVB-2640 (FASN Inhibitor) for the Treatment of Nonalcoholic Steatohepatitis: FASCINATE-1, a Randomized, Placebo-Controlled Phase 2a Trial

Gastroenterology, Journal Year: 2021, Volume and Issue: 161(5), P. 1475 - 1486

Published: July 23, 2021

Background & AimsIncreased de novo lipogenesis creates excess intrahepatic fat and lipotoxins, propagating liver damage in nonalcoholic steatohepatitis. TVB-2640, a fatty acid synthase inhibitor, was designed to reduce directly inhibit inflammatory fibrogenic pathways. We assessed the safety efficacy of TVB-2640 patients with steatohepatitis United States.Methods3V2640-CLIN-005 (FASCINATE-1) randomized, placebo-controlled, single-blind study at 10 US sites. Adults ≥8% fat, by magnetic resonance imaging proton density fraction, evidence fibrosis elastography ≥2.5 kPa or biopsy were eligible. Ninety-nine randomized receive placebo 25 mg 50 (orally, once-daily for 12 weeks). The primary end points this relative change after treatment.ResultsLiver increased cohort 4.5% baseline; contrast reduced 9.6% 25-mg (n = 30; least squares mean: –15.5%; 95% confidence interval, –31.3 –0.23; P .053), 28.1% 50-mg 28; –28.0%; –44.5 –11.6; .001). Eleven percent group achieved ≥30% reduction compared 23% group, 61% (P < Secondary analyses showed improvements metabolic, pro-inflammatory fibrotic markers. well tolerated; adverse events mostly mild balanced among groups.ConclusionsTVB-2640 significantly improved biochemical, inflammatory, biomarkers weeks, dose-dependent manner ClinicalTrials.gov, Number NCT03938246. Increased States. 3V2640-CLIN-005 treatment. Liver groups.

Language: Английский

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Novel therapeutic targets for cholestatic and fatty liver disease

Gut, Journal Year: 2021, Volume and Issue: 71(1), P. 194 - 209

Published: Oct. 6, 2021

Cholestatic and non-alcoholic fatty liver disease (NAFLD) share several key pathophysiological mechanisms which can be targeted by novel therapeutic concepts that are currently developed for both areas. Nuclear receptors (NRs) ligand-activated transcriptional regulators of metabolic processes including hepatic lipid glucose metabolism, energy expenditure bile acid (BA) homoeostasis, as well inflammation, fibrosis cellular proliferation. Dysregulation these contributes to the pathogenesis progression cholestatic disease, placing NRs at forefront approaches. This includes BA activated such farnesoid-X receptor (FXR) peroxisome proliferator-activated receptors, respectively, high affinity ligands targeting specific or multiple isoforms have been developed. Moreover, liver-specific thyroid hormone beta 1 complete spectrum available NR-targeted drugs. Apart from FXR ligands, signalling mimetics FXR-activated fibroblast growth factor 19, modulation their enterohepatic circulation through uptake inhibitors in hepatocytes enterocytes, derivatives undergoing cholehepatic shunting (instead circulation). Other approaches more directly target inflammation and/or critical events progression. Combination strategies synergistically disturbances, may ultimately necessary successful treatment complex multifactorial disorders.

Language: Английский

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Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial

˜The œLancet. Gastroenterology & hepatology, Journal Year: 2023, Volume and Issue: 8(12), P. 1080 - 1093

Published: Oct. 3, 2023

Language: Английский

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The FGF21 analog pegozafermin in severe hypertriglyceridemia: a randomized phase 2 trial

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(7), P. 1782 - 1792

Published: June 24, 2023

Abstract Pegozafermin, a long-acting glycopegylated analog of human fibroblast growth factor 21, is in development for the treatment severe hypertriglyceridemia (SHTG) and nonalcoholic steatohepatitis. Here we report results phase 2, double-blind, randomized, five-arm trial testing pegozafermin at four different doses ( n = 67; 52 male) versus placebo 18; 12 8 weeks patients with SHTG (triglycerides (TGs), ≥500 mg dl −1 ≤2,000 ). Treated showed significant reduction median TGs pooled group (57.3% 11.9%, difference −43.7%, 95% confidence interval (CI): −57.1%, −30.3%; P < 0.001), meeting primary endpoint trial. Reductions ranged from 36.4% to 63.4% across all arms were consistent regardless background lipid-lowering therapy. Results secondary endpoints included decreases mean apolipoprotein B non-high-density lipoprotein cholesterol concentrations (−10.5% −18.3% compared 1.1% −0.6% (95% CI: −21.5%, −2.0%; 0.019 −30.7%, −5.1%; 0.007, respectively), as well decrease liver fat fraction 17) 6; −42.2% pegozafermin, −8.3% placebo; −60.9%, −8.7%; 0.012), assessed magnetic resonance imaging sub-study. No serious adverse events observed be related study drug. If these are confirmed 3 trial, could promising (ClinicalTrials.gov registration: NCT0441186).

Language: Английский

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Steatotic Liver Disease: Pathophysiology and Emerging Pharmacotherapies

Pharmacological Reviews, Journal Year: 2024, Volume and Issue: 76(3), P. 454 - 499

Published: Jan. 30, 2024

Steatotic liver disease (SLD) displays a dynamic and complex phenotype. Consequently, the metabolic dysfunction-associated steatotic (MASLD)/metabolic steatohepatitis (MASH) therapeutic pipeline is expanding rapidly in multiple directions. In parallel, non-invasive tools for diagnosing monitoring responses to interventions are being studied, clinically feasible findings explored as primary outcomes interventional trials. The realization that distinct subgroups exist under umbrella of SLD should guide more precise personalized treatment recommendations facilitate advancements pharmacotherapeutics. This review summarizes recent updates pathophysiology-based nomenclature outlines both effective pharmacotherapeutics those MASLD/MASH, detailing their mode action current status phase 2 3 clinical Of extensive arsenal MASLD/MASH pipeline, several have been rejected, whereas other, mainly monotherapy options, shown only marginal benefits now tested part combination therapies, yet others still development monotherapies. Although successful drug candidate (or combinations) remains elusive, such approaches will ideally target MASH fibrosis while improving cardiometabolic risk factors. Due urgent need novel strategies potential availability safety tolerability data, repurposing existing approved drugs an appealing option. Finally, it essential highlight and, by extension, MASLD be recognized approached systemic affecting organs, with vigorous implementation interdisciplinary coordinated plans. Significance Statement SLD, including, among others, MASH, considered most prevalent chronic condition than one-fourth global population. aims provide information regarding pathophysiology, diagnosis, management line guidelines Collectively, hoped provided furthers understanding state direct implications stimulates additional research initiatives.

Language: Английский

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Tumor-secreted FGF21 acts as an immune suppressor by rewiring cholesterol metabolism of CD8+T cells

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(3), P. 630 - 647.e8

Published: Feb. 2, 2024

Language: Английский

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Adipokines regulate the development and progression of MASLD through organellar oxidative stress

Hepatology Communications, Journal Year: 2025, Volume and Issue: 9(2)

Published: Jan. 29, 2025

The prevalence of metabolic dysfunction–associated steatotic liver disease (MASLD), which is increasingly being recognized as a leading cause chronic pathology globally, increasing. pathophysiological underpinnings its progression, currently under active investigation, involve oxidative stress. Human adipose tissue, an integral endocrine organ, secretes array adipokines that are modulated by dietary patterns and lifestyle choices. These intricately orchestrate regulatory pathways impact glucose lipid metabolism, stress, mitochondrial function, thereby influencing the evolution hepatic steatosis progression to steatohepatitis (MASH). This review examines recent data, underscoring critical interplay reactive oxygen species, redox signaling in adipokine-mediated mechanisms. role various regulating onset MASLD/MASH through dysfunction endoplasmic reticulum stress underlying mechanisms discussed. Due emerging correlation between development MASLD positions, these potential targets for innovative therapeutic interventions management. A comprehensive understanding pathogenesis instrumental identifying therapies MASH.

Language: Английский

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Non-Alcoholic Steatohepatitis (NASH) – A Review of a Crowded Clinical Landscape, Driven by a Complex Disease

Drug Design Development and Therapy, Journal Year: 2021, Volume and Issue: Volume 15, P. 3997 - 4009

Published: Sept. 1, 2021

Non-alcoholic steatohepatitis (NASH) is a progressive form of non-alcoholic fatty liver disease (NAFLD), characterized by chronic inflammation and accumulation fat in tissue. Affecting estimated 35 million people globally, NASH the most common condition Western populations, with patient numbers growing rapidly, market for therapy projected to rise $27.2 B 2029. Despite this clinical need attractive commercial opportunity, there are no Food Drug Administration (FDA)-approved therapies specifically disease. Many have tried unfortunately failed find drug, or drug combination, capable unravelling complexities metabolic condition. At time writing review, only Zydus Cadila's new application Saroglitazar had been approved (2020) India. However, it hoped that dearth options will improve as several candidates progress through late-stage development. Obeticholic acid (Intercept Pharmaceuticals), Cenicriviroc (Allergan), Aramchol (Galmed Resmetirom (Madrigal Dapagliflozin Semaglutide (Novo Nordisk) advanced Phase 3 trials, while Belapectin (Galectin Therapeutics), MSDC-0602K (Cirius Lanifibranor (Inventiva), Efruxifermin (Akero) Tesamorelin (Theratechnologies) expected start trials soon. Here, we performed an exhaustive review current therapeutic landscape compared, some detail, fortunes different classes (biologics vs small molecules) target molecules. Given complex pathophysiology NASH, use mechanisms actions targeting each stage likely be required. Hence, development single seems challenging unlikely, despite plethora later due report. We therefore predict clinical, company interest pipeline next-generation remain high come.

Language: Английский

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Safety, pharmacokinetics, and pharmacodynamics of pegozafermin in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 1b/2a multiple-ascending-dose study

˜The œLancet. Gastroenterology & hepatology, Journal Year: 2022, Volume and Issue: 8(2), P. 120 - 132

Published: Dec. 12, 2022

Language: Английский

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