GSK4532990 / GSK, Arrowhead - LARVOL DELTA

GSK presents data from its advancing liver pipeline at AASLD 2025 (GSK Press Release) - "21 abstracts highlight advances in the treatment of liver conditions, building from GSK’s expertise in inflammation and fibrosis; Phase II B-Sure study sub-analysis shows durability of functional cure in chronic hepatitis B (CHB) patients treated with bepirovirsen and pegylated interferon (Peg-IFN); Late breaking results for once-monthly efimosfermin in metabolic dysfunction-associated steatohepatitis (MASH), supporting the start of phase III clinical trials"

Clinical data • Hepatitis B • Metabolic Dysfunction-Associated Steatohepatitis

SKYLINE: Dose Exploration Study of GSK4532990 in. Participants With NASH or Suspected NASH (clinicaltrials.gov) - P2 | N=61 | Completed | Sponsor: GlaxoSmithKline | Active, not recruiting ➔ Completed

Trial completion • Hepatology • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

GSK4532990 PHARMACOKINETIC–PHARMACODYNAMIC (PK–PD) MODELING SUPPORTS QUARTERLY AND MONTHLY SIRNA DOSING FOR MASH IN THE HORIZON PHASE 2B STUDY (AASLD 2025) - P1/2, P2 | "PK–PD modeling of hepatic HSD17B13 protein and ALT predicted that doses of 100mg every 4 weeks and 200mg every 3 months have the potential to maintain robust HSD17B13 and ALT reduction over the respective dosing intervals despite the rapid elimination of GSK4532990 from the systemic circulation. These data support the once-quarterly or once-monthly dosing strategy in the ongoing HORIZON Phase 2b study."

P2b data • PK/PD data • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

HSD17B13 EXPRESSION IS INCREASED IN BALLOONED HEPATOCYTES FROM PATIENTS WITH STEATOTIC LIVER DISEASE (SLD) AND CAN BE THERAPEUTICALLY TARGETED BY GSK4532990 IN PATIENTS WITH ALCOHOL-ASSOCIATED LIVER DISEASE (ALD) (AASLD 2025) - P2 | "C-P A participants had ALT 55 (35–117) vs 39 (13–53) IU/L and AST 120 (180–73) vs 80 (144–53) IU/L, despite consistent alcohol consumption during follow-up (PEth 758 [427-1273] vs 796 [417–1169] µg/L) at baseline vs W8, (median [IQR]; Fig. HSD17B13 expression is increased in ballooned hepatocytes. Preliminary data from the ongoing STARLIGHT ALD study have not identified safety concerns from a single dose of GSK4532990. There was a trend toward reduced aminotransferases, despite ongoing alcohol consumption, that may correspond to improvements in hepatocyte ballooning."

Clinical • Addiction (Opioid and Alcohol) • Fibrosis • Hepatology • Immunology

SKYLINE: Dose Exploration Study of GSK4532990 in. Participants With NASH or Suspected NASH (clinicaltrials.gov) - P2 | N=61 | Active, not recruiting | Sponsor: GlaxoSmithKline | Recruiting ➔ Active, not recruiting

Enrollment closed • Hepatology • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

STARLIGHT: A Study to Investigate the Safety and Efficacy of GSK4532990 Compared With Placebo in Adult Participants Aged 18 to 65 Years With Alcohol-related Liver Disease (clinicaltrials.gov) - P2 | N=393 | Recruiting | Sponsor: GlaxoSmithKline | Not yet recruiting ➔ Recruiting | Trial completion date: Mar 2027 ➔ Aug 2027

Enrollment open • Trial completion date • Hepatology

HORIZON: Phase 2b Study of GSK4532990 in Adults With NASH (clinicaltrials.gov) - P2 | N=284 | Active, not recruiting | Sponsor: GlaxoSmithKline | Trial completion date: May 2026 ➔ Apr 2027

Trial completion date • Hepatology • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

A quantitative systems pharmacology model identifies mechanisms attenuated by knockdown of HSD17B13 expression and associated with a reduction in hepatocellular ballooning (EASL 2025) - P1/2 | "ARO-HSD, a hepatocyte-targeted siRNA therapeutic designed to silence HSD17B13 expression, improved markers of liver injury in participants with MASH in a Phase 1/2a clinical trial (NCT04202354)... This QSP study suggests that TG lipolysis and mitochondrial biogenesis may be a key MoA behind HSD17B13 knockdown. The QSP model predicts that HSD17B13 knockdown results in reductions in ALT, as seen in the Phase 1/2a trial, and additionally reduces PRO-C3. The small dataset available for calibration limits the strength of the conclusions that can be drawn."

Hepatology • Liver Failure • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

HORIZON: Phase 2b Study of GSK4532990 in Adults With NASH (clinicaltrials.gov) - P2 | N=271 | Active, not recruiting | Sponsor: GlaxoSmithKline | Recruiting ➔ Active, not recruiting | Trial primary completion date: Sep 2025 ➔ Dec 2025

Enrollment closed • Trial primary completion date • Hepatology • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

STARLIGHT: A Study to Investigate the Safety and Efficacy of GSK4532990 Compared With Placebo in Adult Participants Aged 18 to 65 Years With Alcohol-related Liver Disease (clinicaltrials.gov) - P2 | N=393 | Not yet recruiting | Sponsor: GlaxoSmithKline

New P2 trial • Hepatology

A Phase 2 Clinical Trial to Evaluate the Efficacy and Safety of VSA006 in Chinese NASH Patients (clinicaltrials.gov) - P2 | N=45 | Not yet recruiting | Sponsor: Visirna Therapeutics HK Limited

New P2 trial • Hepatology • Metabolic Dysfunction-Associated Steatohepatitis

SKYLINE: Dose Exploration Study of GSK4532990 in Participants With NASH or Suspected NASH (clinicaltrials.gov) - P2 | N=48 | Recruiting | Sponsor: GlaxoSmithKline | Not yet recruiting ➔ Recruiting

Enrollment open • Hepatology • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

SKYLINE: Dose Exploration Study of GSK4532990 in Participants With NASH or Suspected NASH (clinicaltrials.gov) - P2 | N=48 | Not yet recruiting | Sponsor: GlaxoSmithKline | Phase classification: P2a ➔ P2

Phase classification • Hepatology • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

HORIZON: Phase 2b Study of GSK4532990 in Adults With NASH (clinicaltrials.gov) - P2 | N=246 | Recruiting | Sponsor: GlaxoSmithKline | Phase classification: P2b ➔ P2

Phase classification • Hepatology • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

SKYLINE: Dose Exploration Study of GSK4532990 in Participants With NASH or Suspected NASH (clinicaltrials.gov) - P2a | N=48 | Not yet recruiting | Sponsor: GlaxoSmithKline

New P2a trial • Hepatology • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis

HORIZON: Phase 2b Study of GSK4532990 in Adults With NASH (clinicaltrials.gov) - P2b | N=246 | Recruiting | Sponsor: GlaxoSmithKline | Trial completion date: Jun 2025 ➔ Dec 2025 | Trial primary completion date: Mar 2025 ➔ Sep 2025

Trial completion date • Trial primary completion date • Hepatology • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • TIMP1

HORIZON: Phase 2b Study of GSK4532990 in Adults With NASH (clinicaltrials.gov) - P2b | N=246 | Recruiting | Sponsor: GlaxoSmithKline | Not yet recruiting ➔ Recruiting

Enrollment open • Hepatology • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • TIMP1

A phase I/II study of ARO-HSD, an RNA interference therapeutic, for the treatment of non-alcoholic steatohepatitis. (PubMed, J Hepatol) - P1/2 | "ARO-HSD was well tolerated at doses ≤200 mg. This proof-of-concept study demonstrated that short-term treatment with ARO-HSD reduces hepatic HSD17β13 mRNA and protein, which is accompanied by reductions in ALT. Impacts and Implications: TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number, NCT04202354."

Journal • P1/2 data • Hepatology • Non-alcoholic Steatohepatitis

HORIZON: Phase 2b Study of GSK4532990 in Adults With NASH (clinicaltrials.gov) - P2b | N=246 | Not yet recruiting | Sponsor: GlaxoSmithKline | Trial completion date: Mar 2025 ➔ Jun 2025

Trial completion date • Hepatology • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • TIMP1

HORIZON: Phase 2b Study of GSK4532990 in Adults With NASH (clinicaltrials.gov) - P2b | N=246 | Not yet recruiting | Sponsor: GlaxoSmithKline

New P2b trial • Hepatology • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • TIMP1