ION224 / Ionis - LARVOL DELTA

NOVEL DGAT2 ANTISENSE INHIBITOR DEMONSTRATES SIGNIFICANT HISTOLOGICAL BENEFIT IN BIOPSY-PROVEN MASH PATIENTS WITH ADVANCED LIVER FIBROSIS STAGE F3: SUBSET ANALYSIS OF A 51-WEEK MULTICENTER RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED PHASE 2 TRIAL (AASLD 2024) - P2 | "The current analysis provides evidence of clinical benefit of ION224 in patients with advanced fibrosis independent of changes in body weight. These data support the potential for ION224 treatment to provide benefit to MASH patients with advanced liver fibrosis."

Biopsy • Clinical • Metastases • P2 data • Diabetes • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Type 2 Diabetes Mellitus

Novel DGAT2 antisense inhibitor demonstrates significant MASH resolution in biopsy-proven F2/F3 MASH: results from a 51-week multicenter randomized double-blind placebo-controlled phase 2 trial (EASL-ILC 2024) - "This study provides the first clinical evidence that reduction of hepatic fat after DGAT2 inhibition leads to MASH resolution. ION224 was safe and well-tolerated in this study with once-monthly subcutaneous dosing. These data support the potential for ION224 treatment to provide benefit to patients with MASH and liver fibrosis."

Biopsy • Clinical • Late-breaking abstract • P2 data • Diabetes • Dyslipidemia • Fibrosis • Hepatology • Hypertriglyceridemia • Immunology • Inflammation • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis • Type 2 Diabetes Mellitus

Ionis announces positive results from Phase 2 study of ION224, an investigational medicine demonstrating clinical efficacy in the treatment of NASH/MASH (PRNewswire) - P2 | N=160 | NCT04932512 | Sponsor: Ionis Pharmaceuticals, Inc. | "Ionis Pharmaceuticals...announced positive results from a Phase 2 study of ION224, an investigational DGAT2 antisense inhibitor in development for the treatment of metabolic dysfunction-associated steatohepatitis (MASH), previously referred to as nonalcoholic steatohepatitis (NASH). The study met its primary endpoint at both doses (120 mg and 90 mg), achieving liver histologic improvement, and also met the important secondary endpoint of MASH resolution....ION224 achieved statistically significant liver histologic improvement as measured by at least a 2-point reduction in NAFLD Activity Score (NAS) (p<0.001 (120 mg) and p=0.015 (90 mg))."

P2 data • Metabolic Dysfunction-Associated Steatohepatitis

ION224-CS2: A Study to Assess the Safety, Efficacy, and Pharmacokinetics of Multiple Doses of ION224 (clinicaltrials.gov) - P2 | N=160 | Completed | Sponsor: Ionis Pharmaceuticals, Inc. | Active, not recruiting ➔ Completed

Trial completion • Hepatology • Metabolic Dysfunction-Associated Steatohepatitis

The translational potential of miR-26 in atherosclerosis and development of agents for its target genes ACC1/2, COL1A1, CPT1A, FBP1, DGAT2, and SMAD7. (PubMed, Cardiovasc Diabetol) - "Many agents targeting these genes, such as the ACC1/2 inhibitors GS-0976, PF-05221304, and MK-4074; the DGAT2 inhibitors IONIS-DGAT2Rx, PF-06427878, PF-0685571, and PF-07202954; the COL1A1 inhibitor HT-100; the stimulants Ga-CBP8 and RCT-01; the CPT1A inhibitors etomoxir, perhexiline, and teglicar; the FBP1 inhibitors CS-917 and MB07803; and the SMAD7 inhibitor mongersen, have been investigated in clinical trials...Many PCSK9 inhibitors, including alirocumab, evolocumab, inclisiran, AZD8233, Civi-007, MK-0616, and LIB003, have been investigated in clinical trials...Multiple materials can be used to deliver miR-26, but it is unclear which material is most suitable for mass production and clinical applications. This review focuses on the potential use of miR-26 in treating atherosclerosis to support the development of agents targeting it."

Journal • Review • Atherosclerosis • Cardiovascular • Dyslipidemia • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • ABCA1 • ACACA • ACSL3 • BMP2 • CD36 • COL1A1 • CPT1A • CTGF • EHHADH • HMGB1 • IFNA1 • IL1B • IL6 • MALT1 • RUNX2 • SCARB1 • SMAD7 • TCF7L2 • TNFA

ION224-CS2: A Study to Assess the Safety, Efficacy, and Pharmacokinetics of Multiple Doses of ION224 (clinicaltrials.gov) - P2 | N=160 | Active, not recruiting | Sponsor: Ionis Pharmaceuticals, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Hepatology • Non-alcoholic Steatohepatitis

ION224-CS2: A Study to Assess the Safety, Efficacy, and Pharmacokinetics of Multiple Doses of ION224 (clinicaltrials.gov) - P2 | N=150 | Recruiting | Sponsor: Ionis Pharmaceuticals, Inc. | Trial primary completion date: Oct 2023 ➔ Feb 2024

Trial primary completion date • Hepatology • Non-alcoholic Steatohepatitis

ION224-CS2: A Study to Assess the Safety, Efficacy, and Pharmacokinetics of Multiple Doses of ION224 (clinicaltrials.gov) - P2 | N=150 | Recruiting | Sponsor: Ionis Pharmaceuticals, Inc. | Trial completion date: Sep 2023 ➔ Jan 2024

Trial completion date • Hepatology • Non-alcoholic Steatohepatitis

ION224-CS2: A Study to Assess the Safety, Efficacy, and Pharmacokinetics of Multiple Doses of ION224 (clinicaltrials.gov) - P2; N=150; Recruiting; Sponsor: Ionis Pharmaceuticals, Inc.; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open • Hepatology • Non-alcoholic Steatohepatitis • MRI

A Study to Assess the Safety, Efficacy, and Pharmacokinetics of Multiple Doses of ION224 (clinicaltrials.gov) - P2; N=150; Not yet recruiting; Sponsor: Ionis Pharmaceuticals, Inc.

Clinical • New P2 trial • Hepatology • Non-alcoholic Steatohepatitis • MRI

Safety, Tolerability, and Pharmacodynamics of IONIS-DGAT2Rx in Adult Patients With Type 2 Diabetes (clinicaltrials.gov) - P2; N=44; Active, not recruiting; Sponsor: Ionis Pharmaceuticals, Inc.; Recruiting ➔ Active, not recruiting

Enrollment closed • Biosimilar • Diabetes • Metabolic Disorders

An international, randomized, placebo-controlled phase 2 trial demonstrates novel effects of DGAT2 antisense inhibition in reducing steatosis without causing hypertriglyceridemia in T2DM patients (EASL-ILC 2019) - "These data suggest that DGAT2 inhibition may be a novel, safe and effective strategy for treatment of NAFLD and associated disorders. These data support further investigation of this agent™s efficacy in biopsy-proven NASH."

Clinical • P2 data