A Study to Assess the Safety, Efficacy, and Pharmacokinetics of Multiple Doses of ION224

NCT04932512 | Completed Phase 2 FDA Drug

• 1 other identifier: ION224-CS2
• Study Type: interventional
• Target: 160
• Locations: 2 countries
• Sites: 51

Brief Summary

The purpose of this study is to assess the effect of multiple ION224 doses when administered by subcutaneous (SC) injection for 49 weeks (end of the treatment \[EOT\]) on non-alcoholic steatohepatitis (NASH) histologic improvement and to assess the effect on liver steatosis by magnetic resonance imaging-determined proton density fat fraction (MRI-PDFF), additional changes in NASH histologic features, liver biochemistry tests, and plasma lipid profile.

Conditions

Steatohepatitis, Nonalcoholic

Keywords

Non-Alcoholic Steatohepatitis; Non-alcoholic Fatty Liver Disease Activity Score; Alanine Aminotransferase; Aspartate Aminotransferase

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With at Least 2-point Reduction in Non-alcoholic Fatty Liver Disease Activity Score (NAS) With at least 1-point Improvement in Hepatocellular Ballooning or Lobular Inflammation, and Without Worsening in Fibrosis Stage at EOT

  The NAS is a histology grading score composed on the assessment of steatosis (scale 0-3), hepatocellular ballooning (scale 0-2), and lobular inflammation (scale 0-3), with higher scores indicating more severe hepatitis. Worsening of fibrosis is defined as an increase in fibrosis of at least one stage on the Kleiner fibrosis classification: fibrosis stages range from 0-4, with higher scores indicating greater fibrosis (0=None, 4=Cirrhosis).

  Up to Week 49

Secondary Outcomes (17)

• Change From Baseline in Hepatic Fat Content Measurement as Evaluated by MRI-PDFF and Calculated by an Independent, Blinded-To-Treatment, Central Reader

  Baseline up to Week 15, Week 29 and Week 49

• Percentage of Participants Achieving Non-alcoholic Steatohepatitis (NASH) Resolution, as Defined by Scores of 0 for Ballooning and 0 or 1 for Inflammation by the NAS, and Without Worsening of Fibrosis, Assessed Through Liver Biopsy at the EOT

  Up to Week 49

• Percentage of Participants Achieving Reduction of at Least 1 Stage in the Fibrosis Score, and Without Worsening of Steatohepatitis by the NAS, Assessed Through Liver Biopsy at the EOT

  Up to Week 49

• Percentage of Participants Achieving a Combination of NASH Resolution and a 1 Stage Improvement in Fibrosis at the EOT

  Up to Week 49

• Percentage of Participants With Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) Less than or Equal to (≤) 1.5 Upper Limit of Normal (ULN) at the EOT

  Up to Week 49

Study Arms (2)

ION224

EXPERIMENTAL

Multiple doses of ION224 will be administered by SC injection once every 4 weeks for up to 49 weeks.

Drug: ION224

Placebo

PLACEBO COMPARATOR

Multiple doses of matching placebo will be administered by SC injection once every 4 weeks for up to 49 weeks.

Other: Placebo

Interventions

ION224 DRUG

ION224 will be administered by SC injection.

ION224

Placebo OTHER

ION224-matching placebo solution will be administered by SC injection.

Placebo

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Males or females greater than or equal to (≥) 18 and less than or equal to (≤) 75 years old at the time of informed consent
• Body mass index ≥ 25 kg/m\^2 and ≥ 22 kg/m\^2 for participants of Asian race, as assessed during screening
• Liver fat ≥ 10% as assessed by MRI-PDFF before randomization
• Presence of NASH confirmed by centrally read liver biopsy
• Weight loss \< 5% after historical biopsy. Otherwise, weight loss \< 5% in the previous 3 months prior to randomization
• ALT and AST ≤ 200 units per liter (U/L) and confirmed to be stable
• Total Bilirubin ≤ 1.3 milligrams per deciliter (mg/dL) and confirmed to be stable

You may not qualify if:

• Prior or planned (during the Study Period) bariatric surgery or previous bariatric surgery within 2 years prior to screening
• History of solid organ transplant
• Clinically significant albuminuria or proteinuria
• Positive test for blood on urinalysis
• Estimated glomerular filtration rate (eGFR) \< 60 milliliters (mL)/minute (min)/1.73 square meter (m\^2)
• Hemoglobin A1c (HbA1c) \> 9.5%
• Platelet count \< 170 × 10\^9/liter (L)
• Diagnosis of Gilbert's syndrome
• Known history of or evidence of liver disease other than NASH
• Clinical evidence of liver decompensation
• Active SARS-CoV-2 infection (COVID-19) or confirmed SARS-CoV-2 infection-related complication within 8 weeks of Screening
• Uncontrolled arterial hypertension
• History of bleeding diathesis or coagulopathy
• Participants with known intolerance to magnetic resonance imaging (MRI) or with conditions contraindicated for MRI Procedures
• History of, or current hard drug or alcohol abuse within 2 years prior to Screening

Sponsors & Collaborators

• Ionis Pharmaceuticals, Inc.: lead

Study Sites (51)

Arizona Liver Health-Chandler

Chandler, Arizona, 85224, United States

Location

Arizona Liver Health

Glendale, Arizona, 85306, United States

Location

Arizona Liver Health

Tucson, Arizona, 85712, United States

Location

Arkansas Gastroenterology - North Little Rock

North Little Rock, Arkansas, 72117, United States

Location

GW Research, Inc.

Chula Vista, California, 91910, United States

Location

National Research Institute - Gardena

Gardena, California, 90247, United States

Location

National Research Institute

Huntington Park, California, 90255, United States

Location

National Research Institute

Los Angeles, California, 90057, United States

Location

National Research Institute Panorama City

Panorama City, California, 91402, United States

Location

National Research Institute - Santa Ana

Santa Ana, California, 92704, United States

Location

South Denver Gastroenterology, PC

Englewood, Colorado, 80113, United States

Location

Excel Medical Clinical Trials, LLC

Boca Raton, Florida, 33434, United States

Location

Tampa Bay Medical Research, Inc.

Clearwater, Florida, 33761, United States

Location

Southwest General Medical Center

Fort Myers, Florida, 33907, United States

Location

Evolution Clinical Trials, INC

Hialeah Gardens, Florida, 33016, United States

Location

ClinCloud, LLC.

Maitland, Florida, 32751, United States

Location

Advanced Pharma CR, LLC

Miami, Florida, 33147, United States

Location

La Salud Research

Miami, Florida, 33155, United States

Location

Entrust Clinical Research

Miami, Florida, 33176, United States

Location

Floridian Clinical Research, LLC.

Miami Lakes, Florida, 33016, United States

Location

Sensible Healthcare, LLC

Ocoee, Florida, 34761, United States

Location

Covenant Metabolic Specialists, LLC

Sarasota, Florida, 34240, United States

Location

Metabolic Research Institute, Inc.

West Palm Beach, Florida, 33401, United States

Location

Gastrointestinal Specialists of Georgia

Marietta, Georgia, 30060, United States

Location

Tandem Clinical Research GI

Houma, Louisiana, 70363, United States

Location

Tandem Clinical Research GI, LLC.

Marrero, Louisiana, 70072, United States

Location

Tandem Clinical Research GI

Metairie, Louisiana, 70006, United States

Location

Delta Research Partners

Monroe, Louisiana, 71201, United States

Location

Louisiana Research Center, LLC

Shreveport, Louisiana, 71105, United States

Location

Southern Therapy and Advanced Research

Jackson, Mississippi, 39216, United States

Location

Advanced Research Institute

Reno, Nevada, 89511, United States

Location

Clarity Clinical Research

East Syracuse, New York, 13057, United States

Location

Tandem Clinical Research GI, LLC.

New York, New York, 10033, United States

Location

Cumberland Research Associates, LLC

Fayetteville, North Carolina, 28304, United States

Location

Aventiv Research, Inc.

Columbus, Ohio, 43213, United States

Location

Clinical Research Institute of Ohio

Westlake, Ohio, 44145, United States

Location

WR-ClinSearch, LLC

Chattanooga, Tennessee, 37421, United States

Location

Pinnacle Clinical Research

Austin, Texas, 78757, United States

Location

South Texas Research Institute

Brownsville, Texas, 78520, United States

Location

Dallas Diabetes Research Center

Dallas, Texas, 75230, United States

Location

Velocity Clinical Research

Dallas, Texas, 75230, United States

Location

South Texas Research Institute

Edinburg, Texas, 78539, United States

Location

R&H Clinical Research, Inc.

Katy, Texas, 77494, United States

Location

DHR Health Institute for Research and Development

McAllen, Texas, 78504, United States

Location

Quality Research, Inc.

San Antonio, Texas, 78209, United States

Location

Pinnacle Clinical Research

San Antonio, Texas, 78229, United States

Location

Advanced Research Institute

Ogden, Utah, 84405, United States

Location

Granger Medical Clinic

Riverton, Utah, 84096, United States

Location

Advanced Research Institute

Sandy City, Utah, 84092, United States

Location

Manassas Clinical Research Center

Manassas, Virginia, 20110, United States

Location

FDI Clinical Research

San Juan, 00927, Puerto Rico

Location

Related Publications (1)

• Loomba R, Morgan E, Yousefi K, Li D, Geary R, Bhanot S, Alkhouri N; ION224-CS2 Investigators. Antisense oligonucleotide DGAT-2 inhibitor, ION224, for metabolic dysfunction-associated steatohepatitis (ION224-CS2): results of a 51-week, multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2025 Aug 23;406(10505):821-831. doi: 10.1016/S0140-6736(25)00979-1.

  PMID: 40849139 DERIVED

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 10, 2021
• First Posted: June 21, 2021
• Study Start: June 17, 2021
• Primary Completion: January 10, 2024
• Study Completion: February 28, 2024
• Last Updated: November 27, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (50); PR (1)