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

An Adaptive Two-Part Phase 2, Multi-Center, Randomized, Double Blind, Placebo-Controlled Study to Assess the Safety, Efficacy, and Pharmacokinetics of Multiple Doses of ION224 Administered Once Monthly in Adult Subjects With Confirmed Non-Alcoholic Steatohepatitis

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.

Study Overview

• Status: Completed
• Conditions: Steatohepatitis, Nonalcoholic
• Intervention / Treatment: Drug: ION224; Other: Placebo

Detailed Description

This is a Phase 2, double-blind, randomized, placebo-controlled study of ION224 in up to 150 participants. The study consists of 3 periods: 1) Screening Period: Week -8 to Week -1 (up to 8 weeks); 2) Treatment Period up to Week 49; and 3) Post-Treatment Period: Week 50 to Week 62 (12 weeks).

Initially, 48 patients will be enrolled in three different dose cohorts to receive ION224 or placebo every four weeks and based on safety and effects on liver steatosis (assessed at Week 15), two dose cohorts will be selected to be expanded. After dose selection, an additional 102 patients will be enrolled in the 2 selected dose cohorts and will receive ION224 or placebo for up to 49 weeks. Participants in the 3rd cohort (not selected) will continue to complete up to 49 weeks of treatment without any cohort expansion.

• Study Type: Interventional
• Enrollment (Actual): 160
• Phase: Phase 2

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico, 00927
    • FDI Clinical Research
• United States
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Arizona Liver Health-Chandler
    • Glendale, Arizona, United States, 85306
      • Arizona Liver Health
    • Tucson, Arizona, United States, 85712
      • Arizona Liver Health
  • Arkansas
    • North Little Rock, Arkansas, United States, 72117
      • Arkansas Gastroenterology - North Little Rock
  • California
    • Chula Vista, California, United States, 91910
      • GW Research, Inc.
    • Gardena, California, United States, 90247
      • National Research Institute - Gardena
    • Huntington Park, California, United States, 90255
      • National Research Institute
    • Los Angeles, California, United States, 90057
      • National Research Institute
    • Panorama City, California, United States, 91402
      • National Research Institute Panorama City
    • Santa Ana, California, United States, 92704
      • National Research Institute - Santa Ana
  • Colorado
    • Englewood, Colorado, United States, 80113
      • South Denver Gastroenterology, PC
  • Florida
    • Boca Raton, Florida, United States, 33434
      • Excel Medical Clinical Trials, LLC
    • Clearwater, Florida, United States, 33761
      • Tampa Bay Medical Research, Inc.
    • Fort Myers, Florida, United States, 33907
      • Southwest General Medical Center
    • Hialeah Gardens, Florida, United States, 33016
      • Evolution Clinical Trials, INC
    • Maitland, Florida, United States, 32751
      • ClinCloud, LLC.
    • Miami, Florida, United States, 33147
      • Advanced Pharma CR, LLC
    • Miami, Florida, United States, 33176
      • Entrust Clinical Research
    • Miami, Florida, United States, 33155
      • La Salud Research
    • Miami Lakes, Florida, United States, 33016
      • Floridian Clinical Research, LLC.
    • Ocoee, Florida, United States, 34761
      • Sensible Healthcare, LLC
    • Sarasota, Florida, United States, 34240
      • Covenant Metabolic Specialists, LLC
    • West Palm Beach, Florida, United States, 33401
      • Metabolic Research Institute, Inc.
  • Georgia
    • Marietta, Georgia, United States, 30060
      • Gastrointestinal Specialists of Georgia
  • Louisiana
    • Houma, Louisiana, United States, 70363
      • Tandem Clinical Research GI
    • Marrero, Louisiana, United States, 70072
      • Tandem Clinical Research GI, LLC.
    • Metairie, Louisiana, United States, 70006
      • Tandem Clinical Research GI
    • Monroe, Louisiana, United States, 71201
      • Delta Research Partners
    • Shreveport, Louisiana, United States, 71105
      • Louisiana Research Center, LLC
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • Southern Therapy and Advanced Research
  • Nevada
    • Reno, Nevada, United States, 89511
      • Advanced Research Institute
  • New York
    • East Syracuse, New York, United States, 13057
      • Clarity Clinical Research
    • New York, New York, United States, 10033
      • Tandem Clinical Research GI, LLC.
  • North Carolina
    • Fayetteville, North Carolina, United States, 28304
      • Cumberland Research Associates, LLC
  • Ohio
    • Columbus, Ohio, United States, 43213
      • Aventiv Research, Inc.
    • Westlake, Ohio, United States, 44145
      • Clinical Research Institute of Ohio
  • Tennessee
    • Chattanooga, Tennessee, United States, 37421
      • WR-ClinSearch, LLC
  • Texas
    • Austin, Texas, United States, 78757
      • Pinnacle Clinical Research
    • Brownsville, Texas, United States, 78520
      • South Texas Research Institute
    • Dallas, Texas, United States, 75230
      • Dallas Diabetes Research Center
    • Dallas, Texas, United States, 75230
      • Velocity Clinical Research
    • Edinburg, Texas, United States, 78539
      • South Texas Research Institute
    • Katy, Texas, United States, 77494
      • R&H Clinical Research, Inc.
    • McAllen, Texas, United States, 78504
      • DHR Health Institute for Research and Development
    • San Antonio, Texas, United States, 78209
      • Quality Research, Inc.
    • San Antonio, Texas, United States, 78229
      • Pinnacle Clinical Research
  • Utah
    • Ogden, Utah, United States, 84405
      • Advanced Research Institute
    • Riverton, Utah, United States, 84096
      • Granger Medical Clinic
    • Sandy, Utah, United States, 84092
      • Advanced Research Institute
  • Virginia
    • Manassas, Virginia, United States, 20110
      • Manassas Clinical Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• Prior or planned (during the Study Period) bariatric surgery or previous bariatric surgery within 2 years prior to screening
• History of solid organ transplant

• Screening laboratory values that would render a participant unsuitable for inclusion, including but not limited to:

  • 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
• Use of drugs historically associated with NAFLD for more than 2 weeks in the year prior to Screening
• Use of obeticholic acid, ursodeoxycholic acid, icosapent ethyl, niacin, PCSK9 inhibitors, and bile acid sequestrants

• Participants taking the following medicines UNLESS on a stable dose:

  • Anti-diabetic medications
  • statins, fenofibrate, and ezetimibe
  • Estrogen containing contraceptives
  • Glucagon-like peptide (GLP)-1 agonists
  • Pioglitazone
  • Vitamin E at doses ≤ 800 international unit (IU)/day
  • Herbal medicines, other prescription medicines, vitamins or supplements known to affect lipid metabolism
• Other protocol-defined inclusion/exclusion criteria could apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ION224; Multiple doses of ION224 will be administered by SC injection once every 4 weeks for up to 49 weeks.	Drug: ION224; ION224 will be administered by SC injection.
Placebo Comparator: Placebo; Multiple doses of matching placebo will be administered by SC injection once every 4 weeks for up to 49 weeks.	Other: Placebo; ION224-matching placebo solution will be administered by SC injection.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Time Frame
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 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
Absolute Change From Baseline in Liver-related Laboratory Test - ALT	Baseline up to Week 49
Absolute Change From Baseline in Liver-related Laboratory Test - AST	Baseline up to Week 49
Absolute Change From Baseline in Liver-related Laboratory Test - Total Bilirubin	Baseline up to Week 49
Absolute Change From Baseline in Liver-related Laboratory Test - Gamma-glutamyl Transferase	Baseline up to Week 49
Absolute Change From Baseline in Plasma Fasting Lipid Profile Test - Triglyceride (TG)	Baseline up to Week 49
Absolute Change From Baseline in Plasma Fasting Lipid Profile Test - Total Cholesterol	Baseline up to Week 49
Absolute Change From Baseline in Plasma Fasting Lipid Profile Test - Low-density Lipoprotein-cholesterol (LDL-c)	Baseline up to Week 49
Absolute Change From Baseline in Plasma Fasting Lipid Profile Test - High-density Lipoprotein-cholesterol (HDL-c)	Baseline up to Week 49
Maximum Observed Plasma Concentration (Cmax) of ION224 and Metabolites	Baseline up to Week 49
Time to Cmax (Tmax) of ION224 and Metabolites	Baseline up to Week 49
Area Under the Plasma Concentration-time Curve (AUC) of ION224 and Metabolites	Baseline up to Week 49
Plasma Half-life (t½) of ION224 and Metabolites	Baseline up to 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

Collaborators and Investigators

• Sponsor: Ionis Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): June 17, 2021
• Primary Completion (Actual): January 10, 2024
• Study Completion (Actual): February 28, 2024

Study Registration Dates

• First Submitted: June 10, 2021
• First Submitted That Met QC Criteria: June 10, 2021
• First Posted (Actual): June 21, 2021

Study Record Updates

• Last Update Posted (Actual): March 29, 2024
• Last Update Submitted That Met QC Criteria: March 28, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Non-Alcoholic Steatohepatitis; Aspartate Aminotransferase; Non-alcoholic Fatty Liver Disease Activity Score; Alanine Aminotransferase
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: ION224-CS2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No