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

Phase 2

Completed

Conditions: Steatohepatitis, Nonalcoholic

Interventions: Drug: ION224
Other: Placebo

Registration Number: NCT04932512

Lead Sponsor: Ionis Pharmaceuticals, Inc.

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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 160

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
ION224	ION224	Multiple doses of ION224 will be administered by SC injection once every 4 weeks for up to 49 weeks.
Placebo	Placebo	Multiple doses of matching placebo will be administered by SC injection once every 4 weeks for up to 49 weeks.

Primary Outcome Measures

Name	Time	Method
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	Up to Week 49	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).

Secondary Outcome Measures

Name	Time	Method
Absolute Change From Baseline in Liver-related Laboratory Test - ALT	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
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 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 - AST	Baseline up to Week 49
Absolute Change From Baseline in Liver-related Laboratory Test - Total Bilirubin	Baseline up to Week 49
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
Absolute Change From Baseline in Plasma Fasting Lipid Profile Test - High-density Lipoprotein-cholesterol (HDL-c)	Baseline 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
Absolute Change From Baseline in Plasma Fasting Lipid Profile Test - Triglyceride (TG)	Baseline up to Week 49
Time to Cmax (Tmax) of ION224 and Metabolites	Baseline up to Week 49
Plasma Half-life (t½) of ION224 and Metabolites	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 - 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
Maximum Observed Plasma Concentration (Cmax) 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

Trial Locations

Locations (43): Excel Medical Clinical Trials, LLC
🇺🇸
Boca Raton, Florida, United States
Covenant Metabolic Specialists, LLC
🇺🇸
Sarasota, Florida, United States
Louisiana Research Center, LLC
🇺🇸
Shreveport, Louisiana, United States
Clarity Clinical Research
🇺🇸
East Syracuse, New York, United States
Pinnacle Clinical Research
🇺🇸
San Antonio, Texas, United States
Quality Research, Inc.
🇺🇸
San Antonio, Texas, United States
Arizona Liver Health
🇺🇸
Tucson, Arizona, United States
Arizona Liver Health-Chandler
🇺🇸
Chandler, Arizona, United States
GW Research, Inc.
🇺🇸
Chula Vista, California, United States
National Research Institute Panorama City
🇺🇸
Panorama City, California, United States
National Research Institute
🇺🇸
Los Angeles, California, United States
National Research Institute - Gardena
🇺🇸
Gardena, California, United States
Arkansas Gastroenterology - North Little Rock
🇺🇸
North Little Rock, Arkansas, United States
National Research Institute - Santa Ana
🇺🇸
Santa Ana, California, United States
South Denver Gastroenterology, PC
🇺🇸
Englewood, Colorado, United States
Tampa Bay Medical Research, Inc.
🇺🇸
Clearwater, Florida, United States
Southwest General Medical Center
🇺🇸
Fort Myers, Florida, United States
Evolution Clinical Trials, INC
🇺🇸
Hialeah Gardens, Florida, United States
ClinCloud, LLC.
🇺🇸
Maitland, Florida, United States
Floridian Clinical Research, LLC.
🇺🇸
Miami Lakes, Florida, United States
Advanced Pharma CR, LLC
🇺🇸
Miami, Florida, United States
La Salud Research
🇺🇸
Miami, Florida, United States
Entrust Clinical Research
🇺🇸
Miami, Florida, United States
Sensible Healthcare, LLC
🇺🇸
Ocoee, Florida, United States
Gastrointestinal Specialists of Georgia
🇺🇸
Marietta, Georgia, United States
Metabolic Research Institute, Inc.
🇺🇸
West Palm Beach, Florida, United States
Tandem Clinical Research GI, LLC.
🇺🇸
New York, New York, United States
Delta Research Partners
🇺🇸
Monroe, Louisiana, United States
Southern Therapy and Advanced Research
🇺🇸
Jackson, Mississippi, United States
Advanced Research Institute
🇺🇸
Sandy, Utah, United States
Cumberland Research Associates, LLC
🇺🇸
Fayetteville, North Carolina, United States
Clinical Research Institute of Ohio
🇺🇸
Westlake, Ohio, United States
Aventiv Research, Inc.
🇺🇸
Columbus, Ohio, United States
WR-ClinSearch, LLC
🇺🇸
Chattanooga, Tennessee, United States
South Texas Research Institute
🇺🇸
Edinburg, Texas, United States
Velocity Clinical Research
🇺🇸
Dallas, Texas, United States
DHR Health Institute for Research and Development
🇺🇸
McAllen, Texas, United States
Granger Medical Clinic
🇺🇸
Riverton, Utah, United States
Manassas Clinical Research Center
🇺🇸
Manassas, Virginia, United States
FDI Clinical Research
🇵🇷
San Juan, Puerto Rico
Tandem Clinical Research GI
🇺🇸
Metairie, Louisiana, United States
R&H Clinical Research, Inc.
🇺🇸
Katy, Texas, United States
Dallas Diabetes Research Center
🇺🇸
Dallas, Texas, United States