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.

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.

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