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

Prior treatment

• Prior or planned (during the Study Period) bariatric surgery or previous bariatric surgery within 2 years prior to screening
• 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 illness

• History of solid organ transplant
• Diagnosis of Gilbert's syndrome
• Known history of or evidence of liver disease other than NASH
• 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

Lab values

• 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)

Other

• Clinical evidence of liver decompensation
• Other protocol-defined inclusion/exclusion criteria could apply

• 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