A Study to Investigate the Safety and Efficacy of Efimosfermin Alfa Compared With Placebo in Adult Participants With Alcohol-related Liver Disease (ALD)

• Efimosfermin alfa (Drug): Efimosfermin alfa will be administered.
• Placebo (Drug): Placebo will be administered.

Primary outcomes

• Change from Baseline in vibration-controlled transient elastography-liver stiffness measurement (VCTE-LSM) [Baseline (Day 1) and up to Week 60]: VCTE-LSM is a non-invasive test that uses vibration-controlled transient elastography to measure the stiffness of the liver in kilopascals (kPa)
• Change from Baseline in model for end-stage liver disease (MELD) score [Baseline (Day 1) and up to Week 60]: MELD is a scoring system for assessing the severity of chronic liver disease. MELD scores range between 6 and 40, with 40 being the most severe.

Secondary outcomes

• Change from Baseline in serum aspartate aminotransferase (AST) (International units per liter) [Baseline (Day 1) and up to Week 60]: This is a measurement of the AST enzyme in the blood.
• Change from Baseline in a blood test that helps predict the risk of disease progression in liver disease [Baseline (Day 1) and up to Week 52]
• Trough Concentration at steady state (Ctrough,ss) following administration of efimosfermin alfa [Up to Week 56]
• Area Under the concentration-time Curve from Time 0 (pre-dose) to the last quantifiable concentration (AUC[0-t]) of efimosfermin alfa in the subset of participants with optional intensive pharmacokinetics (PK) sampling [Up to Week 4]
• Maximum observed drug concentration (Cmax) of efimosfermin alfa in the subset of participants with optional intensive PK sampling [Up to Week 4]
• Number of Participants with Anti-drug antibodies (ADA) against efimosfermin alfa [Up to Week 56]
• Number of participants with treatment-emergent adverse events (TEAEs) and TEAEs by severity [Up to Week 60]
• Number of participants with TEAEs leading to discontinuation and TEAEs leading to discontinuation by severity [Up to Week 60]
• Number of participants with Grade 3 and Grade 4 laboratory abnormalities [Up to Week 60]
• Number of participants with clinically significant changes in Vital signs [Up to Week 60]
• Number of participants with clinically significant changes in 12-lead electrocardiogram (ECG) findings [Up to Week 60]

Sex: All, ages: 18 Years to 75 Years

Inclusion Criteria:

* Participant must be 18 to 75 years of age inclusive, at the time of Screening.
* Capable of giving signed informed consent prior to the performance of any study-specific procedures.
* Able and willing to comply with all study assessments and adhere to the protocol schedule of activities.
* History of heavy alcohol consumption for greater than 6 months at any time prior to Screening.
* A female participant is eligible to participate if they are not pregnant or breastfeeding, and one of the following conditions applies:

  * Is a Participant of non-childbearing potential (PONCBP) OR
  * Is a Participant of childbearing potential (POCBP) and using a contraceptive method that is highly effective, with a failure rate of less than (<)1 percentage (%), 30 days prior to and during the study intervention period and for at least 16 weeks after the last dose of study intervention.

Exclusion Criteria:

* Other primary causes of liver disease (e.g., viral hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis, drug-induced hepatotoxicity, Wilson disease, hemochromatosis, alpha-1-antitryspin deficiency, etc.). Alcohol must be the primary cause of liver disease.
* Co-infection with Hepatitis B virus (HBV), Hepatitis C virus (HCV), or Human immunodeficiency virus (HIV) as indicated from the central lab
* History of diabetes mellitus (DM), either:

  * Type 1 DM
  * Type 2 DM with unstable glycemic control or with major complications.
* History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within the 3 years prior to Screening 1, regardless of any evidence of local recurrence or metastasis.
* Current, or history of known hepatocellular carcinoma (HCC).
* Any major surgery within 3 months prior to Screening 1 or planned during the study
* Any surgical or medical condition that might jeopardize the individual's safety or compliance with study procedures in the opinion of the investigator.
* All organ transplant recipients, except for history of corneal transplants, or current listing or active consideration for liver transplant during the Screening period.
* Poorly controlled hypertension.
* Evidence of Wernicke-Korsakoff syndrome or alcohol-related dementia.
* Prior use of a Fibroblast growth factor 21 (FGF21) analogue, including efimosfermin, within the 6 months prior to Screening 1.
* Individuals with a history of resmetirom use within 3 months prior to Day 1 are to be excluded.
* Concomitant use of investigational drugs for Metabolic dysfunction-associated steatohepatitis (MASH) or ALD.
* Current or planned participation in any clinical trial of investigational therapies or medical devices.
* Exceeding pre-defined laboratory parameters for Triglycerides, Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), International normalised ratio (INR), Albumin, Urine albumin-creatinine ratio (uACR) or Glycosylated Hemoglobin (HbA1c).
* History of drug abuse within the 12 months prior to Day 1 or evidence of such abuse as indicated by laboratory assays conducted at Screening.
* History of hypersensitivity (such as anaphylaxis or hepatotoxicity) to study intervention and/or its excipients, drugs of similar biological class, FGF21 protein analogs, Fc-fusion proteins, or other protein-based therapeutics.
* Overt hepatic encephalopathy (West Haven grade >=2).

• GSK Clinical Trials, Study director, GlaxoSmithKline