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Efficacy and Safety Evaluation of GSK4532990 in Adults with Alcohol-Related Liver Disease: A Phase 2, Double-Blind, Placebo-Controlled, Dose-Finding Study

Trial ID
2024-511596-15-00
Protocol
222291
Sponsor
Glaxosmithkline Research & Development Limited

Trial statistics

science
2
test molecules
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46
research sites
public
8
countries
medical_information
1
disease
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47
investigators
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39
vendors

Diseases & Conditions

Alcoholic liver disease

Objectives

The primary objective of this Phase 2 study is to assess the **safety** and tolerability of a single subcutaneous dose of GSK4532990 in adult participants with alcohol-related liver disease (ALD). Additionally, the study aims to evaluate the efficacy of GSK4532990 in reducing baseline liver stiffness measurement (LSM) and Model for End-Stage Liver Disease (MELD) scores in this population. These objectives are clinically relevant as they address the potential therapeutic benefits and safety profile of GSK4532990, which could offer a novel treatment option for patients with ALD, a condition with limited effective therapies.

Secondary objectives include:

  • Assessing the effect of hepatic impairment on the plasma pharmacokinetic (PK) parameters of GSK4532990.
  • Evaluating the efficacy of GSK4532990 in participants with ALD during the main study period.
  • Evaluating GSK4532990 exposure parameters in participants with ALD.
These secondary objectives provide additional insights into the drug's pharmacokinetics and further substantiate its efficacy in the target population.

Participants

The clinical trial involves a total of **219 participants** diagnosed with **alcoholic liver disease**. The study population includes both male and female subjects, aged between **18 to 70 years**. Participants were selected based on their history of alcohol consumption compatible with alcoholic liver disease or metabolic alcoholic liver disease, and may present with concomitant features of metabolic syndrome such as type 2 diabetes mellitus, obesity, dyslipidemia, and hypertension. The trial includes individuals who are capable of providing informed consent and are willing to comply with study requirements. Participants are required to have a stable medication regimen if applicable, and women of childbearing potential must adhere to strict contraceptive measures. The trial population is considered vulnerable, and the selection process ensures that participants meet specific health criteria, including a clinical diagnosis of liver cirrhosis corroborated by medical history or diagnostic evidence.

Plans and Procedures

The clinical trial is designed to evaluate the **efficacy** and safety of GSK4532990 in adult participants with **alcohol-related liver disease** (ALD). This study is a randomized, double-blind, placebo-controlled Phase 2 trial. The trial is structured to include a safety lead-in phase followed by the main study period. The estimated duration of the trial is from October 2024 to March 2027, with participant involvement expected to last approximately 28 weeks. The trial will assess the primary endpoints of incidence of adverse events (AEs) and serious adverse events (SAEs), as well as changes in liver stiffness measurement (LSM) and Model for End-Stage Liver Disease (MELD) score at Week 28.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to determine eligibility based on criteria such as age, history of alcohol consumption, and liver cirrhosis classification. The main study period will involve regular follow-up visits at Weeks 4, 8, 12, 16, 20, and 24 to monitor changes in LSM and MELD score, as well as to collect pharmacokinetic data. The end-of-study visit will occur at Week 28, where final assessments will be conducted. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety.

Inclusion criteria require participants to be between 18 and 65 years of age, with a history of alcohol consumption compatible with ALD or metabolic ALD (MetALD). Female participants must not be pregnant or breastfeeding and must adhere to effective contraceptive measures. Participants must also be capable of providing informed consent and willing to comply with study requirements. The trial will exclude individuals who do not meet these criteria or who are unable to adhere to the study protocol.

Treatment

The clinical trial involves the evaluation of **GSK4532990**, an experimental medication developed by GlaxoSmithKline. This investigational product is chemically synthesized and classified as a **nucleic acid**-based substance, specifically known by the synonym ADS-006 sodium. The pharmaceutical form, dosage, and specific route of administration for GSK4532990 are not explicitly detailed in the provided data. However, the study is designed to assess the safety and tolerability of a single subcutaneous dose of GSK4532990 in the safety lead-in phase, followed by an evaluation of its efficacy in reducing liver stiffness measurement (LSM) and Model for End-Stage Liver Disease (MELD) scores in participants with alcohol-related liver disease (ALD) during the main study period.

The trial also includes a **placebo** as a comparator treatment. The placebo is utilized in a double-blind manner to ensure unbiased assessment of the efficacy and safety of GSK4532990. The placebo is administered in a manner consistent with the experimental treatment to maintain the integrity of the study design. Details regarding the pharmaceutical form, dosage, and administration route of the placebo are not specified in the available data.

Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the protocol. The trial is structured as a dose-finding, double-blind, placebo-controlled Phase 2 study, focusing on adult participants diagnosed with steatohepatitis associated with alcohol-related liver disease. The primary objective is to evaluate the efficacy of GSK4532990 in this patient population, with safety and tolerability being key considerations during the initial phase of the trial.

Efficacy

The efficacy of GSK4532990 in the treatment of **alcohol-related liver disease (ALD)** will be assessed through a series of primary and secondary endpoints. The primary efficacy endpoints for the main study period include the change from baseline in liver stiffness measurement (LSM) using FibroScan® and the Model for End-Stage Liver Disease (MELD) score at Week 28. These measurements will consider adverse outcomes such as death, liver-related hospitalization, liver transplantation, and hepatocellular carcinoma (HCC) as poor outcomes. Secondary endpoints will further evaluate changes in LSM and MELD score at multiple timepoints, specifically at Weeks 4, 8, 12, 16, 20, and 24. Additionally, plasma exposure parameters of GSK4532990, including the area under the concentration-time curve (AUC0-t) and maximum observed concentration (Cmax), will be assessed in a subset of participants with intensive pharmacokinetic sampling.

Inclusion and Exclusion Criteria

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Inclusion Criteria

  • Main Study Period A female participant is eligible to participate, if she is not pregnant or breastfeeding and one of the following conditions applies: INC#5 − Is a woman of nonchildbearing potential (WONCBP) as defined in Section 10.4 (Appendix 4: Contraceptive and barrier guidance). OR – Is a WOCBP and using a contraceptive method that is highly effective, with a failure rate of <1%, as described in Section 10.4. Contraceptive measures must start at least 28 days prior to the first dose of study intervention and should continue during the study intervention period, for a minimum of 18 weeks after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study intervention. A WOCBP must have a negative highly sensitive pregnancy test (serum or urine as required by local regulations) within 24 hours before the first dose of study intervention (see Section 8.3.5 Pregnancy testing).
  • Main Study Period Participants using any of the specified medications listed below can be included, but only if all these requirements are met: INC#6 − the dose has been stable for ≥3 months prior to D1, and − the participant is expected to continue the same dosing regimen throughout study participation. The specified medications are: incretin analogues such as glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), or glucagon receptor agonist, alone or in combination; PPAR agonists (e.g., pioglitazone, saroglitazar), sodium glucose cotransporter 2 (SGLT2) inhibitors; thyroid hormone receptor beta agonists; farnesoid X receptor (FXR) agonists; fatty acid synthase inhibitors; fibroblast growth factor 21 (FGF21) agonists; or Vitamin E (at doses greater than 400 IU/day). NOTE: If a switch to another medication within the same class is required, this will only be permitted if the new medication dose is equivalent to the prior medication dose. Switches to a different medication class are not permitted during the study.
  • Main Study Period Participant must be 18 to 70 years of age inclusive, at the time of screening. (Participants in South Korea must be ≥19 years of age.) INC#1
  • Main Study Period Capable of giving signed informed consent prior to the performance of any study-specific procedures, as described in Section 10.1.3. INC#2
  • Participant has advanced chronic liver disease. INC#7
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Exclusion Criteria

  • Main Study Period Presence of hepatitis B surface antigen (HBsAg) at Screening 1 or within 3 months prior to first dose of study intervention (Based on local or central laboratory measurements; 1 repeat test is allowed). EXC#14
  • Main Study Period Positive hepatitis C antibody test result at Screening 1 or within 3 months prior to first dose of study intervention. Note: Participants with positive hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative hepatitis C RNA test is obtained and provided treatment for HCV infection occurred 2 years or more prior to screening (Based on central laboratory measurements; 1 repeat test is allowed). EXC#15
  • Main Study Period Positive hepatitis C RNA test result at screening or within 3 months prior to first dose of study intervention. (Based on central laboratory measurements; 1 repeat test is allowed) Note: Test is optional and participants with negative hepatitis C antibody test are not required to also undergo hepatitis C RNA testing. EXC#16
  • Main Study Period Other primary causes of liver disease (including but not limited to primary biliary cholangitis, primary sclerosing cholangitis, autoimmune hepatitis, drug-induced hepatotoxicity, Wilson disease, hemochromatosis, and alpha-1-antitryspin deficiency), based on medical history, blood tests including autoantibody serology and serum immunoglobulins, and/or the liver histology. ALD or MetALD must be the primary cause of liver disease. EXC#17
  • Main Study Period Current, or history of known hepatocellular carcinoma (HCC). EXC#18
  • Main Study Period All organ transplant recipients, except for history of corneal transplants, or current listing or active consideration for listing for liver transplant during the screening period. EXC#19
  • Main Study Period Chronic or acute, including partial, known portal vein thrombosis. EXC#20
  • Main Study Period Prior transjugular intrahepatic portosystemic shunt (TIPSS) insertion. EXC#21
  • Main Study Period Positive HIV antibody test at Screening 1 (central laboratory measurements; 1 repeat test is allowed). EXC#22
  • Main Study Period Any acute cardiovascular event including myocardial infarction, unstable angina, symptomatic heart failure, or cerebrovascular accident in the 6 months prior to Screening 1. EXC#23
  • Main Study Period Poorly controlled hypertension defined as systolic blood pressure ≥160 mmHg and diastolic blood pressure ≥90 mmHg at both Screening 1 and Screening 2 despite standard medical management EXC#24
  • Main Study Period BMI >35 kg/m2. EXC#25
  • Main Study Period HbA1≥9.5% (80.3 mmol/mol or 12.5 mmol/L) at screening visits 1 and 2. EXC#26
  • Main Study Period Any history of anaphylaxis or hypersensitivity to GSK4532990 or any of the constituents of the injection. EXC#27
  • Main Study Period Current use of other GalNAc conjugated siRNA therapy. EXC#28
  • Main Study Period Previous use of other investigational therapies targeting HSD17B13 and/or PNPLA3. EXC#29
  • Main Study Period Prior investigational therapies unless beyond washout period of at least 5 half-lives or 6 weeks (whichever is longer) from Screening 1. EXC#30
  • Main Study Period Use of therapies known to induce steatohepatitis (e.g., methotrexate, tamoxifen, amiodarone, 5-fluorouracil) for more than 2 weeks in the year prior to D1. EXC#31
  • Main Study Period Recent major surgery within previous 6 weeks prior to D1. EXC#32
  • Main Study Period Current or ongoing malignancy (except for basal cell carcinoma or uterine carcinoma-in-situ) at Screening 1. Participants under evaluation for possible malignancy at Screening 1 are not eligible. EXC#33
  • Main Study Period Any symptomatic infection including COVID-19 during Screening. Participants may be eligible 2 weeks after resolution of symptoms. EXC#34
  • Main Study Period Current or planned participation in any clinical trial of investigational therapies or medical devices. Participation in clinical trial of investigational software applications for the treatment of Alcohol Use Disorder is permitted. EXC#35
  • Main Study Period Clinical suspicion of rhabdomyolysis during the screening period. EXC#36
  • Main Study Period Clinical suspicion of a bleeding episode during the screening period related to either portal hypertension or low blood fibrinogen level (
  • Main Study Period Any abnormality on a 12-lead ECG during the screening period that, in the opinion of the Investigator, compromises the participant’s safety in this study. EXC#38
  • Main Study Period ALP ≥250 U/L at either Screening 1 or Screening 2 (Based on central laboratory measurement; 1 repeat test is allowed for each screening visit). EXC#8
  • Main Study Period ALT or AST ≥250 U/L at either Screening 1 or Screening 2 (Based on central laboratory measurement; 1 repeat test is allowed for each screening visit). EXC#9
  • Main Study Period Average of triplicate QTc >450 msec for males or QTc >470 msec for females or QTc >480 msec in participants with bundle branch block (1 repeat test is allowed). EXC#52
  • Main Study Period Platelets <50,000/μL, INR >2.3, or albumin <2.5 g/dL at either Screening 1 or Screening 2 (Based on central laboratory measurement; 1 repeat test is allowed for each screening visit). EXC#10
  • Main Study Period Evidence of Wernicke-Korsakoff syndrome or alcohol-related dementia in the opinion of investigator. EXC#41
  • Main Study Period Current use of anticoagulants that increase prothrombin time (PT) and INR. EXC#11
  • Main Study Period Urinary albumin to creatinine ratio ≥300 mg/g creatinine (≥33.9 mg/mmol creatinine) at Screening 1 (Based on central laboratory measurement; 1 repeat test is allowed for each screening visit). EXC#13
  • Main Study Period Meeting any definition of organ system failure as defined by the North American Consortium for Study of End-stage Liver Disease (NACSELD) (see Section 10.10.5). EXC#2

Trial Status by Country

Country Status Start of Recruitment Planned Patients
Denmark DenmarkRecruiting28 Oct 202416
France FranceRecruiting28 Oct 202422
Germany GermanyRecruiting28 Oct 202416
Greece GreeceRecruiting28 Oct 20246
Italy ItalyRecruiting28 Oct 202432
Poland PolandRecruiting28 Oct 20245
Spain SpainRecruiting28 Oct 202438
Sweden SwedenRecruiting28 Oct 202412

Sites & Investigators

Conditions Studied in This Trial