First-Time-in-Human (FTIH) Study to Evaluate the Safety, Tolerability and Pharmacokinetics (PK) of VH4011499 in Healthy Participants

First-Time-in-Human (FTIH) Study to Evaluate the Safety, Tolerability and Pharmacokinetics (PK) of VH4011499 in Healthy Participants

A Randomized, Double-Blind (Sponsor Unblinded), Placebo-Controlled Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Orally Administered VH4011499 in Healthy Participants

This FTIH study aims to evaluate the safety, tolerability and PK of the novel investigational Human immunodeficiency virus (HIV)-1 capsid inhibitor VH4011499 in healthy adults. The study will be conducted in 3 parts: Part 1 will investigate single ascending doses (SAD) and Part 2 will investigate multiple ascending doses (MAD). Part 3 will investigate single dose of a new formulation of VH4011499. The transition from SAD to MAD will be based on the assessment of the Safety and Dose Escalation Committee.

GSK4011499, VH4011499, First-time-in-human, HIV-1 capsid inhibitor, Single ascending doses, Multiple ascending doses, Drug-drug Interaction

Part 1: Absolute values of liver panel parameters: Direct bilirubin, total bilirubin (Micromoles per liter)

Part 1: Absolute values of liver panel parameters: Alanine aminotransferase (ALT), Alkaline phosphatase (ALP) and Aspartate aminotransferase (AST) (International units per Liter)

Part 2: Absolute values of liver panel parameters: Direct bilirubin, total bilirubin (Micromoles per liter)

Part 3: Absolute values of liver panel parameters: Direct bilirubin, total bilirubin (Micromoles per liter)

Part 1: Change from Baseline in liver panel parameters: Direct bilirubin, total bilirubin (Micromoles per liter)

Part 1: Change from Baseline in liver panel parameters: ALT, ALP and AST (International units per Liter)

Part 2: Change from Baseline in liver panel parameters: Direct bilirubin, total bilirubin (Micromoles per liter)

Part 2: Change from Baseline in liver panel parameters: ALT, ALP and AST (International units per Liter)

Part 3: Change from Baseline in liver panel parameters: Direct bilirubin, total bilirubin (Micromoles per liter)

Part 3: Change from Baseline in liver panel parameters: ALT, ALP and AST (International units per Liter)

Part 1: Percentage of participants with maximum toxicity grade increase from Baseline for liver panel parameters

Part 2: Percentage of participants with maximum toxicity grade increase from Baseline for liver panel parameters

Part 3: Percentage of participants with maximum toxicity grade increase from Baseline for liver panel parameters

Part 1: Area under the plasma concentration time curve from time zero to infinity (AUC[0-infinity]) following single dose administration of VH4011499

Part 2: Area under the plasma concentration time curve over a dosing interval from time of dosing to the time of the subsequent dose (AUC[0-tau]) following repeat dose administration of VH4011499

Part 1: Maximum observed plasma concentration (Cmax) following single dose administration of VH4011499

Part 1: Time to maximum observed plasma concentration (Tmax) and Apparent terminal half-life (T1/2) following single dose administration of VH4011499 (Hours)

Inclusion Criteria: Participants who are overtly healthy. Participants must have two consecutive Severe Acute Respiratory Syndrome Coronavirus 2 (SARs-CoV-2) Polymerase chain reaction (PCR) negative results prior to dosing. Participants must have body weight > 50 kilograms (kg) and body mass index (BMI) within the range 19-32 kilograms per meter square (kg/m^2). Male or female participants (either of non-childbearing potential or of child-bearing potential and using acceptable contraception). Capable of giving signed informed consent. Exclusion Criteria: History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, neurological or psychiatric disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study drug or interfering with the interpretation of data. Abnormal blood pressure. Lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years. Breast cancer within the past 10 years. Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). QT interval corrected for heart rate according to Fridericia's formula (QTcF) greater than (>)450 milliseconds (msec). Past or intended use of over-the-counter or prescription medication including herbal medications within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to dosing and for the duration of the study, unless in the opinion of the Investigator and Sponsor, the medication will not interfere with the study medications, procedures, or compromise participant safety. Live vaccine(s) within 1 month prior to screening or plans to receive such vaccines during the study. Exposure to more than 4 investigational products within 12 months prior to dosing. Current enrollment or recent past participation in another investigational study. ALT >1.5 times upper limit of normal (ULN), total bilirubin >1.5 times ULN, and/or estimated serum creatinine clearance less than 60 milliliters per minute. History of or current infection with hepatitis B or hepatitis C. Positive Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) test, having signs and symptoms, or having contact with known Coronavirus Disease-2019 (COVID-19) positive person/s within 14 days. Positive HIV antibody test. Use of tobacco or nicotine-containing products, regular alcohol consumption and/or regular use of known drugs of abuse. Sensitivity to the study drug, or components thereof midazolam, excipients contained therein, benzodiazepines, or drug or other allergy that, contraindicates participation in the study.

Qualified researchers may request access to anonymized individual patient-level data (IPD) and related study documents of the eligible studies via the Data Sharing Portal. Details on GSK's data sharing criteria can be found at: https://www.gsk.com/en-gb/innovation/trials/data-transparency/

Anonymized IPD will be made available within 6 months of publication of primary, key secondary and safety results for studies in product with approved indication(s) or terminated asset(s) across all indications.

Anonymized IPD is shared with researchers whose proposals are approved by an Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension may be granted, when justified, for up to 6 months.