Evaluation of Antiviral Efficacy and Safety of GSK4004280 and GSK4011499 in Treatment-Naïve Adults with HIV-1 Infection

The primary objective of this study is to evaluate the **antiviral activity** of orally administered VH4004280 and VH4011499 monotherapy over a 10-day period in treatment-naïve adults infected with HIV-1. This objective is clinically relevant as it aims to determine the efficacy of these capsid inhibitors in reducing viral load, which is crucial for managing HIV infections and improving patient outcomes.

Secondary objectives include:

• Assessing the safety and tolerability of orally administered VH4004280 and VH4011499, which is essential for understanding the risk-benefit profile of these investigational drugs.
• Characterizing the pharmacokinetic profiles of these compounds to understand their absorption, distribution, metabolism, and excretion, which informs dosing regimens.
• Determining the relationship between the exposure levels of these drugs and changes in plasma HIV-1 RNA, which could provide insights into the dose-response relationship and optimize therapeutic strategies.

The clinical trial involves a total of **26 participants** diagnosed with **HIV Infections**. The study population includes both male and female subjects, aged between 18 to 65 years, who are treatment-naïve and overtly healthy aside from their HIV-1 infection. Participants are required to have a screening CD4+ T-cell count of at least 200 cells/µL and a plasma HIV-1 RNA level of 3000 copies/mL or higher. The trial population was selected based on specific criteria, including a body mass index (BMI) within the range of 18.5 to 31.0 kg/m². Lifestyle considerations include the use of male condoms for participants male at birth and acceptable forms of birth control for participants female at birth who are of childbearing potential. Participants must be willing and able to commence combination antiretroviral therapy on Study Day 11. The trial does not exclude vulnerable populations, ensuring a comprehensive evaluation of the antiviral activity of the investigational drugs.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the antiviral activity, safety, tolerability, and pharmacokinetics of orally administered capsid inhibitors in treatment-naïve adults with **HIV infections**. The trial involves the administration of two investigational products, VH4004280 and VH4011499, in tablet form, with a maximum daily dose of 600 mg and 250 mg, respectively. The study is set to last for a total of 10 days, with participants receiving the treatment orally. The primary objective is to assess the maximum change from baseline in plasma HIV-1 ribonucleic acid through Day 11. Secondary endpoints include the incidence and severity of adverse events, changes in liver panel laboratory parameters, and pharmacokinetic measures such as maximum observed plasma drug concentration and time to maximum concentration.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, health status, and documented HIV-1 infection. The inclusion criteria specify that participants must be between 18 to 65 years of age, have a CD4+ T-cell count of at least 200 cells/µL, and a plasma HIV-1 RNA level of at least 3000 copies/mL. Participants must also be treatment-naïve, with prior use of oral PreP permitted. The study will include follow-up visits to monitor safety and efficacy, with the end-of-study visit occurring on Day 11, at which point participants will be required to start a locally accessible and commercially available combination antiretroviral therapy.

The expected length of participant involvement is 11 days, with conditions for early termination including the occurrence of severe adverse events or any other safety concerns that may arise during the trial. The trial is not classified as low intervention and is categorized as a phase 2 study. The trial is scheduled to commence recruitment on November 1, 2023, with an estimated end date of April 30, 2024. Participants will be monitored closely throughout the trial to ensure adherence to the protocol and to assess the investigational products' impact on HIV-1 infection.

The clinical trial involves the administration of **GSK4011499**, an experimental medication provided in the form of a **tablet**. The active substance, GSK4011499, is of chemical origin and is manufactured by ViiV Healthcare Limited. The medication is administered orally with a maximum daily dose of 250 mg and a total maximum dose of 500 mg over a treatment period of 10 days. The dosing schedule is designed to ensure participant compliance, with regular monitoring to assess adherence to the prescribed regimen.

Another experimental medication used in the trial is **GSK4004280**, also provided in tablet form. This chemical-origin substance is similarly produced by ViiV Healthcare Limited. The administration route is oral, with a maximum daily and total dose of 600 mg over a 10-day treatment period. As with GSK4011499, participant compliance is closely monitored to ensure adherence to the dosing schedule.

The study also includes a **placebo** group, where participants receive tablets that are identical in appearance to the active medication tablets. These placebo tablets are oval, biconvex, plain, and white to off-white, designed for oral administration. The use of placebo allows for a double-blind, controlled comparison to evaluate the efficacy and safety of the experimental treatments.

The efficacy of the investigational drugs VH4004280 and VH4011499 in the treatment of **HIV-1** infection will be assessed through a randomized, double-blind, placebo-controlled clinical trial. The primary endpoint for evaluating efficacy is the maximum change from baseline in plasma HIV-1 ribonucleic acid (RNA) levels through Day 11. This measurement will provide insight into the antiviral activity of the drugs over the 10-day monotherapy period.

Secondary endpoints include the incidence and severity of adverse events (AEs), as well as any AEs leading to discontinuation of the study treatment. Additionally, changes from baseline and maximum toxicity grade increases for liver panel laboratory parameters will be monitored. Pharmacokinetic (PK) measures will also be evaluated, including the maximum observed plasma drug concentration (Cmax), time to maximum observed plasma drug concentration (tmax), and drug concentrations on Day 11 for both VH4004280 and VH4011499. These PK parameters will be correlated with the maximum change in plasma HIV-1 RNA from baseline through Day 11 to further assess the efficacy of the treatment.