Evaluation of Antiviral Efficacy, Safety, and Pharmacokinetics of VH4524184 in Treatment-Naïve Adults with HIV-1: A Randomized, Double-Blind, Placebo-Controlled Study

Trial ID: 2023-507173-18-00
Protocol: 218806
Sponsor: Viiv Healthcare UK Limited

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Diseases & Conditions

HIV infection

Objectives

The primary objective of this study is to evaluate the **antiviral activity** of VH4524184 in treatment-naïve participants with **HIV-1** during 10 days of monotherapy. This is clinically relevant as it aims to determine the efficacy of VH4524184 in reducing viral load in individuals who have not previously received treatment, potentially offering a new therapeutic option for managing HIV-1 infections.

Secondary objectives include:

To assess the safety and tolerability of VH4524184.
To characterize the pharmacokinetic profile of VH4524184.
To evaluate any relationship between VH4524184 exposure and change in plasma HIV-1 RNA (Ribonucleic Acid).
To assess the occurrence of emergent genotypic or phenotypic resistance after 10 days of monotherapy with VH4524184.
To assess the immunologic effects of VH4524184 when administered over 10 days in participants living with HIV.

Participants

The clinical trial involves a total of **17 participants** diagnosed with **HIV infections**. The study population includes both male and female subjects, aged between **18 to 65 years**, who are treatment-naïve, meaning they have not received any antiretrovirals following their HIV-1 diagnosis. Participants are required to be overtly healthy aside from their HIV infection, as determined by comprehensive medical evaluations. The trial population was selected based on specific inclusion criteria, such as a positive HIV antibody test, a documented HIV infection with a screening plasma HIV-1 RNA of at least 3,000 copies/mL, and a CD4+ T-cell count of 200 cells/mm³ or higher. Participants must also meet certain body weight and BMI requirements, with men weighing at least 50 kg and women at least 45 kg, and a BMI range of 18.5-31.0 kg/m². Lifestyle considerations, such as diet and physical activity, are not specified. The trial includes a vulnerable population, and all participants must be capable of providing informed consent and willing to commence standard-of-care antiretroviral therapy on Study Day 10.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind** (sponsor unblinded), **placebo-controlled** study to evaluate the antiviral effect, safety, tolerability, and pharmacokinetics of VH4524184 in treatment-naïve adults infected with **HIV-1**. The trial will involve a 10-day monotherapy period with VH4524184, administered in tablet form via oral use. The primary objective is to assess the maximum change from baseline in plasma HIV-1 RNA levels through Day 10. Secondary endpoints include the evaluation of adverse events, changes in liver panel laboratory parameters, and pharmacokinetic parameters such as maximum observed plasma drug concentration and time to maximum concentration.

Participants will be involved in the study for an estimated duration from the recruitment start date on April 15, 2024, to the trial's estimated end date on August 8, 2024. The study will include several key visits: an initial screening visit to confirm eligibility, followed by regular follow-up visits to monitor safety and efficacy, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to be between 18 and 65 years of age, with a documented HIV infection and a screening plasma HIV-1 RNA level of at least 3,000 copies/mL. Participants must be treatment-naïve, with no prior antiretroviral therapy, and must have a body weight of at least 50 kg for men and 45 kg for women, with a BMI within the range of 18.5-31.0 kg/m².

Participants may be terminated early from the study if they experience severe adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The study will ensure that all participants provide informed consent and are capable of starting standard-of-care antiretroviral therapy on Study Day 10. The trial is not classified as a low-intervention study and is categorized as a Phase 2a proof-of-concept trial.

Treatment

The clinical trial involves the administration of the experimental medication **VH4524184**, which is provided in a **tablet** form. The active substance, VH4524184, is of chemical origin and is manufactured by VIIV Healthcare Limited. The medication is administered orally. Participants in the trial will receive the medication for a maximum treatment period of 10 days. The dosage is measured in milligrams, although specific daily and total dose amounts are not provided. The trial aims to evaluate the antiviral activity of VH4524184 in treatment-naïve participants with HIV-1.

In addition to the experimental medication, a **placebo** is used as a comparator treatment in this study. The placebo is designed to visually match the experimental product to maintain the double-blind nature of the trial. The placebo is also administered in tablet form and taken orally. The administration schedule for the placebo mirrors that of the experimental medication, ensuring consistency in the treatment regimen across all participants. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the **maximum change from baseline in logarithm in 10 base (log10) Plasma HIV-1 Ribonucleic Acid (RNA)** through Day 10. This parameter will be measured to evaluate the antiviral activity of VH4524184 in treatment-naïve participants with HIV-1. Secondary endpoints include a variety of measures such as the number of participants with adverse events (AEs), changes from baseline in liver panel laboratory parameters (including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, direct bilirubin, albumin, and total protein), and pharmacokinetic parameters of VH4524184 such as maximum observed plasma drug concentration (Cmax) and time to maximum observed plasma drug concentration (tmax). Additionally, the study will assess the correlation of VH4524184 pharmacokinetic parameters with maximum plasma HIV-1 RNA change from baseline through Day 10, as well as changes in CD4+ T-cell counts at Day 10. The efficacy assessments will be conducted using validated laboratory tests and scales at specified timepoints, including baseline and Day 10, to ensure accurate and reliable data collection and analysis.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Participant must be 18 to 65 years of age inclusive at the time of signing the informed consent.
Participants who are overtly healthy (other than HIV infection) as determined by the Investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests, and cardiac monitoring.
Positive HIV antibody test
Documented HIV infection and Screening plasma HIV-1 RNA ≥ 3,000 copies/mL. A single repeat of this test is allowed within a single Screening period to determine eligibility.
Screening CD4+ T-cell count ≥200 cells/mm3
Treatment-naïve: No antiretrovirals (ARVs, in combination or monotherapy) received after the diagnosis of HIV-1 infection.
HIV Pre-exposure or post-exposure prophylaxis: No prior use of any INSTI (including cabotegravir) for HIV pre-exposure or post-exposure prophylaxis.
Body weight ≥50.0 kg (110 lbs.) for men and ≥45.0 kg (99 lbs) for women and BMI within the range 18.5-31.0 kg/m2 (inclusive - applies to males and females).
A participant of childbearing potential must have a negative serum hCG test at screening, and negative urine hCG test at Day 1, before the first dose of study intervention.
If a urine test cannot be confirmed as negative (e.g. ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease risk for inclusion of a female with an early undetected pregnancy.
Capable of giving signed informed consent
Participant must be willing and able to start standard-of-care ART as selected with the investigator on Study Day 10.

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Exclusion Criteria

Participants with primary HIV infection.
Any evidence of an active CDC Stage 3 disease, except cutaneous Kaposi’s sarcoma not requiring systemic therapy during the study.
Untreated syphilis infection [positive RPR at screen] without documentation of treatment.
Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical, anal or penile intraepithelial neoplasia; or other localized malignancies
Any pre-existing physical or mental condition which, in the opinion of the Investigator, may interfere with the participant’s ability to comply with the dosing schedule and/or protocol evaluations or which may compromise the safety of the participant.
Any history of significant underlying psychiatric disorder, or a clinical assessment of suicidality based on the responses on the eCSSRS.
Any history of major depressive disorder with or without suicidal features, or anxiety disorders, that required medical intervention (pharmacologic or not) such as hospitalization or other inpatient treatment and/or chronic (>6 months) outpatient treatment.
Current or chronic history of liver disease or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
Medical history of cardiac arrhythmias or cardiac disease or a family or personal history of long QT syndrome or sudden cardiac death. Treatment with immunomodulating agents (such as systemic corticosteroids, interleukins, interferons) or any agent with known anti-HIV activity (such as hydroxyurea or foscarnet) within 30 days of study drug administration.
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. Specific medications listed in Section 6.9.1 may be allowed.
Participants who require concomitant medications known to be associated with a prolonged QTc.
Participants receiving any protocol-prohibited medication(s) and who are unwilling or unable to switch to an alternate medication).
The participant has ever received an investigational HIV vaccine (immunotherapeutic or immunomodulatory).
Exposure to an experimental drug or experimental vaccine within either 30 days, 5 half-lives of the test agent, or twice the duration of the biological effect of the test agent, whichever is longer, prior to the first dose of study intervention.
Participation in the study would result in donation of blood in excess of 500 mL within 56 days.
Exposure to more than four new investigational drugs or vaccines within 12 months prior to the first dosing day.
Current enrollment or past participation within the last 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer) before signing of consent in any other clinical study involving an investigational study intervention or any other type of medical research.
Diagnostic Assessments: • Presence of HBsAg or HBcAb at screening • Positive Hepatitis C antibody test result at Screening • Positive Hepatitis C RNA test result at Screening. • Creatinine clearance (eGFR) of < 60 mL/min/1.73 m2 using CKD-EPI equation (2021)