A Phase 2b Randomized, Open-Label Active Controlled Study Evaluating the Safety and Efficacy of oral VH4524184 Coadministered with Emtricitabine and Tenofovir Alafenamide in Treatment Naïve Viremic Persons with HIV-1.( INNOVATE Study)

The primary objective of this study is to evaluate the antiviral efficacy of oral VH4524184 containing regimens compared to dolutegravir/lamivudine (DTG/3TC) fixed-dose combination (FDC) oral control arm in treatment naïve viremic adults living with HIV-1. This objective is clinically relevant as it assesses whether VH4524184-based regimens can achieve comparable viral suppression to an established first-line antiretroviral therapy in treatment naïve individuals, potentially expanding therapeutic options for initial HIV-1 management.

The secondary objectives include:

• To further evaluate the antiviral efficacy of oral VH4524184 containing regimens compared to the DTG/3TC FDC oral control arm

• To evaluate the immunologic effects of oral VH4524184 containing regimens compared to the DTG/3TC FDC oral control arm

• To assess the safety and tolerability of oral VH4524184 containing regimens compared to the DTG/3TC FDC oral control arm

• To assess the pharmacokinetics (PK) of VH4524184 during the treatment period

This clinical trial enrolled a total of **265 participants** who were **treatment-naïve adults** living with **HIV-1 infection**. The study population included both **male and female participants** who were at least **18 years of age** or older at the time of informed consent. Participants were required to have a **screening CD4+ T-cell count** of at least **200 cells/µL** and documented **plasma HIV-1 RNA** levels of **≥1000 copies/mL** at screening. Treatment-naïve status was defined as no prior use of **antiretrovirals** in combination or monotherapy following HIV-1 diagnosis, although prior use of oral **pre-exposure prophylaxis** or oral **post-exposure prophylaxis** was permitted. Participants assigned male at birth were required to have a body weight of at least **50.0 kg**, while those assigned female at birth required a minimum body weight of **45.0 kg**. All participants were required to have a **body mass index (BMI)** within the range of **18.5-35.5 kg/m²**. Female participants of childbearing potential were required to use highly effective contraceptive methods and have negative pregnancy tests at screening and prior to the first dose of study intervention. The trial population was selected based on documented viremic HIV-1 infection status and specific clinical parameters to evaluate the antiviral efficacy of the investigational regimen.

This is a Phase 2b **randomized**, **open-label**, **active-controlled** clinical trial evaluating the safety and efficacy of oral **VH4524184** (also known as **GSK4524184**) coadministered with **emtricitabine** and **tenofovir alafenamide** in treatment-naïve viremic persons with **HIV-1 infection**. The study compares investigational regimens containing VH4524184 administered as **tablets** for oral use with a control arm receiving **Dovato** (a fixed-dose combination containing **dolutegravir sodium** and **lamivudine** in **film-coated tablets**) or **Descovy** (containing emtricitabine and tenofovir alafenamide in film-coated tablets) as part of **antiretroviral treatment**. The maximum treatment period for all study medications is **24 months**. The trial is expected to begin recruitment in February 2026 and is estimated to conclude in October 2028.

The primary objective is to evaluate the antiviral efficacy of oral VH4524184-containing regimens compared to the control arm in treatment-naïve viremic adults living with HIV-1. The **primary endpoint** is the proportion of participants achieving plasma **HIV-1 RNA** levels below 50 copies/mL using the FDA snapshot algorithm at **Month 12**. Secondary endpoints include plasma HIV-1 RNA suppression below 50 copies/mL (both observed and FDA snapshot) through Month 24, change from baseline in **CD4+ T-cell count** through Month 24, assessment of safety and tolerability of VH4524184-containing regimens compared to the control arm, and evaluation of the **pharmacokinetics** of VH4524184 during the treatment period.

Eligible participants must be at least 18 years of age at the time of informed consent and must have documented HIV-1 infection with screening plasma HIV-1 RNA of at least 1000 copies/mL. A single repeat of this test is permitted within the screening period. Participants must have a screening **CD4+ T-cell count** of at least 200 cells/µL and must be treatment-naïve, defined as having received no antiretroviral medications (in combination or monotherapy) after diagnosis of HIV-1 infection. Prior use of oral **pre-exposure prophylaxis** or oral **post-exposure prophylaxis** is permitted, but prior use of long-acting cabotegravir is exclusionary. Body weight requirements are at least 50.0 kg for participants assigned male at birth and at least 45.0 kg for participants assigned female at birth, with **body mass index** within the range of 18.5 to 35.5 kg/m² inclusive. Participants assigned female at birth must not be pregnant or breastfeeding and must either be persons of non-childbearing potential or persons of childbearing potential using highly effective contraception with a failure rate of less than 1% prior to and during the study intervention period and for at least one week after the last dose of VH4524184 plus the fixed-dose combination or through the end of study if in the control arm. A negative highly sensitive **pregnancy test** at screening (serum) and on Day 1 (urine) is required before the first dose of study intervention for persons of childbearing potential. Participants enrolled in France must be affiliated with or be a beneficiary of a social security system. All participants must be capable of giving signed informed consent and complying with study requirements and restrictions.

The trial involves a screening visit to assess eligibility criteria, followed by randomization and initiation of study treatment. Study visits occur at regular intervals throughout the 24-month treatment period to monitor antiviral efficacy, safety, tolerability, and pharmacokinetic parameters. Clinical assessments, laboratory evaluations including plasma HIV-1 RNA levels and CD4+ T-cell counts, and safety monitoring are conducted at designated timepoints. An end-of-study visit is performed to complete final assessments. Participant involvement is expected to last approximately 24 months from randomization to study completion. Early termination from the study may occur due to participant withdrawal of consent, loss to follow-up, pregnancy, adverse events, protocol violations, or investigator decision based on safety or efficacy concerns.

The experimental treatment regimens consist of **VH4524184** (also known as **GSK4524184**) administered orally in **tablet** form. VH4524184 is co-administered with other **antiretroviral treatment** agents. The maximum treatment period for the experimental regimen is 24 weeks. The active substance VH4524184 is of chemical origin and is formulated as tablets for **oral use**.

The experimental regimen includes **emtricitabine** and **tenofovir alafenamide** as part of the combination therapy. These agents are available as **Descovy 200 mg/25 mg film-coated tablets**. Descovy is administered orally and contains emtricitabine and tenofovir alafenamide, both of chemical origin. The maximum treatment period for this component is 24 weeks.

The **comparator treatment** consists of **Dovato 50 mg/300 mg film-coated tablets**, which is a fixed-dose combination containing **dolutegravir sodium** and **lamivudine**. Dovato is administered via **oral use** as film-coated tablets. Both active substances, dolutegravir sodium and lamivudine, are of chemical origin. This comparator regimen serves as the active control arm and is also administered for a maximum treatment period of 24 weeks. Dovato is a marketed product authorized in the European Union with marketing authorization number EU/1/19/1370/001.

All study medications are administered as part of antiretroviral treatment regimens in treatment-naïve viremic adults living with **HIV-1**. The study employs an open-label design comparing the experimental VH4524184-containing regimens against the dolutegravir/lamivudine fixed-dose combination control arm. None of the products used in this clinical trial are **paediatric formulations**.

The primary efficacy endpoint is the proportion of participants achieving plasma HIV-1 RNA levels below 50 copies/mL at Month 12, assessed using the FDA snapshot algorithm. Secondary efficacy endpoints include the proportion of participants achieving plasma HIV-1 RNA below 50 copies/mL using both the observed method and the FDA snapshot algorithm through Month 24. Additionally, change from baseline in CD4+ T-cell count will be evaluated through Month 24. These endpoints will be assessed during the treatment period, which extends up to 24 months.