Randomized, Active-Controlled Phase 2/3 Study of GS-1720 and GS-4182 Versus Biktarvy in Treatment-Naive HIV-1 Patients

The primary objective of this study is to evaluate the **efficacy** of an oral weekly regimen of GS-1720 in combination with GS-4182 compared to Biktarvy® (BVY; bictegravir/emtricitabine/tenofovir alafenamide, coformulated) in treatment-naive individuals with **HIV-1 infection**. This evaluation will occur at Week 24 during Phase 2 and at Week 48 during Phase 3. The clinical relevance of this objective lies in determining the potential of GS-1720 and GS-4182 as an effective treatment alternative to the established regimen of Biktarvy, which could offer new therapeutic options for individuals newly diagnosed with HIV-1.

Secondary objectives include: - Phase 2: Evaluating the efficacy of oral weekly GS-1720 coadministered with GS-4182 versus BVY at Weeks 12, 24, and 48. - Evaluating the safety and tolerability of oral weekly GS-1720 coadministered with GS-4182 at Weeks 12, 24, and 48. - Evaluating the pharmacokinetics (PK) of oral weekly GS-1720 coadministered with GS-4182. - Phase 3: Evaluating the efficacy of oral weekly GS-1720/GS-4182 fixed-dose combination (FDC) versus BVY at Weeks 48 and 96. - Evaluating the safety and tolerability of oral weekly GS-1720/GS-4182 FDC at Weeks 48 and 96.

The clinical trial involves a total of **489 participants** diagnosed with **HIV-1 Infection**. The study population includes individuals aged 18 years and older, encompassing both male and female subjects. Participants are required to be treatment-naive, with the exception of those who have used oral pre-exposure or post-exposure prophylaxis with emtricitabine/tenofovir disoproxil fumarate or emtricitabine/tenofovir alafenamide up to one month prior to screening. The trial population was selected based on their ability to understand and provide written informed consent, and they must have an HIV-1 RNA level of at least 500 copies/mL at screening. Both male and female participants of childbearing potential who engage in heterosexual intercourse are required to use protocol-specified methods of contraception. The study includes a vulnerable population, ensuring comprehensive representation of the affected demographic. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, and **active-controlled** study to evaluate the safety and efficacy of an oral weekly regimen of GS-1720 in combination with GS-4182 compared to Biktarvy in treatment-naive individuals with **HIV-1 infection**. The trial is structured in two phases: Phase 2 aims to assess the efficacy at Week 24, while Phase 3 extends the evaluation to Week 48. The trial is expected to commence recruitment on February 18, 2025, and conclude by August 21, 2030. Participants will be involved for a maximum treatment period of 48 weeks.

The study involves several key visits: an initial **screening visit** to confirm eligibility, followed by regular follow-up visits at Weeks 12, 24, and 48 to monitor efficacy and safety outcomes. The primary endpoint is the proportion of participants achieving HIV-1 RNA levels of less than 50 copies/mL at Weeks 24 and 48, as determined by the US FDA-defined snapshot algorithm. Secondary endpoints include similar assessments at Weeks 12 and 96, changes in HIV-1 RNA and CD4 cell counts, and the incidence of treatment-emergent adverse events.

Participants are required to meet specific inclusion criteria, such as being 18 years or older, having HIV-1 RNA levels of at least 500 copies/mL at screening, and being antiretroviral treatment-naive, with certain exceptions for pre-exposure or post-exposure prophylaxis. The study will terminate early for participants who do not adhere to the protocol, experience significant adverse events, or withdraw consent. The trial's design ensures rigorous assessment of the investigational products' efficacy and safety, contributing valuable data to the field of HIV treatment.

The clinical trial involves the administration of **GS-4182**, an experimental medication provided in the form of a **tablet**. Each tablet contains 300 mg of the active substance **GS-4182**, which is of chemical origin. The medication is administered orally with a maximum daily dose of 300 mg and a total maximum dose of 600 mg over a treatment period of 48 weeks. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

Another experimental treatment in the study is **GS-1720**, also provided as a **tablet**. Each tablet contains 325 mg of the active substance **GS-1720**, which is chemically derived. The oral administration of GS-1720 follows a dosing schedule with a maximum daily dose of 650 mg and a total maximum dose of 1300 mg over a 48-week period. Compliance monitoring is implemented to ensure participants adhere to the dosing regimen.

The comparator treatment in this trial is **Biktarvy**, a coformulated medication consisting of **bictegravir**, **emtricitabine**, and **tenofovir alafenamide**. Biktarvy is provided as a **film-coated tablet** and is administered orally. The specific dosage of Biktarvy is 50 mg of bictegravir, 200 mg of emtricitabine, and 25 mg of tenofovir alafenamide per tablet. The maximum daily and total dose amounts are consistent with the standard dosing guidelines for Biktarvy, and the treatment period is 48 weeks. Participant adherence to the Biktarvy regimen is monitored to ensure compliance with the study protocol.

Efficacy in this clinical trial will be assessed by evaluating the proportion of participants achieving **HIV-1 RNA** levels of less than 50 copies/mL at specified time points, as determined by the United States Food and Drug Administration (FDA)-defined snapshot algorithm. The primary endpoints for Phase 2 and Phase 3 are the proportion of participants with **HIV-1 RNA** < 50 copies/mL at Week 24 and Week 48, respectively. Secondary endpoints include the proportion of participants with **HIV-1 RNA** < 50 copies/mL at Weeks 12 and 48, the change from baseline in log10 **HIV-1 RNA** and CD4 cell count at Weeks 12, 24, and 48, and the proportion of participants experiencing treatment-emergent adverse events (TEAEs) and treatment-emergent laboratory abnormalities through Weeks 12, 24, and 48. Additionally, pharmacokinetic parameters such as Cmax, Tmax, Ctau, and AUCtau for GS-1720 and lenacapavir (LEN) will be evaluated. In Phase 3, the proportion of participants with **HIV-1 RNA** < 50 copies/mL at Week 96 and the change from baseline in log10 **HIV-1 RNA** and CD4 cell count at Weeks 48 and 96 will also be assessed. The efficacy assessments will be conducted at various time points throughout the trial, including Weeks 12, 24, 48, and 96, using validated laboratory tests and algorithms to ensure accurate and reliable data collection and analysis.