Evaluation of the Efficacy and Safety of GS-1720 and GS-4182 Versus Bictegravir/Emtricitabine/Tenofovir Alafenamide in Virologically Suppressed HIV-1 Patients

The primary objective of this study is to evaluate the **efficacy** of switching to an oral weekly regimen of GS-1720 in combination with GS-4182 compared to continuing the use of bictegravir/emtricitabine/tenofovir alafenamide (BVY; coformulated as Biktarvy®) in virologically suppressed people with HIV-1 (PWH). This evaluation will occur at Week 24 for Phase 2 and at Week 48 for Phase 3. The clinical relevance of this objective lies in determining whether the new regimen can maintain viral suppression, which is crucial for long-term management of HIV-1 infection.

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

The clinical trial involves a total of **47 participants** diagnosed with **HIV-1 Infection**. The study population includes both male and female subjects, aged 18 years and older, who are virologically suppressed and have been receiving the coformulated regimen of bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy®) for at least 24 weeks prior to screening. Participants are required to have documented plasma HIV-1 RNA levels of less than 50 copies/mL for a minimum of 24 weeks before and at the time of screening. The trial does not include a vulnerable population. Participants were selected based on their ability to understand and provide written informed consent, and those of childbearing potential engaging in heterosexual intercourse must adhere to protocol-specified contraception methods. The trial aims to evaluate the efficacy of switching to an oral weekly regimen in comparison to continuing the current treatment in this specific population.

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 virologically suppressed individuals with **HIV-1 infection**. The trial is structured in two phases: Phase 2 aims to assess the efficacy of switching to the GS-1720/GS-4182 regimen versus continuing Biktarvy at Week 24, while Phase 3 extends this evaluation to Week 48. The primary endpoint for both phases is the proportion of participants with HIV-1 RNA ≥ 50 copies/mL at specified weeks, as determined by the US FDA-defined snapshot algorithm. Secondary endpoints include the proportion of participants with HIV-1 RNA < 50 copies/mL, changes in CD4+ T-cell count, and the incidence of treatment-emergent adverse events (TEAEs) and laboratory abnormalities.

The trial is expected to last until September 2029, with participant recruitment starting in December 2024. Participants will be involved for a maximum treatment period of 48 weeks. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor efficacy and safety, and an end-of-study visit to assess final outcomes. Participants must be 18 years or older, virologically suppressed with documented plasma HIV-1 RNA < 50 copies/mL for at least 24 weeks before and at screening, and currently receiving Biktarvy for at least 24 weeks prior to screening. Conditions for early termination from the study include significant protocol deviations, adverse events, or withdrawal of consent.

The clinical trial involves the administration of **GS-1720**, an investigational medication formulated as a **tablet**. Each tablet contains 325 mg of the active substance GS-1720, which is of chemical origin. The medication is administered orally with a maximum daily dose of 650 mg, equating to two tablets per day. The total maximum dose over the treatment period is 1300 mg. The treatment is designed to be administered weekly, with a maximum treatment period of 48 weeks. Participant compliance with the dosing schedule will be monitored throughout the trial.

Another investigational medication used in the trial is **GS-4182**, also formulated as a **tablet**. Each tablet contains 300 mg of the active substance GS-4182, which is chemically derived. The administration route is oral, with a maximum daily dose of 300 mg, corresponding to one tablet per day. The total maximum dose over the treatment period is 600 mg. Similar to GS-1720, GS-4182 is administered weekly, with a maximum treatment period of 48 weeks. Compliance with the dosing regimen will be closely monitored.

The comparator treatment in this study is **Biktarvy**, a co-formulated medication consisting of **emtricitabine**, **tenofovir alafenamide**, and **bictegravir**. It is provided as **film-coated tablets** and is administered orally. The specific dosages for each active substance in Biktarvy are 50 mg of bictegravir, 200 mg of emtricitabine, and 25 mg of tenofovir alafenamide. The treatment is administered daily, and the maximum treatment period is 48 weeks. Participant adherence to the daily dosing schedule will be monitored to ensure compliance.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint for Phase 2 is the proportion of participants with **HIV-1 RNA** levels ≥ 50 copies/mL at Week 24, as determined by the United States Food and Drug Administration (FDA)-defined snapshot algorithm. For Phase 3, the primary endpoint is the proportion of participants with **HIV-1 RNA** levels ≥ 50 copies/mL at Week 48, also determined by the FDA-defined snapshot algorithm.

Secondary endpoints for Phase 2 include the proportion of participants with **HIV-1 RNA** levels ≥ 50 copies/mL at Weeks 12 and 48, and those with **HIV-1 RNA** levels < 50 copies/mL at Weeks 12, 24, and 48. Additionally, changes from baseline in CD4+ T-cell count at Weeks 12, 24, and 48 will be evaluated. The trial will also assess the proportion of participants experiencing treatment-emergent adverse events (TEAEs) and treatment-emergent laboratory abnormalities through Weeks 12, 24, and 48. Pharmacokinetic parameters such as Cmax, Tmax, Ctau, and AUCtau for GS-1720 and lenacapavir (LEN) will be measured.

For Phase 3, secondary endpoints include the proportion of participants with **HIV-1 RNA** levels ≥ 50 copies/mL at Week 96, and those with **HIV-1 RNA** levels < 50 copies/mL at Weeks 48 and 96. Changes from baseline in CD4+ T-cell count at Weeks 48 and 96, as well as the proportion of participants experiencing TEAEs and treatment-emergent laboratory abnormalities through Weeks 48 and 96, will also be assessed.