A Study of GS-5423 and GS-2872 in Combination With Capsid Inhibitor Lenacapavir in Virologically Suppressed Adults With HIV-1 Infection

Study Overview
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Brief Summary
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The goal of this study is to test the effectiveness, safety, and tolerability of the combination of broadly neutralizing antibodies (bNAbs) (teropavimab (formerly GS-5423) and zinlirvimab (formerly GS-2872)) with lenacapavir (LEN) in virologically suppressed adults with HIV-1 infection. The purpose of this study is to evaluate the efficacy of switching to a regimen of LEN, teropavimab, and zinlirvimab, versus continuing on baseline oral antiretroviral therapy (ART) as determined by the proportion of participants with human immunodeficiency virus-1 (HIV-1) ribonucleic acid (RNA) ≥ 50 copies/mL at Week 26.

Official Title
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A Phase 2 Randomized, Open-label Study to Evaluate the Safety and Efficacy of Broadly Neutralizing Antibodies (bNAbs) GS-5423 and GS-2872 in Combination With the Capsid Inhibitor Lenacapavir as Long-Acting Treatment Dosed Every 6 Months in Virologically Suppressed Adults With HIV-1 Infection

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Teropavimab
* Drug: Zinlirvimab
* Drug: Lenacapavir Tablet
* Drug: Lenacapavir Injection
* Drug: Antiretroviral Therapy


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: On stable oral antiretroviral therapy (ART) consisting of no more than 2 drug classes (with the exception of pharmacologic boosters cobicistat or ritonavir) for ≥ 1 year prior to screening visit 2. A change in ART regimen ≥ 28 days prior to screening visit 2 for reasons other than virologic failure (VF) (eg, tolerability, simplification, drug-drug interaction profile) is allowed. No clinically significant documented historical resistance to the current ART regimen with the exception of isolated nucleoside reverse transcriptase inhibitor mutations including M184V or ≤ 2 thymidine analog mutations (TAMs: M41L, D67N, K70R, L210W, T215Y, and/or K219Q). Plasma HIV-1 RNA < 50 copies/mL at screening visit 2. Documented plasma HIV-1 RNA < 50 copies/mL for ≥ 12 months preceding screening visit 2 (or undetectable HIV-1 RNA level according to the local assay being used if the limit of detection is ≥ 50 copies/mL). Virologic elevations of ≥ 50 copies/mL (transient detectable viremia or blips) prior to screening are acceptable. Proviral pheynotypic sensitivity to both teropavimab and zinlirvimab at screening or from protocol GS-US-536-5816 within 24 months prior to screening. Screening CD4+ T-cell count ≥ 200 cells/μL at screening visit 2. Key Exclusion Criteria: Comorbid condition requiring ongoing immunosuppression. Evidence of hepatitis C virus (HCV) infection (prior infection cleared spontaneously or with treatment is acceptable) Evidence of current hepatitis B virus (HBV) infection regardless of HBV surface antigen status, at the screening visit 2. History of opportunistic infection or illness indicative of Stage 3 HIV disease. Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Randomized Phase: Lenacapavir (LEN) + Teropavimab Dose A + Zinlirvimab Dose B<br>Participants will receive oral LEN 600mg, subcutaneous (SC) LEN 927 mg, teropavimab Dose A, and zinlirvimab Dose B on Day 1. Participants will self-administer oral LEN 600 mg on Day 2. The last treatment regimen will include SC LEN + teropavimab Dose A + zinlirvimab Dose B. | Drug: Teropavimab<br>* Administered intravenously<br>* Other names: GS-5423;Drug: Zinlirvimab<br>* Administered intravenously<br>* Other names: GS-2872;Drug: Lenacapavir Tablet<br>* Administered orally<br>* Other names: GS-6207;Drug: Lenacapavir Injection<br>* Administered subcutaneously<br>* Other names: GS-6207;|
| Experimental: Randomized Phase: Antiretroviral Therapy (ART)<br>Participants will continue their baseline oral ART through Week 52. | Drug: Antiretroviral Therapy<br>* Antiretroviral therapy, administered orally may include regimens such as: bictegravir/emtricitabine/tenofovir alafenamide, darunavir/cobicistat/emtricitabine/tenofovir alafenamide, dolutegravir/abacavir lamivudine, and rilpivirine/emtricitabine/tenofovir alafenamide.<br>|
| Experimental: Extension Phase: LEN + Teropavimab Dose A + Zinlirvimab Dose B<br>At Week 52, participants who receive the study drug of LEN, teropavimab, zinlirvimab, and complete study through Week 52 with human immunodeficiency virus type 1 (HIV-1) ribonucleic acid (RNA) < 50 copies/mL will be given the option to participate in the study extension phase, where they will continue to receive their randomized study drugs treatment regimen until after completion of the primary analysis (unless modified based on the data monitoring committee (DMC) analysis), up to approximately 5 years. | Drug: Teropavimab<br>* Administered intravenously<br>* Other names: GS-5423;Drug: Zinlirvimab<br>* Administered intravenously<br>* Other names: GS-2872;Drug: Lenacapavir Injection<br>* Administered subcutaneously<br>* Other names: GS-6207;|
| Experimental: Extension Phase: ART<br>Participants who complete study through Week 52 with HIV-1 RNA < 50 copies/mL and in the absence of confirmed virologic rebound (VR) throughout the randomized phase of the study will be given the option to participate in the extension phase and receive the study drugs of LEN, teropavimab, and zinlirvimab at the dose specified for randomized phase until after completion of the primary analysis (unless modified based on the data monitoring committee (DMC) analysis), up to approximately 5 years. Treatment with study drug will begin at Week 52 and at that time the baseline oral ART will be discontinued. | Drug: Teropavimab<br>* Administered intravenously<br>* Other names: GS-5423;Drug: Zinlirvimab<br>* Administered intravenously<br>* Other names: GS-2872;Drug: Lenacapavir Tablet<br>* Administered orally<br>* Other names: GS-6207;Drug: Lenacapavir Injection<br>* Administered subcutaneously<br>* Other names: GS-6207;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants with Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) ≥ 50 copies/mL at Week 26 as Determined by the United States Food and Drug Administration (US FDA)-defined Snapshot Algorithm |  | Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants with HIV-1 RNA ≥ 50 copies/mL at Week 52 as Determined by the US FDA-defined Snapshot Algorithm |  | Week 52 | 
| Proportion of Participants with HIV-1 RNA < 50 copies/mL at Week 26 as Determined by the US FDA-defined Snapshot Algorithm |  | Week 26 | 
| Proportion of Participants with HIV-1 RNA < 50 copies/mL at Week 52 as Determined by the US FDA-defined Snapshot Algorithm |  | Week 52 | 
| Change from Baseline in Clusters of Differentiation 4 (CD4)+ T-cell Counts at Week 26 |  | Baseline, Week 26 | 
| Change from Baseline in Clusters of Differentiation 4 (CD4)+ T-cell Counts at Week 52 |  | Baseline, Week 52 | 
| Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) |  | First dose date up to end of study (Up to approximately 6 years) | 
| Trough Concentration at Week 26 for GS-5423, GS-2872, and LEN | Trough Concentration is defined as the concentration of the drug in plasma/serum at the end of the dosing interval. | Week 26 | 
| Trough Concentration at Week 52 for GS-5423, GS-2872, and LEN | Trough Concentration is defined as the concentration of the drug in plasma/serum at the end of the dosing interval. | Week 52 | 
| Pharmacokinetic (PK) Parameter: AUC0-t for GS-5423, GS-2872, and LEN | AUC0-t is defined as the partial area under the concentration versus time curve from time 0 to time t. | First dose date up to end of study (Up to approximately 6 years) | 
| PK Parameter: AUClast for GS-5423, GS-2872, and LEN | AUClast is defined as the area under the concentration versus time curve from time zero to the last quantifiable concentration. | First dose date up to end of study (Up to approximately 6 years) | 
| PK Parameter: t1/2 for GS-5423, GS-2872, and LEN | t1/2 is defined as the terminal elimination half-life. | First dose date up to end of study (Up to approximately 6 years) | 
| PK Parameter: Cmax for GS-5423, GS-2872, and LEN | Cmax is defined as the maximum observed concentration of drug. | First dose date up to end of study (Up to approximately 6 years) | 
| PK Parameter: Tmax for GS-5423, GS-2872, and LEN | Tmax is defined as the time (observed time point) of Cmax. | First dose date up to end of study (Up to approximately 6 years) | 
| Proportion of Participants with Treatment-emergent Anti-GS-5423 Antibodies |  | Up to end of study (Up to approximately 6 years) | 
| Proportion of Participants with Treatment-emergent Anti-GS-2872 Antibodies |  | Up to end of study (Up to approximately 6 years) |