Study of Lenacapavir, Teropavimab, and Zinlirvimab in Virologically Suppressed Adults With HIV-1 on Stable Oral Treatment Regimens

A Phase 3, Randomized, Open-label Study to Evaluate the Efficacy and Safety of Switching to a Regimen of Broadly Neutralizing Antibodies Teropavimab and Zinlirvimab in Combination With Capsid Inhibitor Lenacapavir Twice-Yearly in Virologically Suppressed Adults With HIV-1 on Stable Oral Treatment Regimens

The goal of this clinical study is to compare how effective a long-acting treatment of injectable combination of lenacapavir (LEN), teropavimab (TAB), and zinlirvimab (ZAB) is versus continuing a daily oral HIV treatment in adults with HIV-1 whose virus is already well controlled, after 1 year (52 weeks) of treatment.

The primary objective of this study is to evaluate the efficacy of switching to the regimen of LEN, TAB, and ZAB versus continuing an oral stable baseline regimen (SBR) in virologically suppressed people with HIV-1 (PWH) as determined by the proportion of participants with HIV-1 RNA ≥ 50 copies/mL at Week 52.

Study Overview

• Status: Not yet recruiting
• Conditions: HIV-1-infection
• Intervention / Treatment: Drug: Lenacapavir Tablet; Drug: Lenacapavir; Drug: Teropavimab; Drug: Zinlirvimab; Drug: SBR

• Study Type: Interventional
• Enrollment (Estimated): 590
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Gilead Clinical Study Information Center; Phone Number: 1-833-445-3230 (GILEAD-0); Email: GileadClinicalTrials@gilead.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Human immunodeficiency virus type 1 (HIV-1) susceptibility results from screening meeting specific criteria:

  1) Proviral phenotypic susceptibility to both TAB and ZAB by the investigational protocol-defined assay at screening.

• Plasma HIV-1 RNA levels < 50 copies/mL at screening.
• At least 1 documented HIV-1 RNA level measured between 6 months and 12 months (+2 months) prior to screening. This and any other HIV-1 RNA measurements documented in this period must be < 50 copies/mL (undetectable HIV-1 RNA level according to the local assay being used if the limit of detection is ≥ 50 copies/mL). A single virologic elevation of ≥ 50 copies/mL and < 400 copies/mL (transient detectable viremia or "blips") prior to screening are acceptable if the subsequent plasma HIV-1 RNA level is < 50 copies/mL.
• A plasma HIV-1 RNA test < 50 copies/mL (undetectable HIV-1 RNA level according to the local assay being used if the limit of detection is ≥ 50 copies/mL) within the last 6 months prior.
• If > 1 plasma HIV-1 RNA measurements in the last 6 months prior to screening are available, all must be < 50 copies/mL (undetectable HIV-1 RNA level according to the local assay being used if the limit of detection is ≥ 50 copies/mL).
• On a stable oral antiretroviral (ARV) therapy (ART) for ≥ 6 months prior to screening.
• A change in ART regimen ≥ 3 months prior to the screening visit for reasons other than virologic failure (eg, tolerability, simplification, drug-drug interaction profile) is allowed; individuals with a change in ART regimen ≥ 3 months prior to screening must have been on the regimen for ≥ 3 months prior to screening, and all HIV-1 RNA measurements in that period must be < 50 copies/mL. There are no permitted changes to ART regimens between screening and Day 1.

Key Exclusion Criteria:

• History of an opportunistic infection or illness indicative of Stage 3 HIV disease.
• Known hypersensitivity to the study intervention, its metabolites, or formulation excipients.
• Active, serious infections (other than HIV-1) requiring therapy < 30 days prior to randomization.
• Active tuberculosis infection.
• Acute hepatitis of any cause < 30 days before randomization.
• History of, or current clinical decompensated liver cirrhosis (eg, ascites, encephalopathy, or variceal bleeding) or severe hepatic impairment (Child-Pugh Class C).
• Active malignancy requiring acute systemic therapy.
• Have poor venous access that would limit phlebotomy or intravenous (IV) infusion of study drugs.
• Prior use of, or exposure to, LEN or a broadly neutralizing antibody (bNAb) for HIV-1.
• Prior use of, or exposure to, long-acting (LA) injectable cabotegravir (CAB) or LA injectable rilpivirine (RPV).
• Prior use of, or exposure to, ibalizumab, fostemsavir, or maraviroc.
• Current use of, or exposure to, nevirapine or zidovudine.
• Baseline regimen consisting of monotherapy with any single ARV.
• Treatment with immunosuppressant therapies (eg, corticosteroids, immunoglobulins, and other immune- or cytokine-based therapies) within 4 weeks of screening (with the exception of a single short course of corticosteroids lasting ≤ 7 days) or have a comorbid condition with an anticipated need ongoing immunosuppressive treatment during the study.
• Hepatitis C virus (HCV) antibody positive and HCV RNA detectable.

• Chronic hepatitis B virus (HBV) infection, as determined by either:

  1. Positive HBV surface antigen and negative HBV surface antibody, regardless of HBV core antibody status, at the screening visit.
  2. Positive HBV core antibody and negative HBV surface antibody, regardless of HBV surface antigen status, at the screening visit.

Note: Individuals found to be susceptible to HBV infection (eg, negative hepatitis B surface antibody at the screening visit, regardless of prior HBV vaccination history) should be recommended to receive an HBV vaccination. Those who remain non-immune will receive regular testing for HBV.

• Severe renal impairment-estimated glomerular filtration rate < 30 mL/min according to the Cockcroft-Gault formula.
• Abnormal electrocardiogram (ECG) at the screening visit that is clinically significant, as determined by the investigator.

• Any of the following laboratory values at screening:

  1. Alanine aminotransferase > 5 × upper limit of normal (ULN).
  2. Direct bilirubin > 1.5 × ULN
  3. Platelets < 50,000/mm^3.
  4. Hemoglobin < 8.0 g/dL.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Group 1: Lenacapavir(LEN)+ Teropavimab(TAB)+ Zinlirvimab (ZAB); Participants will receive oral LEN 600 mg, subcutaneous (SC) LEN 927 mg, and intravenously (IV) infusions of TAB and ZAB on Day 1. Participants will self-administer oral LEN 600 mg on Day 2. Every 26 weeks, participants will receive SC LEN and IV infusions of TAB and ZAB up to Week 92. After Week 92, eligible participants will have an option to continue LEN + TAB + ZAB in the study extension phase until completion of the extension phase, permanently discontinuing the extension phase or the extension is discontinued at the sponsor's sole discretion, whichever occurs first.	Drug: Lenacapavir Tablet; Administered orally; Other Names: GS-5423; TAB; Drug: Lenacapavir; Administered subcutaneously; Other Names: LEN; Drug: Teropavimab; Administered intravenously (IV); Other Names: GS-5423; TAB; Drug: Zinlirvimab; Administered IV; Other Names: GS-2872
Experimental: Treatment Group 2: Stable Baseline Regimen (SBR); Participants will continue their SBR through at least Week 92. Oral SBRs will be taken per local prescribing information. After Week 92, eligible participants will have an option to switch to LEN + TAB + ZAB in the study extension phase until completion of the extension phase, permanently discounting the extension phase or the extension is discontinued at the sponsor's sole discretion, whichever occurs first.	Drug: SBR; SBRs administered orally. SBRs include medicines like bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) or dolutegravir (DTG)+ tenofovir alafenamide (TAF)+ emtricitabine (FTC).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Proportion of Participants With HIV-1 RNA ≥ 50 Copies/mL at Week 52 as Defined by the United States (US) Food and Drug Administration (FDA) Snapshot Algorithm.	Week 52

Secondary Outcome Measures

Outcome Measure	Time Frame
Proportion of Participants With HIV-1 RNA ≥ 50 Copies/mL at Week 92 as Defined by the US FDA Snapshot Algorithm.	Week 92
Proportion of Participants With HIV-1 RNA < 50 Copies/mL at Week 52 as Determined by the US FDA Snapshot Algorithm.	Week 52
Proportion of Participants With HIV-1 RNA < 50 copies/mL at Week 92 as Determined by the US FDA Snapshot Algorithm.	Week 92
Changes from Baseline in Clusters of Differentiation 4 (CD4)+ T-cell Counts at Week 52	Baseline, Week 52
Changes from Baseline in CD4+ T-cell Counts at Week 92	Baseline, Week 92
Percentage of Participants Experiencing Treatment-Emergent Adverse Events (AEs)	First dose up to 92 weeks
Percentage of Participants Prematurely Discontinuing Their Study Treatment due to an AE	First dose up to 92 weeks
Trough Concentrations for LEN, TAB, and ZAB at Week 26	Week 26
Trough Concentrations for LEN, TAB, and ZAB at Week 52	Week 52
Trough Concentrations for LEN, TAB, and ZAB at Week 104	Week 104
Percentages of Participants With Antidrug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) to TAB	Up to 92 Weeks
Percentages of Participants With ADAs and NAbs to ZAB.	Up to 92 Weeks

Collaborators and Investigators

• Sponsor: Gilead Sciences
• Investigators: Study Director: Gilead Study Director, Gilead Sciences

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): March 1, 2029
• Study Completion (Estimated): March 1, 2033

Study Registration Dates

• First Submitted: June 26, 2026
• First Submitted That Met QC Criteria: June 26, 2026
• First Posted (Actual): July 6, 2026

Study Record Updates

• Last Update Posted (Actual): July 6, 2026
• Last Update Submitted That Met QC Criteria: June 26, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: lenacapavir
• Other Study ID Numbers: GS-US-536-6544; 2025-524336-19 (Other Identifier: European Medicines Agency)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No