Study of Oral Weekly Lepetegravir (Formerly GS-1720) and Lenacapavir Pacfosacil (Formerly GS-4182) Versus Biktarvy in People With HIV-1 Who Are Virologically Suppressed (WONDERS1)

An Operationally Seamless Phase 2/3, Randomized, Active-Controlled Study Evaluating the Safety and Efficacy of an Oral Weekly Regimen of GS-1720 in Combination With GS-4182 Versus Biktarvy in Virologically Suppressed People With HIV-1

The goal of this clinical study is to learn more about the experimental drugs lepetegravir and lenacapavir pacfosacil; to compare the combination of lepetegravir and lenacapavir pacfosacil with the current standard-of-care treatment bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF, BVY), to see if the combination of lepetegravir and lenacapavir pacfosacil is safe and if it works for treating human immunodeficiency virus type 1 (HIV-1) infection.

This study has two phases: Phase 2 and Phase 3.

The primary objectives of this study are:

Phase 2: To evaluate the efficacy of switching to oral weekly lepetegravir in combination with lenacapavir pacfosacil versus continuing BVY in virologically suppressed people with HIV-1 (PWH) at Week 24.

Phase 3: To evaluate the efficacy of switching to oral weekly lepetegravir /lenacapavir pacfosacil Fixed-dose combination (FDC) tablet regimen versus continuing BVY in virologically suppressed PWH at Week 48.

Study Overview

• Status: Active, not recruiting
• Conditions: HIV-1-Infection
• Intervention / Treatment: Drug: Bictegravir/emtricitabine/tenofovir alafenamide; Drug: Placebo to Match BVY; Drug: Placebo to Match GS1720/GS-4182 FDC; Drug: Lepetegravir; Drug: Lenacapavir pacfosacil; Drug: Lepetegravir/Lenacapavir pacfosacil FDC

• Study Type: Interventional
• Enrollment (Estimated): 675
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Puerto Rico
  • PR
    • San Juan, PR, Puerto Rico, 00717
      • Centro Ararat, Inc.
    • San Juan, PR, Puerto Rico, 00909-1711
      • Clinical Research Puerto Rico
    • San Juan, PR, Puerto Rico, 00909
      • HOPE Clinical Research
    • San Juan, PR, Puerto Rico, 00935
      • Proyecto ACTC
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • UAB 1917 Research Clinic
  • California
    • Beverly Hills, California, United States, 90211
      • Pacific Oaks Medical Group
    • Los Angeles, California, United States, 90036
      • Ruane Clinical Research Group
    • Los Angeles, California, United States, 90069
      • Mills Clinical Research
    • Palm Springs, California, United States, 92262
      • BIOS Clinical Research
    • San Francisco, California, United States, 94110
      • UCSF Division of HIV, Infectious Diseases & Global Medicine
    • Torrance, California, United States, 90502
      • Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20007
      • Georgetown University Medical Center
  • Florida
    • DeLand, Florida, United States, 32720
      • Midland Florida Clinical Research Center, LLC
    • Fort Lauderdale, Florida, United States, 33316
      • CAN Community Health
    • Ft. Pierce, Florida, United States, 34982
      • Midway and Immunology Research Center
    • Miami, Florida, United States, 33133
      • AIDS Healthcare Foundation - The Kinder Medical Group
    • Miami Lakes, Florida, United States, 33016
      • Floridian Clinical Research
    • Orlando, Florida, United States, 32803
      • Orlando Immunology Center
    • Sarasota, Florida, United States, 34237
      • CAN Community Health
    • West Palm Beach, Florida, United States, 33407
      • Triple O Research Institute, P.A.
  • Georgia
    • Decatur, Georgia, United States, 30033
      • Metro Infectious Disease Consultants, P.L.L.C.
    • Macon, Georgia, United States, 31201
      • Mercer University, Department of Internal Medicine
    • Savannah, Georgia, United States, 31401
      • Chatham County Health Department
  • Michigan
    • Berkley, Michigan, United States, 48072
      • Be Well Medical Center
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • KC Care Health Center
  • New Jersey
    • Newark, New Jersey, United States, 07102
      • Saint Michael's Medical Center
  • New Mexico
    • Santa Fe, New Mexico, United States, 87505
      • AXCES Research Group, LLC
  • New York
    • Flushing, New York, United States, 11355
      • NewYork-Presbyterian Queens
    • New York, New York, United States, 10016
      • NYU Langone Health Vaccine Center
  • North Carolina
    • Huntersville, North Carolina, United States, 28078
      • Rosedale Health and Wellness
  • Texas
    • Austin, Texas, United States, 78705
      • Central Texas Clinical Research
    • Bellaire, Texas, United States, 77401
      • St Hope Foundation, Inc.
    • Dallas, Texas, United States, 75246
      • North Texas Infectious Diseases Consultants, PA
    • Dallas, Texas, United States, 75215
      • Prism Health North Texas, Oak Cliff Health Center
    • El Paso, Texas, United States, 79902
      • AXCES Research Group, LLC
    • Fort Worth, Texas, United States, 76104
      • Texas Centers for Infectious Disease Associates
    • Houston, Texas, United States, 77098
      • The Crofoot Research Center, INC.
    • Longview, Texas, United States, 75605
      • DCOL Center for Clinical Research
  • Washington
    • Seattle, Washington, United States, 98104
      • Peter Shalit, MD

Participation Criteria

Eligibility Criteria

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

Description

Key Inclusion Criteria:

• Documented plasma HIV-1 RNA < 50 copies/mL for ≥ 24 weeks before and at screening.
• Receiving BVY for ≥ 24 weeks prior to screening.

Key Exclusion Criteria:

• Prior use of, or exposure to LEN, lepetegravir, or lenacapavir pacfosacil.
• History of virologic failure while on an integrase strand-transfer inhibitor (INSTI)-based regimen.
• Documented integrase strand-transfer inhibitor (INSTI) resistance, specifically, resistance-associated mutations (RAMs) E92G/Q, G118R, F121Y, Y143C/H/R, S147G, Q148H/K/R, N155H/S, or R263K in the integrase gene.
• Prior use of any long-acting (LA) parenteral antiretrovirals (ARV) such as monoclonal antibodies (mAbs) or broadly neutralizing antibodies (bNAbs) targeting HIV-1, injectable cabotegravir (including oral cabotegravir lead-in), or injectable rilpivirine.

• Any of the following laboratory values at screening:

  • Clusters of differentiation 4 (CD4) cell count < 200 cells/mm^3 at screening
  • Glomerular filtration rate < 60 mL/min according to the Modification of Diet in Renal Disease formula
  • Hepatic transaminases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT) > 1.5 × upper limit of normal (ULN)
  • Direct bilirubin > 1.5 × ULN
  • Platelets count < 50,000 cells/mm^3
  • Hemoglobin < 8.0 g/dL
• Active or occult hepatitis B virus (HBV) infection.
• Active hepatitis C virus (HCV).

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: Sequential Assignment
• Masking: Double

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Phase 2: Bictegravir/emtricitabine/tenofovir alafenamide (BVY) (Treatment Group 2); Participants who have been virologically suppressed on bictegravir/emtricitabine/tenofovir alafenamide (BVY) will continue receiving BVY daily for at least 48 weeks.	Drug: Bictegravir/emtricitabine/tenofovir alafenamide; Tablets administered orally without regard to food; Other Names: Biktarvy®
Experimental: Phase 2: Lepetegravir + Lenacapavir pacfosacil (Treatment Group 1); Participants who have been virologically suppressed on bictegravir/emtricitabine/tenofovir alafenamide (BVY) will switch to lepetegravir (650 mg tablet) and lenacapavir pacfosacil (300 mg tablet) coadministered. Participants will receive a 1-day loading dose of lepetegravir (1300 mg) and lenacapavir pacfosacil (600 mg) on Day 1. Thereafter, participants will take weekly doses of single agent lepetegravir (650 mg) and lenacapavir pacfosacil (300 mg) coadministered for at least 48 weeks.	Drug: Lepetegravir; Tablets administered orally without regard to food; Other Names: GS-1720; Drug: Lenacapavir pacfosacil; Tablets administered orally without regard to food; Other Names: GS-4182
Experimental: Phase 2 Extension Phase: Lepetegravir /Lenacapavir pacfosacil Fixed-dose Combination (FDC); At the end of the randomized treatment, Phase 2 participants will be given the option to participate in the Extension Phase. Phase 2 Treatment Group 1 will switch to lepetegravir /lenacapavir pacfosacil FDC weekly. Phase 2 Treatment Group 2 will receive a loading dose of lepetegravir /lenacapavir pacfosacil FDC on Extension Phase Day 1 then, lepetegravir/lenacapavir pacfosacil FDC weekly. Participants who choose to enter the Extension Phase will receive lepetegravir /lenacapavir pacfosacil FDC tablets until the product becomes available or until Gilead Sciences elects to discontinue the study, whichever occurs first.	Drug: Lepetegravir/Lenacapavir pacfosacil FDC; Tablets administered orally without regard to food; Other Names: GS-1720/GS-4182 FDC
Experimental: Phase 3: Lepetegravir /Lenacapavir pacfosacil FDC + Placebo to Match (PTM) BVY (Treatment Group 1); Participants who have been virologically suppressed on BVY will switch from BVY to lepetegravir/lenacapavir pacfosacil FDC tablets weekly + placebo-to-match (PTM) BVY once daily. In addition, participants will receive a 1-day loading dose regimen of lepetegravir /lenacapavir pacfosacil FDC on Day 1. Participants will receive treatment for at least 96 weeks.	Drug: Placebo to Match BVY; Tablets administered orally without regard to food; Drug: Lepetegravir/Lenacapavir pacfosacil FDC; Tablets administered orally without regard to food; Other Names: GS-1720/GS-4182 FDC
Active Comparator: Phase 3: BVY Placebo to Match Lepetegravir /Lenacapavir pacfosacil FDC + BVY (Treatment Group 2); Participants who have been virologically suppressed on BVY will continue receiving oral BVY daily. In addition, participants will receive a 1-day loading dose of PTM lepetegravir /lenacapavir pacfosacil on Day 1 and weekly PTM thereafter. Participants will receive treatment for at least 96 weeks.	Drug: Bictegravir/emtricitabine/tenofovir alafenamide; Tablets administered orally without regard to food; Other Names: Biktarvy®; Drug: Placebo to Match GS1720/GS-4182 FDC; Tablets administered orally without regard to food
Experimental: Phase 3 Extension Phase: Lepetegravir/Lenacapavir pacfosacil Fixed-dose Combination (FDC); After the end of blinded treatment, Phase 3 participants will be given the option to participate in the Extension Phase. Phase 3 Treatment Group 1 will switch to lepetegravir/lenacapavir pacfosacil FDC weekly. Phase 3 Treatment Group 2 will receive a 1-day loading dose of lepetegravir/lenacapavir pacfosacil FDC on Extension Phase Day 1, then lepetegravir/lenacapavir pacfosacil FDC weekly. Participants who choose to enter the Extension Phase will receive lepetegravir/lenacapavir pacfosacil FDC tablets until the product becomes available or until Gilead Sciences elects to discontinue the study, whichever occurs first.	Drug: Lepetegravir/Lenacapavir pacfosacil FDC; Tablets administered orally without regard to food; Other Names: GS-1720/GS-4182 FDC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Phase 3: Proportion of Participants With HIV-1 RNA ≥ 50 Copies/mL at Week 48 as Determined by the US FDA-defined Snapshot Algorithm	Week 48
Phase 2: Proportion of Participants With HIV-1 RNA ≥ 50 Copies/mL at Week 24 as Determined by the United States (US) Food and Drug Administration (FDA)-defined Snapshot Algorithm	Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 2: Proportion of Participants With HIV-1 RNA < 50 Copies/mL at Week 24 as Determined by the US FDA-defined Snapshot Algorithm		Week 24
Phase 2: Proportion of Participants With HIV-1 RNA ≥ 50 copies/mL at Week 12 as Determined by the US FDA-defined Snapshot Algorithm		Week 12
Phase 2: Proportion of Participants With HIV-1 RNA ≥ 50 copies/mL at Week 48 as Determined by the US FDA-defined Snapshot Algorithm		Week 48
Phase 2: Proportion of Participants With HIV-1 RNA < 50 Copies/mL at Week 12 as Determined by the US FDA-defined Snapshot Algorithm		Week 12
Phase 2: Proportion of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 as Determined by the US FDA-defined Snapshot Algorithm		Week 48
Phase 2: Change From Baseline in Clusters of Differentiation 4 (CD4+) T-cell Count at Week 12		Baseline, Week 12
Phase 2: Change From Baseline in CD4+ T-cell Count at Week 24		Baseline, Week 24
Phase 2: Change From Baseline in CD4+ T-cell Count at Week 48		Baseline, Week 48
Phase 2: Percentage of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) Through Week 12		First dose date up to Week 12
Phase 2: Percentage of Participants Experiencing TEAEs Through Week 24		First dose date up to Week 24
Phase 2: Percentage of Participants Experiencing TEAEs Through Week 48		First dose date up to Week 48
Phase 2: Percentage of Participants Experiencing Treatment-emergent Laboratory Abnormalities Through Week 12		First dose date up to Week 12
Phase 2: Percentage of Participants Experiencing Treatment-emergent Laboratory Abnormalities Through Week 24		First dose date up to Week 24
Phase 2: Percentage of Participants Experiencing Treatment-emergent Laboratory Abnormalities Through Week 48		First dose date up to Week 48
Phase 3: Proportion of Participants With HIV-1 RNA ≥ 50 copies/mL at Week 96 as Determined by the US FDA-defined Snapshot Algorithm		Week 96
Phase 3: Proportion of Participants With HIV-1 RNA < 50 copies/mL at Week 48 as Determined by the US FDA-defined Snapshot Algorithm		Week 48
Phase 3: Proportion of Participants With HIV-1 RNA < 50 copies/mL at Week 96 as Determined by the US FDA-defined Snapshot Algorithm		Week 96
Phase 3: Change From Baseline in CD4+ T-cell Count at Week 48		Baseline, Week 48
Phase 3: Change From Baseline in CD4+ T-cell Count at Week 96		Baseline, Week 96
Phase 3: Percentage of Participants Experiencing TEAEs Through Week 48		First dose date up to Week 48
Phase 3: Proportion of Participants Experiencing TEAEs Through Week 96		First dose date up to Week 96
Phase 3: Percentage of Participants Experiencing Treatment-emergent Laboratory Abnormalities Through Week 48		First dose date up to Week 48
Phase 3: Percentage of Participants Experiencing Treatment-emergent Laboratory Abnormalities Through Week 96		First dose date up to Week 96
Phase 2: Pharmacokinetic (PK) Parameter: Cmax of Lepetegravir and Lenacapavir (LEN)	Cmax is defined as the maximum observed concentration of drug.	Day 1 up to Week 48
Phase 2: PK Parameter: Tmax of Lepetegravir and LEN	Tmax is defined as the time (observed time point) of Cmax.	Day 1 up to Week 48
Phase 2: PK Parameter: Ctau of Lepetegravir and LEN	Ctau is defined as the observed drug concentration at the end of the dosing interval.	Day 1 up to Week 48
Phase 2: PK Parameter: AUCtau of Lepetegravir and LEN	AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).	Day 1 up to Week 48

Collaborators and Investigators

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

Publications and helpful links

Helpful Links

• Gilead Clinical Trials Website

Study record dates

Study Major Dates

• Study Start (Actual): August 20, 2024
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): June 1, 2029

Study Registration Dates

• First Submitted: August 5, 2024
• First Submitted That Met QC Criteria: August 5, 2024
• First Posted (Actual): August 9, 2024

Study Record Updates

• Last Update Posted (Actual): April 17, 2026
• Last Update Submitted That Met QC Criteria: April 14, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Anti-Infective Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Nucleic Acid Synthesis Inhibitors; Antiviral Agents; Reverse Transcriptase Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; bictegravir, emtricitabine, tenofovir alafenamide, drug combination
• Other Study ID Numbers: GS-US-695-6509; 2024-511054-50 (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