Study of Oral Weekly GS-1720 and GS-4182 Compared With Biktarvy in People With HIV-1 Who Have Not Been Treated (WONDERS2)

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 Treatment-Naive People With HIV-1

The goal of this clinical study is to learn more about the experimental drugs lepetegravir (formerly GS-1720) (an oral, long-acting integrase strand transfer inhibitor (INSTI)) and lenacapavir pacfosacil (formerly GS-4182) (a prodrug of Lenacapavir (LEN)); to compare the combination of lepetegravir and lenacapavir pacfosacil with the current standard-of-care treatment bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) (Biktarvy), 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 in treatment-naive people with HIV-1 (PWH).

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

The primary objectives of this study are:

Phase 2: To evaluate the efficacy of oral weekly lepetegravir coadministered with lenacapavir pacfosacil versus continuing Biktarvy (BVY) in treatment-naive PWH at Week 24.

Phase 3: To evaluate the efficacy of oral weekly lepetegravir/lenacapavir pacfosacil fixed-dose combination (FDC) tablet regimen versus continuing BVY in treatment-naive PWH at Week 48.

Study Overview

• Status: Terminated
• 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 (Actual): 73
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Canada
  • Montreal, Canada, H2L 4P9
    • Clinique Médicale l'Actuel
  • Montreal, Canada, H4A 3J1
    • Chronic Viral Illness Service / McGill University Health Centre
  • Ottawa, Canada, K1H 8L6
    • Ottawa Hospital Research Institute
• Germany
  • Bonn, Germany, 53127
    • Universitätsklinikum Bonn, Medizinische Klinik und Poliklinik I, Immunologische Studienambulanz
  • Essen, Germany, 45122
    • Universitätsmedizin Essen, Universitätsklinikum Essen, Klinik für Dermatologie, Venerologie und Allergologie, HPSTD-Ambulanz
  • Hamburg, Germany, 20146
    • ICH Study Center GmbH & Co. KG
  • Hanover, Germany, 30625
    • Medizinische Hochschule Hannover, Klinik für Rheumatologie und Immunologie, Gebäude K14
  • München, Germany, 81675
    • Klinikum rechts der Isar, Technische Universität München, Klinik und Poliklinik für Innere Medizin II
• Poland
  • Bydoszcz, Poland, 85-030
    • Wojewódzki Szpital Obserwacyjno-Zakaźny im. Tadeusza Browicza
  • Gdansk, Poland, 80-172
    • Punkt Zdrowia
  • Szczecin, Poland, 71-455
    • Samodzielny Publiczny Wojewódzki Szpital Zespolony w Szczecinie
• Portugal
  • Amadora, Portugal, 2720- 276
    • Unidade Local de Saude de Amadora Sinatra EPE, Hospital Prof. Doutor Fernando Fonseca
  • Lisbon, Portugal, 1249-019
    • Unidade Local De Saúde De Lisboa Ocidental E.P.E. - Hospital Egas Moniz
  • Lisbon, Portugal, 1649-035
    • Unidade Local de Saúde de Santo Maria E.P.E. - Hospital Santa Maria
  • Porto, Portugal, 4050
    • Unidade Local de Saude de Santo Antonio, E.P.E.
  • Porto, Portugal, 4200-319
    • Unidade Local de Saúde de São João E.P.E.
• Puerto Rico
  • PR
    • San Juan, PR, Puerto Rico, 00909
      • HOPE Clinical Research
    • San Juan, PR, Puerto Rico, 00935
      • Proyecto ACTU
• Romania
  • Bucharest, Romania, 021105
    • Institutul National De Boli Infectioase Prof. Dr. Matei Bals
  • Bucharest, Romania
    • Spitalul Clinic De Urgenta Prof Dr Agrippa Ionescu
  • Cluj-Napoca, Romania, 400003
    • Spitalul Clinic de Boli Infectioase Cluj-Napoca
  • Constanța, Romania, 00709
    • Spitalul Clinic de Boli Infectioase Constanta
  • Timișoara, Romania
    • Clinical Hospital of Infectious Diseases and Pneumophysiology Dr. Victor Babes Timisoara
• South Africa
  • Bloemfontein, South Africa, 9301
    • Josha Research
  • Durban, South Africa, 4013
    • Durban International Clinical Research Site, Enhancing Care Foundation
  • East London, South Africa, 5241
    • Synergy Biomed Research Institute
  • Germiston, South Africa, 1401
    • CRISMO Research Center
  • Johannesburg, South Africa, 2038
    • WITS RHI Research Centre
  • KwaZulu-Natal, South Africa, 4449
    • Clinical Research Institute of South Africa (CRISA)
  • Ndevana, South Africa, 5660
    • FPD Ndevana Community Research Site
  • Tembisa, South Africa, 1632
    • The Aurum Institute Tembisa Clinic 4
• Spain
  • Barcelona, Spain, 8036
    • Hospital Clínic de Barcelona
  • Madrid, Spain, 28040
    • Hospital Clinico San Carlos
  • Madrid, Spain, 28040
    • Hospital Universitario Fundacion Jimenez Diaz
  • Málaga, Spain, 29010
    • Hospital Universitario Virgen de la Victoria
  • Pontevedra, Spain, 36312
    • Hospital Universitario Álvaro Cunqueiro
  • Valencia, Spain, 46015
    • Hospital Arnau de Vilanova de Valencia
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35222
      • UAB 1917 Research Clinic
  • California
    • Torrance, California, United States, 90502
      • The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
    • West Hollywood, California, United States, 90046
      • Mills Clinical Research
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20007
      • Georgetown University Medical School
  • Florida
    • DeLand, Florida, United States, 32720
      • Midland Florida Clinical Research Center, LLC
    • Ft. Pierce, Florida, United States, 34982
      • Midway Immunology and Research Center
    • Miami Lakes, Florida, United States, 33016
      • Floridian Clinical Research, LLC
    • Orlando, Florida, United States, 32803
      • Orlando Immunology Center
    • West Palm Beach, Florida, United States, 33407
      • Triple O Research Institute, P.A.
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • Emory University Hospital Midtown Infectious Disease Clinic
    • Macon, Georgia, United States, 31201
      • Mercer University, Department of Internal Medicine
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • New Jersey
    • Newark, New Jersey, United States, 07102
      • Saint Michael's Medical Center
  • New York
    • New York, New York, United States, 10016
      • NYU Langone Health Vaccine Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina (MUSC) Research Nexus
  • Texas
    • Bellaire, Texas, United States, 77401
      • St Hope Foundation, Inc.
    • Dallas, Texas, United States, 75246
      • North Texas Infectious Diseases Consultants, PA
    • Dallas, Texas, United States, 75208
      • Prism Health North Texas, Aids Arms
    • Fort Worth, Texas, United States, 76104
      • Texas Centers for Infectious Disease Associates
    • San Antonio, Texas, United States, 78229
      • UT Health San Antonio
  • Washington
    • Spokane, Washington, United States, 99202
      • MultiCare Rockwood Main Clinic

Participation Criteria

Eligibility Criteria

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

Description

Key Inclusion Criteria:

• HIV-1 RNA ≥ 500 copies/mL at screening.
• Antiretroviral (ARV) treatment-naive, except the use of oral pre-exposure prophylaxis (PrEP) or postexposure prophylaxis (PEP) with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) or F/TAF, up to 1 month prior to screening.

Key Exclusion Criteria:

• Prior use of any long acting parenteral antiretrovirals (ARVs) such as monoclonal antibodies, broadly neutralizing antibodies targeting HIV-1, LEN, injectable cabotegravir (including oral cabotegravir lead-in), and/or injectable rilpivirine.
• Documented resistance to the integrase strand-transfer inhibitor class, specifically, resistance-associated mutations E92G/Q, G118R, F121Y, Y143C/H/R, S147G, Q148H/K/R, N155H/S, or R263K in the integrase gene.

• Any of the following laboratory values at screening:

  1. CD4 cell count < 200 cells/mm3 at screening.
  2. Estimated glomerular filtrations arate < 60 mL/min according to the Modification of Diet in Renal Disease formula.
  3. Hepatic transaminases (aspartate aminotransferase and alanine aminotransferase) > 1.5 × upper limit of normal (ULN).
  4. Direct bilirubin > 1.5 × ULN.
  5. Platelets count < 50,000 cells/mm3.
  6. Hemoglobin < 8.0 g/dL.
• Active or occult hepatitis B virus infection.
• Active hepatitis C virus infection.

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: B/F/TAF (Treatment Group 2); Participants will receive B/F/TAF (50/200/25 mg) 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 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 (650/300 mg) weekly. Phase 2 Treatment Group 2 will receive a loading dose of lepetegravir/lenacapavir pacfosacil FDC (1300 mg/600 mg) on Extension Phase Day 1, then lepetegravir/lenacapavir pacfosacil FDC (650/300 mg) 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
Experimental: Phase 3: Lepetegravir/Lenacapavir Pacfosacil FDC + Placebo to Match B/F/TAF (Treatment Group 1); Participants will receive a 1-day loading dose of lepetegravir/lenacapavir pacfosacil FDC on Day 1. Thereafter, participants will receive lepetegravir/lenacapavir pacfosacil FDC tablets weekly + placebo to match (PTM) B/F/TAF once daily. 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
Active Comparator: Phase 3: B/F/TAF + PTM lepetegravir/Lenacapavir Pacfosacil FDC (Treatment Group 2); Participants will receive oral B/F/TAF daily along with PTM lepetegravir/lenacapavir pacfosacil FDC weekly for at least 96 weeks. Additionally, participants will receive a 1-day loading dose of PTM lepetegravir/lenacapavir pacfosacil on Day 1.	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 continue to receive lepetegravir/lenacapavir pacfosacil FDC weekly while PTM B/F/TAF will be discontinued. Phase 3 Treatment Group 2 will switch to receive lepetegravir/lenacapavir pacfosacil FDC tablets weekly. Participants in Treatment Group 2 will also receive a 1-day loading dose of lepetegravir/lenacapavir pacfosacil FDC on Extension Phase Day 1. Participants who choose to enter the Phase 3 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

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: Change From Baseline in CD4 Cell Count at Week 24		Baseline, Week 24
Phase 3: Change From Baseline in CD4 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: Percentage of Participants Experiencing TEAEs Through Week 48		First dose date up to Week 48
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: 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 log10 HIV-1 RNA at Week 12		Baseline, Week 12
Phase 2: Change From Baseline in log10 HIV-1 RNA at Week 24		Baseline, Week 24
Phase 2: Change From Baseline in log10 HIV-1 RNA at Week 48		Baseline, Week 48
Phase 2: Change From Baseline in Clusters of Differentiation 4 (CD4) Cell Count at Week 12		Baseline, Week 12
Phase 2: Change From Baseline in CD4 Cell Count at Week 48		Baseline, Week 48
Phase 3: Change From Baseline in log10 HIV-1 RNA at Week 48		Baseline, Week 48
Phase 3: Change From Baseline in log10 HIV-1 RNA at Week 96		Baseline, Week 96
Phase 3: Change From Baseline in CD4 Cell Count at Week 96		Baseline, Week 96
Phase 3: Percentage of Participants Experiencing TEAEs Through Week 96		First dose date up to Week 96
Phase 2: Pharmacokinetic (PK) Parameter: Cmax of Lepetegravir and Lenacapavir (LEN), as Applicable	Cmax is defined as the maximum observed concentration of drug.	Day 1 up to Week 24
Phase 2: PK Parameter: Tmax of Lepetegravir and LEN, as Applicable	Tmax is defined as the time (observed time point) of Cmax.	Day 1 up to Week 24
Phase 2: PK Parameter: Ctau of Lepetegravir and LEN, as Applicable	Ctau is defined as the observed drug concentration at the end of the dosing interval.	Day 1 up to Week 24
Phase 2: PK Parameter: AUCtau of Lepetegravir and LEN, as Applicable	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 24

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): October 21, 2024
• Primary Completion (Actual): March 16, 2026
• Study Completion (Actual): March 16, 2026

Study Registration Dates

• First Submitted: September 23, 2024
• First Submitted That Met QC Criteria: September 23, 2024
• First Posted (Actual): September 26, 2024

Study Record Updates

• Last Update Posted (Actual): April 15, 2026
• Last Update Submitted That Met QC Criteria: April 10, 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-695-7156; 2024-512505-66 (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