GS-1720 + GS-4182 for HIV

(WONDERS1 Trial)

Not currently recruiting at 41 trial locations

Overseen By Study Director

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: Gilead Sciences

Must be taking: BVY

Must not be taking: LEN, LA ARVs

Disqualifiers: INSTI resistance, HBV, HCV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two experimental drugs, GS-1720 and GS-4182, to determine their safety and effectiveness in treating HIV-1 compared to current treatments. It consists of two parts: the first evaluates the effectiveness of switching to weekly doses of these drugs over 24 weeks, and the second extends the observation to 48 weeks. People with HIV-1 who are on stable treatment and have low virus levels might be suitable candidates. As a Phase 2 and Phase 3 trial, this research measures the treatment's effectiveness in an initial, smaller group and represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking advancements in HIV-1 treatment.

Do I have to stop taking my current medications for this trial?

Yes, you will need to stop taking your current medication, BVY, as the trial involves switching to the experimental drugs GS-1720 and GS-4182.

Do I need to stop my current medications for the trial?

The trial does not specify if you need to stop your current medications, but it seems you must have been on the standard treatment (BVY) for at least 24 weeks before joining. It's best to discuss with the trial team for specific guidance.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that GS-1720 and GS-4182 are generally safe for people. One study tested GS-1720 by administering increasing doses to individuals without HIV-1. The results indicated that most participants did not experience serious side effects, suggesting the treatment is safe for further testing.

GS-1720 is designed for once-weekly oral administration, allowing it to work effectively in the body over time without causing major issues. This bodes well for its potential use in treating HIV-1. These treatments are currently undergoing Phase 2 and Phase 3 trials, as earlier studies found them safe enough for testing on larger populations. These phases involve larger groups and help gather more information about safety and any side effects.

Overall, current research and ongoing studies suggest that these treatments are well-tolerated. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the GS-1720 and GS-4182 combination for HIV treatment because it offers a novel approach compared to current standard therapies like bictegravir/emtricitabine/tenofovir alafenamide (BVY). Unlike existing options, which require daily dosing, this new treatment involves weekly dosing, potentially improving convenience and adherence for patients. Additionally, the combination of GS-1720 and GS-4182 may offer enhanced efficacy or a different mechanism of action, which could provide better management of the virus. These innovations could represent a significant advancement in the way HIV is treated, making it easier for patients to stick to their treatment plans.

What evidence suggests that this trial's treatments could be effective for HIV?

Research has shown that GS-1720 and GS-4182 are promising new treatments for HIV-1. In this trial, participants will receive either the GS-1720 and GS-4182 combination or continue with standard HIV treatments. Early results suggest that GS-1720 might allow for a weekly dose, offering more convenience than daily medication. Previous studies found that these drugs have a good safety record, as they did not cause serious side effects in early tests. Although still under study and not yet approved, these drugs aim to provide an effective and easier alternative to current treatments. Researchers are comparing this new combination to standard HIV treatments to determine if it works as well or better. ^{1 2 3 6 7}

Who Is on the Research Team?

Gilead Study Director

Principal Investigator

Gilead Sciences

Are You a Good Fit for This Trial?

This trial is for people with HIV who have their virus levels under control. Participants should be currently taking and responding well to standard HIV treatment. The study will exclude individuals based on certain medical conditions or treatments that could interfere with the trial.

Inclusion Criteria

I have been taking BVY for at least 24 weeks.

My HIV viral load has been undetectable for at least 24 weeks.

Exclusion Criteria

I have previously used LEN, GS-1720, or GS-4182.

Clusters of differentiation 4 (CD4) cell count < 200 cells/mm^3 at screening

Direct bilirubin > 1.5 × ULN

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 2 Treatment

Participants switch to oral weekly GS-1720 in combination with GS-4182 or continue BVY for 48 weeks

48 weeks

Phase 3 Treatment

Participants switch to oral weekly GS-1720/GS-4182 FDC or continue BVY for 96 weeks

96 weeks

Extension Phase

Participants may opt into continuation of GS-1720/GS-4182 FDC treatment until the product becomes available or study is discontinued

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• GS-1720
• GS-4182

Trial Overview

The study is testing new drugs, GS-1720 and GS-4182, alone and in combination, against a current standard HIV treatment (Biktarvy). It's designed to see if these new drugs are safe and effective when taken weekly by people whose HIV is already suppressed.

How Is the Trial Designed?

Group I: Phase 3: GS-1720/GS-4182 FDC + Placebo to Match (PTM) BVY (Treatment Group 1) Experimental Treatment 2 Interventions

Participants who have been virologically suppressed on BVY will switch from BVY to GS-1720/GS-4182 FDC tablets weekly + placebo-to-match (PTM) BVY once daily. In addition, participants will receive a 1-day loading dose regimen of GS-1720/GS-4182 FDC on Day 1. Participants will receive treatment for at least 96 weeks.

Group II: Phase 3 Extension Phase: GS-1720/GS-4182 Fixed-dose Combination (FDC) Experimental Treatment 1 Intervention

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 GS-1720/GS-4182 FDC weekly. Phase 3 Treatment Group 2 will receive a 1-day loading dose of GS-1720/GS-4182 FDC on Extension Phase Day 1, then GS-1720/GS-4182 FDC weekly. Participants who choose to enter the Extension Phase will receive GS-1720/GS-4182 FDC tablets until the product becomes available or until Gilead Sciences elects to discontinue the study, whichever occurs first.

Group III: Phase 2: GS-1720 + GS-4182 (Treatment Group 1) Experimental Treatment 2 Interventions

Participants who have been virologically suppressed on bictegravir/emtricitabine/tenofovir alafenamide (BVY) will switch to GS-1720 (650 mg tablet) and GS-4182 (300 mg tablet) coadministered. Participants will receive a 1-day loading dose of GS-1720 (1300 mg) and GS-4182 (600 mg) on Day 1. Thereafter, participants will take weekly doses of single agent GS-1720 (650 mg) and GS-4182 (300 mg) coadministered for at least 48 weeks.

Group IV: Phase 2 Extension Phase: GS-1720/GS-4182 Fixed-dose Combination (FDC) Experimental Treatment 1 Intervention

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 GS-1720/GS-4182 FDC weekly. Phase 2 Treatment Group 2 will receive a loading dose of GS-1720/GS-4182 FDC on Extension Phase Day 1 then, GS-1720/GS-4182 FDC weekly. Participants who choose to enter the Extension Phase will receive GS-1720/GS-4182 FDC tablets until the product becomes available or until Gilead Sciences elects to discontinue the study, whichever occurs first.

Group V: Phase 2: Bictegravir/emtricitabine/tenofovir alafenamide (BVY) (Treatment Group 2) Active Control 1 Intervention

Participants who have been virologically suppressed on bictegravir/emtricitabine/tenofovir alafenamide (BVY) will continue receiving BVY daily for at least 48 weeks.

Group VI: Phase 3: BVY Placebo to Match GS-1720/GS-4182 FDC + BVY (Treatment Group 2) Active Control 2 Interventions

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 GS-1720/GS-4182 on Day 1 and weekly PTM thereafter. Participants will receive treatment for at least 96 weeks.

Who Is Running the Clinical Trial?

Gilead Sciences

Lead Sponsor

Trials

1,150

Recruited

878,000+

Daniel O'Day

Gilead Sciences

Chief Executive Officer since 2019

MBA from Columbia University

Dietmar Berger

Gilead Sciences

Chief Medical Officer

MD and PhD from Albert-Ludwigs University School of Medicine

Published Research Related to This Trial

GSK3532795, a second-generation maturation inhibitor for HIV-1, showed specific resistance development linked to mutations near the capsid/spacer peptide 1 junction, indicating a targeted mechanism of action.

In a Phase 2a study involving HIV-1 infected participants, certain mutations associated with reduced susceptibility to GSK3532795 were observed, suggesting that resistance can develop during treatment and may impact the drug's effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Resistance profile of the HIV-1 maturation inhibitor GSK3532795 in vitro and in a clinical study. Dicker, I., Zhang, S., Ray, N., et al.[2020]

BMS-663068, an oral prodrug for HIV treatment, showed promising efficacy with 80% of patients on the 400 mg twice daily dose achieving an HIV-1 RNA viral load of less than 50 copies per mL at week 24, comparable to the 75% response rate in the ritonavir-boosted atazanavir group.

The safety profile of BMS-663068 was favorable, with no serious adverse events linked to the drug and a lower incidence of grade 2-4 adverse events compared to ritonavir-boosted atazanavir, suggesting it is a viable option for treatment-experienced HIV-1 patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of the HIV-1 attachment inhibitor prodrug BMS-663068 in treatment-experienced individuals: 24 week results of AI438011, a phase 2b, randomised controlled trial. Lalezari, JP., Latiff, GH., Brinson, C., et al.[2019]

Early initiation of antiretroviral treatment is crucial for symptomatic patients or those with low CD4+ T cell counts, while asymptomatic patients with higher counts may defer treatment, highlighting the need for personalized approaches based on individual health status.

Combination therapies remain the cornerstone of HIV treatment, with specific regimens like lopinavir + ritonavir showing better efficacy than others, and ongoing monitoring of viral load and CD4+ counts is essential to ensure treatment effectiveness and manage potential adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antiretroviral treatment. HIV infection in adults: better-defined first-line treatment. [2013]

The G118R mutation in HIV-1 was identified in a patient on dolutegravir-based combination antiretroviral therapy (cART), indicating a rare but significant resistance to integrase inhibitors.

The presence of the M184I/V mutation may have contributed to the development of G118R, highlighting the importance of monitoring drug resistance in patients with compliance issues on HIV treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emergence of the G118R Pan-Integrase Resistance Mutation as a Result of Low Compliance to a Dolutegravir-Based cART. Mens, H., Fjordside, L., Fonager, J., et al.[2022]

All antiretroviral regimens studied effectively reduced viral load to undetectable levels and increased CD4 counts similarly at 6 and 12 months, indicating their efficacy in treating HIV.

The single-pill regimen Atripla® not only matched the effectiveness of two- and three-pill regimens but also resulted in significantly lower healthcare costs, saving approximately 20% at six months and 17% at twelve months compared to the two-pill regimen Truvada®+EFV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lower healthcare costs associated with the use of a single-pill ARV regimen in the UK, 2004-2008. Beck, EJ., Mandalia, S., Sangha, R., et al.[2021]

Antiretroviral therapy for HIV has significantly increased life expectancy for 20-year-olds starting treatment, adding ten years since the mid-1990s.

This improvement highlights the effectiveness of modern HIV treatments in extending the lives of individuals living with the virus in Europe and the US.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Life expectancy rises for people with HIV, study finds. [2019]

The study identified the first intersubtype B/G recombinant strain of HIV-1 in Germany, which has significant implications for diagnosis and treatment due to its genetic diversity.

This strain was undetectable in one viral load assay and underquantitated in another, highlighting how genetic variations can affect the reliability of HIV detection and quantification methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The first B/G intersubtype recombinant form of human immunodeficiency virus type 1 (HIV-1) identified in Germany was undetected or underquantitated by some commercial viral load assays. von Truchsess, I., Harris, B., Schätzl, HM., et al.[2008]

GSK364735, an HIV integrase strand transfer inhibitor, was found to be safe and well tolerated in a phase I study involving 79 healthy subjects, with no serious adverse events reported.

The drug showed effective absorption and increased exposure when taken with food, suggesting that it could maintain therapeutic levels in HIV-infected individuals, warranting further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and pharmacokinetics of GSK364735, a human immunodeficiency virus type 1 integrase inhibitor, following single and repeated administration in healthy adult subjects. Reddy, YS., Min, SS., Borland, J., et al.[2021]

In a Phase IIb trial involving 206 treatment-naive HIV-1-infected participants, GSK3532795 demonstrated similar efficacy to efavirenz, with 76-83% of participants achieving undetectable HIV-1 RNA levels (<40 copies/mL) after 24 weeks of treatment.

While GSK3532795 was effective, it had a higher incidence of gastrointestinal side effects and treatment-emergent resistance compared to efavirenz, indicating a need for careful monitoring of tolerability and resistance patterns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, efficacy, and dose response of the maturation inhibitor GSK3532795 (formerly known as BMS-955176) plus tenofovir/emtricitabine once daily in treatment-naive HIV-1-infected adults: Week 24 primary analysis from a randomized Phase IIb trial. Morales-Ramirez, J., Bogner, JR., Molina, JM., et al.[2020]

The new integrase inhibitor S/GSK1349572 shows strong efficacy against HIV-2, with a median effective concentration (EC₅₀) of 0.8 nM, comparable to HIV-1 strains, indicating its potential as a treatment option.

However, HIV-2 mutants from patients previously treated with raltegravir exhibited significantly higher EC₅₀ values, suggesting that these mutations can reduce the effectiveness of S/GSK1349572, highlighting the need for careful monitoring of resistance in treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In-vitro phenotypic susceptibility of HIV-2 clinical isolates to the integrase inhibitor S/GSK1349572. Charpentier, C., Larrouy, L., Collin, G., et al.[2022]

The HIV subtype B' variant, characterized by the amino acid sequence GWG, is associated with slower disease progression and higher CD4 counts in mono-infected patients, suggesting a potential better prognosis.

In coinfected patients with HIV and hepatitis C, the GWG variant did not show the same protective effects, indicating that its benefits may be lost in the presence of co-infection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of the HIV GWG variant in the HIV infection progression in mono and HCV coinfected patients. Hebeler-Barbosa, F., Massolini, VM., Watanabe, T., et al.[2021]

S/GSK1349572, an integrase inhibitor for HIV, showed no significant impact on its pharmacokinetics when coadministered with lopinavir/ritonavir, indicating it can be safely used together without dosage adjustments.

While there was a minor reduction in S/GSK1349572 levels when taken with darunavir/ritonavir, the overall safety profile was good, with no serious adverse events reported, and common side effects included diarrhea, dizziness, and headache.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of lopinavir/ritonavir and darunavir/ritonavir on the HIV integrase inhibitor S/GSK1349572 in healthy participants. Song, I., Min, SS., Borland, J., et al.[2015]

GSK2248761, a novel nonnucleoside reverse transcriptase inhibitor, was well tolerated in treatment-naive HIV-infected subjects over 7 days, with no serious adverse events reported, indicating a good safety profile.

The drug demonstrated significant antiviral activity, with mean viral load reductions of up to 1.87 log(10) copies/ml at higher doses, and showed a favorable pharmacokinetic profile without the emergence of resistance mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of GSK2248761, a next-generation nonnucleoside reverse transcriptase inhibitor, in treatment-naive HIV-1-infected subjects. Zala, C., St Clair, M., Dudas, K., et al.[2021]

Citations

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Gilead Provides Update on Clinical Studies Evaluating GS ...

GS-1720 and GS-4182 are investigational agents and have not been approved anywhere globally. We intend to investigate and pursue the potential ...

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gileadclinicaltrials.com

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Study of Oral Weekly GS-1720 and GS-4182 Compared ...

The primary objectives of this study are: Phase 2: To evaluate the efficacy of oral weekly GS-1720 coadministered with GS-4182 versus continuing ...

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clinicaltrials.gov

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NCT06544733 | Study of Oral Weekly GS-1720 and ...

The goal of this clinical study is to learn more about the experimental drugs GS-1720 and GS-4182; to compare the combination of GS-1720 and GS-4182 with ...

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eatg.org

eatg.org/hiv-news/gileads-phase-1a-trial-results-indicate-gs-1720-as-a-potential-long-acting-hiv-treatment/

Gilead's Phase 1a trial results indicate GS-1720 as a ...

GS-1720 could offer a weekly dosing option for individuals living with HIV, supported by a good safety profile with no serious adverse events, ...

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infectiousdiseaseadvisor.com

infectiousdiseaseadvisor.com/news/fda-puts-clinical-hold-on-gileads-trials-for-two-hiv-drug-candidates/

FDA Puts Clinical Hold on Gilead's Trials for 2 HIV Drug ...

Gilead's HIV treatment trials involving GS-1720 and GS-4182 have been put on clinical hold by the Food and Drug Administration.

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pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11778217/

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GS-1720 exhibits a PK and safety profile supportive of oral QW dosing. The data support the development of GS-1720 as part of a first INSTI-containing oral QW ...

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academic.oup.com

academic.oup.com/ofid/article/12/Supplement_1/ofae631.040/7988049

154. Pharmacokinetics and Safety of GS-1720 Following ...

Pharmacokinetics (PK) and safety of single ascending GS-1720 doses in participants without HIV-1 have been previously reported. Here, we report ...