GS-1720 + GS-4182 for HIV

(WONDERS1 Trial)

Recruiting at 39 trial locations

Overseen By Study Director

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2 & 3

Waitlist Available

Sponsor: Gilead Sciences

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

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 the current standard-of-care treatment bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF, BVY), to see if the combination of GS-1720 and GS-4182 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 GS-1720 in combination with GS-4182 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 GS-1720/GS-4182 Fixed-dose combination (FDC) tablet regimen versus continuing BVY in virologically suppressed PWH at Week 48.

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.

What data supports the idea that GS-1720 + GS-4182 for HIV is an effective drug?

The available research does not provide specific data on the effectiveness of GS-1720 + GS-4182 for HIV. Instead, it discusses another drug, GSK3532795, which is a maturation inhibitor used in HIV treatment. This drug was tested in a Phase IIb trial and showed some effectiveness in reducing the virus in treatment-naive adults. However, there is no direct comparison or data available for GS-1720 + GS-4182 in the provided information. ^{1 2 3 4 5}

What safety data is available for the HIV treatment GS-1720 + GS-4182?

The provided research does not contain specific safety data for the treatment GS-1720 + GS-4182. The studies mentioned focus on different HIV treatments and compounds, such as S/GSK1349572, GSK2248761, and GSK364735, none of which are identified as GS-1720 or GS-4182. Therefore, no relevant safety data for GS-1720 + GS-4182 can be extracted from the given information. ^{6 7 8 9 10}

Is the drug GS-1720 + GS-4182 a promising treatment for HIV?

The information provided does not directly mention GS-1720 or GS-4182, so we cannot determine if it is a promising treatment for HIV based on the given research articles. ^{1 6 11 12 13}

Research Team

Gilead Study Director

Principal Investigator

Gilead Sciences

Eligibility Criteria

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.

I have used long-acting HIV drugs like injectable cabotegravir or rilpivirine.

Direct bilirubin > 1.5 × ULN

Treatment Details

Interventions

• GS-1720 (Anti-retroviral)
• GS-4182 (Anti-retroviral)

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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 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]

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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Resistance profile of the HIV-1 maturation inhibitor GSK3532795 in vitro and in a clinical study. [2020]

2. United States 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. [2020]

3. France pubmed.ncbi.nlm.nih.gov

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

4. United States pubmed.ncbi.nlm.nih.gov

Lower healthcare costs associated with the use of a single-pill ARV regimen in the UK, 2004-2008. [2021]

5. England pubmed.ncbi.nlm.nih.gov

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

6. England pubmed.ncbi.nlm.nih.gov

In-vitro phenotypic susceptibility of HIV-2 clinical isolates to the integrase inhibitor S/GSK1349572. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Safety and efficacy of GSK2248761, a next-generation nonnucleoside reverse transcriptase inhibitor, in treatment-naive HIV-1-infected subjects. [2021]

8. United States 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. [2021]

9. England pubmed.ncbi.nlm.nih.gov

The effect of lopinavir/ritonavir and darunavir/ritonavir on the HIV integrase inhibitor S/GSK1349572 in healthy participants. [2015]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Emergence of the G118R Pan-Integrase Resistance Mutation as a Result of Low Compliance to a Dolutegravir-Based cART. [2022]

11. United States 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. [2008]

12. Netherlands 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. [2019]

13. United States pubmed.ncbi.nlm.nih.gov

Influence of the HIV GWG variant in the HIV infection progression in mono and HCV coinfected patients. [2021]