Study to Evaluate the Safety and Efficacy of Lenacapavir (GS-6207) in Combination With an Optimized Background Regimen (OBR) in Heavily Treatment Experienced Participants Living With HIV-1 Infection With Multidrug Resistance

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the antiviral activity of lenacapavir (formerly GS-6207) administered as an add-on to a failing regimen (functional monotherapy) in people living with HIV (PLWH) with multi-drug resistance (MDR).

Official Title
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A Phase 2/3 Study to Evaluate the Safety and Efficacy of Long Acting Capsid Inhibitor GS-6207 in Combination With an Optimized Background Regimen in Heavily Treatment Experienced People Living With HIV-1 Infection With Multidrug Resistance

Conditions
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HIV-1-infection

Intervention / Treatment
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* Drug: Oral Lenacapavir
* Drug: Oral Lenacapavir Placebo
* Drug: Subcutaneous Lenacapavir
* Drug: Failing ARV Regimen
* Drug: Optimized Background Regimen (OBR)


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Adult aged ≥ 18 years (at all sites) or adolescent aged ≥ 12 and weighing ≥ 35 kg (at sites in North America and Dominican Republic) Currently receiving a stable failing ARV regimen for > 8 weeks Have HIV-1 RNA ≥ 400 copies/mL at screening Have multidrug resistance (resistance to ≥2 agents from ≥3 of the 4 main classes of ARV) Have no more than 2 fully active ARV remaining from the 4 main classes that can be effectively combined to form a viable regimen Able and willing to receive an OBR together with lenacapavir No Hepatitis C virus (HCV) ongoing infection Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1A: Lenacapavir<br>Participants with human-immunodeficiency virus-1 ribonucleic acid (HIV-1 RNA) ≥ 400 copies/mL and with a <0.5 log10 HIV-1 RNA decline at Cohort Selection visit compared with screening visit will receive oral lenacapavir 600 mg tablet on Days 1 and 2 and 300 mg tablet on Day 8, while continuing their failing regimen in blinded Functional Monotherapy Period (Baseline to Day 14); followed by unblinded Maintenance Period where participants will receive subcutaneous (SC) lenacapavir 927 mg and will initiate an OBR at Day 1 SC Visit (14 days after the first dose of oral lenacapavir). Participants will receive their subsequent SC lenacapavir injection at Week 26 Visit (relative to Day 1 SC). At Week 52 (relative to Day 1 SC), participants will be given an option to receive SC lenacapavir injections every 6 months (26 weeks), while continuing their OBR, until product becomes accessible to participants through an access program or until Gilead elects to discontinue the study in the country. | Drug: Oral Lenacapavir<br>* Tablets administered without regard to food<br>* Other names: GS-6207;Drug: Subcutaneous Lenacapavir<br>* Administered in the abdomen via subcutaneous injections<br>* Other names: GS-6207;Drug: Failing ARV Regimen<br>* Failing antiretroviral (ARV) regimen defined by the lack of efficacy. Any combination of approved and unapproved agents that could potentially be part of the failing regimen.<br>Drug: Optimized Background Regimen (OBR)<br>* Optimized background regimen as prescribed by the Investigator<br>|
| Placebo Comparator: Cohort 1B: Placebo to Lenacapavir<br>Participants with HIV-1 RNA ≥ 400 copies/mL and with a <0.5 log10 HIV-1 RNA decline at the Cohort Selection visit compared with screening visit will receive oral lenacapavir placebo on Days 1, 2, and 8 while continuing their failing regimen in blinded Functional Monotherapy Period (Baseline to Day 14); followed by unblinded Maintenance Period where participants will receive oral lenacapavir 600 mg on Days 15 and 16 and 300 mg on Day 22, and will initiate an OBR on Day 15. At Day 1 SC (14 days after the first dose of oral lenacapavir), participants will receive SC lenacapavir 927 mg while continuing OBR. Participants will receive their next SC injection at the Week 26 Visit (relative to Day 1 SC). At Week 52 (relative to Day 1 SC), participants will be given an option to receive SC lenacapavir every 6 months (26 weeks), while continuing their OBR, until the product becomes accessible to participants through an access program or until Gilead elects to discontinue study in the country. | Drug: Oral Lenacapavir<br>* Tablets administered without regard to food<br>* Other names: GS-6207;Drug: Oral Lenacapavir Placebo<br>* Tablets administered without regard to food<br>Drug: Subcutaneous Lenacapavir<br>* Administered in the abdomen via subcutaneous injections<br>* Other names: GS-6207;Drug: Failing ARV Regimen<br>* Failing antiretroviral (ARV) regimen defined by the lack of efficacy. Any combination of approved and unapproved agents that could potentially be part of the failing regimen.<br>Drug: Optimized Background Regimen (OBR)<br>* Optimized background regimen as prescribed by the Investigator<br>|
| Experimental: Cohort 2: Lenacapavir<br>Participants with a ≥ 0.5 log10 copies/mL HIV-1 RNA decline at the Cohort Selection Visit compared with the screening visit or with HIV-1 RNA < 400 copies/mL or if Cohort 1 is fully enrolled will receive oral lenacapavir 600 mg tablet on Days 1 and 2 and 300 mg tablet on Day 8, and will initiate an OBR on Day 1 in Oral Lead-in Period (Baseline to Day 14); followed by Maintenance Period where participants will receive SC lenacapavir 927 mg at Day 1 SC Visit (14 days after the first dose of oral lenacapavir) while continuing their OBR. Participants will receive their subsequent SC lenacapavir injection at the Week 26 Visit (relative to Day 1 SC). At Week 52 (relative to Day 1 SC), participants will be given the option to receive SC lenacapavir injections every 6 months (26 weeks), while continuing their OBR, until the product becomes accessible to participants through an access program or until Gilead elects to discontinue the study in the country. | Drug: Oral Lenacapavir<br>* Tablets administered without regard to food<br>* Other names: GS-6207;Drug: Subcutaneous Lenacapavir<br>* Administered in the abdomen via subcutaneous injections<br>* Other names: GS-6207;Drug: Optimized Background Regimen (OBR)<br>* Optimized background regimen as prescribed by the Investigator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants in Cohort 1 Achieving a Reduction of ≥ 0.5 log10 Copies/mL in Human Immunodeficiency Virus-1 Ribonucleic Acid (HIV-1 RNA) From Baseline to the End of Functional Monotherapy Period |  | Baseline up to Day 1 SC Visit (14 days after the first dose of oral lencapavir) or Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants in Cohort 1 With Plasma HIV-1 RNA < 50 Copies/mL at Week 26 Based on the US FDA-defined Snapshot Algorithm | The percentage of participants in cohort 1 with plasma HIV-1 RNA < 50 copies/mL at Week 26 was analyzed using the United States Food and Drug Administration (US FDA)-defined snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. | Week 26 (26 weeks after first dose of subcutaneous lenacapavir) | 
| Percentage of Participants in Cohort 1 With Plasma HIV-1 RNA < 200 Copies/mL at Week 26 Based on the US FDA-defined Snapshot Algorithm | The percentage of participants in cohort 1 with plasma HIV-1 RNA < 200 copies/mL at Week 26 was analyzed using the US FDA-defined snapshot algorithm, which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. | Week 26 (26 weeks after first dose of subcutaneous lenacapavir) | 
| Percentage of Participants in Cohort 1 With Plasma HIV-1 RNA < 50 Copies/mL at Week 52 Based on the US FDA-defined Snapshot Algorithm |  | Week 52 | 
| Percentage of Participants in Cohort 1 With Plasma HIV-1 RNA < 200 Copies/mL at Week 52 Based on the US FDA-defined Snapshot Algorithm |  | Week 52 |