Study to Evaluate Safety, Pharmacokinetics, and Antiviral Activity of Lenacapavir Administered Subcutaneously in Human Immunodeficiency Virus (HIV) -1 Infected Adults

Study Overview
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Brief Summary
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The primary objectives of this study are: Part A: To evaluate the short-term antiviral activity of lenacapavir (formerly GS-6207) with respect to the maximum reduction of plasma HIV-1 RNA (log10 copies/mL) from Day 1 through Day 10 compared to placebo in HIV-1 infected adults who are antiretroviral treatment naive or are experienced but capsid inhibitor (CAI) naive. Part B: To evaluate the short-term antiviral activity of tenofovir alafenamide (TAF) with respect to the maximum reduction of plasma HIV-1 RNA (log10 copies/mL) from Day 1 through Day 10 in HIV-1 infected adult subjects who are antiretroviral treatment naïve or are experienced but without resistance to TAF.

Official Title
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A Phase 1b Randomized, Double-Blinded, Placebo Controlled, Multi-Cohort Study of the Safety, Pharmacokinetics, and Antiviral Activity of GS-6207 Administered Subcutaneously in HIV-1 Infected Subjects

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: Lenacapavir
* Drug: Placebo
* Drug: B/F/TAF
* Drug: TAF


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Plasma HIV-1 RNA ≥ 5,000 copies/mL but ≤ 400,000 copies/mL and CD4+ cell count > 200 cells/mm^3 Treatment naive or experienced but CAI (for Part A only) and integrase strand transfer inhibitor (INSTI) naïve, and have not received any antiretroviral therapy (ART) within 12 weeks of screening Screening genotype report must show sensitivity to B/F/TAF to allow its initiation on Day 10 Screening genotype report must show sensitivity to at least one agent in either non-nucleoside reverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI) class to allow its use as part of standard of care oral antiretroviral treatment in the future Have adequate renal function (estimated glomerular filtration rate ≥ 70 mL/min) No clinically significant abnormalities in electrocardiography (ECG) at Screening Willing to initiate B/F/TAF on Day 10 after completion of all assessments Key Exclusion Criteria: Pregnant or lactating females Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Lenacapavir 20 mg<br>Participants will receive single dose of lenacapavir 20 mg on Day 1 followed by bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) as per standard-care therapy starting on Day 10 through Day 225. | Drug: Lenacapavir<br>* Administered subcutaneously in the abdomen<br>* Other names: GS-6207;Drug: B/F/TAF<br>* 50/200/25 mg tablets administered orally once daily<br>* Other names: Biktarvy®;|
| Experimental: Part A: Lenacapavir 50 mg<br>Participants will receive single dose of lenacapavir 50 mg on Day 1 followed by B/F/TAF as per standard-care therapy starting on Day 10 through Day 225. | Drug: Lenacapavir<br>* Administered subcutaneously in the abdomen<br>* Other names: GS-6207;Drug: B/F/TAF<br>* 50/200/25 mg tablets administered orally once daily<br>* Other names: Biktarvy®;|
| Experimental: Part A: Lenacapavir 150 mg<br>Participants will receive single dose of lenacapavir 150 mg on Day 1 followed by B/F/TAF as per standard-care therapy starting on Day 10 through Day 225. | Drug: Lenacapavir<br>* Administered subcutaneously in the abdomen<br>* Other names: GS-6207;Drug: B/F/TAF<br>* 50/200/25 mg tablets administered orally once daily<br>* Other names: Biktarvy®;|
| Experimental: Part A: Lenacapavir 450 mg<br>Participants will receive single dose of lenacapavir 450 mg on Day 1 followed by B/F/TAF as per standard-care therapy starting on Day 10 through Day 225. | Drug: Lenacapavir<br>* Administered subcutaneously in the abdomen<br>* Other names: GS-6207;Drug: B/F/TAF<br>* 50/200/25 mg tablets administered orally once daily<br>* Other names: Biktarvy®;|
| Experimental: Part A: Lenacapavir 750 mg<br>Participants will receive single dose of lenacapavir 750 mg on Day 1 followed by B/F/TAF as per standard-care therapy starting on Day 10 through Day 225. | Drug: Lenacapavir<br>* Administered subcutaneously in the abdomen<br>* Other names: GS-6207;Drug: B/F/TAF<br>* 50/200/25 mg tablets administered orally once daily<br>* Other names: Biktarvy®;|
| Placebo Comparator: Part A: Placebo<br>Participants will receive single dose of placebo matched to lenacapavir on Day 1 followed by B/F/TAF as per standard-care therapy starting on Day 10 through Day 225. | Drug: Placebo<br>* Administered subcutaneously in the abdomen<br>Drug: B/F/TAF<br>* 50/200/25 mg tablets administered orally once daily<br>* Other names: Biktarvy®;|
| Experimental: Part B: TAF 200 mg<br>Participants will receive a single dose of TAF 200 mg on Day 1 followed by B/F/TAF as per standard-care therapy starting on Day 10 through Day 225. | Drug: B/F/TAF<br>* 50/200/25 mg tablets administered orally once daily<br>* Other names: Biktarvy®;Drug: TAF<br>* Tablets administered orally<br>|
| Experimental: Part B: TAF 600 mg<br>Participants will receive a single dose of TAF 600 mg on Day 1 followed by B/F/TAF as per standard-care therapy starting on Day 10 through Day 225. | Drug: B/F/TAF<br>* 50/200/25 mg tablets administered orally once daily<br>* Other names: Biktarvy®;Drug: TAF<br>* Tablets administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A and Part B: Maximum Reduction From Day 1 (Baseline) Through Day 10 in Plasma HIV-1 RNA | Maximum reduction is defined as the minimum of change from baseline in plasma HIV-1 RNA (i.e. smallest change in HIV-RNA from baseline). | Day 1 through Day 10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A and Part B: Percentage of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) | An AE was any untoward medical occurrence in a clinical study participant administered a medicinal product, which does not necessarily have a causal relationship with the treatment. An AE could therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. TEAEs were defined as any AE with an onset date on or after the study drug start date. | Day 1 through 225 days | 
| Part A and Part B: Percentage of Participants Experiencing Treatment Emergent Laboratory Abnormalities | Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. The most severe graded abnormality from all tests was counted for each participant. | Day 1 through 225 days | 
| Part A and Part B Pharmacokinetic (PK) Parameter: AUCinf of Lenacapavir, TAF and Its Metabolite TFV | AUCinf is defined as area under the concentration versus time curve from time zero to infinity. | Part A: 0 (predose),1,2,4,8,12,24 h postdose on Day 1, anytime on Days 3,4,7,8,9,10,14,29,43,57,85,113,141,169,197,225; Part B: 0 (predose),0.5,1,2,3,4,6,8,10,12,24 and 48 h postdose on Day 1, approximately Day 1 predose time on Days 4,5,6,7,8,9,10 | 
| Part A and Part B PK Parameter: AUClast of Lenacapavir, TAF and Its Metabolite TFV | AUClast is defined as area under the concentration versus time curve from time zero to the last quantifiable concentration. | Part A: 0 (predose),1,2,4,8,12,24 h postdose on Day 1, anytime on Days 3,4,7,8,9,10,14,29,43,57,85,113,141,169,197,225; Part B: 0 (predose),0.5,1,2,3,4,6,8,10,12,24 and 48 h postdose on Day 1, approximately Day 1 predose time on Days 4,5,6,7,8,9,10 | 
| Part A and Part B PK Parameter: Cmax of Lenacapavir, TAF and Its Metabolite TFV | Cmax is defined as the maximum observed concentration of drug. | Part A: 0 (predose),1,2,4,8,12,24 h postdose on Day 1, anytime on Days 3,4,7,8,9,10,14,29,43,57,85,113,141,169,197,225; Part B: 0 (predose),0.5,1,2,3,4,6,8,10,12,24 and 48 h postdose on Day 1, approximately Day 1 predose time on Days 4,5,6,7,8,9,10 | 
| Part B PK Parameter: AUCinf of TFV-DP Metabolite of TAF | AUCinf is defined as area under the concentration versus time curve from time zero to infinity. | Part B: 0 (predose), 1, 2, 4, 6, 8, 12, 24 and 48 hours post dose on Day 1, approximately Day 1 predose time on Days 4, 5 (if possible), 6 (if possible), 7, 8, 9, 10 | 
| Part B PK Parameter: AUClast of TFV-DP Metabolite of TAF | AUClast is defined as area under the concentration versus time curve from time zero to the last quantifiable concentration. | Part B: 0 (predose), 1, 2, 4, 6, 8, 12, 24 and 48 hours post dose on Day 1, approximately Day 1 predose time on Days 4, 5 (if possible), 6 (if possible), 7, 8, 9, 10 | 
| Part B PK Parameter: Cmax of TFV-DP Metabolite of TAF | Cmax is defined as the maximum observed concentration of drug. | Part B: 0 (predose), 1, 2, 4, 6, 8, 12, 24 and 48 hours post dose on Day 1, approximately Day 1 predose time on Days 4, 5 (if possible), 6 (if possible), 7, 8, 9, 10 | 
| Part A: Percentage of Participants Ever Achieving HIV-1 RNA < 50 Copies/mL by Day 10 |  | Day 10 | 
| Part A: Number of Participants Experiencing Any Emergence of Capsid Inhibitor Resistance |  | Day 10 | 
| Part A: Number of Participants Experiencing Any Emergence of Capsid Inhibitor Resistance | Post-Monotherapy Resistance Analysis Population analyzed for this outcome measure included any participant who received at least 1 dose of study drug/placebo, maintained their study drug regimen, & met one of following virologic failure criteria: HIV-1 RNA ≥ 50 copies/mL & < 1 log10 HIV-1 RNA reduction from Day 10 at Day 57 visit, confirmed at a scheduled or unscheduled visit at least 2 weeks following Day 57 At any visit following Day 10, after achieving HIV-1 RNA < 50 copies/mL, a rebound in HIV-1 RNA to ≥ 50 copies/mL, which was subsequently confirmed at following scheduled or unscheduled visit; OR At any visit, a > 1 log10 increase in HIV-1 RNA from nadir, which was subsequently confirmed at following scheduled or unscheduled visit; Any participant with HIV-1 RNA ≥ 50 copies/mL at study endpoint or study discontinuation who didn't meet any of criteria above also had protease (PR)/reverse transcriptase (RT), integrase (IN), &capsid (CA) genotyping & phenotyping performed. | Day 10 through Day 225 | 
| Part B: Number of Participants Experiencing Any Emergence of TAF Resistance |  | Day 10 | 
| Part B: Number of Participants Experiencing Any Emergence of TAF Resistance | TAF Resistance testing was performed for any participant meeting Post-Monotherapy Resistance Analysis Population criteria - it included any participant who received at least 1 dose of study drug/placebo, maintained their study drug regimen, & met one of the following virologic failure criteria: HIV-1 RNA ≥50 copies/mL & < 1 log10 HIV-1 RNA reduction from D10 at the D57 visit, confirmed at scheduled or unscheduled visit at least 2 weeks following D57 At any visit following D10, after achieving HIV-1 RNA< 50 copies/mL, a rebound in HIV-1 RNA to ≥50 copies/mL, which was subsequently confirmed at the following scheduled/unscheduled visit; OR At any visit, a > 1 log10 increase in HIV-1 RNA from nadir, which was subsequently confirmed at the following scheduled or unscheduled visit; Any participant with HIV-1 RNA ≥50 copies/mL at study endpoint or study discontinuation who didn't meet any of the criteria above also had PR/RT, IN, and CA genotyping & phenotyping performed. D = Day | Day 10 through Day 225 |