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

• ClinicalTrials.gov Identifier: NCT03739866
• Recruitment Status: Completed
• First Posted: November 14, 2018
• Results First Posted: December 9, 2020
• Last Update Posted: April 9, 2021
• Sponsor: Gilead Sciences
• Information provided by (Responsible Party): Gilead Sciences

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
HIV-1 Infection	Drug: Lenacapavir; Drug: Placebo; Drug: B/F/TAF; Drug: TAF	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 53 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: November 26, 2018
• Actual Primary Completion Date: November 14, 2019
• Actual Study Completion Date: June 15, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part A: Lenacapavir 20 mg; 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; Administered subcutaneously in the abdomen; Other Name: GS-6207; Drug: B/F/TAF; 50/200/25 mg tablets administered orally once daily; Other Name: Biktarvy®
Experimental: Part A: Lenacapavir 50 mg; 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; Administered subcutaneously in the abdomen; Other Name: GS-6207; Drug: B/F/TAF; 50/200/25 mg tablets administered orally once daily; Other Name: Biktarvy®
Experimental: Part A: Lenacapavir 150 mg; 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; Administered subcutaneously in the abdomen; Other Name: GS-6207; Drug: B/F/TAF; 50/200/25 mg tablets administered orally once daily; Other Name: Biktarvy®
Experimental: Part A: Lenacapavir 450 mg; 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; Administered subcutaneously in the abdomen; Other Name: GS-6207; Drug: B/F/TAF; 50/200/25 mg tablets administered orally once daily; Other Name: Biktarvy®
Experimental: Part A: Lenacapavir 750 mg; 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; Administered subcutaneously in the abdomen; Other Name: GS-6207; Drug: B/F/TAF; 50/200/25 mg tablets administered orally once daily; Other Name: Biktarvy®
Placebo Comparator: Part A: Placebo; 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; Administered subcutaneously in the abdomen; Drug: B/F/TAF; 50/200/25 mg tablets administered orally once daily; Other Name: Biktarvy®
Experimental: Part B: TAF 200 mg; 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; 50/200/25 mg tablets administered orally once daily; Other Name: Biktarvy®; Drug: TAF; Tablets administered orally
Experimental: Part B: TAF 600 mg; 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; 50/200/25 mg tablets administered orally once daily; Other Name: Biktarvy®; Drug: TAF; Tablets administered orally

Outcome Measures

Primary Outcome Measures :

1. Part A and Part B: Maximum Reduction From Day 1 (Baseline) Through Day 10 in Plasma HIV-1 RNA [ Time Frame: Day 1 through Day 10 ]
   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).

Secondary Outcome Measures :

1. Part A and Part B: Percentage of Participants Experiencing Treatment Emergent Adverse Events (TEAEs) [ Time Frame: Day 1 through 225 days ]
   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.
2. Part A and Part B: Percentage of Participants Experiencing Treatment Emergent Laboratory Abnormalities [ Time Frame: Day 1 through 225 days ]
   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.
3. Part A and Part B Pharmacokinetic (PK) Parameter: AUCinf of Lenacapavir, TAF and Its Metabolite TFV [ Time Frame: 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 ]
   AUCinf is defined as area under the concentration versus time curve from time zero to infinity.
4. Part A and Part B PK Parameter: AUClast of Lenacapavir, TAF and Its Metabolite TFV [ Time Frame: 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 ]
   AUClast is defined as area under the concentration versus time curve from time zero to the last quantifiable concentration.
5. Part A and Part B PK Parameter: Cmax of Lenacapavir, TAF and Its Metabolite TFV [ Time Frame: 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 ]
   Cmax is defined as the maximum observed concentration of drug.
6. Part B PK Parameter: AUCinf of TFV-DP Metabolite of TAF [ Time Frame: 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 ]
   AUCinf is defined as area under the concentration versus time curve from time zero to infinity.
7. Part B PK Parameter: AUClast of TFV-DP Metabolite of TAF [ Time Frame: 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 ]
   AUClast is defined as area under the concentration versus time curve from time zero to the last quantifiable concentration.
8. Part B PK Parameter: Cmax of TFV-DP Metabolite of TAF [ Time Frame: 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 ]
   Cmax is defined as the maximum observed concentration of drug.
9. Part A: Percentage of Participants Ever Achieving HIV-1 RNA < 50 Copies/mL by Day 10 [ Time Frame: Day 10 ]
10. Part A: Number of Participants Experiencing Any Emergence of Capsid Inhibitor Resistance [ Time Frame: Day 10 ]
11. Part A: Number of Participants Experiencing Any Emergence of Capsid Inhibitor Resistance [ Time Frame: Day 10 through Day 225 ]

    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.
12. Part B: Number of Participants Experiencing Any Emergence of TAF Resistance [ Time Frame: Day 10 ]
13. Part B: Number of Participants Experiencing Any Emergence of TAF Resistance [ Time Frame: Day 10 through Day 225 ]

    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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, California

Ruane Clinical Research Group, Inc.

Los Angeles, California, United States, 90036

Mills Clinical Research

Los Angeles, California, United States, 90069

One Community

Sacramento, California, United States, 95817

The Lundquist Institute for BioMedical Innovation at Harbor-UCLA Medical Center

Torrance, California, United States, 90502

United States, Florida

Midway Immunology and Research Center

Fort Pierce, Florida, United States, 34982

Orlando Immunology Center PA

Orlando, Florida, United States, 32803-1851

Triple O Research Institute, P.A.

West Palm Beach, Florida, United States, 33401

United States, Michigan

Be Well Medical Center

Berkley, Michigan, United States, 48072-3436

United States, Texas

AIDS Arms, Inc., DBA Prism Health North Texas

Dallas, Texas, United States, 75208

North Texas Infectious Diseases Consultants, P.A.

Dallas, Texas, United States, 75246

Tarrant County Infectious Disease Associates

Fort Worth, Texas, United States, 76104

The Crofoot Research Center, INC (dba Gordon E. Crofoot MD PA)

Houston, Texas, United States, 77098

Sponsors and Collaborators

Gilead Sciences

Investigators

• Study Director: Gilead Study Director; Gilead Sciences

  Study Documents (Full-Text)

Documents provided by Gilead Sciences:

Study Protocol  [PDF] June 13, 2019

Statistical Analysis Plan  [PDF] September 14, 2020

More Information

Publications of Results:

Daar ES, McDonald C, Crofoot G, Ruane P, Sinclair G, Begley R, et al. Dose-response relationship of subcutaneous long-acting HIV capsid inhibitor GS-6207 [Poster]. Presented at: Conference on Retroviruses and Opportunistic Infections; 2020 March 8-11; Boston, MA, USA

Daar ES, McDonald C, Crofoot G, Ruane P, Sinclair G, Patel H, et al. Single doses of long acting capsid inhibitor GS-6207 administered by subcutaneous injection are safe and efficacious in people living with HIV [Poster]. Presented at: 17th European AIDS Conference; 2019 November 6-9; Basel, Switzerland.

Daar ES, McDonald C, Crofoot G, Ruane P, Sinclair G, Patel H, et al. Safety and antiviral activity over 10 days following a single dose of subcutaneous GS-6207, a first-in-class, long acting HIV capsid inhibitor in people living with HIV [Poster]. Presented at: 10th IAS Conference on HIV Science; 2019 21-24 July; Mexico City, Mexico.

Link JO, Rhee MS, Tse WC, Zheng J, Somoza JR, Rowe W, Begley R, Chiu A, Mulato A, Hansen D, Singer E, Tsai LK, Bam RA, Chou CH, Canales E, Brizgys G, Zhang JR, Li J, Graupe M, Morganelli P, Liu Q, Wu Q, Halcomb RL, Saito RD, Schroeder SD, Lazerwith SE, Bondy S, Jin D, Hung M, Novikov N, Liu X, Villasenor AG, Cannizzaro CE, Hu EY, Anderson RL, Appleby TC, Lu B, Mwangi J, Liclican A, Niedziela-Majka A, Papalia GA, Wong MH, Leavitt SA, Xu Y, Koditek D, Stepan GJ, Yu H, Pagratis N, Clancy S, Ahmadyar S, Cai TZ, Sellers S, Wolckenhauer SA, Ling J, Callebaut C, Margot N, Ram RR, Liu YP, Hyland R, Sinclair GI, Ruane PJ, Crofoot GE, McDonald CK, Brainard DM, Lad L, Swaminathan S, Sundquist WI, Sakowicz R, Chester AE, Lee WE, Daar ES, Yant SR, Cihlar T. Clinical targeting of HIV capsid protein with a long-acting small molecule. Nature. 2020 Aug;584(7822):614-618. doi: 10.1038/s41586-020-2443-1. Epub 2020 Jul 1.

Margot N, Ram R, Parvangada P, Martin R, Hyland R, Rhee M, Callebaut C. Lenacapavir resistance analysis in a phase Ib clinical proof-of-concept study [oral]. Presented at: HIV Glasgow; 2020 October 5 - 8; Virtual.

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT03739866
• Other Study ID Numbers: GS-US-200-4072
• First Posted: November 14, 2018
• Results First Posted: December 9, 2020
• Last Update Posted: April 9, 2021
• Last Verified: March 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No