HIV Infection
Conditions
Brief summary
The goal of this study is to test the effectiveness, safety, and tolerability of the combination of broadly neutralizing antibodies (bNAbs) (teropavimab (TAB; GS-5423) and zinlirvimab (ZAB; GS-2872)) with lenacapavir (LEN) in virologically suppressed adults with HIV-1 infection. The purpose of this study is to evaluate the efficacy of switching to a regimen of LEN, TAB and ZAB, versus continuing on baseline oral antiretroviral therapy (ART) as determined by the proportion of participants with human immunodeficiency virus-1 (HIV-1) ribonucleic acid (RNA) ≥ 50 copies/mL at Week 26.
Detailed description
Participants will be randomized in Treatment Groups 1 and 2 to receive LEN, TAB, and ZAB, with differing doses of TAB and ZAB between the 2 groups and in Treatment Group 3 to continue their baseline oral ART for 52 weeks. Eligible participants in Treatment Groups 1 through 3 will have the option of participating in the study extension phase to receive LEN, TAB and ZAB after completing study follow-up through Week 52. Treatment Group 2 was removed prior to dosing of all groups during Protocol Amendment 2.
Interventions
DRUGTeropavimab
Administered intravenously
DRUGZinlirvimab
Administered intravenously
Administered orally
Administered subcutaneously
DRUGAntiretroviral Therapy
Antiretroviral therapy, administered orally may include regimens such as: bictegravir/emtricitabine/tenofovir alafenamide, darunavir/cobicistat/emtricitabine/tenofovir alafenamide, dolutegravir/abacavir lamivudine, and rilpivirine/emtricitabine/tenofovir alafenamide.
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * On stable oral antiretroviral therapy (ART) consisting of no more than 2 drug classes (with the exception of pharmacologic boosters cobicistat or ritonavir) for ≥ 1 year prior to screening visit 2. A change in ART regimen ≥ 28 days prior to screening visit 2 for reasons other than virologic failure (VF) (eg, tolerability, simplification, drug-drug interaction profile) is allowed. * No clinically significant documented historical resistance to the current ART regimen with the exception of isolated nucleoside reverse transcriptase inhibitor mutations including M184V or ≤ 2 thymidine analog mutations (TAMs: M41L, D67N, K70R, L210W, T215Y, and/or K219Q). * Plasma human immunodeficiency virus-1 (HIV-1) ribonucleic acid (RNA) \< 50 copies/mL at screening visit 2. * Documented plasma HIV-1 RNA \< 50 copies/mL for ≥ 12 months preceding screening visit 2 (or undetectable HIV-1 RNA level according to the local assay being used if the limit of detection is ≥ 50 copies/mL). Virologic elevations of ≥ 50 copies/mL (transient detectable viremia or blips) prior to screening are acceptable. * Proviral phenotypic sensitivity to both teropavimab and zinlirvimab at screening or from protocol GS-US-536-5816 within 24 months prior to screening. * Screening clusters of differentiation 4 (CD4)+ T-cell count ≥ 200 cells/μL at screening visit 2. Key
Exclusion criteria
* Comorbid condition requiring ongoing immunosuppression. * Evidence of hepatitis C virus (HCV) infection (prior infection cleared spontaneously or with treatment is acceptable) * Evidence of current hepatitis B virus (HBV) infection regardless of HBV surface antigen status, at the screening visit 2. * History of opportunistic infection or illness indicative of Stage 3 HIV disease. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) ≥ 50 Copies/mL at Week 26 as Determined by the United States Food and Drug Administration (US FDA)-Defined Snapshot Algorithm | Week 26 | Percentage of participants with HIV-1 RNA ≥ 50 copies/mL at Week 26 was analyzed using US FDA-defined snapshot algorithm, which defines a participant's virologic outcome and included participants a) who had last available on-treatment HIV-1 RNA ≥ 50 copies/mL in the Week 26 analysis window; b) who did not have on-treatment HIV-1 RNA data in the Week 26 analysis window and i) discontinued study drug prior to or in the Week 26 analysis window due to lack of efficacy, or ii) discontinued study drug prior to or in the Week 26 analysis window due to adverse event (AE) or death and had last available on-treatment HIV-1 RNA ≥ 50 copies/mL, or iii) discontinued study drug prior to or in the Week 26 analysis window due to reasons other than AE, death, or lack of efficacy and had the last available on-treatment HIV-1 RNA ≥ 50 copies/mL. Clopper-Pearson exact method was used to calculate the 95% confidence interval (CI) for the outcome measure of each treatment. Percentages were rounded off. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 26 as Determined by the US FDA-defined Snapshot Algorithm | Week 26 | Percentage of participants with HIV-1 RNA \< 50 copies/mL at Week 26 was analyzed using the US FDA-defined snapshot algorithm, which defined a participant's virologic outcome and included participants who had the last available on-treatment HIV-1 RNA \< 50 copies/mL in the Week 26 analysis window. The Clopper-Pearson exact method was used to calculate the 95% CI for the outcome measure of each treatment. Percentages were rounded off. |
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 52 as Determined by the US FDA-defined Snapshot Algorithm | Week 52 | — |
| Change From Baseline in Clusters of Differentiation 4 (CD4) + T-cell Counts at Week 26 | Baseline, Week 26 | — |
| Change From Baseline in CD4+ T-cell Counts at Week 52 | Baseline, Week 52 | — |
| Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) | Up to approximately 6 years | — |
| Trough Concentration at Week 26 for TAB and ZAB | Week 26 | Trough concentration is defined as the concentration of the drug in plasma/serum at the end of the dosing interval. |
| Trough Concentration at Week 26 for LEN | Week 26 | Trough concentration is defined as the concentration of the drug in plasma/serum at the end of the dosing interval. |
| Percentage of Participants With HIV-1 RNA ≥ 50 Copies/mL at Week 52 as Determined by the US FDA-defined Snapshot Algorithm | Week 52 | — |
| Trough Concentration at Week 52 for LEN | Week 52 | Trough concentration is defined as the concentration of the drug in plasma/serum at the end of the dosing interval. |
| Pharmacokinetic (PK) Parameter: AUC0-tau for TAB and ZAB | Up to approximately 6 years | AUC0-tau is defined as the partial area under the concentration versus time curve from time 0 to time t. |
| PK Parameter: t1/2 for TAB and ZAB | Up to approximately 6 years | t1/2 is defined as the terminal elimination half-life. |
| PK Parameter: Cmax for TAB and ZAB | Up to approximately 6 years | Cmax is defined as the maximum observed concentration of drug. |
| PK Parameter: Cmax for LEN | Up to approximately 6 years | Cmax is defined as the maximum observed concentration of drug. |
| PK Parameter: Tmax for TAB, ZAB, and LEN | Up to approximately 6 years | Tmax is defined as the time (observed time point) of Cmax. |
| Percentage of Participants With Treatment-emergent Anti-TAB and Anti-ZAB Antibodies | Up to approximately 6 years | Anti-TAB and anti-ZAB antibodies incidence referred to the percentage of participants who have treatment-emergent anti-TAB and anti-ZAB antibodies among all participants evaluable for anti-drug antibody (ADA) incidence. |
| Trough Concentration at Week 52 for TAB and ZAB | Week 52 | Trough concentration is defined as the concentration of the drug in plasma/serum at the end of the dosing interval. |
Countries
Australia, Canada, Puerto Rico, United States
Participant flow
Recruitment details
241 participants were screened. The study planned to enroll participants in Treatment Groups 1, 2 and 3. However, per review of the programmatic data overall and from study GS-US-536-5816 (NCT04811040), Treatment Group 2 was removed prior to dosing of all groups in the study and did not enroll any participants. Therefore, data is reported only for Treatment Groups 1 and 3.
Pre-assignment details
Participants were enrolled at study sites in the United States, Puerto Rico, Australia, and Canada. Data submitted represent primary analysis performed on data collected by the Primary Analysis Completion Date (02-July-2024). Complete data will be submitted within 1 year of actual study completion date.
Participants by arm
| Arm | Count |
|---|---|
| Randomized Phase Treatment Group 1: LEN + TAB + ZAB Participants received loading dose of LEN 600 mg tablets, orally, on Day 1 and Day 2. They received LEN 927 mg SC injection along with TAB 2550 mg IV infusion and ZAB 2550 mg IV infusion on Day 1 and Q6M up to Week 52 in the Randomized Phase.
At Week 52, participants in this group with HIV-1 RNA \< 50 copies/mL are given the option to participate in the study extension phase. In the study extension phase, participants continued to receive their randomized study drugs every 26 weeks. | 53 |
| Randomized Phase Treatment Group 3: SBR Participants in SBR group continued their baseline oral ART up to Week 52. Antiretroviral therapy included drugs like bictegravir/emtricitabine/tenofovir alafenamide, darunavir/cobicistat/emtricitabine/tenofovir alafenamide, dolutegravir/abacavir lamivudine, and rilpivirine/emtricitabine/tenofovir alafenamide, administered as per standard of care.
At Week 52, participants in this group with HIV-1 RNA \< 50 copies/mL and in the absence of confirmed virologic rebound throughout the Randomized Phase of the study are given the option to participate in the Extension Phase to switch from ART to LEN, TAB and ZAB, every 26 weeks at the dose specified for Treatment Group 1. | 27 |
| Total | 80 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Investigator's Discretion | 1 | 0 |
| Overall Study | Randomized but Never Treated | 3 | 0 |
| Overall Study | Still on Study | 52 | 26 |
Baseline characteristics
| Characteristic | Randomized Phase Treatment Group 1: LEN + TAB + ZAB | Randomized Phase Treatment Group 3: SBR | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 52 Participants | 26 Participants | 78 Participants |
| Age, Continuous | 44 years STANDARD_DEVIATION 13.7 | 53 years STANDARD_DEVIATION 9.6 | 47 years STANDARD_DEVIATION 13 |
| Clusters of Differentiation 4 (CD4)+ T-cell Counts | 740 cells/µL STANDARD_DEVIATION 239.3 | 768 cells/µL STANDARD_DEVIATION 260 | 749 cells/µL STANDARD_DEVIATION 245.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Participants | 7 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 40 Participants | 20 Participants | 60 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 21 Participants | 8 Participants | 29 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 28 Participants | 16 Participants | 44 Participants |
| Region of Enrollment Australia | 2 Participants | 6 Participants | 8 Participants |
| Region of Enrollment Canada | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment Puerto Rico | 2 Participants | 1 Participants | 3 Participants |
| Region of Enrollment United States | 48 Participants | 19 Participants | 67 Participants |
| Sex: Female, Male Female | 8 Participants | 4 Participants | 12 Participants |
| Sex: Female, Male Male | 45 Participants | 23 Participants | 68 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 56 | 0 / 27 |
| other Total, other adverse events | 40 / 53 | 4 / 27 |
| serious Total, serious adverse events | 0 / 53 | 1 / 27 |
Outcome results
Primary
Percentage of Participants With Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) ≥ 50 Copies/mL at Week 26 as Determined by the United States Food and Drug Administration (US FDA)-Defined Snapshot Algorithm
Percentage of participants with HIV-1 RNA ≥ 50 copies/mL at Week 26 was analyzed using US FDA-defined snapshot algorithm, which defines a participant's virologic outcome and included participants a) who had last available on-treatment HIV-1 RNA ≥ 50 copies/mL in the Week 26 analysis window; b) who did not have on-treatment HIV-1 RNA data in the Week 26 analysis window and i) discontinued study drug prior to or in the Week 26 analysis window due to lack of efficacy, or ii) discontinued study drug prior to or in the Week 26 analysis window due to adverse event (AE) or death and had last available on-treatment HIV-1 RNA ≥ 50 copies/mL, or iii) discontinued study drug prior to or in the Week 26 analysis window due to reasons other than AE, death, or lack of efficacy and had the last available on-treatment HIV-1 RNA ≥ 50 copies/mL. Clopper-Pearson exact method was used to calculate the 95% confidence interval (CI) for the outcome measure of each treatment. Percentages were rounded off.
Time frame: Week 26
Population: Participants in the Full Analysis Set were analyzed. The Full Analysis Set included all randomized participants who have received at least one dose of the complete long acting study drug regimen (ie, SC LEN + TAB, ZAB) or continued with their baseline ART regimen.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized Phase Treatment Group 1: LEN + TAB+ ZAB | Percentage of Participants With Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) ≥ 50 Copies/mL at Week 26 as Determined by the United States Food and Drug Administration (US FDA)-Defined Snapshot Algorithm | 1.9 percentage of participants |
| Randomized Phase Treatment Group 3: SBR | Percentage of Participants With Human Immunodeficiency Virus Type 1 (HIV-1) Ribonucleic Acid (RNA) ≥ 50 Copies/mL at Week 26 as Determined by the United States Food and Drug Administration (US FDA)-Defined Snapshot Algorithm | 0.0 percentage of participants |
Secondary
Change From Baseline in CD4+ T-cell Counts at Week 52
Time frame: Baseline, Week 52
Secondary
Change From Baseline in Clusters of Differentiation 4 (CD4) + T-cell Counts at Week 26
Time frame: Baseline, Week 26
Population: Participant in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Phase Treatment Group 1: LEN + TAB+ ZAB | Change From Baseline in Clusters of Differentiation 4 (CD4) + T-cell Counts at Week 26 | 23 cells/µL | Standard Deviation 143.4 |
| Randomized Phase Treatment Group 3: SBR | Change From Baseline in Clusters of Differentiation 4 (CD4) + T-cell Counts at Week 26 | 74 cells/µL | Standard Deviation 202.6 |
p-value: 0.143695% CI: [-132, 20]ANCOVA
Secondary
Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs)
Time frame: Up to approximately 6 years
Secondary
Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 26 as Determined by the US FDA-defined Snapshot Algorithm
Percentage of participants with HIV-1 RNA \< 50 copies/mL at Week 26 was analyzed using the US FDA-defined snapshot algorithm, which defined a participant's virologic outcome and included participants who had the last available on-treatment HIV-1 RNA \< 50 copies/mL in the Week 26 analysis window. The Clopper-Pearson exact method was used to calculate the 95% CI for the outcome measure of each treatment. Percentages were rounded off.
Time frame: Week 26
Population: Participants in the Full Analysis Set were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized Phase Treatment Group 1: LEN + TAB+ ZAB | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 26 as Determined by the US FDA-defined Snapshot Algorithm | 96.2 percentage of participants |
| Randomized Phase Treatment Group 3: SBR | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 26 as Determined by the US FDA-defined Snapshot Algorithm | 96.3 percentage of participants |
Secondary
Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 52 as Determined by the US FDA-defined Snapshot Algorithm
Time frame: Week 52
Secondary
Percentage of Participants With HIV-1 RNA ≥ 50 Copies/mL at Week 52 as Determined by the US FDA-defined Snapshot Algorithm
Time frame: Week 52
Secondary
Percentage of Participants With Treatment-emergent Anti-TAB and Anti-ZAB Antibodies
Anti-TAB and anti-ZAB antibodies incidence referred to the percentage of participants who have treatment-emergent anti-TAB and anti-ZAB antibodies among all participants evaluable for anti-drug antibody (ADA) incidence.
Time frame: Up to approximately 6 years
Secondary
Pharmacokinetic (PK) Parameter: AUC0-tau for TAB and ZAB
AUC0-tau is defined as the partial area under the concentration versus time curve from time 0 to time t.
Time frame: Up to approximately 6 years
Secondary
PK Parameter: Cmax for LEN
Cmax is defined as the maximum observed concentration of drug.
Time frame: Up to approximately 6 years
Secondary
PK Parameter: Cmax for TAB and ZAB
Cmax is defined as the maximum observed concentration of drug.
Time frame: Up to approximately 6 years
Secondary
PK Parameter: t1/2 for TAB and ZAB
t1/2 is defined as the terminal elimination half-life.
Time frame: Up to approximately 6 years
Secondary
PK Parameter: Tmax for TAB, ZAB, and LEN
Tmax is defined as the time (observed time point) of Cmax.
Time frame: Up to approximately 6 years
Secondary
Trough Concentration at Week 26 for LEN
Trough concentration is defined as the concentration of the drug in plasma/serum at the end of the dosing interval.
Time frame: Week 26
Population: Participants in the LEN PK Analysis Set with available data were analyzed. LEN PK Analysis Set included all randomized participants who have received at least 1 dose of study drug, and have at least 1 nonmissing LEN concentration value reported by the PK laboratory test.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Phase Treatment Group 1: LEN + TAB+ ZAB | Trough Concentration at Week 26 for LEN | 20.2 ng/mL | Standard Deviation 10.6 |
Secondary
Trough Concentration at Week 26 for TAB and ZAB
Trough concentration is defined as the concentration of the drug in plasma/serum at the end of the dosing interval.
Time frame: Week 26
Population: Participants in the TAB PK Analysis Set and ZAB PK Analysis Set with available data were analyzed.~TAB PK Analysis Set included all randomized participants who have received at least 1 dose of study drug, and have at least 1 non-missing TAB concentration value reported by the PK laboratory test.~ZAB PK Analysis Set included all randomized participants who have received at least 1 dose of study drug, and have at least 1 non-missing ZAB concentration value reported by the PK laboratory test.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Randomized Phase Treatment Group 1: LEN + TAB+ ZAB | Trough Concentration at Week 26 for TAB and ZAB | TAB | 41.8 µg/mL | Standard Deviation 22.7 |
| Randomized Phase Treatment Group 1: LEN + TAB+ ZAB | Trough Concentration at Week 26 for TAB and ZAB | ZAB | 72.0 µg/mL | Standard Deviation 39.2 |
Secondary
Trough Concentration at Week 52 for LEN
Trough concentration is defined as the concentration of the drug in plasma/serum at the end of the dosing interval.
Time frame: Week 52
Secondary
Trough Concentration at Week 52 for TAB and ZAB
Trough concentration is defined as the concentration of the drug in plasma/serum at the end of the dosing interval.
Time frame: Week 52