Study to Evaluate the Safety and Efficacy of Teropavimab and Zinlirvimab in Combination With Lenacapavir (GS-6207) in Virologically Suppressed Adults With HIV-1 Infection

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the safety and tolerability of a combination of the broadly neutralizing antibodies (bNAbs) teropavimab (formerly GS-5423) and zinlirvimab (formerly GS-2872) in combination with the HIV capsid inhibitor lenacapavir (LEN).

Official Title
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A Phase 1b Randomized, Blinded, Proof-of-Concept Study to Evaluate the Safety and Efficacy of Broadly Neutralizing Antibodies (bNAbs) GS-5423 and GS-2872 in Combination With Capsid Inhibitor Lenacapavir (GS-6207) in Virologically Suppressed Adults With HIV-1 Infection

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: Oral Lenacapavir
* Drug: Subcutaneous Lenacapavir
* Drug: Teropavimab
* Drug: Zinlirvimab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: On first-line antiretroviral therapy (ART) for ≥ 2 years prior to screening. A change in ART regimen ≥ 28 days prior to screening for reasons other than virologic failure (VF) (eg, tolerability, simplification, drug-drug interaction profile) is allowed No documented historical resistance to the current ART regimen Plasma HIV-1 RNA < 50 copies/mL at screening Documented plasma HIV-1 RNA < 50 copies/mL for ≥ 18 months preceding the screening visit (or undetectable HIV-1 RNA level according to the local assay being used if the limit of detection is ≥ 50 copies/mL). Unconfirmed virologic elevations of ≥ 50 copies/mL (transient detectable viremia, or blip) prior to screening are acceptable. Proviral phenotypic sensitivity to both teropavimab and zinlirvimab at screening by the PhenoSense mAb Assay (Monogram Biosciences) for inclusion in the Primary Cohort; sensitivity at screening by the PhenoSense mAb Assay (Monogram Biosciences) to 1 mAb, either teropavimab or zinlirvimab, within 18 months prior to enrollment for inclusion in the optional Pilot Cohort -- In both cohorts, teropavimab sensitivity is defined as 90% inhibitory concentration (IC90) ≤ 2 μg/mL; zinlirvimab sensitivity is defined as IC90 ≤ 2 μg/mL; CD4+ count nadir ≥ 350 cells/μL Screening CD4+ count ≥ 500 cells/μL Availability of a fully active alternative ART regimen, in the opinion of the investigator, in the event of discontinuation of the current ART regimen with development of resistance Key Exclusion Criteria: Comorbid condition requiring ongoing immunosuppression Evidence of current hepatitis B virus (HBV) infection Evidence of current hepatitis C virus (HCV) infection (prior infection cleared spontaneously or with treatment is acceptable) History of opportunistic infection or illness indicative of Stage 3 HIV disease 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: Primary Cohorts: Lenacapavir (LEN), Teropavimab, Zinlirvimab Dose C<br>Participants will begin treatment by receiving LEN Dose A + LEN Dose B + teropavimab + zinlirvimab Dose C followed by LEN Dose A on the next day. The last treatment regimen will include LEN Dose B + teropavimab + zinlirvimab Dose C. | 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: Teropavimab<br>* Administered intravenously<br>* Other names: GS-5423;Drug: Zinlirvimab<br>* Administered intravenously<br>* Other names: GS-2872;|
| Experimental: Primary Cohorts: LEN, Teropavimab, Zinlirvimab Dose D<br>Participants will begin treatment by receiving LEN Dose A + LEN Dose B + teropavimab + zinlirvimab Dose D followed by LEN Dose A on the next day. The last treatment regimen will include LEN Dose B + teropavimab + zinlirvimab Dose D. | 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: Teropavimab<br>* Administered intravenously<br>* Other names: GS-5423;Drug: Zinlirvimab<br>* Administered intravenously<br>* Other names: GS-2872;|
| Experimental: Optional Cohorts: Lenacapavir (LEN), Teropavimab, Zinlirvimab Dose C<br>Optional cohort included participants from primary cohort who could not qualify for primary cohort at the study start. Participants in optional cohort will begin treatment by receiving LEN Dose A + LEN Dose B + teropavimab + zinlirvimab Dose C followed by LEN Dose A on the next day. The last treatment regimen will include LEN Dose B + teropavimab + zinlirvimab Dose C. | 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: Teropavimab<br>* Administered intravenously<br>* Other names: GS-5423;Drug: Zinlirvimab<br>* Administered intravenously<br>* Other names: GS-2872;|
| Experimental: Optional Cohorts: LEN, Teropavimab, Zinlirvimab Dose D<br>Optional cohort included participants screened for primary cohort but could not qualify for primary cohort at the study start. Participants in optional cohort will begin treatment by receiving LEN Dose A + LEN Dose B + teropavimab + zinlirvimab Dose D followed by LEN Dose A on the next day. The last treatment regimen will include LEN Dose B + teropavimab + zinlirvimab Dose D. | 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: Teropavimab<br>* Administered intravenously<br>* Other names: GS-5423;Drug: Zinlirvimab<br>* Administered intravenously<br>* Other names: GS-2872;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing Treatment-Emergent Serious Adverse Events (SAEs) |  | First dose date up to Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants With HIV-1 RNA < 50 Copies/mL at Week 26 as Determined by the US FDA-defined Snapshot Algorithm |  | Week 26 | 
| Proportion of Participants With HIV-1 RNA ≥ 50 Copies/mL at Week 26 as Determined by the US FDA-defined Snapshot Algorithm |  | Week 26 | 
| Proportion of Participants With Positive Anti-Teropavimab Antibodies |  | Week 26 | 
| Proportion of Participants With Positive Anti-zinlirvimab Antibodies |  | Week 26 | 
| Change from Baseline in CD4+ Cell Count at Week 26 |  | Baseline; Week 26 | 
| Proportion of Participants Who Develop Treatment-Emergent Resistance to Lenacapvir (LEN), Teropavimab, and Zinlirvimab |  | Day 1 up to Week 26 | 
| Percentage of Participants Experiencing Treatment-Emergent Adverse Events (AEs) |  | First dose date up to Week 26 | 
| Pharmacokinetic (PK) Parameter: AUC0-t of Teropavimab, and Zinlirvimab, and LEN | AUC0-t is defined as the concentration of drug over time from time zero to time t. | Day 1 up to Week 52 | 
| PK Parameter: AUClast of Teropavimab, and Zinlirvimab, and LEN | AUClast is defined as the concentration of drug from time zero to the last observable concentration. | Day 1 up to Week 52 | 
| PK Parameter: T1/2 of Teropavimab, and Zinlirvimab, and LEN | T1/2 is defined as the estimate of the terminal elimination half-life of the drug. | Day 1 up to Week 52 | 
| PK Parameter: Cmax of Teropavimab, and Zinlirvimab, and LEN | Cmax is defined as the maximum observed concentration of drug. | Day 1 up to Week 52 | 
| PK Parameter: Tmax of Teropavimab, and Zinlirvimab, and LEN | Tmax is defined as the time (observed time point) of Cmax. | Day 1 up to Week 52 | 
| PK Parameter: Tlast of Teropavimab, and Zinlirvimab, and LEN | Tlast is defined as the time (observed time point) of Clast (the last observable concentration of drug). | Day 1 up to Week 52 | 
| PK Parameter: Ct of Teropavimab, and Zinlirvimab, and LEN | Ct is the concentration at a particular time (t). | Day 1 up to Week 52 |