Drug-Drug Interaction Study of Vesatolimod in Adults With HIV-1 Who Have Very Low or Undetectable Virus Levels

Study Overview
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Brief Summary
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The goal of this clinical study is to learn more about the impact of cobicistat (COBI) (P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and strong cytochrome P450 enzyme [CYP]3A inhibitor), voriconazole (VOR) (strong CYP3A inhibitor), and rifabutin (RFB) (moderate CYP3A inducer) on the study drug, vesatolimod (VES), in people with HIV-1 on antiretroviral therapy (ART).

Official Title
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A Phase 1, Open-label, Multicohort Study to Evaluate the Impact of Inhibitors and Inducers of Cytochrome P450 Enzyme (CYP)3A, P-glycoprotein (P-gp), and Breast Cancer Resistant Protein (BCRP) on the Pharmacokinetics (PK) of Vesatolimod (VES) in Virologically Suppressed Adults With HIV-1 on Antiretroviral Therapy (ART)

Conditions
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Human Immunodeficiency Virus Type 1 (HIV-1) Infection

Intervention / Treatment
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* Drug: Vesatolimod
* Drug: Cobicistat
* Drug: Voriconazole
* Drug: Rifabutin


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: On an antiretroviral therapy (ART) regimen for at least 6 consecutive months, with no change in the ART regimen within 2 months prior to screening. Permitted ARTs are as follows: Cohort 1: A regimen of (BIC, DTG, RAL, or DOR) plus Nucleoside Reverse Transcriptase Inhibitors (NRTIs). Examples of acceptable regimens include BIC/emtricitabine/tenofovir, DTG/ABC/3TC, DTG/3TC, DTG + emtricitabine/tenofovir, or DOR/3TC/tenofovir Cohort 2: A DTG-based regimen is required (DTG/ABC/3TC), (DTG/3TC), or (DTG + NRTIs) Plasma HIV-1 RNA levels less than 50 copies/mL at screening Have normal hematologic function with an absolute neutrophil count greater than or equal to 1.5 × 10^9/L, platelets greater than or equal to 150 × 10^9/L; hemoglobin greater than or equal to 10.5 g/dL for females and greater than or equal to 11.5 g/dL for males Clusters of differentiation (CD) 4 T cell count greater than or equal to 350 cells/μL Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 2.5 x upper limit of normal (ULN) and total bilirubin less than or equal to 1.5 mg/dL, or normal direct bilirubin and creatinine less than or equal to 1.25 x ULN Have a calculated creatinine clearance (CLcr) of at least 60 mL/min (using the Cockcroft-Gault method) based on serum creatinine and actual body weight as measured at screening and upon admission Individuals assigned female at birth and of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception Must be willing and able to comply with all study requirements and available to complete the study schedule of assessments In the judgment of the investigator, be in good general health, based on review of the results from a screening visit Key Exclusion Criteria: Have received any study drug within 30 days prior to study dosing Participation in any other clinical study (including observation studies) without prior approval from the sponsor is prohibited while participating in this study Have current alcohol or substance abuse judged by the investigator to potentially interfere with individual compliance or individual safety, or a positive drug or alcohol test at screening or baseline No Evidence of chronic hepatitis B virus (HBV) infection (defined as positive hepatitis B surface antigen [HBsAg] and/or positive HBV core antibody with positive reflex HBV DNA polymerase chain reaction (PCR)). Note: positive HBV core antibody with negative reflex HBV DNA PCR results are acceptable No Evidence of active hepatitis C virus (HCV) infection (defined as positive hepatitis C antibody and HCV RNA above lower limit of quantitation). Note: positive anti-HCV antibody and negative HCV PCR results are acceptable Acute febrile illness within 35 days prior to Day 1 Have been treated with systemic steroids, immunosuppressant therapies, or chemotherapeutic agents within 3 months prior to screening or is expected to receive these agents during the study Received any vaccine or immunomodulatory medication within 4 weeks prior to screening. Elective vaccination (eg, flu shot, hepatitis A or B vaccine) during the course of the study will require prior approval from the sponsor Coronavirus disease of 2019 (COVID-19) vaccinations are allowed, with the requirement that they should not be administered within 7 ± 2 days of receiving VES Have a history of any of the following: Significant serious skin disease, such as but not limited to rash, food allergy, eczema, psoriasis, or urticaria Significant drug sensitivity or drug allergy (such as anaphylaxis or hepatoxicity) Known hypersensitivity to the study drugs, their metabolites, or to formulation excipients Autoimmune disease Significant cardiac disease or a family history of long QT syndrome, or unexplained death in an otherwise healthy individual between the ages of 1 and 30 years Syncope, palpitations, or unexplained dizziness Implanted defibrillator or pacemaker Liver disease, including Gilbert syndrome Severe peptic ulcer disease requiring prolonged (≥ 6 months) medical treatment Medical or surgical treatment that permanently altered gastric absorption (eg, gastric or intestinal surgery). A history of cholecystectomy is not exclusionary Have any serious or active medical or psychiatric illness (including depression) that, in the opinion of the investigator, would interfere with individual treatment, assessment, or compliance with the protocol For Cohort 1, individuals with CYP2C19 genotype of CYP2C19*2/*2, CYP2C19*2/*3, or CYP2C19*3/*3 Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vesatolimod (VES) + Cobicistat (COBI) + Voriconazole (VOR)<br>Participants will receive: In Period 1 (duration 1 day): a single dose of VES 2 mg on Day 1 In Period 2 (duration 5 days): COBI 150 mg once daily on Days 1 to 5; a single dose of VES 2 mg will be coadministered on Day 2 In Period 3 (duration 6 days): a loading dose of VOR 400 mg twice daily on Day 1, then VOR 200 mg twice daily on Days 2 to 6; a single dose of VES 2 mg will be coadministered in the morning on Day 3 There will be a washout period of 7 to 14 days between treatments in Period 1 Day 1 and Period 2 Day 1 and a washout period of 14 to 21 days between treatments in Period 2 Day 5 and Period 3 Day 1. Participants should inform the site of any adverse event (AE) during the washout period. | Drug: Vesatolimod<br>* Administered orally<br>* Other names: GS-9620;Drug: Cobicistat<br>* Administered orally<br>* Other names: Tybost®;Drug: Voriconazole<br>* Administered orally<br>* Other names: Vfend®;|
| Experimental: Vesatolimod (VES) + Rifabutin (RFB)<br>Participants will receive: In Period 1 (duration 1 day): participants will receive a single dose of VES 6 mg on Day 1 In Period 2 (duration 9 days): participants will receive RFB 300 mg once daily on Days 1 to 9; a single dose of VES 6 mg will be coadministered on Day 6 There will be a washout period of 7 to 14 days between treatments in Period 1 Day 1 and Period 2 Day 1. Participants should inform the site of any AE during the washout period. | Drug: Vesatolimod<br>* Administered orally<br>* Other names: GS-9620;Drug: Rifabutin<br>* Administered orally<br>* Other names: Mycobutin®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) Parameter : AUClast of Vesatolimod (VES) | AUClast is defined as an area under the concentration versus time curve from time zero to the last quantifiable concentration. | Predose up to 96 hours postdose | 
| PK Parameter : AUCinf of VES | AUCinf is defined as an area under the concentration versus time curve extrapolated to infinite time, calculated as AUClast + (Clast/Lambda z). | Predose up to 96 hours postdose | 
| PK Parameter : Cmax of VES | Cmax is defined as the maximum observed concentration of drug. | Predose up to 96 hours postdose | 
| PK Parameter : %AUCexp of VES | %AUCexp is defined as the percentage of AUC extrapolated between AUClast and AUCinf. | Predose up to 96 hours postdose | 
| PK Parameter : Tmax of VES | Tmax is defined as the time (observed time point) of Cmax. | Predose up to 96 hours postdose | 
| PK Parameter : Clast of VES | Clast is defined as the last observed quantifiable concentration of the drug. | Predose up to 96 hours postdose | 
| PK Parameter : Tlast of VES | Tlast is defined as the time (observed time point) of Clast. | Predose up to 96 hours postdose | 
| PK Parameter : Lambda z of VES | Lambda z is defined as the terminal elimination rate constant, estimated by linear regression of the terminal elimination phase of the log concentration of drug versus time curve of the drug. | Predose up to 96 hours postdose | 
| PK Parameter : t1/2 of VES | t1/2 is defined as the terminal elimination half-life. | Predose up to 96 hours postdose | 
| PK Parameter : CL/F of VES | CL/F is defined as an apparent oral clearance. | Predose up to 96 hours postdose | 
| PK Parameter : Vz/F of VES | Vz/F is defined as an apparent volume of distribution of the drug. | Predose up to 96 hours postdose | 
| Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) |  | First dose date up to Week 7 plus 30 days | 
| Percentage of Participants Experiencing Treatment-Emergent Graded Laboratory Abnormalities |  | First dose date up to Week 7 plus 30 days |