Study of Lenacapavir, Teropavimab, and Zinlirvimab Versus Cabotegravir and Rilpivirine in Virologically Suppressed Adults With HIV-1 on Oral Daily Antiretroviral Therapy

Prior treatment

• MC11. Have poor venous access that would limit phlebotomy or IV infusion of study drugs
• Prior/Concurrent Therapy or Clinical Study Experience PT1. Prior use of, or exposure to, LEN or a bNAb for HIV-1.
• PT2. Prior use of, or exposure to, LA injectable CAB or LA injectable RPV.
• PT3. Prior use of, or exposure to, ibalizumab, fostemsavir, or maraviroc.
• PT5. Treatment with immunosuppressant therapies (eg, corticosteroids, immunoglobulins, and other immune- or cytokine-based therapies) within 4 weeks of screening (with the exception of a single short course of corticosteroids lasting ≤ 7 days) or have a comorbid condition with an anticipated need ongoing immunosuppressive treatment during the study.
• PT6. Requirement for ongoing therapy with or prior use of any prohibited medications listed in Section 5.3.1.
• PT7. Participation or planned participation in any other clinical study (including observational studies) without prior approval from the sponsor.
• DA2. Chronic HBV infection, as determined by either: Positive HBV surface antigen and negative HBV surface antibody, regardless of HBV core antibody status, at the screening visit. Positive HBV core antibody and negative HBV surface antibody, regardless of HBV surface antigen status, at the screening visit. Note: Participants found to be susceptible to HBV infection (eg, negative hepatitis B surface antibody at the screening visit, regardless of prior HBV vaccination history) should be recommended to receive an HBV vaccination. Those who remain non immune will receive regular testing for HBV.
• Other Exclusion Criteria OE1. Have other concurrent medical or psychiatric conditions, or prior therapies that, in the investigator’s opinion, may be likely to confound study interpretation, prevent completion of study procedures and follow-up examinations, or poses an undue risk to the participant.
• MC6. Active, serious infections (other than HIV-1) requiring therapy < 30 days prior to randomization.
• MC8. Acute hepatitis of any cause < 30 days before randomization.

Other illness

• Medical Conditions/History MC1. History of an opportunistic infection or illness indicative of Stage 3 HIV disease.
• MC10. Active malignancy requiring acute systemic therapy.
• MC2. History of treatment failure.
• Diagnostic Assessments DA1. Hepatitis C virus (HCV) antibody positive and HCV RNA detectable.
• DA3. Severe renal impairment-estimated glomerular filtration rate < 30 mL/min according to the Cockcroft-Gault formula {Cockcroft 1976}.
• MC4. Participants with a dermatologic condition or implanted prothesis overlying the gluteal injection site for CAB + RPV.
• MC5. Known hypersensitivity to the study intervention, its metabolites, or formulation excipients.
• MC7. Active tuberculosis infection.
• MC9. History of, or current clinical decompensated liver cirrhosis (eg, ascites, encephalopathy, or variceal bleeding) or severe hepatic impairment (Child-Pugh Class C).

Lab values

• DA5. Any of the following laboratory values at screening: A) ALT > 5 × upper limit of normal (ULN). B) Direct bilirubin > 1.5 × ULN. C) Platelets < 50,000/mm3. D) Hemoglobin < 8.0 g/dL.

Other

• MC12. Participants assigned female sex at birth who are pregnant, nursing a child (breastfeeding), or plan to become pregnant, or begin nursing (breastfeeding) a child during the study.
• PT4. Baseline regimen consisting of monotherapy with any single ARV.
• DA4. Abnormal electrocardiogram (ECG) at the screening visit that is clinically significant, as determined by the investigator.
• OE2. Participants under guardianship, curatorship, or legal protection may not participate in the study.
• MC3. Known or suspected resistance to either CAB or RPV. Resistance to CAB defined as the following mutations: G118R, Q148K, Q148R, T66K+L74M, E92Q+N155H, E138A+Q148R, E138K+Q148K/R, G140C+Q148R, G140S+Q148H/K/R, Y143H+N155H, and Q148R+N155H. Resistance to RPV defined as the following mutations: K101E and P; E138A, G, K, R, and Q; V179L; Y181C, I, and V; Y188L; H221Y; F227C; M230I and L, and the combination of L100I/K103N.

• General G1. Participants assigned male or female at birth, 18 years of age or older at screening, able to understand and give written informed consent and comply with treatment and follow-up.
• G2. Participants assigned female at birth who are of childbearing potential and engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception as described in Appendix 11.5.
• Medical History/Physical Characteristics MH1. Body weight ≥ 35 kg at screening.
• MH2. HIV-1 susceptibility results from screening meeting specific criteria: Proviral phenotypic susceptibility to both TAB and ZAB by the investigational PhenoSense HIV mAb assay (Labcorp-Monogram Biosciences) at screening. TAB phenotypic susceptibility is defined as IC90 ≤ 2 µg/mL; ZAB phenotypic susceptibility is defined as IC90 ≤ 2 µg/mL.
• MH3. Plasma HIV-1 RNA levels < 50 copies/mL at screening (SV2).
• MH4. At least 1 documented HIV-1 RNA level measured between 6 months and 12 months (+2 months) prior to screening (SV1). This and any other HIV-1 RNA measurements documented in this period must be < 50 copies/mL (undetectable HIV-1 RNA level according to the local assay being used if the limit of detection is ≥ 50 copies/mL). A single virologic elevation of ≥ 50 copies/mL and < 400 copies/mL (transient detectable viremia or “blips”) prior to screening are acceptable if the subsequent plasma HIV-1 RNA level is < 50 copies/mL.
• MH5. A plasma HIV-1 RNA test < 50 copies/mL (undetectable HIV-1 RNA level according to the local assay being used if the limit of detection is ≥ 50 copies/mL) within the last 6 months prior to SV1. If > 1 plasma HIV-1 RNA measurements in the last 6 months prior to screening are available, all must be < 50 copies/mL (undetectable HIV-1 RNA level according to the local assay being used if the limit of detection is ≥ 50 copies/mL).
• MH6. On a stable oral ART for ≥ 6 months prior to screening. A change in ART regimen ≥ 3 months prior to the screening visit for reasons other than VF (eg, tolerability, simplification, DDI profile) is allowed; participants with a change in ART regimen ≥ 3 months prior to screening must have been on the regimen for ≥ 3 months prior to screening, and all HIV-1 RNA measurements in that period must be < 50 copies/mL. There are no permitted changes to ART regimens between SV1 and Day 1.
• Laboratory Assessments LA1. For participants of childbearing potential, a negative serum pregnancy test at screening, prior to Day 1 randomization, and enrollment (per Appendix 11.5). A negative urine pregnancy test is required on Day 1 visit prior to the dosing of study drugs.