Heavily Treatment Experienced People Living with HIV-1 Infection

The primary objective of this study is:  To evaluate the antiviral activity of GS-6207 administered as an add-on to a failing regimen (functional monotherapy) for PLWH with MDR as determined by the proportion of participants achieving at least 0.5 log10 reduction from baseline in HIV-1 RNA at the end of Functional Monotherapy Period The secondary objective of this study is:  To evaluate the safety and efficacy of GS-6207 in combination with an optimized background regimen at Weeks 26 and 52 The exploratory objectives of this study are:  To evaluate the emergence of capsid inhibitor (CAI) resistance  To evaluate the plasma pharmacokinetics (PK) of GS-6207  To identify or validate genetic markers that may be predictive of the natural history of disease, response to therapy, and/or tolerability of medical therapies through genetic discovery research (eg, pharmacogenomics), in participants who provide their specific consent  To assess the effect of treatment on health related quality of life

Lenacapavir (LEN: previously referred to as GS-6207)

Lenacapavir (GS-6207)

tablet; injection

300 (tablet); 309 (injection)

The primary endpoint of this study is:
 The proportion of participants in Cohort 1 achieving ≥ 0.5 log10 copies/ml reduction from baseline in HIV-1 RNA at the end of Functional Monotherapy Period
The secondary endpoint of this study is:
 The proportion of participants in Cohort 1 with plasma HIV-1 RNA < 50 copies/mL and < 200 copies/mL at Weeks 26 and 52 treatment based on the US FDA-defined snapshot algorithm

Inclusion Criteria
Participants must meet all of the following inclusion criteria to be eligible for participation in this study:
1) Willing and able to provide written informed consent (participants 18 years of age) and assent (participants 12 and < 18 years of age) prior to performing study procedures.
For participants 12 and < 18 years of age, parent or legal guardian willing and able to provide written informed consent prior to performing study procedures as required by local law
2) Adult aged ≥ 18 years (at all sites) or adolescent aged ≥ 12 and weighing ≥ 35 kg (at sites in North America and Dominican Republic)
3) Are receiving a stable failing ARV regimen for > 8 weeks before Screening and willing to continue the regimen until Day 1. Participants in Cohort 1 must also be willing to continue the failing regimen until completing the Functional Monotherapy Period (Day 1 to Day 14)
4) Have HIV-1 RNA 400 copies/mL at Screening
5) Have screening or available historical HIV resistance reports showing resistance to ≥ 2 antiretroviral medications from each of ≥ 3 of the 4 main classes of antiretroviral medications (NRTI, NNRTI, PI, INSTI). Resistance to FTC or 3TC associated with the presence of the M184V/I RT mutation cannot be used for the purpose of determining this eligibility criterion
6) Have ≤ 2 fully active ARV remaining from the 4 main classes that can be effectively combined to form a viable regimen in the opinion of the investigator based on resistance, tolerability, contraindication, safety, drug access, or acceptability to the participant. Refer to Table 5-2 for list of disallowed ARVs
7) Able and willing to receive an optimized background regimen together with GS-6207.
Participants with an OBR without a fully active agent may be enrolled if the investigator considers that there is a favorable risk-benefit ratio for the participant. With prior approval from Gilead Sciences, components of the OBR may be investigational (ie not-yet-approved)
8) A negative serum pregnancy test is required for all women at Screening
9) Men and women of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception as described in Appendix 4
10) Lactating women must agree to discontinue nursing before administration of GS-6207

Exclusion Criteria
Participants who meet any of the following exclusion criteria are not to be enrolled in this study:
1) An opportunistic illness requiring acute therapy within the 30 days prior to screening
2) Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or
antifungal therapy within 30 days before screening
3) Active tuberculosis infection
4) Acute hepatitis within 30 days prior to Screening visit
5) Untreated or newly treated (< 3 months prior to screening) Hepatitis B Virus (HBV)
infection. Hepatitis B infection is defined as screening results showing either or both of:
a. Positive HBV surface antigen
b. Positive HBV core antibody and negative HBV surface antibody
6) Hepatitis C virus (HCV) antibody positive and HCV RNA > LLOQ
7) A history of or current clinical decompensated liver cirrhosis (eg ascites, encephalopathy, or
variceal bleeding)
8) Treatment with immunosuppressant therapies or chemotherapeutic agents < 3 months before
screening, or expected to receive these agents or systemic steroids during the study
(eg, corticosteroids, immunoglobulins, and other immune- or cytokine-based therapies)
9) A history (< 5 years) of or ongoing malignancy (including untreated carcinoma in-situ) other
than cutaneous Kaposi's sarcoma (KS), basal cell carcinoma, or resected, non-invasive
cutaneous squamous carcinoma. Participants with biopsy-confirmed cutaneous KS are
eligible, but must not have received any systemic therapy for KS within 30 days of Day 1 and
are not anticipated to require systemic therapy during the study
10) Current alcohol or substance use judged by the Investigator to potentially interfere with the
participant’s study compliance
11) Clinically significant abnormal ECG at the Screening visit
12) Any of the following laboratory values at screening:
a. Estimated GFR ≤ 60 mL/min using Cockcroft-Gault formula for participants ≥ 18 years
of age {Cockcroft 1976} and Schwartz Formula for participants < 18 years of age for
creatinine clearance
b. ALT > 5 x upper limit of normal (ULN)
c. Direct bilirubin > 1.5 x ULN
d. Platelets < 50,000/mm3
e. Hemoglobin < 8.0 g/dL
13) Participation or planned participation in any other clinical trial (including observational
trials) without prior approval from the sponsor throughout the study
14) Prior use of, or exposure to, GS-6207
15) Known hypersensitivity to the IMP, the metabolites, or formulation excipient
16) Use or planned use of exclusionary medications, refer to Section 5.4
17) Any other clinical condition or prior therapy that, in the opinion of the Investigator, would
make the participant unsuitable for the study or unable to comply with dosing requirements