A Proof of Concept Study of GSK3640254 in Human Immunodeficiency Virus-1 (HIV-1) Infected Treatment-naive Adults

A Randomized, Double-Blind (Sponsor-unblinded), Placebo-Controlled, Adaptive Trial to Investigate the Antiviral Effect, Safety, Tolerability and Pharmacokinetics of GSK3640254 in HIV-1 Infected Treatment-Naïve Adults

Infection with HIV-1 continues to be a serious health threat throughout the world. Chronic exposure to combination anti-retroviral therapy identified anti-retroviral associated long-term toxicities. Hence, there is a need to prevent these co-morbidities. GSK3640254 is a next-generation HIV-1 Maturation Inhibitor (MI) which may be effective for HIV-1 infection. This study will evaluate the antiviral effect, safety, tolerability and pharmacokinetics/ pharmacodynamics of GSK3640254 in HIV-1 infected treatment-naive adults. This study will consists of two parts; Part 1 and Part 2. Part 1 will evaluate two active doses of GSK3640254, 200 milligrams (mg) (Cohort 1) and 10 mg (Cohort 2) along with placebo to match GSK3640254 Mesylate salt. Part 2 will evaluate three active doses of GSK3640254. Dose level 1 of GSK3640254 that can provide at least 30 percent of the maximum effect (Cohort 1), dose level 2 of GSK3640254 that can provide at least 75 percent of the maximum effect (Cohort 2) and dose level 3 of GSK3640254 that can provide at least 90 percent of the maximum effect (Cohort 3). These doses are anticipated to be 5 mg, 40 mg and 100 mg respectively, but could be modified based on data obtained in Part 1. Subjects will also receive placebo to match GSK3640254 Mesylate salt in Part 2 of the study. All doses will be administered after a moderate fat meal. This study will consist of Screening period (up to 14 days), Treatment period (Day 1- Day 10), post-dose Follow-up (Day 11- Day 17) and final Follow-up (Day 18-24). A total of approximately 34 subjects will be enrolled, of which, 14 subjects will be randomized in Part 1 and 20 in Part 2 of the study. Six subjects will be enrolled in each of the active dose cohorts and 2 subjects will be enrolled in each of the placebo cohorts.

Inclusion Criteria:

• Subject must be 18 to 65 years of age inclusive, at the time of signing the informed consent.
• Subjects who are healthy (other than HIV infection) as determined by the Investigator or medically qualified designee based on a medical evaluation including medical history, laboratory tests, and cardiac monitoring.
• Screening Cluster of designation 4 positive (CD4+) T-cell count >=350 cells per millimeter cube (cells/mm^3).
• Documented HIV infection and Screening plasma HIV-1 RNA >=5000 copies/milliliter (mL). A single repeat of this test is allowed within a single Screening period to determine eligibility.
• Treatment-naive: No anti-retrovirals (in combination or monotherapy) received after the diagnosis of HIV-1 infection.
• Body weight >=50.0 kilograms (kg) (110 Pounds) for men and >=45.0 kg (99 pounds) for women and body mass index (BMI) within the range 18.5-31.0 kg/meter square (kg/m^2) (inclusive).
• A female subject is eligible to participate if she is not pregnant, not breastfeeding, and not a woman of childbearing potential (WOCBP).
• Capable of giving signed informed consent.
• For subjects enrolled in France: a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

Exclusion Criteria:

• Presence of Hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to starting study treatment.
• Positive Hepatitis C antibody test result at screening or within 3 months prior to starting study treatment and positive on reflex to Hepatitis C RNA.
• ALT >2 times upper limit of normal (ULN). A single repeat of ALT is allowed within a single Screening period to determine eligibility.
• Bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent).
• Subjects with primary HIV infection, evidenced by acute retroviral syndrome (example given [e.g.], fever, malaise, fatigue, etc) and/or evidence of recent (within 3 months) documented viremia without antibody production and/or evidence of recent (within 3 months) documented seroconversion.
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones);
• A pre-existing condition interfering with normal gastrointestinal anatomy or motility (e.g., gastroesophageal reflux disease [GERD], gastric ulcers, gastritis), hepatic and/or renal function, that could interfere with the absorption, metabolism, and/or excretion of the study drugs or render the subject unable to take oral study treatment.
• Any acute laboratory abnormality at screen which, in the opinion of the investigator, should preclude participation in the study of an investigational compound.
• Any Grade 2-4 laboratory abnormality at screen, with the exception of creatine phosphokinase (CPK) and lipid abnormalities (e.g., total cholesterol, triglycerides, etc), and ALT (described above), will exclude a subject from the study unless the investigator can provide a compelling explanation for the laboratory result(s) and has the assent of the sponsor. A single repeat of any lab abnormality is allowed within a single screening period to determine eligibility.
• Any history of significant underlying psychiatric disorder, including but not limited to schizophrenia, bipolar disorder with or without psychotic symptoms, other psychotic disorders, or schizotypal (personality) disorder.
• Any history of major depressive disorder with or without suicidal features, or anxiety disorders, that required medical intervention (pharmacologic or not) such as hospitalization or other inpatient treatment and/or chronic (>6 months) outpatient treatment. Subjects with other conditions such as adjustment disorder or dysthymia that have required shorter term medical therapy (<6 months) without inpatient treatment and are currently well-controlled clinically or resolved may be considered for entry after discussion and agreement with the ViiV Medical Monitor.
• Any pre-existing physical or other psychiatric condition (including alcohol or drug abuse), which, in the opinion of the investigator (with or without psychiatric evaluation), could interfere with the subject's ability to comply with the dosing schedule and protocol evaluations or which might compromise the safety of the subject.
• Medical history of cardiac arrhythmias or cardiac disease or a family or personal history of long QT syndrome.
• History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
• The subject has participated in a clinical trial and has received an investigational product within the 30 days prior to the first dosing day in the current study.
• Any positive (abnormal) response confirmed by the investigator on a Screening clinician- (or qualified designee-) administered Columbia Suicide Severity Rating Scale (CSSRS).
• Any positive result for illicit drug use (e.g., cocaine, heroin) at Screening. A positive screen for marijuana is not exclusionary, though if positive for delta-9-tetrahydrocannabinol (THC).
• Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 56 days.
• Exposure to more than four new investigational drugs or vaccines within 12 months prior to the first dosing day.
• Treatment with radiation therapy or cytotoxic chemotherapeutic agents within 30 days of study drug administration or anticipated need for such treatment within the study.
• Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous cell carcinoma, or cervical, anal or penile intraepithelial neoplasia; or other localized malignancies require agreement between the investigator and the study medical monitor for inclusion of the subject prior to randomization.
• Treatment with immunomodulating agents (such as systemic corticosteroids, interleukins, interferons) or any agent with known anti-HIV activity (such as hydroxyurea or foscarnet) within 30 days of study drug administration.
• An active Center for Disease Control and Prevention (CDC) Category C disease except cutaneous Kaposi's sarcoma not requiring systemic therapy during the trial.
• Treatment with any vaccine within 30 days prior to receiving study medication.
• Exclusion criteria for screening electrocardiogram (a single repeat is allowed for eligibility determination): Heart rate of <45 or >100 beats per minute (bpm) for males and <50 or >100 bpm for females; PR Interval of <120 or >200 milliseconds (msec) for both males and females; QRS duration of <70 or >110 msec for both males and females; QT interval corrected (QTc) for heart rate according to Fridericia's formula (QTcF) of >450 msec for males and >470 msec for females. A heart rate from 100 to 110 bpm can be rechecked by electrocardiogram or vitals within 30 minutes to verify eligibility. QTcF is either machine read or manually over-read.
• Any significant arrhythmia or electrocardiogram finding (e.g., prior myocardial infarction, sinoatrial pauses, bundle branch block, or conduction abnormality) which, in the opinion of the Investigator OR ViiV Medical Monitor, will interfere with the safety for the individual subject.