A Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics (PD) of GSK3888130B in Healthy Participants

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is any serious adverse event that, at any dose: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or any other situation according to medical or scientific judgment.

Blood samples were collected for analysis of following hematology parameters: Basophils, Eosinophils, Hematocrit, Hemoglobin (Hg), Lymphocytes, Mean corpuscular Hg, Mean corpuscular volume, Monocytes, Platelet count, Red blood cell count, Reticulocytes, Total Neutrophils, and White blood cells count (WBC). Number of participants with clinically significant changes in hematology were reported. Clinical significance was determined by the investigator.

Blood samples were collected for the analysis of CD4+ T Cell Counts. The CD4+ T Cell Counts were graded according to National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI-CTCAE). Grade 0: Above 0.5*10^9 cells/Liter (L), Grade 1: <0.5 to 0.2*10^9 cells/L, Grade 2: <0.2 to 0.05*10^9 cells/L, Grade 3: Below 0.05*10^9 cells/L. Baseline was defined as the latest pre-dose assessment. An increase was defined as an increase in grade relative to Baseline grade. Any worst-case post Baseline increase to Grade 1, Grade 2 and Grade 3 are presented.

Blood samples were collected for the analysis of Creatinine. Creatinine was graded according to the NCI-CTCAE. Grade 0: <1.5* Baseline, or increase from Baseline <26 micromoles per liter (umol/L), Grade 1: 1.5 to 1.9* Baseline, or increase from Baseline >=26 umol/L, Grade 2: 2.0 to 2.9* Baseline, Grade 3: >=3.0* Baseline, or >=354 umol/L. Baseline was defined as the latest pre-dose assessment. An increase was defined as an increase in grade relative to Baseline grade. Any worst-case post Baseline increase to Grade 1, Grade 2 and Grade 3 are presented.

Blood samples were collected for analysis of following clinical chemistry parameters: Alanine Aminotransferase, Alkaline Phosphatase, Aspartate Aminotransferase, Calcium, Total and Direct bilirubin, Glucose, Potassium, Sodium, Total protein, Lactate dehydrogenase, Haptoglobins and Urea. Number of participants with clinically significant changes in clinical chemistry were reported. Clinical significance was determined by the investigator.

Urine samples were collected for analysis of Specific gravity, potential of hydrogen (pH), glucose, protein, erythrocytes, ketones, bilirubin, urobilinogen, nitrite, and leukocyte in urine by dipstick. The dipstick test gives results in a semi-quantitative manner, and results for urinalysis parameters can be read as negative, trace, 1+, 2+, 3+ indicating proportional concentrations in the urine sample. Any increase means any increase to trace, 1+, 2+ or 3+ post-Baseline relative to Baseline. Baseline was defined as the latest pre-dose assessment. Number of participants with worst-case any increase in urinalysis results post-Baseline relative to Baseline has been presented.

Vital signs included systolic and diastolic blood pressure, pulse and respiratory rate and were measured with the participant in semi-supine position after 5 minutes rest. Temperature was also measured as a vital sign but did not require positioning or rest prior to measuring. Clinical significance was determined by the investigator.

VZV-Nucleic acid from blood samples were extracted using the QIASymphony SP followed by TaqMan real time polymerase chain reaction (PCR) for amplification and detection. Murine cytomegalovirus (mCMV) was used as an internal control (IC) and was introduced during the extraction process. CMV-Nucleic acid was extracted using the QIASymphony SP/AS followed by automated set up of Artus real time PCR using the Rotor-Gene Q for amplification and detection. Baseline was defined as the latest pre-dose assessment. Number of participants with Positive CMV DNA and VZV DNA has been presented.

EBV DNA was assessed and qualitative data has been presented. Data has been categorized into 'Positive >=LLQ' and 'Positive < LLQ'. LLQ is lower limit of quantification. Participants who had EBV DNA values >=LLQ were categorized as 'Positive >=LLQ'. This represents a positive result that is above the assay limit of quantification. Participants who had EBV DNA values <LLQ were categorized as 'Positive <LLQ'. This represents a positive result that is below the assay limit of quantification. Baseline was defined as the latest pre-dose assessment.

Twelve lead ECGs were obtained using an ECG machine that automatically calculated the heart rate and measured PR, QRS, QT, and QT corrected interval. Abnormal findings were categorized as clinically significant (CS) and not clinically significant (NCS). Clinically significant abnormal findings are those which are not associated with the underlying disease, unless judged by the investigator to be more severe than expected for the participant's condition. Data for number of participants with worst case post-Baseline abnormal ECG findings have been presented.

Blood samples were collected at indicated time points for measurement of serum concentrations of GSK3888130B following intravenous administration. Pharmacokinetic (PK) Population consisted of all participants in the Safety analysis set who had received an active study intervention and had at least 1 non-missing post dose PK assessment (Non-quantifiable [NQ] values were considered as non-missing values).

Blood samples were collected at indicated time points for measurement of serum concentrations of GSK3888130B following subcutaneous administration.

Blood samples were collected at indicated time points for measurement of serum concentrations of GSK3888130B following intravenous administration. Pharmacokinetic (PK) Population consisted of all participants in the Safety analysis set who had received an active study intervention and had at least 1 non-missing post dose PK assessment (Non-quantifiable [NQ] values were considered as non-missing values).

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3888130B following intravenous administration.

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3888130B following subcutaneous administration.

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3888130B following intravenous administration.

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3888130B following intravenous administration.

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3888130B following subcutaneous administration.

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3888130B following intravenous administration.

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3888130B following intravenous administration.

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3888130B following subcutaneous administration.

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3888130B following intravenous administration.

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3888130B following intravenous administration.

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3888130B following subcutaneous administration.

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3888130B following intravenous administration.

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3888130B following intravenous administration.

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3888130B following subcutaneous administration.

Blood samples were collected at indicated time points for pharmacokinetic analysis of GSK3888130B following intravenous administration.

Serum samples were collected for the determination of anti-drug antibodies (ADA) using a validated electrochemiluminescent (ECL) immunoassay. The assay involved screening, confirmation and titration steps. If serum samples tested positive in the screening assay, they were considered 'potentially positive' and were further analyzed for specificity using the confirmation assay. Samples that confirmed positive in the confirmation assay were reported as 'positive'. Confirmed positive ADA samples were further characterized in the titration assay to quasi-quantitate the amount of ADA in the sample. Baseline was defined as the latest pre-dose assessment.

Free IL-7 levels were derived from total IL-7 and total GSK3888130B concentrations (named as Derived Free IL-7) over time using a nonlinear mixed effects modelling approach. A target-mediated drug disposition model was used to fit the total IL-7 and total GSK3888130B assay concentration data to derive the free-IL-7 concentrations. Peak reduction relative to Baseline (Percent change) was calculated for each participant as; Peak reduction = (1 - minimum [Free IL7/IL7 Baseline])*100. Baseline was defined as the latest pre-dose assessment.

Blood samples were collected at indicated time points to measure Bcl-2 Expression in CD4+ T Cells as median fluorescence intensity (MdFI). Baseline was defined as the latest pre-dose assessment. MdFI values as a measure of Bcl-2 expression in CD4+ T cells was measured by flow cytometry. Placebo arms were combined as pre-specified in reporting and analysis plan.