Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Clinical Effect of GSK2646264 in Cutaneous Lupus Erythematosus Subjects

Triplicate 12-lead ECGs were obtained using an ECG machine that automatically measured PR, QRS, QT, and QT interval corrected using Fridericia's formula (QTcF) intervals. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. All participants received both treatment interventions at the same time (on different skin sites), hence data for these participants were combined.

Time frame: Baseline (Day 1), Day 14 and follow-up (up to Day 56)

Population: Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles). Data was not collected for Group A as no participants were dosed.

Triplicate 12-lead ECGs were obtained using an ECG machine that automatically calculated the heart rate. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. All participants received both treatment interventions at the same time (on different skin sites), hence data for these participants were combined.

Time frame: Baseline (Day 1), Day 14 and follow-up (up to Day 56)

Population: Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles). Data was not collected for Group A as no participants were dosed

Urine samples were collected to monitor the pH. pH is a measure of hydrogen ion concentration and is used to determine the acidity or alkalinity of urine. pH scale ranges from 0 to 14. A neutral pH is 7.0. The higher number indicates the more basic (alkaline) nature of urine and lower number indicates the more acidic urine. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. All participants received both treatment interventions at the same time (on different skin sites), hence data for these participants were combined.

Time frame: Baseline (Day 1), Day 14, Day 28 and follow-up (up to Day 56)

Population: Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles). Data was not collected for Group A as no participants were dosed

Urine samples were collected to monitor the specific gravity. Specific gravity is a measure of urine concentration and is measured using a chemical test. Specific gravity measurements provide a comparison of the amount of substances dissolved in urine as compared to pure water. If there were no solutes present, the specific gravity of urine would be 1.000 the same as pure water. Specific gravity between 1.002 and 1.035 could be considered as normal. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. All participants received both treatment interventions at the same time (on different skin sites), hence data for these participants were combined.

Time frame: Baseline (Day 1), Day 14, Day 28 and follow-up (up to Day 56)

Population: Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles). Data was not collected for Group A as no participants were dosed

An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is a congenital anomaly/birth defect and other situations according to medical or scientific judgement or events associated with liver injury and impaired liver function.

Time frame: Up to Day 56

Population: Safety Population. All participants received both treatment interventions at the same time (on different skin sites), hence data for these participants were combined. Data was not collected for Group A as no participants were dosed.

Blood samples were collected to analyze the clinical chemistry parameters; albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), calcium, glucose, potassium (Pot) and sodium. PCI ranges were albumin (low: \<30 grams per liter), calcium (low: \<2 millimoles per liter \[mmol/L\] and high: \>2.75 mmol/L), glucose (low: \<3 mmol/L and high: \>9 mmol/L), Pot (low: \<3 mmol/L and high: \>5.5 mmol/L), sodium (low: \<130 mmol/L and high: \>150 mmol/L), ALT (high: \>=2 times upper limit of normal \[ULN\] units per liter {U/L}), AST (high: \>=2 times ULN U/L), ALP (high: \>=2 times ULN U/L) and TB (high: \>=1.5 times ULN micromoles per liter). Safety Population comprised of all participants who received at least one dose of study treatment. All participants received both treatment interventions at the same time (on different skin sites), hence data for these participants were combined.

Time frame: Day 14, Day 28 and follow-up (up to Day 56)

Population: Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles). Data was not collected for Group A as no participants were dosed.

PCI ranges were hematocrit \[Hct\] (high: \>0.54 proportion of red blood cell \[RBC\] in blood), hemoglobin \[Hb\] (high: \>180 grams per liter), RBC (low: \<4.2x10\^12 cells per liter and high: \>5.9x10\^12 cells per liter), lymphocytes \[Lympho\] (low: \<0.8x10\^9 cells per liter), monocytes \[Mono\] (low: \<0.14x10\^9 cells per liter and high: \>1.3x10\^9 cells per liter), neutrophils \[Neutro\] (low: \<1.5x10\^9 cells per liter), platelet count \[PC\] (low: \<100x10\^9 cells per liter and high: \>550x10\^9 cells per liter), eosinophils \[Eos\] (high: \>0.55x10\^9 cells per liter), basophils \[Baso\] (high: \>0.22x10\^9 cells per liter), white blood cell \[WBC\] (low: \<3x10\^9 cells per liter and high: \>20x10\^9 cells per liter). All participants received both treatment interventions at the same time (on different skin sites), hence data for these participants were combined.

Time frame: Day 14, Day 28 and follow-up (up to Day 56)

Population: Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles). Data was not collected for Group A as no participants were dosed.

Vital signs such as diastolic blood pressure (DBP), heart rate (HR) and systolic blood pressure (SBP) were measured in semi-supine position after 5 minutes rest for the participants. PCI ranges were SBP (lower: \<85 millimeters of mercury \[mmHg\] and upper: \>160 mmHg), DBP: (lower: \<45 mmHg and upper: \>100 mmHg) and HR (lower: \<40 beats per minute \[bpm\] and upper: \>110 bpm). All participants received both treatment interventions at the same time (on different skin sites), hence data for these participants were combined.

Time frame: Day 14 and Day 28

Population: Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles). Data was not collected for Group A as no participants were dosed

The score ranges for different components were; erythema \[0 (absent) to 3 (dark red, purple/violaceous/crusted/hemorrhagic)\], scaling/hyperkeratosis \[0 (absent) to 2 (verrucous hyperkeratosis)\], edema/infiltration \[0 (absent) to 2 (palpable and visible)\] and dyspigmentation \[0 (absent) to 2 (hypo and hyper pigmentation)\]. For all components, 0 (better) and 3 (worse). Modified RCLASI activity score was derived by adding score for erythema, scaling hyperkeratosis and edema/infiltration. Modified change from Baseline ranged from -7 to 7, 0 (no change), minus (better) and positive (worse). Overall RCLASI modified score was derived by summing the activity and dyspigmentation scores. Overall change from Baseline ranged from -9 to 9, 0 (no change), minus (better) and positive (worse). Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value. Data was not collected for Group A as no participants were dosed.

Time frame: Baseline (Day 1), Day 14 and Day 28

Population: Safety Population. Only those participants with data available at the specified data points were analyzed (represented by n=X in the category titles). All participants received both treatment interventions at the same time (on different skin sites), hence data for these participants were combined.

Blood samples were collected at designated timepoints and pharmacokinetic (PK) analysis was performed. Cmax was calculated by non-compartmental analysis using WinNonlin. PK Population comprised of all participants in the safety population for whom a PK sample was obtained and analyzed.

Time frame: Day 1 (pre-dose and 5 hours post-dose), Day 2 to Day 13, Day 14 (pre-dose), Day 21 to Day 27, Day 28 (post-dose), Day 29 to Day 42 and Follow-up (up to Day 56)

Population: PK Population. All participants received both treatment interventions at the same time (on different skin sites), hence data for these participants were combined. Data was not collected for Group A as no participants were dosed.

Microarray mRNA data was collected from the skin biopsy in both GSK2646264 and placebo treated lesions on Day -5 to -3 visit (Baseline) and Day 28. Fold change represents the change at Day 28 relative to Baseline for each treatment group. Analysis was conducted using mixed model with participant as a random effect and treatment as a fixed effect where treatment is set to not applicable at Baseline. Mean fold change and 95% confidence interval is presented for different genes and probesets. IFI16 indicated interferon, gamma-inducible protein 16, IFI44 indicated interferon-induced protein 44, IFIH1 indicated interferon induced with helicase C domain 1, IFIT1 and 3 indicated interferon-induced protein with tetratricopeptide repeats 1 and 3, MX1 indicated myxovirus (influenza virus) resistance 1, interferon-inducible protein p78 (mouse), MX2 indicated myxovirus (influenza virus) resistance 2 (mouse) and OAS indicated 2'-5'-oligoadenylate synthetase.

Time frame: Baseline (Day -5 to -3) and Day 28

Population: Safety Population. Only those participants with data available at the specified data points were analyzed. Data was not collected for Group A as no participants were dosed.

Blood samples were collected at designated timepoints and PK analysis was performed. Tmax was calculated by non-compartmental analysis using WinNonlin.

Time frame: Day 1 (pre-dose and 5 hours post-dose), Day 2 to Day 13, Day 14 (pre-dose), Day 21 to Day 27, Day 28 (post-dose), Day 29 to Day 42 and Follow-up (up to Day 56)

Population: PK Population. All participants received both treatment interventions at the same time (on different skin sites), hence data for these participants were combined. Data was not collected for Group A as no participants were dosed.