A First in Human Study to Evaluate Safety, Tolerability, and Pharmacology of PF-06826647 in Healthy Subjects and Subjects With Plaque Psoriasis

Maximum absolute values and changes from baseline for vital signs (for supine systolic/diastolic blood pressure [BP] and supine pulse rate [PR]) were summarized descriptively by treatment. Numbers of participants meeting the categorical criteria were provided.

Number of participants in PBO SAD cohorts = number of participants in [PBO SAD (3mg, 10mg)] cohorts + number of participants in [PBO SAD -> PBO QD MAD] cohorts.

Maximum absolute values and changes from baseline for vital signs (for supine systolic/diastolic blood pressure and supine pulse rate) were summarized descriptively by treatment. Numbers of participants meeting the categorical criteria were provided.

Maximum absolute values and changes from baseline for vital signs (for supine systolic/diastolic blood pressure and supine pulse rate) were summarized descriptively by treatment. Numbers of participants meeting the categorical criteria were provided.

Physical examinations were conducted by a physician, trained physician assistant, or nurse practitioner as acceptable according to local regulation. A full physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. The examination assessed the participants for any potential changes in general appearance, the respiratory and cardiovascular systems, as well as towards participant reported symptoms. Findings were considered to be clinically significant based on investigator's decision.

Number of participants in PBO SAD cohorts = number of participants in [PBO SAD (3mg, 10mg)] cohorts + number of participants in [PBO SAD -> PBO QD MAD] cohorts.

Physical examinations were conducted by a physician, trained physician assistant, or nurse practitioner as acceptable according to local regulation. A full physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. The examination assessed the participants for any potential changes in general appearance, the respiratory and cardiovascular systems, as well as towards participant reported symptoms. Findings were considered to be clinically significant based on investigator's decision.

Physical examinations were conducted by a physician, trained physician assistant, or nurse practitioner as acceptable according to local regulation. A full physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. The examination assessed the participants for any potential changes in general appearance, the respiratory and cardiovascular systems, as well as towards participant reported symptoms. Findings were considered to be clinically significant based on investigator's decision.

ECG endpoints and changes from baseline (QTcF, PR and QRS) were summarized descriptively by cohort and treatment using pre-defined categories. Numbers of participants meeting the categorical criteria were provided. All planned and unplanned post-dose time points were counted in these categorical summaries. Categorical summarization criteria for ECG were as follows: 1) QTcF maximum absolute value ≥450 and <480 millisecond (msec), ≥480 and <500 msec. ≥500 msec; 2) QTcF maximum increase ≥30 and <60 msec, ≥60 msec; 3) PR maximum absolute value ≥300 msec; 4) PR maximum increases from baseline ≥25% if baseline >200 msec, ≥50% if baseline ≤200 msec; 5) QRS maximum absolute value ≥140 msec; 6) QRS maximum increase from baseline ≥50%.

Number of participants in PBO SAD cohorts = number of participants in [PBO SAD (3mg, 10mg)] cohorts + number of participants in [PBO SAD -> PBO QD MAD] cohorts.

ECG endpoints and changes from baseline (QTcF, PR and QRS) were summarized descriptively by cohort and treatment using pre-defined categories. Numbers of participants meeting the categorical criteria were provided. All planned and unplanned post-dose time points were counted in these categorical summaries. Categorical summarization criteria for ECG were as follows: 1) QTcF maximum absolute value ≥450 and <480 millisecond (msec), ≥480 and <500 msec. ≥500 msec; 2) QTcF maximum increase ≥30 and <60 msec, ≥60 msec; 3) PR maximum absolute value ≥300 msec; 4) PR maximum increases from baseline ≥25% if baseline >200 msec, ≥50% if baseline ≤200 msec; 5) QRS maximum absolute value ≥140 msec; 6) QRS maximum increase from baseline ≥50%.

ECG endpoints and changes from baseline (QTcF, PR and QRS) were summarized descriptively by cohort and treatment using pre-defined categories. Numbers of participants meeting the categorical criteria were provided. All planned and unplanned post-dose time points were counted in these categorical summaries. Categorical summarization criteria for ECG were as follows: 1) QTcF maximum absolute value ≥450 and <480 millisecond (msec), ≥480 and <500 msec. ≥500 msec; 2) QTcF maximum increase ≥30 and <60 msec, ≥60 msec; 3) PR maximum absolute value ≥300 msec; 4) PR maximum increases from baseline ≥25% if baseline >200 msec, ≥50% if baseline ≤200 msec; 5) QRS maximum absolute value ≥140 msec; 6) QRS maximum increase from baseline ≥50%.

An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; life-threatening (immediate risk of death); initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect. All events occurring following start of the treatment or increasing in severity were counted as treatment emergent. Events that occurred in a non-treatment period (eg, washout or follow-up) were counted as treatment emergent and attributed to the previous treatment taken. For each event, the investigator pursued and obtained adequate information both to determine the outcome and to assess whether it meets the criteria for classification as an SAE.

PBO SAD cohorts = [PBO SAD (3mg, 10mg)] cohorts + [PBO SAD -> PBO QD MAD] cohorts.

An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; life-threatening (immediate risk of death); initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect. All events occurring following start of the treatment or increasing in severity were counted as treatment emergent. Events that occurred in a non-treatment period (eg, washout or follow-up) were counted as treatment emergent and attributed to the previous treatment taken. For each event, the investigator pursued and obtained adequate information both to determine the outcome and to assess whether it meets the criteria for classification as an SAE.

An AE was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; life-threatening (immediate risk of death); initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect. All events occurring following start of the treatment or increasing in severity were counted as treatment emergent. Events that occurred in a non-treatment period (eg, washout or follow-up) were counted as treatment emergent and attributed to the previous treatment taken. For each event, the investigator pursued and obtained adequate information both to determine the outcome and to assess whether it meets the criteria for classification as an SAE.

Laboratory data were listed and summarized by treatment in accordance with the sponsor reporting standards. Parameters for laboratory abnormalities evaluation included: erythrocyte mean corpuscular volume (Ery. MCV), erythrocyte mean corpuscular hemoglobin (Ery. MCH), reticulocytes/erythrocytes (%), limphocytes, eosinophils, bilirubin, aspartate aminotransferase (AST), urate, high-density lipoproteins (HDL) cholesterol, low-density lipoproteins (LDL) cholesterol, triglycerides, cholesterol, ketones, nitrite, leukocyte esterase, epithelial cells, urinalysis-bacteria.

Number of participants in PBO SAD cohorts = number of participants in [PBO SAD (3mg, 10mg)] cohorts + number of participants in [PBO SAD -> PBO QD MAD] cohorts.

Laboratory data were listed and summarized by treatment in accordance with the sponsor reporting standards. Parameters and corresponding primary criteria for laboratory abnormalities evaluation included: Ery. MCV <0.9 × LLN, Ery. Mean corpuscular hemoglobin (Ery. MCH) <0.9 × LLN or >1.1 ULN, reticulocytes/erythrocytes (%) >1.5 × ULN, lymphocytes <0.8 × LLN or >1.2 × ULN, neutrophils <0.8 × LLN, eosinophils >1.2 × ULN, bilirubin >1.5 × ULN, urate >1.2 × ULN, HDL cholesterol <0.8 × LLN, LDL cholesterol >1.2 × ULN, triglycerides >1.3 × ULN, bicarbonate >1.1 × ULN, cholesterol >1.3 × ULN, urine glucose ≥1, urine hemoglobin ≥1, nitrite ≥1, leukocyte esterase ≥1, epithelial cells ≥6/LPF, urinalysis-casts >1/LPF, urinalysis-bacteria >20/HPF, urine 24 hours creatinine >1.1 × ULN.

Laboratory data were listed and summarized by treatment in accordance with the sponsor reporting standards. Parameters and corresponding primary criteria for laboratory abnormalities evaluation included: reticulocytes/erythrocytes (%) >1.5 × ULN, lymphocytes <0.8 × LLN, neutrophils <0.8 × LLN or >1.2 × ULN, eosinophils >1.2 × ULN, bilirubin >1.5 × ULN, alanine aminotransferase (ALT) >3.0 × ULN, creatinine >1.3 × ULN, urate >1.2 × ULN, HDL cholesterol <0.8 × LLN, LDL cholesterol >1.2 × ULN, triglycerides >1.3 × ULN, potassium >1.1 × ULN, bicarbonate >1.1 × ULN, glucose <0.6 × LLN or >1.5 × ULN, Creatine Kinase (CK) >2.0 × ULN, cholesterol >1.3 × ULN, urine glucose ≥1, ketones ≥1, urine hemoglobin ≥1, urine bilirubin ≥1, leukocyte esterase ≥1, epithelial cells ≥6/LPF, urinalysis-bacteria/HPF.

Change in 24-hour creatinine clearance at Day 10 from Day -1 (baseline) during the MAD was presented by treatment group.

AUCinf = Area under the plasma concentration versus time curve (AUC) from time 0 (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0-t) plus AUC (t-inf).

AUCinf = Area under the plasma concentration versus time curve (AUC) from time 0 (pre-dose) to extrapolated infinite time (0-inf). It is obtained from AUC (0-t) plus AUC (t-inf). AUCinf(dn) = AUCinf / dose. Dose normalized AUC values of PF-06826647 was plotted against dose and included individual participant values and the geometric means for each dose. These plots were used to help understand the relationship between the plasma PK parameters and dose.

AUC24 was summarized by dosing regimen and period. It was determined by linear/log trapezoidal method.

AUClast was summarized by dosing regimen and period. It was determined by linear/log trapezoidal method.

AUClast(dn) = AUClast / dose. Dose normalized AUC values of PF-06826647 were plotted against dose and included individual participant values and the geometric means for each dose. These plots was used to help understand the relationship between the plasma PK parameters and dose.

Cmax was summarized by dosing regimen and period. It was observed directly from data.

Cmax(dn) = Cmax / dose. To assess the relationship between Cmax and dose, dose normalized Cmax was plotted against dose, and included individual participant values and the geometric means for each dose.

Tmax was summarized by dosing regimen and period. It was observed directly from data as time of first occurrence.

t1/2 was summarized by dosing regimen and period. It was determined by loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log linear concentration time curve. Only those data points judged to describe the terminal log linear decline were used in the regression.

MRT = AUMCinf / AUCinf, where AUMCinf is the area under the first moment curve from time 0 to infinity.

Vz/F is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.

CL/F is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

AUCτ was summarized by dosing regimen and period. Dosing interval was the interval τ between administration of doses of drug. In this study, the dosing interval was 24 hours for QD dosing and 12 hours for BID dosing. It was determined by linear/log trapezoidal method.

Area Under the Plasma Concentration-Time Profile over the Dosing interval τ (AUCτ). Dosing interval was the interval τ between administration of doses of drug. In this study, the dosing interval τ was 24 hours for QD dosing and 12 hours for BID dosing.

AUCτ(dn) = AUCτ / Dose. To assess the relationship between the PK parameters and the dose, dose normalized AUCτ was plotted against dose, and included individual participant values and the geometric means for each dose.

Cmax was summarized by dosing regimen and period. It was observed directly from data.

Cmax(dn) = Cmax / dose. To assess the relationship between Cmax and dose, dose normalized Cmax was plotted against dose, and included individual participant values and the geometric means for each dose.

Tmax was summarized by dosing regimen and period. It was observed directly from data as time of first occurrence.

AUCτ was summarized by dosing regimen and period. Dosing interval was the interval τ between administration of doses of drug. In this study, the dosing interval was 24 hours for QD dosing and 12 hours for BID dosing. It was determined by linear/log trapezoidal method.

Area Under the Plasma Concentration-Time Profile over the Dosing interval τ (AUCτ). Dosing interval was the interval τ between administration of doses of drug. In this study, the dosing interval τ was 24 hours for QD dosing and 12 hours for BID dosing.

AUCτ(dn) = AUCτ / Dose. To assess the relationship between the PK parameters and the dose, dose normalized AUCτ was plotted against dose, and included individual participant values and the geometric means for each dose.

Cmax was summarized by dosing regimen and period. It was observed directly from data.

Cmax(dn) = Cmax / dose. To assess the relationship between Cmax and dose, dose normalized Cmax was plotted against dose, and included individual participant values and the geometric means for each dose.

Tmax was summarized by dosing regimen and period. It was observed directly from data as time of first occurrence.

Cav = AUCτ,ss / τ, where ss means 'at steady state', and where the dosing interval τ was 24 hours for QD dosing and 12 hours for BID dosing. Cav was summarized by dosing regimen and period.

Cmin was observed directly from data. It was summarized by dosing regimen and period. Dosing interval was the interval τ between administration of doses of drug. In this study, the dosing interval τ was 24 hours for QD dosing and 12 hours for BID dosing.

t1/2 was summarized by dosing regimen and period. It was determined by loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log linear concentration time curve. Only those data points judged to describe the terminal log linear decline were used in the regression.

MRT = AUMCinf / AUCinf, where AUMCinf is the area under the first moment curve from time 0 to infinity.

PTR = Cmax,ss / Cmin,ss, where ss means 'at steady state'. It was summarized by dosing regimen and period.

Rac = AUCτ,ss / AUCτ,sd, where ss means 'at steady state' and sd 'single dose'. In this study, Rac = AUCτ(Day 10) / AUCτ(Day 1). Rac was summarized by dosing regimen and period.

Rac,Cmax = Cmax,ss / Cmax,sd, where ss means 'at steady state' and sd 'single dose'. In this study, Rac,Cmax = Cmax(Day10) / Cmax(Day 1). Rac,Cmax was summarized by dosing regimen and period.

Vz/F is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.

CL/F is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

Dosing interval was the interval τ between administration of doses of drug. In this study, the dosing interval τ was 24 hours for QD dosing and 12 hours for BID dosing. Aeτ = Sum of [urine concentration * sample volume] for each collection interval. Aer was summarized by dosing regimen and period.

Dosing interval was the interval τ between administration of doses of drug. In this study, the dosing interval τ was 24 hours for QD dosing and 12 hours for BID dosing. Aeτ% = Aeτ / Dose * 100. Aeτ%was summarized by dosing regimen and period.

Renal clearance was calculated as cumulative amount of drug recovered unchanged in urine during the dosing interval (Aeτ) divided by area under the plasma concentration time-curve from time zero to end of dosing interval (AUCτ), where dosing interval is 24 hours for QD dosing and 12 hours for BID dosing.

AUCτ was summarized by dosing regimen and period. It was determined by linear/log trapezoidal method.

AUCτ(dn) = AUCτ / Dose. To assess the relationship between the PK parameters and the dose, dose normalized AUCτ was plotted against dose, and included individual participant values and the geometric means for each dose.

Cmax was summarized by dosing regimen and period. It was observed directly from data.

Cmax was summarized by dosing regimen and period. It was observed directly from data.

Tmax was summarized by dosing regimen and period. It was observed directly from data as time of first occurrence.

Cav = AUCτ,ss / τ, where ss means 'at steady state'. Cav was summarized by dosing regimen and period.

Cmin was observed directly from data. It was summarized by dosing regimen and period.

t1/2 was summarized by dosing regimen and period. It was determined by loge(2)/kel, where kel is the terminal phase rate constant calculated by a linear regression of the log linear concentration time curve. Only those data points judged to describe the terminal log linear decline were used in the regression.

MRT = AUMCinf / AUCinf, where AUMCinf is the area under the first moment curve from time 0 to infinity.

PTR = Cmax,ss / Cmin,ss, it was summarized by dosing regimen and period.

Vz/F is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.

CL/F is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

Combined assessment of lesion severity and area affected into single score. Body was divided into 4 sections: head, arms, trunk, legs. For each section, percent area of skin involved was estimated: 0= 0% to 6= 90-100%. Severity was estimated by clinical signs: erythema, induration, desquamation; scale: 0= none to 4= maximum. Final PASI = sum of severity parameters for each section*area score*weight of section (head: 0.1, arms: 0.2, body: 0.3, legs: 0.4); total possible score range: 0= no disease to 72= maximal disease.