Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of PF-06649751 in Parkinson's Disease

According to Parkinson's disease diaries of participants OFF time was a time period when the medication no longer providing benefit with regard to mobility, slowness, and stiffness and participants experienced relatively poor overall function with worsening of tremor, rigidity, balance, or bradykinesia. ON time was a time period when medication was providing benefit with regard to mobility, slowness, and stiffness. ON time was classified as associated with or without troublesome dyskinesia (TD) that interfere with activities of daily living and with or without dyskinesia. OFF time and ON time with TD were generally considered to be bad time with regard to motor function, whereas ON time without dyskinesia (WD) and with non- troublesome dyskinesia (NTD) were generally considered to be good time.

Time frame: Baseline, Day 13

Population: Safety analysis set included all participants who received at least 1 dose of study medication(L-Dopa or PF-06649751) in Period 2. Here,'n' signifies those participants who were evaluable at specified time points for each reporting arm.This outcome measure was not planned to be assessed in lead-in period (L-dopa).

According to Parkinson's disease diaries of participants OFF time was a time period when the medication no longer providing benefit with regard to mobility, slowness, and stiffness and participants experienced relatively poor overall function with worsening of tremor, rigidity, balance, or bradykinesia. ON time was a time period when medication was providing benefit with regard to mobility, slowness, and stiffness. ON time was classified as associated with or without troublesome dyskinesia (TD) that interfere with activities of daily living and with or without dyskinesia. OFF time and ON time with TD were generally considered to be bad time with regard to motor function, whereas ON time without dyskinesia (WD) and with non- troublesome dyskinesia (NTD) were generally considered to be good time.

Time frame: Baseline, Day 20

Population: Safety analysis set included all participants who received at least 1 dose of study medication(L-Dopa or PF-06649751) in Period 2. Here,'n' signifies those participants who were evaluable at specified time points for each reporting arm. This outcome measure was not planned to be assessed in lead-in period (L-dopa).

The C-SSRS was an interview-based rating scale to systematically assess suicidal ideation and suicidal behavior. C-SSRS assessed whether participant experienced any of the following 1: completed suicide, 2: suicide attempt (response of yes on actual attempt), 3: preparatory acts toward imminent suicidal behavior (yes on aborted attempt, interrupted attempt, preparatory acts or behavior), 4: any suicidal behavior or ideation, suicidal ideation (yes on wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent), 7: self-injurious behavior, no suicidal intent (yes on has participant engaged in non-suicidal self-injurious behavior).

Time frame: Baseline up to Day 30

Population: Safety analysis set included all participants who received at least 1 dose of study medication (L-Dopa or PF-06649751) in Period 2. This outcome measure was not planned to be assessed in lead-in period (L-dopa).

Physical examination included examination of the 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.

Time frame: Baseline up to Day 30

Population: Safety analysis set included all participants who received at least 1 dose of study medication (L-Dopa or PF-06649751) in Period 1 and/or Period 2.

The complete or full neurological examination included assessment of the cranial nerves; muscle strength, tone, cortical drift, abnormal movements; deep tendon reflexes; sensory exam, coordination, gait and station. Higher cortical and motor function was considered part of the complete neurological exam. Findings were considered abnormal as confirmed by a certified neurologist.

Time frame: Baseline up to Day 30

Population: Safety analysis set included all participants who received at least 1 dose of study medication (L-Dopa or PF-06649751) in Period 1 and/or Period 2.

Criteria for ECG abnormalities: maximum PR interval \>=300 milliseconds (msec) and maximum increase PR interval increase from baseline (IFB): percent change (Pctchg) \>=25 percent (%) for baseline value of \>200 msec and Pctchg\>=50% for baseline value of \<=200 msec for PR interval, maximum QRS interval \>=140 msec and a maximum IFB: Pctchg\>=50%, maximum QTCF interval (Fridericia's Correction) of 450 msec to \<480 msec, 480 msec to \<500 msec or \>=500 msec and a maximum change of \<=30change\<60 or \>=60 msec from baseline.

Time frame: Baseline up to Day 30

Population: Safety analysis set included all participants who received at least 1 dose of study medication (L-Dopa or PF-06649751) in Period 1 and/or Period 2. Here, number of participants analyzed (N) signifies those participants who were evaluable for this outcome measure.

Criteria for laboratory abnormalities: Hemoglobin (Hgb),hematocrit, red blood cell(RBC) count: less than(\<)0.8\*lower limit of normal(LLN),mean corpuscular Hgb, mean corpuscular volume, mean corpuscular Hgb concentration:\<0.9\*LLN, greater than (\>)1.1\*upper limit of normal(ULN),platelet:\<0.5\*LLN,\>1.75\*ULN,lymphocyte,neutrophil:\<0.8\*LLN, \>1.2\*ULN, basophil, eosinophil, monocyte:\>1.2\*ULN, WBC:\<0.6\*LLN, \>1.5\*ULN;total bilirubin\>1.5\*ULN, aspartate aminotransferase,alanine aminotransferase,alkaline phosphatase:\>3.0\*ULN,total protein,albumin:\<0.8\*LLN,\>1.2\*ULN;blood urea nitrogen,creatinine:\>1.3\*ULN, uric acid\>1.2\*ULN;sodium\<0.95\*LLN,\>1.05\*ULN,potassium,chloride,calcium,bicarbonate:\<0.9\*LLN,\>1.1\*ULN;glucose\<0.6\*LLN,\>1.5\*ULN,urine pH:\<4.5, \>8; urine: WBC, RBC greater than or equal to (\>=)20/high performance field, bacteria: \>20; urobilinogen, urine: glucose, ketone, protein, Hgb, nitrite, leukocyte esterase, bilirubin: \>=1.

Time frame: Baseline up to Day 30

Population: Safety analysis set included all participants who received at least 1 dose of study medication (L-Dopa or PF-06649751) in Period 1 and/or Period 2. Here, number of participants analyzed (N) signifies those participants who were evaluable for this outcome measure.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; Initial or prolonged in-patient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug to the end of study (up to Day 30) that were absent before treatment or that worsened relative to pre-treatment state. AEs included both serious and non-serious adverse events.

Time frame: Baseline (Day 1) up to Day 30

Population: Safety analysis set included all participants who received at least 1 dose of study medication (L-Dopa or PF-06649751) in Period 1 and/or Period 2.

Criteria for vital sign abnormality included supine pulse rate of \<40 beats per minute (bpm) or \>120 bpm, standing pulse rate of \<40 bpm or \>140 bpm, supine and standing systolic blood pressure (SBP) \<90 millimeter of mercury (mmHg), supine and standing diastolic blood pressure (DBP) \<50 mmHg, supine and standing SBP of \>=30 mmHg maximum (max.) increase from baseline (IFB) and and decrease from baseline (DFB) in same posture, supine and Standing DBP of \>=20 mmHg max. increase and decrease from baseline in same posture. Categories in which there was atleast 1 abnormality are reported in this outcome measure.

Time frame: Baseline up to Day 30

Population: Safety analysis set included all participants who received at least 1 dose of study medication (L-Dopa or PF-06649751) in Period 1 and/or Period 2. Here, 'n' signifies the number of participants evaluable for the specific category.

Clearance of a drug 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. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

Time frame: Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1

Population: The L-Dopa PK parameter analysis set included all participants who received at least 1 dose of L-Dopa in open label Period 1 with at least 1 of the PK parameters of interest. Here, number of participants analyzed signifies those participants who were evaluable for this outcome measure.

Clearance of a drug 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. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

Time frame: Pre-dose, 0.5, 1, 1.5, 2, 4, 8 and 12 hour post-dose on Day 22

Population: The PF-06649751 PK parameter analysis set included all participants treated and who had at least 1 of the PK parameters of interest in at least 1 treatment period during period 2. Here, number of participants analyzed signifies those participants who were evaluable for this outcome measure.

Volume of distribution 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.

Time frame: Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1

Population: The L-Dopa PK parameter analysis set included all participants who received at least 1 dose of L-Dopa in open label Period 1 with at least 1 of the PK parameters of interest. Here, number of participants analyzed (N) signifies those participants who were evaluable for this outcome measure.

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

Time frame: Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1

Population: The L-Dopa PK parameter analysis set included all participants who received at least 1 dose of L-Dopa in open label Period 1 with at least 1 of the PK parameters of interest. Here, number of participants analyzed (N) signifies those participants who were evaluable for this outcome measure.

Area under the concentration curve from time zero to end of dosing interval (AUCtau), where dosing interval was 12 hours.

Time frame: Pre-dose on Day 3, 4, 8, 11, 14, 17, 20, Pre-dose, 0.5, 1, 1.5, 2, 4, 8 and 12 hour post-dose on Day 7, 13, 22

Population: The PF-06649751 PK parameter analysis set included all participants treated and who had at least 1 of the PK parameters of interest in at least 1 treatment period during period 2. Here, 'n' signifies those participants who were evaluable at specified time point for each reporting arm, respectively.

Area under the plasma concentration-time profile from time zero to the time of the last quantifiable concentration (C last).

Time frame: Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1

Population: The L-Dopa PK parameter analysis set included all participants who received at least 1 dose of L-Dopa in open label Period 1 with at least 1 of the PK parameters of interest.

Time frame: Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1

Population: The L-Dopa pharmacokinetic (PK) parameter analysis set included all participants who received at least 1 dose of L-Dopa in open label Period 1 with at least 1 of the PK parameters of interest.

Time frame: Pre-dose on Day 3, 4, 8, 11, 14, 17, 20, Pre-dose, 0.5, 1, 1.5, 2, 4, 8 and 12 hour post-dose on Day 7, 13, 22

Population: The PF-06649751 PK parameter analysis set included all participants treated and who had at least 1 of the PK parameters of interest in at least 1 treatment period during period 2. Here, 'n' signifies those participants who were evaluable at specified time points for each reporting arm, respectively.

Time frame: Pre-dose on Day 3, 4, 8, 11, 14, 17, 20, Pre-dose, 0.5, 1, 1.5, 2, 4, 8 and 12 hour post-dose on Day 7, 13, 22

Population: The PF-06649751 PK parameter analysis set included all participants treated and who had at least 1 of the PK parameters of interest in at least 1 treatment period during period 2. Here, 'n' signifies those participants who were evaluable at specified time point for each reporting arm, respectively.

Rac was obtained from AUCtau after last dose divided by AUCtau after first dose, where AUC(tau) = Area under the concentration curve from time zero to end of dosing interval (AUCtau), where dosing interval was 12 hours.

Time frame: Pre-dose on Day 3, 4, 8, 11, 14, 17, 20, Pre-dose, 0.5, 1, 1.5, 2, 4, 8 and 12 hour post-dose on Day 7, 13, 22

Population: Data was not collected since this outcome measure was not planned to be analyzed.

Terminal half-life is the time measured for the plasma concentration of drug to decrease by one half. It was calculated as dividing the natural logarithm to the base e (Log e)\*2/k el, where k el is the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve.

Time frame: Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1

Population: The L-Dopa PK parameter analysis set included all participants who received at least 1 dose of L-Dopa in open label Period 1 with at least 1 of the PK parameters of interest. Here, number of participants analyzed (N) signifies those participants who were evaluable for this outcome measure.

Time frame: Pre-dose, 0.5, 1, 2, 4 and 8 hours post-dose on Day 1

Population: The L-Dopa PK parameter analysis set included all participants who received at least 1 dose of L-Dopa in open label Period 1 with at least 1 of the PK parameters of interest.

Time frame: Pre-dose on Day 3, 4, 8, 11, 14, 17, 20, Pre-dose, 0.5, 1, 1.5, 2, 4, 8 and 12 hour post-dose on Day 7, 13, 22

Population: The PF-06649751 PK parameter analysis set included all participants treated and who had at least 1 of the PK parameters of interest in at least 1 treatment period during period 2. Here, 'n' signifies those participants who were evaluable at specified time point for each reprting arm, respectively.