synopsis · a summary of the dose decisions in the final group of subjects, cohort 2, can be seen...

CONFIDENTIAL HM2009/00097/00 MAA110623

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Synopsis

Identifier: HM2009/00097/00 Study Number: MAA110623

Title: Single-blind, randomised, placebo controlled study to evaluate the safety, tolerability and pharmacokinetics of GSK1034702 in healthy subjects.

Investigator:

Study center: United Kingdom

Publication: None at the time of this report.

Study period:

Initiation Date: 02 MAY 2008

Completion Date: 15 DEC 2008

Phase of development: I

Objectives:

Primary objectives were:

• To investigate the safety and tolerability of single escalating oral doses of GSK1034702 in healthy male and female (of non-child bearing potential) subjects.

• To investigate the pharmacokinetics (PK) of single escalating oral doses of GSK1034702 in healthy male and female (of non-child bearing potential) subjects.

Secondary objectives were:

• To characterise the single dose pharmacodynamics (PD) of GSK1034702 in healthy male and female (of non-child bearing potential) subjects.

• To explore the PK-PD relationships of GSK1034702 in healthy male and female (of non-child bearing potential) subjects.

Methodology:

GSK1034702 is a highly selective, allosteric partial agonist at Muscarinic 1 (M1) receptor. Binding to the allosteric site on the M1 receptor allows for selective M1 receptor activation, without attenuating M1 receptor function in situations of high


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endogenous acetylcholine tone. This study represents the first occasion an allosteric M1 receptor partial agonist (GSK1034702) has been administered to humans.

The study was a single-blind, randomised, placebo-controlled, single oral dose, dose-rising, cross-over study in healthy male and female (of non-child bearing potential) subjects.

Subjects were randomised into cohorts of 10 subjects. Prior to randomisation the 2D6 metaboliser status of each subject was documented. One or more 2D6 poor metaboliser was enrolled into each cohort.

Subjects were screened up to 30 days before the first dosing session with GSK1034702. Treatment administration was planned in such a way that each subject received no more than 4 doses of GSK1034702 and 1 placebo, that is, a total of 5 dosing sessions (in each dosing session 8 subjects planned to receive GSK1034702 and 2 placebo). Each session was separated by a washout period of a minimum of 7 days or 5 half lives, whichever was longer.

In the 0.1 mg dose group of Cohort 0, seven of 10 subjects had cystatin-C concentrations on Day 2, Period 1 which were within the normal range but which had appeared to increase from screening by more than 20%. According to the protocol, the stopping criteria for cystatin-C was, an increase from baseline of >20%. Consequently, the study was halted to review the findings.

No clinically significant changes were observed in any other renal

function variables and no other renal stopping criteria were met. Also, levels of GSK1034702 in dosing Session 1 were below the lower limit of quantification (0.2 ng/mL).

This re-analysis revealed that the inter-assay variation of cystatin-C levels can be in excess of 20%. Further interrogation of the assay procedure indicates that the intra-assay variation could also be as high as 20%. As such, the stopping criteria expressed as percentage change from baseline levels was not technically appropriate. Further validation work was required to accurately determine the intra and inter-assay variation in order to understand the degree by which normal cystatin-C levels may vary, as a result of this assay procedure.

After discussions with a renal expert, it was agreed that the cystatin-C stopping criteria should be revised to a newly defined upper limit of the reference range of the assay. Going forward, if serum cystatin C was found to be ≥ upper limit of normal range, or serial serum cystatin-C values indicate a potential trend to an increase, an independent expert was consulted.


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With these new criteria in place, the study was then restarted. The cohort was abandoned and all 10 subjects were withdrawn. Ten new subjects were recruited and the 0.5 mg dose was repeated.

Subjects returned for a Follow-up visit approximately 7 to 14 days following the last dose of study medication. Each subject’s participation in the study was approximately 11 weeks. Details are given in Time and Events Table (Attachment 1).

Number of subjects:

Table 1 Subject Disposition and Demographics:

Number of Subjects Cohort 0 Cohort 1 Cohort 2 Number of subjects planned, N: 10 10 10 Number of subjects randomised, N: 10 11 9 Number of subjects included in All subjects (safety) population, n (%):

10(100) 11(100) 9(100)

Number of subjects included in PK population, n (%): 10(100) 11(100) 9(100) Number of subjects completed as planned, n (%): 0 9(82) 6(67) Number of subjects withdrawn (any reason), n (%): 10(100) 2(18) 3(33) Reasons for subject withdrawal, n (%)

Subject reached protocol defined stopping criteria 1(10)1 1(9) 0 Adverse events 0 1(9) 1(11) Protocol deviation 0 0 1(11) Investigator discretion 0 0 1(11) Other 9 (90) 0 0

Demographics Age in Years, Mean (Range) 38.8(24-56) 35.5(21-54) 32(21-49) Sex, n (%)

Female: 1(10) 0 0 Male: 9(90) 11(100) 9(100)

BMI (kg/m2), Mean (Range) 23.59 (19.8-29.2)

23.49 (19.0-28.6)

25.35 (19.3-29.4)

Height (cm), Mean (Range) 175.4 (162-193)

174.7 (169-183)

172.9 (162-190)

Weight (kg), Mean (Range) 72.45 (60.2-85.8)

71.55 (60.2-82.0)

76.06 (58.5-98.3)

Ethnicity, n (%) Hispanic or Latino: 1(10) 0 0 Not Hispanic or Latino: 9(90) 11(100) 9(100)

Race, n (%) African American/African Heritage 1(10) 1(9) 1(11) Asian – Central/ South Heritage 0 1(9) 2(22) White – White/Caucasian/European Heritage 9(90) 9(82) 5(56) Mixed race 0 0 1(11)

Data Source: Table 9.1, Table 9.2 and Table 9.3 1. One subject in Cohort 0 reached Cystatin C protocol stopping criteria. This cohort was subsequently cancelled

and the additional 9 subjects were withdrawn. Protocol stopping criteria amended for Cohort 1 and Cohort 2


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Diagnosis and main criteria for inclusion:

Healthy male and female subjects between 18 to 55 years of age inclusive with body weight ≥50 kg and body mass index (BMI) within the range 19.0 to 29.9 kg/m2 (inclusive) were included in this study. Only females who were postmenopausal or surgically sterile or committed to using an approved method of contraception were included. The subjects had no co-morbid psychiatric disorders as defined using the Mini International Neuropsychiatric Interview (M.I.N.I) scale. All the subjects provided a written informed consent to participate in this study.

Treatment administration:

A total of 30 subjects were dosed with GSK1034702 in 3 Cohorts. Cohort 0 evaluated doses from 0.1 mg to 0.5 mg; Cohort 1 evaluated doses from 0.5 mg to 5 mg and Cohort 2 evaluated doses from 5 mg to 13 mg. Cohort 0 was halted following the second dosing session (see Section Methodology for description). The study re-started with new subjects in Cohort 1. The dose was escalated, from the starting dose of 0.5 mg, by a maximum of five fold or more cautiously if deemed necessary. Safety and PK data from at least 3 subjects treated with GSK1034702 were reviewed at any given dose before escalating to the following one.

A summary of the dose decisions in the final group of subjects, Cohort 2, can be seen below. PK review of Session 1 dosing (Placebo, 5 mg) predicted a maximum exposure of 10 mg. As there were no safety related issues the decision was made to escalate to 8 mg in Session 2. Following PK review of Session 2 it was predicted that a dose of 12 mg could be administered in 95% of the group without exceeding the PK limits. Therefore for Session 3, 11 mg was given, a dose where all subject were predicted to be below the maximum permitted AUC limit. PK review of Session 3 re-assessed the predicted maximum exposure as 13 mg. Therefore, 13 mg was administered in Session 4 supported by the lack of safety issues reported at the 11 mg level. Following PK review of Session 4 the prediction of maximum exposure was refined to 12 mg. As predicted exposures for 11 mg, 12 mg and 13 mg are overlapping remaining subjects were dosed at the 12 mg level in Session 5.

Treatment administration is described in Table 2 and Table 3.


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Table 2 Treatment Administration

Cohort Subject (N)

Poor Metaboliser (N)

Extensive Metaboliser (N)

Doses

Cohort 0 10 1 9 Placebo, 0.1 mg, 0.5 mg Cohort 1 111,2 4 7 Placebo, 0.5 mg, 2 mg,

4 mg, 5 mg Tablet, 5 mg Liquid, 12 mg

Cohort 2 93,4,5 3 6 Placebo, 5 mg Liquid, 8 mg, 11 mg, 12 mg, 13 mg

1. 2. 3. 4. 5. Table 3 Summary of Number of Subjects per Treatment Regimen

Criteria for evaluation:

Primary

• Safety and tolerability endpoints consisting of: adverse events (AEs); 12-lead Electro cardiogram (ECG); 12 lead digital Holter; vital signs (blood pressure, heart rate (HR) & respiration rate); clinical laboratory evaluations (haematology, clinical chemistry, urinalysis), pupil size and body temperature.

• Pharmacokinetic parameters of GSK1034702: Maximum observed concentration (Cmax); area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC(0- ∞)); area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration (AUC(0-t)); terminal phase half-life (t½); time of occurrence of Cmax (tmax); apparent clearance following oral dosing (CL/F), urinary recovery of unchanged drug up to 24 hours (h) (Ae(0-24 h)); renal clearance (CLr).

Treatment Cohort 0 (N=10)

Cohort 1 (N=11)

Cohort 2 (N=9)

Total (N=30)

Placebo 4 11 7 22 0.1 mg GSK1034702 10 0 0 10 0.5 mg GSK1034702 6 11 0 17 2 mg GSK1034702 0 10 0 10 4 mg GSK1034702 0 9 0 9 5 mg Tablet GSK1034702 0 8 0 8 5 mg Liquid GSK1034702 0 1 9 10 8 mg GSK1034702 0 0 8 8 11 mg GSK1034702 0 0 7 7 12 mg GSK1034702 0 1 5 6 13 mg GSK1034702 0 0 2 2


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Secondary

• Assessment of the Bond-Lader Visual Analogue Scale (VAS).

• Assessment of exploratory PD markers: neuroendocrine markers, e.g. growth hormone.

• Relationship between GSK1034702 plasma concentrations and safety/tolerability or exploratory PD end points with selected pharmacodynamic and safety parameters.

Statistical methods:

Sample Size Considerations

A sample size of 10 subjects in each cohort was consistent with the design of previous first time into human (FTIH) single-dose studies and allowed an allocation ratio of 8 active to 2 placebo per dosing session. No statistical techniques were applicable to calculate this sample size, as no information on residual variability of GSK1034702 PK parameters were available prior to this study and no formal treatment comparisons were performed. The sample size was therefore based on feasibility.

Interim Analyses

There was no formal statistical interim analysis. A review of safety and pharmacokinetic data was conducted prior to each dose escalation.

Final Analyses

The final planned analyses was performed after all subjects completed the study and after database freeze.

The programs for tables, figures and listings were developed using SAS version 9.1.3 on a UNIX platform and then loaded into HARP (the GSK reporting tool) once final. The final output was then produced by running the programs in HARP.

Safety

Pupil Diameter

The mean (±Standard Deviation (SD)) of the mean, maximum and minimum pupil diameter, measured for 4 seconds, were plotted by treatment and time.

Body Temperature and Respiration Rate

The mean (±SD) of body temperature was plotted by treatment and time. Respiratory rate and body temperature were summarised in a summary of vital signs.


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QTcF (ECG data)

Change from baseline of QTcF was analysed pooling data from all cohorts using a mixed model repeated measures. The model included subject-baseline (mean of pre-dose values across all periods) and adjusted-baseline (subject-baseline - pre-dose value for relevant period) as covariates. Regimen, time, and period were fitted as fixed effects, and regimen*time, adjusted-baseline*time and subject-baseline*time as interaction terms. Subject was fitted as a random effect.

Point estimates were calculated for the mean difference between each dose of GSK1034702 and placebo at each time point, along with associated 95% confidence intervals (CI). Estimates of the LS means were output for each treatment at each time from the model (including 95% confidence intervals). Plots of the LS Means (and 95% CI) by regimen and time were produced and a summary of the analyses provided.

QTcI (Holter data)

QT individually corrected (QTcI), was derived from the digital Holter data using the following method:

• Using all the digital Holter assessments for Day -1 across all periods and Day 1 for placebo dosing sessions, a linear (QT= βα + *RR ) regression model was fitted between QT (dependant variable) and the RR interval (independent variable) for each subject.

• The estimated slope (β) from the regression models will be used as the correction factor for each individual subject for the derivation of QTcI at all time points, and for each of the 3 replicates within a time point, as follows:

( )RRQTQTci −+= 1β

Throughout this analysis, QT was measured in milliseconds (msec) and RR in seconds.

The time-matched change of QTcI from Day -1 baseline across time points up to 24 h on Day 1 was analysed using mixed model repeated measures, pooling data from all cohorts.

The model included time-matched subject baseline (mean of time-matched baseline values across all periods), time-matched adjusted baseline (subject-baseline – time-matched baseline relevant to that period) as covariates, regimen, time and period as fixed effects, regimen*time as an interaction term and subject as a random effect.

Point estimates were calculated for the mean difference between each dose of GSK1034702 and placebo at each time point, along with associated 95% CI. Estimates of the LS means were output for each treatment at each time from the model (including 95% confidence intervals). Plots of the LS Means (and 95% CI) by regimen and time were produced and a summary of the analyses provided.

QTcF analysis from ECG results was not consistent with results from statistical analysis of QTcI derived from Digital Holter. As an additional exploratory analysis, statistical analysis of QTcF time-matched change from baseline from the digital Holter was also


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performed. The model fitted was equivalent with that fitted to QTcI data. Plots of the LS Means (and 95% CI) by regimen and time were produced and a summary of the analyses provided.

Model assumptions of homogeneity of variance and normality of the distribution underlying the analysis of variance were assessed by visual inspection of residual plots.

PK/QT Analyses:

The QT data from Cohort 1 and Cohort 2 for all subjects including Day-1 and placebo was incorporated to perform pharmacokinetic-QTc analysis. Different corrections were assessed for QT (Fridericia, Bazett and individual correction) and individual correction was retained for the PK/QT analysis. A PK-PD model that takes into account an individualised QT interval correction, a circadian rhythm in baseline QTcI, placebo response and drug effect was evaluated using NONMEM Version 6. Nonlinear Mixed Effects modelling was applied to account for the influence of both fixed effects and random effects (inter and intra subject variability). The potential effect of GSK1034702 plasma concentration on QTc was investigated using a linear model.

Vital Signs

Change from baseline of systolic and diastolic blood pressure, and heart rate, were analysed pooling data from all cohorts using a mixed model repeated measures. The model included subject-baseline (mean of pre-dose values across all periods) and adjusted-baseline (subject-baseline - pre-dose value for relevant period) as covariates. Regimen, time, and cohort were fitted as fixed effects, and regimen*time, adjusted-baseline*time and subject-baseline*time as interaction terms. Subject was fitted as a random effect.

Statistical analysis was completed twice. Once with the top doses (11-13 mg) pooled and once with all doses separate. Point estimates were calculated for the mean difference between each dose of GSK1034702 and placebo at each time point, along with associated 95% confidence intervals (CI). Estimates of the LS means were output for each treatment at each time from the model (including 95% confidence intervals). Plots of the LS Means (and 95% CI) by regimen and time were produced and a summary of the analyses provided.

Ambulatory Blood Pressure

Ambulatory blood pressure (ABP) readings were collected approximately every 30 minutes. Change from baseline ABP at timepoints equivalent to the standard vital signs assessments were selected and a mixed model repeated measures was performed using the same methodology as that applied for the standard vital signs assessments. The model included subject-baseline (mean of pre-dose values across all periods) and adjusted-baseline (subject-baseline - pre-dose value for relevant period) as covariates. Regimen, time, and cohort were fitted as fixed effects, and regimen*time and adjusted-baseline*time as interaction terms. Statistical analysis was completed twice. Once with the top doses (11 to 13 mg) pooled and once with all doses separate. Point estimates were calculated for the mean difference between each dose of GSK1034702 and placebo at


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each time point, along with associated 95% confidence intervals (CI). Estimates of the LS means were output for each treatment at each time from the model (including 95% confidence intervals). Plots of the LS Means (and 95% CI) by regimen and time were produced and a summary of the analyses provided.

Additionally, each subject’s individual ABP readings for systolic and diastolic blood pressure and heart rate were averaged across 8 h intervals post-dose. An 8 h interval was deemed appropriate given individual tmax ranged up to 8 hours post-dose. Change from baseline of ABP results was analysed pooling data from all cohorts using a mixed model repeated measures, with time intervals of 0-8 h, 8-16 h and 16-24 h post-dose. The model included subject-baseline (mean of pre-dose values across all periods) and adjusted-baseline (subject-baseline - pre-dose value for relevant period) as covariates. Regimen, time interval, and cohort were fitted as fixed effects, and regimen*time-interval and adjusted-baseline*time-interval as interaction terms. Point estimates were calculated for the mean difference between each dose of GSK1034702 and placebo at each time point, along with associated 95% CI. Estimates of the LS means were output for each treatment at each time from the model (including 95% confidence intervals). Plots of the estimated mean difference between each dose of GSK1034702 and placebo (and 95% CI) by regimen and time were produced and a summary of the analyses provided.

PK/Vital Signs Analyses:

Systolic and diastolic blood pressure and heart rate data from Cohort 1 and Cohort 2 was incorporated to perform pharmacokinetic-Vital Signs analysis. A population PK/PD analysis was carried out using Nonlinear Mixed Effects Modelling (NONMEM Version 6) to provide a linear regression of the difference between study drug sessions and placebo in change from baseline in blood pressure and heart rate versus plasma concentration.

Similar analysis was also carried out for the Ambulatory blood pressure data.

PK Methods:

Dose Proportionality:

A preliminary assessment of dose proportionality was made with a power model using log-transformed plasma AUC(0-∞), AUC(0-t) and Cmax. A mixed effect model was fitted with log(dose) as a fixed effect, with log(dose) continuous, and subject as a random effect. The coefficient of the slope with 90% CI, on the log scale, was calculated, using the pooled estimate of variance, and used to assess dose proportionality.

As a secondary analysis, the analysis of variance (ANOVA) model was performed using log-transformed dose normalized AUC(0-∞), AUC(0-t) and Cmax by including two factors: dose as fixed effect and subject as random effect. All dose differences were based on LS means with associated 90% CI. Comparisons were obtained by back-transforming the dose differences into the ratios of the PK parameters relative to those at the reference dose.


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Liquid and Tablet Formulation Comparison:

Within Cohort 1, dose-normalised PK parameters AUC(0-∞), AUC(0-t) and Cmax of GSK1034702 from 4 mg liquid formulation and 5 mg tablet formulation were compared. Additionally, AUC(0-∞), AUC(0-t) and Cmax of 5 mg tablet formulation administered in Cohort 1 and 5 mg liquid formulation administered in Cohort 2 were assessed.

Statistical analysis of the endpoints AUC(0-∞), AUC(0-t) and Cmax of GSK1034702 was performed after data were dose-normalised and loge-transformed. A mixed effects analysis of variance model was fitted, with treatment as a fixed effect and subject as a random effect. Point estimates and corresponding 90% CIs were constructed for the comparisons of interest of GSK1034702 liquid – GSK1034702 tablet, using the residual variance. These were then back-transformed to provide point estimates and corresponding 90% CIs for the geometric mean ratios GSK1034702 liquid: GSK1034702 tablet.

Pharmacodynamic

Bond & Lader VAS

The domains of alertness, contentedness and calmness were derived from the Bond and Lader questionnaire. The means (±SD) of the three domains were plotted by time and treatment and data was listed.

Pulmonary Function Tests

Pulmonary function test measurements forced expiratory volume in one second (FEV1), vital capacity (VC)/Force vital capacity (FVC) and FEV1/FVC(%) were summarised and listed.

Changes in conduct of the study or planned analyses

QTcF analysis from ECG results was not consistent with results from statistical analysis of QTcI derived from Digital Holter. As an additional exploratory analysis, statistical analysis of QTcF time-matched change from baseline from the digital Holter was also performed.

Statistical analysis of vital signs and ambulatory blood pressure data was unplanned. Results of this analysis have been presented with the top doses (11 to 13 mg) pooled. Top doses were pooled due to small subject numbers at these doses and considered appropriate given the pharmacokinetic profile of doses in this range. Statistical analysis with treatment regimens separate was also performed and results are provided.

PK/PD analysis of vital signs and ambulatory blood pressure data was unplanned. A population PK/PD analysis was carried out and results are provided.

Laboratory data for Cystatin-C was re-analysed as first samples were deemed unreliable. Data from this re-analysis has been used in study reporting. As baseline samples were taken on Day -1 for Cohort 0 but pre-dose Day 1 for Cohort 1 and Cohort 2, chemistry


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laboratory summary tables were presented separately for Cohort 0, Cohort 1 and Cohort 2.

Details of statistical methods are given in reporting and analysis plan (RAP) (Attachment 2)

Summary of Results:

Safety:

No deaths or serious adverse events occurred during the study. One subject was withdrawn due to meeting the stopping criteria and two subjects were withdrawn due to adverse events. Details are given below:

•

•

•

A total of 54 AEs were experienced by 18 (60%) subjects during this study.


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The most common AE was hypersalivation, which was reported by 7 subjects, all at the highest doses of GSK1034702 (11 mg and above), and all were considered drug-related by the investigator (Data Source Table 10.7 and Table 10.8). At doses of up to 5 mg few adverse events were reported with no dose related trends. Gastrointestinal AEs, including hypersalivation, nausea, vomiting, abdominal cramps, diarrhoea and dyspepsia, were observed at doses of 5 mg and above. Most of these were mild to moderate in intensity, had rapid onset and resolved generally within the same day of dosing. These gastrointestinal AEs are consistent with the muscarinic pharmacology of GSK1034702.

These occurred on placebo as well as study drug sessions, pre and post-

dose, were self-limited, asymptomatic and considered not clinically relevant by the investigator. However, one subject who had a 5 beat run of ventricular tachycardia observed on the pre-dose holter at 4 mg was withdrawn, as described above.

Each episode of cramping lasted about 15 min and the interval between cramps

was about 10 min. The cramps gradually became less intense and the interval became progressively longer until they finally resolved at approximately 8 h post dose. Approximately 2 h post dose he also experienced nausea, mild in severity, which was followed a few minutes after by four episodes of vomiting (rated severe). The nausea resolved 30 min after the vomiting. This subject also reported hypersalivation of moderate intensity starting 90 min post dose and lasting for approximately 3 h.

Following the findings of poor tolerability in this subject, it was decided to stop further dose escalation as the 12 mg dose was not considered tolerated; consequently 8 mg was considered the maximum tolerated dose (MTD) in this FTIH study. These dose limiting adverse effects observed are believed to be consistent with the muscarinic pharmacology of the compound.

A Summary of all AEs is given in Table 4.


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Table 4 Summary of All Adverse Events

GSK1034702 All Adverse Events Placebo 0.1 mg 0.5 mg 2 mg 4 mg 5 mg

Liquid 5 mg

Tablet 8 mg 11 mg 12 mg 13 mg Total

N=22 N=10 N=17 N=10 N=9 N=10 N=8 N=8 N=7 N=6 N=2 N=30 Any AE 3(14) 3(30) 3(18) 0 1(11) 3(30) 3(38) 3(38) 5(71) 5(83) 2(100) 18(60) Drug related AE 0 0 1(6) 0 1(110 1(10) 1(13) 1(13) 4(57) 5(83) 2(100) 12(40) All AE, n(%) Salivary hypersecretion 0 0 0 0 0 0 0 0 3(43) 5(83) 1(50) 7(23) Nausea 0 0 0 0 0 1(10) 0 1(13) 1(14) 2(33) 1(50) 4(13) Abdominal pain 0 0 0 0 0 0 0 1(13) 0 1(17) 1(50) 3(10) Diarrhoea 0 0 0 0 0 0 1(13) 0 1(14) 2(33) 0 3(10) Vomiting 0 0 0 0 0 0 0 1(13) 1(14) 1(17) 0 3(10) Dyspepsia 0 0 0 0 0 0 0 1(13) 0 0 0 1(3) Odynophagia 0 0 0 0 0 0 0 0 0 1(17) 0 1(3) Headache 0 2(20) 0 0 1(11) 0 0 0 0 1(17) 0 4(13) Dizziness 0 0 0 0 0 0 0 0 0 1(17) 0 1(3) Dizziness postural 0 0 1(6) 0 0 0 0 0 0 0 0 1(3) Syncope vasovagal 0 0 1(6) 0 0 0 0 0 0 0 0 1(3) Ventricular tachycardia 1(5) 0 1(6) 0 1(11) 1(10) 1(13) 0 0 0 0 4(13) Supraventricular tachycardia

0 0 0 0 0 0 0 0 0 1(17) 1(50) 2(7)

Accelerated idioventricular rhythm

1(5) 0 0 0 0 0 0 0 0 0 0 1(3)

Hot flush 0 0 0 0 0 0 0 0 2(29) 2(33) 1(50) 4(13) Orthostatic hypotension 1(5) 0 0 0 0 0 0 0 0 0 0 1(3) Rhinorrhoea 0 0 0 0 0 0 0 0 1(14) 1(17) 0 2(7) Cough 0 0 0 0 0 0 1(13) 0 0 0 0 1(3)

Continued

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GSK1034702 All Adverse Events Placebo 0.1 mg 0.5 mg 2 mg 4 mg 5 mg

Liquid 5 mg

Tablet 8 mg 11 mg 12 mg 13 mg Total

N=22 N=10 N=17 N=10 N=9 N=10 N=8 N=8 N=7 N=6 N=2 N=30 Oropharyngeal pain 0 0 0 0 0 1(10) 0 0 0 0 0 1(3) Throat irritation 0 0 0 0 0 0 1(13) 0 0 0 0 1(3) Hyperhidrosis 0 0 0 0 0 0 0 0 2(29) 2(33) 1(50) 4(13) Swelling face 0 0 0 0 0 0 0 0 0 1(17) 0 1(3) Seasonal allergy 0 1(10) 0 0 0 0 0 0 0 0 0 1(3) Nasopharyngitis 0 0 0 0 0 0 0 1(13) 0 0 0 1(3) Musculoskeletal Pain 0 0 0 0 0 1(10) 0 0 0 0 0 1(3) Data Source: Table 10.7 and Table 10.8 Total is total number of subjects experience the event not total number of events.

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Vital Signs

Vital sign measurements comprised HR, systolic and diastolic blood pressure. There were no sustained clinically relevant changes in blood pressure or heart rate observed in any subject at any dose levels tested. No subject met the protocol defined stopping criteria for changes in blood pressure and heart rate.

Statistical analysis via mixed model repeated measures indicated apparent dose-related increases in blood pressure and heart rate. Data Source Table 10.26 contains a summary of the results of the statistical analyses in both semi-supine and standing positions. Data Source Table 10.27 presents results of the statistical analyses with the tops doses, 11 to 13 mg pooled. Data Source Figure 10.9 to Figure10.14 present plots of the LSmeans (and 95% CI) for vital signs change from baseline for each treatment group and position.

The greatest increases were observed in the top doses, (11 to 13 mg pooled, n=8), with a maximum mean increase from baseline of 11.33 mmHg systolic blood pressure (2 h post-dose) and maximum mean increase of 10.32 mmHg diastolic blood pressure (3 h post-dose), in the semi-supine position. Increases were also noted but less pronounced on the 5 mg and 8 mg doses of GSK1034702. The 8 mg dose displayed maximum mean increases of 9.95 mmHg systolic blood pressure (2 h post-dose) and maximum mean increase of 6.59 mmHg diastolic blood pressure (2 h post-dose). The 5 mg liquid dose displayed maximum mean increases of 6.76 mmHg systolic blood pressure (1 h post-dose) and maximum mean increase of 5.71 mmHg diastolic blood pressure (1.5 h post-dose), in the semi-supine position. Such mean increases from baseline were not observed for the placebo regimen.

Figure 1 LS Mean (and 95% CI) of Systolic Blood Pressure Change from Baseline by Treatment and Time point, Semi-Supine Position

Data Source: Figure 10.12


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Figure 2 LS Mean (and 95% CI) of Diastolic Blood Pressure Change from Baseline by Treatment and Time point, Semi-Supine Position

Data Source: Figure 10.13 Increases in HR were also observed, although with a different time course and were also noted following placebo administration. For timepoints at approximately Tmax, increases were observed for both semi-supine and standing positions, pooled 11 to 13 mg GSK1034702 displayed a mean increase of 5.38 bpm and 0.57 bpm for placebo regimens (1.5 h post-dose). The maximum mean increases in heart rate were observed in the standing position, a mean increase of 19.51 bpm on the 8mg regimen at 6 h post-dose and 18.41 bpm for pooled doses 11 to 13 mg at 8 hours post-dose, with the placebo group showing increases of 10.61 bpm (6 h) and 11.49 bpm (8 h). The semi-supine position displayed increases for all regimens but no clear signals of a difference between GSK1034702 doses and placebo from 4 h post-dose.


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Figure 3 LS Mean (and 95% CI) of Heart Rate Pressure Change from Baseline by Treatment and Time point, Standing Position

Data Source: Figure 10.14 Additional exploratory analysis of 24 h ambulatory blood pressure (ABP) measurements was performed. Data Source Table 10.28 and Table10.29 and Figure 10.15 to Figure 10.20 display the results. There was a signal for increase in blood pressure but the magnitude appeared to be less than that seen using the standard vital signs measures. In particular, from the ABP recordings, there are no clear signals of drug-related increases in heart rate.

Analyses of the average BP over 0-8 h post dose showed only modest increases compared to placebo (Figure 4 and Figure 5). Data source Table 10. 30 to Table 10.31 and Figure 10.21 to Figure 10.22 display a summary of statistical analyses on the average ABP in 8 hour intervals post-dose.


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Figure 4 Plot of ABP Difference (and 95% CI) GSK1034702 vs Placebo over 8 Hour Time Intervals

Data Source: Figure 10.22 Figure 5 Plot of ABP Difference (and 95% CI) GSK1034702 vs Placebo over 8

Hour Time Intervals

Data Source: Figure 10.22 PK/Vital Signs Analysis:

The slope of the linear model was estimated to be statistically different from zero at semi supine and standing positions for systolic and diastolic blood pressure and at standing position for heart rate (Table 5, Figure 6, Figure 7 and Figure 8). The results indicate that there is an effect of GSK1034702 plasma concentration on vital signs in the range of the concentrations obtained in the FTIH study.


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Table 5 Summary Results of PK/PD Modelling of Blood Pressure and Heart Rate Data in the FTIH Study

Systolic Blood Pressure (mmHg)

Diastolic Blood Pressure (mmHg)

Heart Rate (bpm)

Slope (95% CI) 0.268 (0.097, 0.439) 0.219 (0.090, 0.348) 0.294 (0.073, 0.515)

Predicted effect at 40 ng/mL Mean (95% CI)

10.72 (3.88, 17.56 ) 8.76 (3.60, 13.92 ) 11.76 (2.92, 20.60)

5th and 95th percentiles 2.37 and 58.09 2.79 and 26.86 -5.05 and 53.64

Data shown for blood pressure taken in the semi-supine position, similar results obtained for measurements in the standing position. Data shown for heart rate taken in the standing position, slope not statistically different from zero for semi-supine position. Figure 6 Delta Delta Systolic Blood Pressure (semi-supine) vs. GSK1034702

Plasma Concentration


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Figure 7 Delta Delta Diastolic Blood Pressure (semi-supine) vs. GSK1034702 Plasma Concentration

Figure 8 Delta Delta Heart Rate (standing) vs. GSK1034702 Plasma

Concentration

Similar analysis was also carried out for ambulatory blood pressure data. The slope of the linear model was positive; however the slope was estimated to be not statistically different from zero.


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Laboratory assessment

There were no clinically significant haematology and biochemistry laboratory results, including liver function tests in all subjects at all doses tested.

No dose related trends were observed in all tests performed.

12-lead ECG and cardiac monitoring

All subjects were monitored on continuous telemetry from 1-hour pre-dose through 24 h after each dose and with 12-lead 24-hour Holter. Twelve-lead ECGs were taken at pre-dose (3 baseline), and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h after each dose.

There were no clinically significant changes in ECG, telemetry or 24 h Holter monitoring readings in subjects in Cohort 1 and Cohort 2, during any period.

QTcI (Digital Holter)

A summary of the statistical analysis of QTcI time-matched change from baseline is provided in Data Source Table 10.21. LS means (and 95% CI) output from the statistical analysis are shown in Figure 9.

Figure 9 LS Mean (and 95% CI) of QTcI Time-matched Change from Baseline by Treatment and Time point



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The statistical analysis showed mean increases in QTcI of 9 msec on the 12 mg regimen. However, there is much variability in the data. The analysis examined many doses and timepoints so it was likely by chance to see some means greater than twice the standard error (>*SE) even if the true mean change is 0. An exploratory analysis pooling the high doses of 11 mg, 12 mg and 13 mg did not show any signals of an increase in QTcI.

QTcF (ECG)

A summary of the statistical analysis of QTcF change from baseline is provided in Data Source Table 10.20. Note that for ECG assessments, baseline was the mean of triplicate pre-dose assessments on Day 1 whereas for the Digital Holter assessments, baseline was the time-matched Day -1 assessments.

LS means (and 95% CI) output from the statistical analysis are shown in Figure 10.

Figure 10 LS Mean (and 95% CI) of QTcF Change from Baseline by Treatment and Time point

Data Source: Figure 10.6 In contrast to QTcI analysis from the digital Holter, there are no signals of an increase on QTcF.

Scatter plots of QTcF (ECG and Holter) vs. RR and QTcI (Holter) vs. RR show no patterns which suggest QT corrections are appropriate (Data Source Figure 10.4, Figure 10.5 and Figure 10.8).


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PK/QT analysis:

The slope of the linear model was estimated and it was found to be statistically not different from zero (p=0.13).Figure 11 shows that ∆QTcI does not vary with GSK1034702 plasma concentration; however it randomly fluctuates between -40 and 40 msec over the range of explored concentration. Figure 12 shows that the baseline-adjusted QTc difference from placebo (∆∆QTcI) does not vary with GSK1034702 plasma concentration. The results indicate that there is no effect of GSK1034702 plasma concentration on QTc in the range of doses tested in FTIH.

Figure 11 ∆QTcI vs. GSK1034702 Concentration – Scatter Plot


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Figure 12 ∆∆QTcI vs. GSK1034702 Plasma Concentration

Pupil Diameter

The mean (±SD) of mean, maximum and minimum pupil diameters over a 4 second interval were plotted by treatment and time point (Data Source Figure 10.2). There were no remarkable trends observed across treatment regimens. The mean (±SD) of the mean pupil diameter in 4 s is displayed in Figure 13.

Figure 13 Plot of mean (±SD) Mean Pupil Diameter by Treatment and Time point



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Body Temperature

The plot of the mean (±SD) of body temperature can be viewed in Figure 14. There were no signals of a trend in body temperature for any treatment regimen.

Figure 14 Plot of Mean (±SD) Body Temperature by Treatment and Time point

Data Source: Source: Figure 10.3 Pharmacokinetics:

Drug Concentration Data

No plasma or urine GSK1034702 concentrations were excluded from the PK analysis.

Pharmacokinetic Parameters

Individual plasma GSK1034702 PK parameters are summarised in Data Source Table 11.2 and Table 11.3. PK parameters of GSK1034702 are summarised in Table 6. Following single administration of 0.1 mg GSK1034702, only one subject had GSK1034702 concentrations above the LLQ. The profiles were more extensive for all other doses (0.5 to 13 mg).


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Table 6 Summary of GSK1034702 Pharmacokinetic Parameters following Single Administration of GSK1034702 (0.1 mg to 13 mg)

Dose (mg) N n Cmax

(ng/mL) tmax (h)

AUC(0-t) (ng.h/mL)

AUC(0-∞) (ng.h/mL)

t½ (h)

CL/F (L/h)

CLr (L/h)

Geometric Mean (CVb%)

0.325 (NA)

NA 0.32 (NA)

NA NA NA NA 0.1 10 1

Median (Range)

0.325 (0.33-0.33)

2.000 (2.00-2.00)

0.32 (0.3-0.3)

NA NA NA NA


0.649 (46.8)

NA 3.75 (156.4)

NA NA NA NA 0.5 17 16

Median (Range)

0.621 (0.32-1.40)

2.000 (1.00-6.03)

4.59 (0.9-52.7)

NA NA NA NA


4.348 (21.4)

NA 94.31 (47.6)

NA NA NA 2.750 (27.5)

2 10 10

Median (Range)

4.150 (3.39-6.64)

2.000 (1.03-4.00)

95.07 (50.6-251.6)

NA NA NA 2.998 (1.65-3.65)


11.356 (29.0)

NA 293.40 (25.1)

NA NA NA 2.809 (19.5)

4 9 9

Median (Range)

10.438 (8.72-21.95)

2.000 (1.00-8.08)

311.54 (166.0-394.1)

NA NA NA 2.786 (2.08-4.17)


15.707 (9.6)

NA 457.13 (20.6)

NA NA NA 2.559 (19.3)

5 Tablet

8 8

Median (Range)

15.522 (13.78-17.87)

4.025 (1.50-8.00)

474.20 (319.0-629.0)

NA NA NA 2.669 (1.81-3.34)


14.497 (26.3)

NA 383.21 (20.6)

404.51 (19.8)

18.810 (20.3)

12.361 (19.8)

2.540 (27.2)

5 Liquid

10 10

Continued

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LH

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MA

A110623

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Dose (mg) N n Cmax

(ng/mL) tmax (h)

AUC(0-t) (ng.h/mL)

AUC(0-∞) (ng.h/mL)

t½ (h)

CL/F (L/h)

CLr (L/h)

Median (Range)

14.686 (9.80-22.52)

2.000 (0.68-4.00)

371.28 (299.1-560.5)

386.82 (329.7-570.4)

17.472 (14.95-29.44)

12.942 (8.77-15.17)

2.570 (1.55-3.57)


25.796 (24.6)

NA 738.20 (23.3)

783.48 (23.2)

23.603 (20.9)

10.211 (23.2)

2.480 (37.5)

8 8 8

Median (Range)

25.294 (18.87-39.75)

2.000 (1.00-4.02)

695.81 (573.5-1064.6)

735.60 (621.4-1123.0)

23.364 (17.18-31.10)

10.927 (7.12-12.87)

2.553 (1.16-3.70)


43.601 (26.3)

NA 1134.94 (21.2)

1219.50 (20.3)

24.494 (15.5)

9.020 (20.3)

2.477 (17.1)

11 7 7

Median (Range)

39.352 (32.02-64.15)

2.000 (1.50-4.08)

1075.10 (905.0-1669.1)

1127.64 (989.1-1750.2)

25.354 (19.69-30.71)

9.755 (6.28-11.12)

2.275 (2.03-3.16)


40.425 (22.7)

NA 1155.68 (22.2)

1245.95 (22.3)

22.573 (21.3)

9.631 (22.3)

2.726 (19.8)

12 6 6

Median (Range)

42.025 (29.95-57.25)

3.515 (1.05-8.00)

1090.15 (950.5-1716.9)

1223.77 (998.6-1809.0)

21.941 (17.46-29.44)

9.810 (6.63-12.02)

2.753 (2.15-3.65)


45.802 (15.8)

NA 1169.72 (28.6)

1335.79 (18.6)

20.947 (15.5)

9.732 (18.6)

2.739 (22.8)

13 2 2

Median (Range)

46.086 (40.98-51.19)

4.515 (3.00-6.03)

1192.73 (959.6-1425.9)

1347.16 (1172.5-1521.8)

21.072 (18.78-23.36)

9.815 (8.54-11.09)

2.774 (2.34-3.21)

Source Data: Table 11.2 and Table 11.3 NA: Not Applicable

CO

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LH

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A110623

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The absorption of GSK1034702 after oral administration was moderately rapid at all investigated doses (median tmax was 2 to 4 h). The compound appeared to be characterised by a low to moderate oral clearance and an extensive oral volume of distribution. Generally, the estimated mean terminal half-life ranged between 15 h and 25 h.

The study was not designed to formally compare exposure in poor and extensive metabolisers. The data collected did not show any clear difference in the exposure and Cmax between poor and extensive CYP2D6 metabolisers (Table 7).

Table 7 Summary of PK parameters of GSK1034702 for 2D6 Poor and Extensive Metabolisers

GSK1034702 Dose (mg)

PM/EM tmax1 (h)

Cmax2 (ng/mL)

AUC(0-t)2 (ng.h/mL)

AUC(0-∞)2 (ng.h/mL)

t½2 (h)

PM (n=1)

2.00 (2.00-2.00)

0.325 (NA)

NA NA NA 0.1 EM

(n=9) NA NA NA NA NA

PM (n=4)

3.01 (1.50-6.03)

1.046 (26.7)

13.08 (139.7)

NA NA 0.5 EM

(n=12) 2.00

(1.00-3.00) 0.554 (38.8)

2.47 (94.3)

NA NA

PM (n=3)

2.02 (2.00-4.00)

5.010 (24.9)

144.86 (52.5)

NA NA 2 EM

(n=7) 2.00

(1.03-3.00) 4.092 (18.2)

78.47 (31.3)

NA NA

PM (n=2)

5.04 (2.00-8.08)

9.721 (1.3)

351.77 (16.2)

388.98 (20.9)

26.084 (11.3) 4 EM

(n=7) 2.00

(1.00-4.00) 11.872 (31.9)

278.57 (25.6)

NA NA

PM (n=2)

2.75 (1.50-4.00)

16.393 (11.1)

531.73 (24.1)

590.41 (31.6)

28.440 (32.1) 5(Tablet) EM

(n=6) 5.025

(1.50-8.00) 15.485 (9.8)

434.66 (18.8)

NA NA

PM (n=4)

2.25 (0.68-4.00)

15.314 (21.8)

410.98 (31.1)

446.67 (28.3)

19.54 (28.1) 5 (Liquid) EM

(n=6) 2.00

(1.02-3.02) 13.977 (30.5)

365.74 (11.6)

378.64 (10.0)

18.338 (15.9)

PM (n=3)

1.13 (1.03-4.00)

26.323 (36.9)

706.32 (36.7)

759.57 (34.9)

27.089 (14.3) 8 EM

(n=5) 2.00

(1.00-4.02) 25.484 (19.8)

758.02 (16.7)

798.18 (18.3)

21.731 (20.7)

PM (n=3)

2.00 (1.53-3.00)

45.953 (29.5)

1138.99 (34.3)

1214.21 (32.6)

23.079 (8.3) 11 EM

(n=4) 2.50

(1.50-4.08) 41.916 (27.5)

1131.91 (11.9)

1223.48 (11.7)

25.612 (19.3)

PM (n=3)

8.00 (4.03-8.00)

38.625 (35.6)

1239.34 (29.9)

1311.28 (30.7)

22.657 (23.4) 12

Continued


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GSK1034702 Dose (mg)

PM/EM tmax1 (h)

Cmax2 (ng/mL)

AUC(0-t)2 (ng.h/mL)

AUC(0-∞)2 (ng.h/mL)

t½2 (h)

EM (n=3)

1.52 (1.05-3.00)

42.309 (1.8)

1077.67 (14.4)

1183.88 (15.6)

22.489 (24.4)

PM (n=1)

3.00 (3.00-3.00)

40.983 (NA)

959.57 (NA)

1172.49 (NA)

18.784 (NA) 13 EM

(n=1) 6.03

(6.03-6.03) 51.188 (NA)

1425.89 (NA)

1521.83 (NA)

23.360

NA: Not applicable 1. Median (range) 2. Geometric Mean (CVb%)

Statistical Analyses of Pharmacokinetic Parameters

Dose Proportionality

A preliminary assessment of dose proportionality was performed for GSK1034702 pharmacokinetic parameters AUC(0-∞), AUC(0-t) and Cmax, over the dose range 0.5 mg to 13 mg. The 0.1 mg liquid and 5 mg tablet regimens were not included in the analysis.

A summary of the results from power model is presented in Table 8.

Table 8 Statistical Summary of Dose Proportionality Analysis using the Power Model (GSK1034702 0.5 to 13 mg)

PK Parameter Adjusted Mean Slope (90% CI)

AUC(0-∞) (ng.h/mL) 1.35 (1.25, 1.45) AUC(0-t) (ng.h/mL) 1.87 (1.75, 2.00)

Cmax (ng/mL) 1.33 (1.27, 1.39) Data Source: Table 11.4 All the adjusted mean slopes are above the value of 1, suggestive of a more than proportional increase of AUC(0-∞), AUC(0-t) and Cmax values with increasing doses.

The estimated increase in dose required to double each parameter is given by 2(1/β) where β represents the adjusted mean slope (similarly for the confidence interval limits). For AUC(0-∞) the estimated increase is 1.67 (90% CI: 1.61 to 1.74). That is, an increase in dose of 67% would result in the doubling of AUC(0-∞) over the dose range 0.5 to 13 mg. An increase in dose of 45% would result in the doubling of AUC(0-t), estimated increase 1.45 (90% CI: 1.42 to 1.49). Similarly, an increase in dose of 69% would result in the doubling of Cmax, estimated increase 1.69 (90% CI: 1.65 to 1.73).

The criteria defined for concluding statistically confirmed dose proportionality for AUC(0-∞), AUC(0-t) and Cmax of GSK1034702 across doses 0.5 to 13 mg would be that the 90% confidence interval for the adjusted mean slope had to fall completely within the range of 0.93 to 1.07. The 90% confidence intervals for AUC(0-∞), AUC(0-t) and Cmax are not contained within this range.


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A secondary analysis was performed using the dose-normalised ANOVA to further compare GSK1034702 exposure across doses and look at the extent of the increase. Each dose was compared to a reference dose of 5mg liquid which was the lowest dose for which AUC(0-∞) could be derived for all subjects. The ANOVA model confirms the interpretation of the power model of a more than proportional increase of AUC(0-∞), AUC(0-t) and Cmax with increasing doses.

Liquid vs. Tablet Formulations

The 5 mg tablet and 5 mg liquid formulation were administered in different cohorts, hence this statistical analysis was based on between subject comparisons. Within subject comparisons were conducted with the dose-normalised 4 mg liquid and 5 mg tablet as both these regimens were studied within the same cohort.

The within-subject and between-subject analysis results are in agreement and indicate a slight decrease in exposure for the liquid formulation compared to tablet. None of the 90% confidence limits for comparisons of GSK1034702 liquid and tablet formulations of AUC(0-∞), AUC(0-t) and Cmax lay within the bioequivalence interval 0.80 to 1.25. However, these results should be interpreted with caution as this comparison was conducted in a small number of subjects and was not powered to demonstrate bioequivalence. In addition, the data used for the analysis had some limitations. Blood samples were only collected up to 48 h for some subjects, whereas other subjects had samples collected up to 96 h. Additionally, it was only possible to derive AUC(0-∞) for 6 of 9 subjects on 4 mg dose and 6 of 8 subjects on 5 mg tablet regimen.

The results are presented in Data Source Table 11.6 with a summary in Table 9.

Table 9 Statistical Summary of Comparison of Liquid and Tablet Formulations

Comparison Parameter Ratio (90% CI) AUC(0-∞) (ng.h/mL) 0.845 (0.775, 0.922) AUC(0-t) (ng.h/mL) 0.810 (0.732, 0.897)

GSK1034702 4 mg Liquid (Test) vs. GSK1034702 5 mg Tablet (Reference) (dose-normalised) Cmax (ng/mL) 0.904 (0.751, 1.09)

AUC(0-∞) (ng.h/mL) 0.767 (0.645, 0.911) AUC(0-t) (ng.h/mL) 0.838 (0.708, 0.993) GSK1034702 5 mg Liquid (Test) vs.

GSK1034702 5 mg Tablet (Reference) Cmax (ng/mL) 0.923 (0.779, 1.09) Data Source: Table 11.6


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Pharmacodynamics:

Bond and Lader VAS

There were no remarkable trends for any of the 3 domains of the Bond and Lader visual analogue scale: alertness, contentedness and calmness. The calmness domain displayed an increase at 2 h post-dose on the 13 mg regimen although there were only 2 subjects who received this treatment and other dose regimens did not display such patterns.

Figure 15 Mean (±SD) of Bond and Lader Calmness Score by Treatment and Time point


Pulmonary Function Tests

Summary statistics of pulmonary function test measurements FEV1, VC/FVC and FEV1/FVC(%) are presented in Data Source Table 12.1. There were no noticeable trends across GSK1034702 doses and placebo.


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Conclusions:

• In this study, single doses of GSK1034702 were generally well tolerated at doses up to 8 mg and this dose was considered the MTD. At the higher dose of 12 mg, one subject experienced adverse events (severe abdominal pain, nausea and vomiting) that were not tolerated.

• Dose related adverse events, i.e. reported only at doses ≥5mg included: salivary hypersecretion, hot flush, hyperhidrosis, nausea, abdominal pain, diarrhoea and vomiting. The severity of these events appeared to increase with increasing dose. These adverse effects are believed to be related to the muscarinic pharmacology of GSK1034702.

• No clinically relevant changes were observed in haematology, chemistry and renal monitoring tests.

• Although this study was not fully powered to make conclusions on a potential drug –related QT effect, following the extensive evaluation (statistical analyses and PK/QTc), there is no clear trend indicating an effect of single doses of GSK1034702 on QTc at the doses tested.

• Analysis (statistical analyses and PK/VS) of the blood pressure and heart rate from standard monitoring revealed evidences for a clinically relevant effect of GSK1034702 on both, which were concentration and dose dependent. Additional data analysis from the ABP monitoring suggests an effect at the highest dose levels (11 to 13 mg) whereas at doses ≤8mg the effect was less clear.

• No noticeable trends were observed for pupil diameter, body temperature, bond & Lader or pulmonary function across doses tested.

• The absorption of GSK1034702 after oral administration was moderately rapid at all investigated doses (median tmax was 2 to 4 h). The compound appeared to be characterised by a low to moderate oral clearance and an extensive oral volume of distribution. Generally, the estimated mean terminal half-life ranged between 15 h and 25 h.

• An assessment of dose proportionality suggested a greater than dose proportional increase in AUC(0-∞), AUC(0-t) and Cmax following single ascending doses of GSK1034702 over the dose range tested.

Date of Report:

September 2009


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synopsis · a summary of the dose decisions in the final group of subjects, cohort 2, can be seen...

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