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CONFIDENTIAL VM2008/00010/00 OXS104092

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Synopsis

Identifier: VM2008/00010/00 Study Number: OXS104092

Title: A single-blind, randomized, placebo-controlled, 15-day repeated dose study to evaluate the safety, tolerability and pharmacokinetics of SB649868 and its interaction with the CYP3A4 isoenzyme in healthy male subjects

Investigator:

Germany

Study Centre:

Germany

Publication:

None as of the date of this report.

Study period:

Initiation Date: 18 APR 2007

Completion Date: 04 AUG 2007

Early Termination Date: 19 DEC 2007

Phase of development: I

Objectives:

Safety and Tolerability

• To assess the safety and tolerability of repeated oral doses of SB649868 administered once daily for 15 days after food in healthy male subjects.

Pharmacokinetics

• To assess the pharmacokinetics of repeated oral doses of SB649868 in healthy male subjects.

• To assess the interaction between single and repeat doses of SB649868 and simvastatin as a probe of CYP3A4 induction/inhibition.

• To determine the metabolite profiles in plasma and urine after both single and repeat administration of SB649868.

• To evaluate the reversibility of SB649868 CYP3A4 induction/inhibition.


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Pharmacodynamics

• To investigate the effect of SB649868 on pharmacodynamic parameters including: Subjective assessments of sleepiness and alertness

Subjective assessments of sleep duration and quality

Cognition tests

Actigraphy

Appetite

• To assess the relationship of plasma levels of SB649868 with pharmacodynamic and safety parameters.

Methodology:

The present study was conducted to evaluate the safety, tolerability and pharmacokinetics of SB649868 administered after food for 15 consecutive days.

Additionally, several tests were performed to evaluate pharmacodynamic characteristics of SB649868. The Leeds Sleep Evaluation Questionnaire (LSEQ) and actigraphy were performed to evaluate the hypnotic effects of SB649868. The Stanford Sleepiness Scale and the Bond & Lader VAS were used to assess sleepiness/alertness at different time points after single and repeat administration of SB649868. The effect of repeat administration of SB649868 on cognitive and psychomotor functions was assessed with the Digit Symbol Substitution Test (DSST), the Verbal Learning and Memory Test (VLMT) and the Romberg/Heel to Toe Test after single and repeat dosing. Further, the effect of repeat SB649868 administration on appetite was assessed by means of the Appetite VAS (AVAS).

The time-dependent interaction of SB649868 with the CYP450 3A4 isoenzyme (CYP3A4) was investigated using simvastatin (10 mg) as probe. Changes in pharmacokinetic parameters of SB649868 and simvastatin served to evaluate the extent of the interaction in human. Also, the reversibility of a possible interaction should have been assessed in Cohort 4. This additional investigation was declared in Amendment 2 but never came to execution because of upcoming data of animal toxicity which indicated a potential for SB649868 to induce cardiac lymphocyte infiltration. Thus, the clinical study was prematurely stopped after the completion of Cohort 3.

SB649868 was administered in doses of 5 mg (Cohort 1), 15 mg (Cohort 2) and 30 mg (Cohort 3). Due to its improved intestinal absorption rate under fed conditions, SB649868 was administered after a standard breakfast. Subjects were screened for eligibility within a 28-day period. They entered the experimental part of the clinical study on Day –11 and received simvastatin 10 mg on Days –10, 1, 4 and 15. SB649868 was administered as a single dose on Day –7 and as repeat once daily doses from Day 1 until Day 15. Subjects were discharged on Day 17 from the treatment phase and were checked in a Follow-up Visit 7–14 days after the last dose of the investigational


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medicinal product. The total length of the clinical study ranged for an individual subject approximately from 5 to 10 weeks.

Number of subjects:

Thirty-six (36) subjects were enrolled into this study and thirty-four (34) completed. Both

subjects received placebo.

Subject disposition is shown in Table 1.

Table 1 Subject disposition

Number of Subjects Placebo 5 mg SB649868

15 mg SB649868

30 mg SB649868

Total

Number of subjects planned, N:

9 9 9 9 36

Number of subjects randomized, N:

9 9 9 9 36

Number of subjects included in All subjects (safety) population, n (%):

9 (100%) 9 (100%) 9 (100%) 9 (100%) 36 (100%)

Number of subjects included in PK population, n (%):

– 9 (100%) 9 (100%) 9 (100%) 27 (75%)

Number of subjects completed as planned, n (%):

7 (78%) 9 (100%) 9 (100%) 9 (100%) 34 (94%)

Number of subjects withdrawn (any reason), n (%):

2 (22%) – – – 2 (6%)

Number of subjects withdrawn for SAE, n (%):

– – – – –

Number of subjects withdrawn for AE, n (%):

2 (22%) – – – 2 (6%)

Reasons for subject withdrawal, n (%)

Lost to follow-up – – – – – Adverse events 2 (22%) – – – 2 (6%) Protocol violation – – – – – Other – – – – –

Source: Modular Appendix Table 9.1 The demographic characteristics of the healthy subjects are shown in Table 2.


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Table 2 Demographic characteristics

Demographics Placebo 5 mg SB649868

15 mg SB649868

30 mg SB649868

Total

Age in Years, Mean (Range)

39.4 (24–64)

36.1 (21–47)

37.1 (25–50)

39.3 (23–52)

38.0 (21–64)

Sex, n (%) Female: – – – – – Male: 9 (100%) 9 (100%) 9 (100%) 9 (100%) 36 (100%)

BMI, [kg/m²] Mean (Range)

23.6 (20.2–27.5)

24.81 (22.4–27.3)

24.31 (22.1–26.6)

24.97 (20.2–27.8)

24.43 (20.2–27.8)

Height, [cm] Mean (Range)

176.2 (168–189)

178.0 (167–186)

179.9 (172–187)

182.9 (170–198)

179.3 (167– 198)

Weight,[kg] Mean (Range)

73.46 (59.8–90.0)

78.78 (64.8–92.5)

78.67 (67.7–86.1)

83.81 (66.5–99.8)

78.68 (59.8–99.8)

Ethnicity, n (%) Hispanic or Latino: – 1 (11%) – – 1 (3%) Not Hispanic or Latino: 9 (100%) 8 (89%) 9 (100%) 9 (100%) 35 (97%)

Race, n (%) Asian Central/South Asian Heritage Japanese/East Asian Heritage/ South East Asian Heritage

1 (11%) – – – 1 (3%)

White – White/Caucasian /European Heritage

8 (89%) 9 (100%) 9 (100%) 9 (100%) 35 (97%)

Source: Modular Appendix Table 9.2 and Table 9.3

Diagnosis and main criteria for inclusion:

The main criteria for inclusion were healthy adult male subjects aged between 18 and 65 years with a body mass index (BMI) of 18.5–28.0 kg/m², and healthy status as defined per medical history, physical examination, laboratory values (including circulating levels of LH, FSH and testosterone), vital signs and ECG-recording. Subjects were excluded from the study if they consumed CYP450-isoenzyme inducing or inhibiting food, beverages or medications within 7 to 14 days prior to first dosing of the investigational medicinal product (IMP) and if they complained of sleep disturbances and/ or were receiving treatment for sleep disorders.

Treatment administration:

In Cohorts 1, 2 and 3, each subject received up to 3 active or placebo tablets once a day (an appropriate combination of SB649868 5 mg, 25 mg and placebo tablets to achieve the required dose) at approximately 08:00 to 09:30, (within 30 minutes after a standardised breakfast).

Simvastatin was administered as commercially available Zocor 10 mg tablets.

The characteristics of the investigational medicinal products are summarised in Table 3.


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Table 3 Investigational medicinal product characteristics

Investigational medicinal product

Package Batch details Storage conditions

Use by date

Placebo matching SB649868

Bottles containing 50 x PTM SB649868 tablets

Input Batch No.: 051071857 Lot No.: 051111094

Store up to 30°C Protect from light

31 March 2010

SB649868 5 mg Bottles containing 50 x SB649868 5 mg tablets



29 February 2008

SB649868 25 mg Bottles containing 50 x SB649868 25 mg tablets



29 February 2008

Simvastatin Bottles containing 100 x Zocor 10 mg tablets

Input Batch No.: 264273

Store below 30°C January 2008

On study days when subjects were administered both SB649868 and simvastatin, SB-649986 was administered 1 hour prior to the administration of simvastatin.

Criteria for evaluation:

Safety and Tolerability

• Safety and tolerability endpoints were evaluated by adverse event monitoring, laboratory values, cardiovascular monitoring (blood pressure, heart rate, ECGs), body temperature, respiratory rate.

Pharmacokinetics

• SB649868 pharmacokinetic parameter values after single dose: AUC(0–t), AUC(0–∞), Cmax, tmax, and t1/2

• SB649868 pharmacokinetic parameter values after repeated dose: AUC(0–24), Cmax, tmax, t1/2, accumulation ratio (Ro) and time invariance (Rs)

• Simvastatin and β-hydroxy-simvastitin acid pharmacokinetic parameter values, Cmax and AUC(0–t), following oral administration of simvastatin alone and in combination with SB649868

• Simvastatin and β-hydroxy-simvastitin acid pharmacokinetic parameter values, Cmax and AUC(0–t), following oral administration of simvastatin alone, in combination with SB649868 and alone following the combined administration with SB649868

Pharmacodynamics

• Leeds Sleep Evaluation Questionnaire (LSEQ) - sleep quality evaluation


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• Stanford Sleepiness Scale (SSS) - to measure sleepiness/alertness

• Bond Lader Visual Analogue Scale (VAS) to measure sleepiness/alertness

• Digit Symbol Substitution Test (DSST) to measure cognitive function

• Verbal Learning and Memory Test (VLMT) to measure cognitive function

• Actigraphy measurements of sleep duration

• Appetite Visual Analogue Scale (AVAS) to assess appetite

• Romberg/ heel-to-toe test

Statistical methods:

Sample Size Considerations

Sample size was primarily based on feasibility. Thirty-six subjects in 3 cohorts taking repeat doses of SB649868 (N=9 per dose cohort) and placebo (N=3 per cohort) allowed a balanced study design, consistent with similar repeat dose-escalating studies.

Preliminary analyses of pharmacokinetics data from the FTIH OXS104096 had estimated a SB649868 within-subject CV of around 20% for AUC(0–∞). Based upon a similar value for AUC(0–t) as well, and with 9 subjects completing the active treatment in each cohort, it was estimated that the lower and upper bounds of the 90% confidence interval for the accumulation ratio and time invariance would have been obtained by dividing/multiplying the point estimates for a factor of 1.18. Hence, if the estimated ratio equalled to 1, the 90% CI would have been 0.85 to 1.18, if it equalled to 1.2, the 90% CI would have been 1.02, 1.41.

Simvastatin within-subject CV of 25.7% and 29.5% was obtained for AUC(0–t) and Cmax, respectively, in the study AVS102130. Based upon the maximum value of 29.5% and with 9 subjects completing the active treatment in each cohort, it was estimated that the lower and the upper bounds of the 90% confidence interval for the ratio of the geometric means (simvastatin + SB649868)/simvastatin alone would have been obtained by dividing/multiplying the point estimates for a factor of 1.30. Hence, if the estimated ratio equalled to 1, the 90% CI would have been 0.77 to 1.30, if it equalled to 1.5, the 90% CI would have been 1.16, 1.95.

Interim Analyses

No formal statistical interim analyses were planned; however a few steps to review the safety, tolerability and preliminary pharmacokinetic data were required. Reviews of data were expected on Day 14 of each cohort in order to evaluate the safety up to Day 14 and the preliminary pharmacokinetics up to Day 7, and therefore decide whether to start dosing the next cohort with the higher dose.

Final Analyses

Formal statistical analyses were carried out on the effect of single and repeat dosing of SB649868 on simvastatin and β-hydroxy-simvastatin acid log-e transformed AUC(0–t)


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and Cmax. A mixed effect analysis of variance model was fitted with day as a fixed effect and subject as a random effect. Point estimates and corresponding 90% CIs were computed for the differences after 4 and 15 days of SB649868 repeat dose and after SB649868 single dose (Day 1) from simvastatin alone (Day –10) for each SB649868 dose (Modular Appendix: Pharmacokinetic Table 11.14).

An estimation of SB649868 time invariance was performed after a log-e transformation of the AUC data from each active treatment dose. A mixed effect model was fitted with day as a fixed effect and subject as a random effect. Day 7 and Day 14 AUC(0–24) were compared with single dose Day 1 AUC(0–∞) in order to assess time invariance for each day and dose level (Modular Appendix: Table 11.11).

Accumulation ratio of SB649868 was estimated on Day 7 and 14 after log-e transformation of AUC(0–24). A mixed effect model was fitted, with day as a fixed effect and subject as a random effect. AUC(0–24) of multiple dose part (Day 7 and Day 14) was compared with AUC(0–∞) of the single dose session (Day –7) in order to asses time invariance for each day and dose level (Modular Appendix: Pharmacokinetic Table 11.10).

An assessment of SB649868 steady state was performed using Cτ levels, after a log-e transformation of the data from all active treatment doses. The assessment of steady state achievement was done separately for Day 2–4 and Day 5–7. Only pre-dose concentrations on Days 2, 3 and 4 were included in the analysis for Day 2–4, while only pre-dose concentration on Days 5, 6 and 7 were included in the analysis for Day 5–7. A mixed effect model was fitted for each active dose separately with day as a continuous covariate and subject as a random effect (Modular Appendix: Pharmacokinetic Table 11.12).

A preliminary assessment of SB649868 dose proportionality both after single dose (Day -7) and after repeat doses (Day 14) was made using the Power Model. The statistical analysis was performed after a log-e transformation of AUC(0–∞) and Cmax

after single dose and AUC(0–24) and Cmax after repeat dosing. The coefficient of the slope with 90% confidence interval were estimated, using the pooled estimate of variance, and used to assess dose proportionality (Modular Appendix: Pharmacokinetic Table 11.13).

Changes in conduct of the study or planned analyses

It was planned to dose a 4th cohort, however the study was terminated after the completion of Cohort 3. Therefore, the pharmacokinetic study objective “to evaluate the reversibility of SB649868 CYP3A4 induction/inhibition” was not accomplished.

The determination of metabolite profiles in plasma and urine after both single and repeat administration of SB649868 will be performed by DMPK. These studies will be conducted under a separate protocol and a report issued accordingly.


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Summary:

Safety:

Adverse events

A total of 27 of the 36 subjects (75%) experienced adverse events. The majority of adverse events (AE) was attributed to the nervous system with 20 subjects being affected (56%), to general disorders and administration site conditions with 17 subjects (47%), and to gastrointestinal disorders with 11 subjects (31%). Most frequent adverse events across all dose-groups, including placebo, were somnolence with 17 subjects (47%) and fatigue with 12 subjects (33%), followed by headache (6 subjects, 17%) and dry mouth (5 subjects, 14%). In the placebo group 56% of subjects experienced any adverse event, and in the SB649868 groups this was 81%. All adverse events observed in this clinical trial were of mild to moderate intensity. There were no serious adverse events or fatal outcomes in this clinical study. See Table 4.

The distribution of all adverse events and drug related adverse events was similar. There was no evidence of a higher frequency or severity of adverse events in subjects who received SB649868, with the exception of somnolence and fatigue which were more frequently reported by subjects treated with SB-649868.

He participated

on Days –10 and –7 and received a single dose of simvastatin and a single dose of placebo to SB649868, but was unable to attend the unit for the repeat dose period.

The subject received two single doses of simvastatin on Day –10 and Day 1, one single dose of SB649868-placebo on Day –7 and eight repeat doses of SB649868-placebo from Day 1 to Day 8. He complained about a series of eye- and vision-related symptoms (red eyes, burning eyes, disturbed accommodation, decreased vision and periorbital swelling). These adverse events were classified as of moderate intensity and were treated with eye drops for allergic conjunctivitis.

After withdrawal the ophthalmic adverse events disappeared within one week. During the course of the study, the eye symptoms were related to the investigational medicinal product by the Investigator. As the subject received placebo any relation to SB649868 could be excluded. A possible relationship to simvastatin might be speculative. More probable was an allergic aetiology in terms of seasonal pollinosis although the subject’s medical history was devoid of allergic events.


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Table 4 Summary of all subjects experiencing adverse events (reported by more than one subject)

Placebo 5 mg SB649868

15 mg SB649868

30 mg SB649868

Total

N 9 9 9 9 36 Any AE 5 (56%) 7 (78%) 8 (89%) 7 (78%) 27 (75%) Nervous system disorders Any event 4 (44%) 3 (33%) 6 (67%) 7 (78%) 20 (56%) Somnolence 4 (44%) 0 6 (67%) 7 (78%) 17 (47%) Headache 1 (11%) 1 (11%) 2 (22%) 2 (22%) 6 (17%) Dizziness 0 1 (11%) 0 3 (33%) 4 (11%) Paraesthesia 0 1 (11%) 0 1 (11%) 2 (6%) General disorders and administration site conditions Any event 3 (33%) 3 (33%) 4 (44%) 7 (78%) 17 (47%) Fatigue 2 (22%) 1 (11%) 2 (22%) 7 (78%) 12 (33%) Asthenia 2 (22%) 0 0 0 2 (6%) Gastrointestinal disorders Any event 3 (33%) 3 (33%) 3 (33%) 2 (22%) 11 (31%) Dry mouth 1 (11%) 0 2 (22%) 2 (22%) 5 (14%) Constipation 2 (22%) 0 0 0 2 (6%) Psychiatric disorders Any event 3 (33%) 1 (11%) 4 (44%) 2 (22%) 10 (28%) Abnormal dreams 1 (11%) 0 2 (22%) 0 3 (8%) Sleep disorder 1 (11%) 0 1 (11%) 1 (11%) 3 (8%) Nightmare 1 (11%) 0 1 (11%) 0 2 (6%) Musculoskeletal and connective tissue disorders Any event 0 2 (22%) 1 (11%) 2 (22%) 5 (14%) Neck pain 0 1 (11%) 1 (11%) 0 2 (6%) Eye disorders Any event 1 (11%) 0 2 (22%) 1 (11%) 4 (11%) Skin and subcutaneous tissue disorders Any event 1 (11%) 2 (22%) 1 (11%) 0 4 (11%) Metabolism and nutrition disorders Any event 0 1 (11%) 0 1 (11%) 2 (6%) Respiratory, thoracic and mediastinal disorders Any event 1 (11%) 0 0 1 (11%) 2 (6%) Vascular disorders Any event 0 0 2 (22%) 0 2 (6%) Source : Modular Appendix Table 10.2


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Concomitant medications

[See also Modular appendix: Data Listing- ICH 10

(Table 10.9) (Attachment 5) for details]

Laboratory findings

There was no evidence for a relationship between the administration of SB649868 and the laboratory findings of any concern. Upon visual inspection of the summary of chemistry and laboratory values (Modular Appendix: Table 10.4), there were no noticeable differences between the groups who received SB649868 and the placebo group. Neither was there a trend indicating a dose relationship.

None of

these results have shown to be of clinical significance, and thus the subjects completed the clinical study with no concerns.

Vital signs

These deviations occurred in the standing position and were distributed almost equally across all dose-groups, including placebo, and occurred at any time point within the clinical study. Therefore, it could be suggested that their incidence is rather due to orthostatic changes in the upright position than attributable to the investigational medicinal product.


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ECG-recordings

Generally, there were no ECG findings of clinical significance within this clinical study. The distribution of abnormal, but clinically not significant findings was approximately equal trough all SB649868 dose-groups, including placebo. There was no pattern that would suggest an impact of SB649868 on ECG-findings (Modular Appendix: Table 10.5).

Changes of ECG parameters (heart rate, PR interval, QRS duration, QT interval, QTcB interval, QTcF interval and RR interval) from Baseline were apparently randomly distributed across all dose groups and across all time points in the clinical study. Thus, the data did not support any impact of SB649868 on these ECG parameters (Modular Appendix: Table 10.8).

The most common abnormal ECG findings were QRS- (8 subjects), QT- (6 subjects) and PR-prolongation (2 subjects). QT-prolongation was most probably caused by relative low heart frequency, and when time corrected (QTcB or QTcF) these values were within normal ranges [for details see Modular Appendix: Data Listing – Other 20 (Table 10.11) (Attachment 5)]. None of these findings influenced the subjects’ health status, neither did they yield any adverse event.

Pharmacokinetics:

Blood samples were collected for quantitative pharmacokinetic analysis of SB-649868 on Day –7 (pre dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36 and 48 hours post dose), Days 1, 7 and 14 of the repeating dosing (pre-dose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 and 24 hours post dose) as well as on Days 3, 4, 5 and 6 (pre dose only). For the analysis of simvastatin and β-hydroxy-simvastatin blood samples were collected on Day –10, 1, 4 and 15 (pre-dose, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post dose). There were no deviations in administration of SB649868. The two subjects who withdrew from study participation belonged to the placebo-controlled subgroup. Table 11.1 – Table 11.3 in modular Appendix contain summary statistics of plasma concentration-time data for SB649868, simvastatin and β-hydroxy-simvastatin by planned relative assessment time.

SB-649868 Pharmacokinetic Parameters

Individual plasma SB-649868 PK parameters are presented and are summarized in Table 11.4 and Table 11.7 of modular Appendix. Selected PK parameters are also summarized in Table 5.


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Table 5 Summary of Selected Plasma SB-649868 Pharmacokinetic Parameters

Dose (mg)

Parameters SB–649868 (SD) alone

SB–649868 (SD) + Simvastatin

SB–649868 (SS) alone

SB–649868 (SS) + Simvastatin

N Day –7 N Day 1 N Day 7 N Day 14 5 Cmax (ng/mL)1 9 158 (40) 9 149 (37) 9 174 (30) 9 187 (33) AUC(0–∞)

(ng.hr/mL)1 9 858 (59) – – – – – –

AUC(0–t) (ng.hr/mL)1

9 810 (59) 9 864 (59) 9 963(55) 9 949 (43)

AUC(0–24) (ng.hr/mL)1

9 843 (56) 9 912 (51) 9 996 (52) 9 982 (40)

tmax (hr) 2 9 2.5 (1–4) 9 3.0 (1.5–4.0) 9 3.0 (2.0–6.0) 9 3.0 (2.5–4.0) t1/2 (hr)1 9 3.47 (32) – – – – 9 3.33 (37) 15 Cmax (ng/mL)1 9 624 (24) 9 620 (30) 9 751 (33) 9 765 (32) AUC(0–∞)

(ng.hr/mL)1 9 4502 (52) – – – – – –


9 4431 (52) 9 4289 (43) 9 5316 (52) 9 5186 (65)


9 4308 (43) 9 4313 (43) 9 5345 (52) 9 5208 (65)

tmax (hr) 2 9 2.5 (2.5–4.0) 9 3.0 (2.0–6.0) 9 2.5 (1.5–4.0) 9 3.0 (1.0–4.0) t1/2 (hr)1 9 4.83 (25) – – – – 9 4.52 (42) 30 Cmax (ng/mL)1 9 964 (34) 9 1091 (32) 9 1278 (35) 9 1212 (31) AUC(0–∞)

(ng.hr/mL)1 9 7594 (46) – – – – – –


9 7490 (46) 9 7660 (34) 9 10543 (64) 9 10724 (57)


9 7229 (43) 7690 (35) 8 9502 (57) 9 10785 (58)

tmax (hr)2 9 3.0 (2.0–6.0) 9 3.0 (2.5–8.0) 9 3.0 (2.0–6.0) 9 3.0 (1.0–4.0) t1/2 (hr)1 9 5.08 (19) – – – – 9 5.74 (44) 1 Geometric mean (CV%), Source: Modular Appendix Table 11.7 2 Median (range) , Source: Modular Appendix Table 11.4 SD = Single dose ; SS = steady–state

After single dose, peak plasma SB-649868 concentrations were typically around 2.5-3.0 hours post dose with individual tmax occurring between 1–8 hours. The t1/2 values ranged from approximately 3 to 7 hours in individual subjects following administration of SB-649868 alone. A slight increase in median t1/2 with increasing doses was observed.

After repeat doses (Day 7 and Day 14), following administration of increasing doses of 5, 15 and 30 mg of SB-649868, time to peak were in the range to those observed after single dose that is a median time of 2.5–3.0 hours and a range of 1.0 to 6.0 hours. On Day 14, the t1/2 values ranged from approximately 2 to 12 hours in individual subjects following SB-649868 repeat administration. Aside for the 30-mg treatment, no apparent differences between single and repeat dose terminal half life were observed.


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Inter-subject variability for Cmax and AUC(0–24), as expressed by CV, was 30–51 % on Day 1 and was within the range of the other days (24–65%).

Accumulation Ratio of SB649868

Table 6 contains a summary of the statistical analysis of AUC(0–24) of SB649868.

Table 6 Summary of statistical analysis of SB649868 accumulation ratio

Comparison (Test versus reference)

SB649868 regimen

Geom. LSmean Test (ng*h/mL)

Geom. LSmean Ref. (ng*h/mL)

Ratio 90% CI for ratio

5 mg 981.64 843.41 1.18 (1.06, 1.32) 15 mg 5208.38 4308.31 1.24 (1.11, 1.39)

Day 7 AUC(0–24) vs. Day 1 AUC(0–24)

30 mg 9976.71 7228.68 1.38 (1.21, 1.57) 5 mg 996.46 843.41 1.16 (1.04, 1.30) 15 mg 5345.35 4308.31 1.21 (1.08, 1.35)

Day 14 AUC(0–24) vs. Day 1 AUC(0–24)

30 mg 10785.12 7228.68 1.49 (1.32, 1.69) Source: Modular Appendix Table 11.10

Overall, after repeated oral dosing with SB-649868 there was an increase in Cmax and AUC of SB-6498687. The average increase of SB649868 exposure was similar after 7 and 14 days of repeat dosing, aside for the 30-mg group, whose exposure was already increased up to +38% after one week and further increased up to 49% after two weeks of treatment. A lower accumulation of about 1.2 fold was observed at 5-mg and 15-mg doses.

Dose Proportionality of SB649868

Table 7 contains a summary of the results from the power model statistical analysis of dose proportionality of SB649868 (doses 5 mg, 15 mg and 30 mg).

Table 7 Summary of statistical analysis (Power Model) on dose proportionality of SB649868 across 5- to 30-mg doses

Day Parameter Adjusted Mean Slope

Standard Error

90% CI for adjusted mean slope

AUC(0–∞) (ng*h/mL) 1.243 0.132 (1.018,1.468) Single dose

Cmax (ng/mL) 1.030 0.090 (0.877, 1.183) AUC(0–24) (ng*h/mL) 1.354 0.134 (1.125,1.583) Day 14 Cmax (ng/mL) 1.066 0.086 (0.919, 1.213)

Source: Modular Appendix Table 11.13 After single and multiple doses, a slightly more than proportional increase of SB-649868 AUCs within the dose range 5 to 30 mg was observed. This was also true for Cmax but in lesser extent. After single dose, an increase in dose of 75% would result in the doubling of AUC over the dose range 5-30 mg. Similarly, an increase in dose of 96%


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would result in the doubling of Cmax. Similar values were estimated for dose proportionality after 14 days repeat dosing.

Steady State of SB649868

SB-649868 was in steady state after 7 days of repeat dosing at all dose levels, but at the lowest and intermediate dose (5 and 15 mg) it was achieved already on Day 4 (Modular Appendix: Pharmacokinetic Table 11.12).

Time Invariance of SB649868

Time invariance analysis was performed on both days of repeat dosing (Days 7 and 14). Table 8 presents a summary of the time invariance analysis.

Table 8 Summary of statistical analysis of assessment of time invariance for SB649868

SB649868 Regimen

Comparison Ratio 90% Confidence interval

AUC(0–24) Day 7 vs. AUC(0–∞) single dose

1.161 (1.030, 1.308) 5 mg SB649868

AUC(0–24) on Day 14 vs. AUC(0–∞) single dose

1.144 (1.015, 1.288)


1.187 (1.064, 1.324) 15 mg SB649868


1.157 (1.037, 1.291)


1.315 (1.163, 1.487) 30 mg SB649868


1.420 (1.263, 1.597)

Source: Modular Appendix Table 11.11 Overall, kinetics of SB-649868 was slightly altered after repeat dosing of 5 and 15 mg. After 7 and 14 days, time invariance ratio ranged from 1.144 to 1.187. This was more pronounced in the 30-mg group and even more on Day 14 than on Day 7 which supported the findings of accumulation and dose-proportionality mentioned above.

These results suggested that at lower doses (5 or 15 mg) the overall PK profile of SB649868 over the repeated dose phase was almost in line with the predictions from the single dose data, while at 30-mg dose the extent of time invariance is higher (40%).

Interaction of SB649868 on Simvastatin

Table 9 contains summary of the statistical analysis of AUC(0–t) and Cmax of plasma simvastatin.


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Table 9 Summary of statistical analysis of the effect of single and repeated SB649868 on AUC(0–t) and Cmax of plasma simvastatin

SB649868 Regimen

Comparison (Test versus reference)

Parameter Geom. LSmean Test

Geom. LSmean Ref.


AUC(0–t) 6.28 5.62 1.12 (0.94, 1.32) Day 1 versus Simvastatin alone Cmax 2.43 2.22 1.09 (0.86, 1.39)


AUC(0–t) 8.63 5.62 1.53 (1.30, 1.82)

5 mg SB649868

Day 15 versus Simvastatin alone Cmax 3.11 2.22 1.40 (1.11, 1.78)



AUC(0–t) 23.30 5.80 4.02 (3.17, 5.09)

15 mg SB649868




AUC(0–t) 24.80 4.03 6.16 (4.79, 7.92)

30 mg SB649868


Source: Modular Appendix Table 11.14 On average, there was an increase in exposure of simvastatin when taken with SB649868 compared to single dose of simvastatin alone. The extent of increase in plasma simvastatin exposure appeared to be slightly higher for AUC(0–t) than for Cmax, and higher with increasing SB649868 doses.

When co-administered simvastatin with SB649868 15 mg, the exposure of simvastatin increased about 3-fold (after SB649868 single dose) to 4-fold (after 2 weeks of SB649868).

When co-administered with the highest dose of 30 mg SB649868, the estimates of simvastatin exposure increased from 3-fold (after SB649868 single dose) to 6-fold (after 2 weeks of SB649868). With the lowest dose of SB649868 5 mg the highest increase estimated was +53%, for simvastatin AUC(0–t) after 2 weeks.

Table 10 contains summary of the statistical analysis of AUC(0–t) and Cmax of β-hydroxy-simvastitin (active metabolite of simvastatin).


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Table 10 Summary of statistical analysis of the effect of single and repeated SB649868 on AUC(0–t) and Cmax of β-hydroxy-simvastatin

SB649868 Regimen

Comparison (Test versus Reference)

Parameter Geom. LSmean Test

Geom. LSmean Ref.




AUC(0–t) 7.83 3.32 2.36 (1.90, 2.93)

5mg SB649868




AUC(0–t) 16.24 5.85 2.77 (2.25, 3.43)

15mg SB649868




AUC(0–t) 16.65 5.52 3.02 (2.09, 4.36)

30mg SB649868


Source: Modular Appendix Table 11.15 On average, there was an overall increase in exposure of β-hydroxy-simvastatin when taken with SB649868 compared to single dose of β-hydroxy-simvastatin alone. The pattern of inhibition of β-hydroxy-simvastatin mirrors that observed with simvastatin although β-hydroxy-simvastatin appeared to be a less sensitive probe of CYP3A4 inhibition.

When coadministered with the highest dose of 30 mg SB649868, the estimates of beta-hydroxy-simvastatin exposure increased from 2-fold (after SB649868 single dose) to 4-fold (after 2 weeks of SB649868). When coadministered with the lowest and intermediate doses of SB649868 (5 mg and 15 mg), the estimates of beta-hydroxy-simvastatin exposures increased 2.4 and 2.8 fold, respectively, after 2 week of SB649868.

Other Measures:

Pharmacodynamics

Bond Lader Visual Analogue Scale (VAS) to measure sleepiness/alertness

With the Bond Lader Visual Analogue Scale (VAS) to measure sleepiness/alertness, 16 bipolar lines flanked by opposed adjectives were evaluated, which resulted in three entities consisting of the following characteristics: “alertness – drowsiness”, “calmness – excitedness” and “contendness – discontendness”. The results of the sleepiness/alertness VAS did not reveal an influence of the investigational medicinal product on these


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qualities, neither was there a dose relationship nor a time effect. For details refer to Modular Appendix Pharmacodynamic Figure 12.3 and Table 12.3.

Digit Symbol Substitution Test (DSST) to measure cognitive function

In the Digital Symbol Substitution Test was a trend towards an increase of the performance during the course of the study which was visible in all treatment groups including placebo. This might be explained by the adaptation or training of the subjects known as a learning effect (see Figure 1).

Figure 1 Digit Symbol Substitution Test – Number Attempted

Source: Modular Appendix Pharmacodynamic Figure 12.4

Looking at the percentage of errors committed there was no obvious time effect during the course of the study, thus supporting the assumption that SB649868 had no dose- or time dependent effect on this cognitive test (see Figure 2).


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Figure 2 Digit Symbol Substitution Test – Percent Error

Source: Modular Appendix Figure 12.4

Verbal Learning and Memory Test (VLMT) to measure cognitive function

The Verbal Learning and Memory Test was used as a test of cognitive function where the total immediate recall and the total number of correctly recalled words were assessed. As shown below for the total number of correctly recalled words there was no indication for a change of the memory function from Day 7 to Day 14 in all groups (see Figure 3).


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Figure 3 Verbal Learning and Memory Test – Total Number of Correctly Recalled Words

Source: Modular Appendix Pharmacodynamic Figure 12.5

Leeds Sleep Evaluation Questionnaire (LSEQ), Stanford Sleepiness Scale (SSS) and Actigraphy measurements of sleep duration

The Leeds Sleep Evaluation Questionnaire (LSEQ), Stanford Sleepiness Scale (SSS) and actigraphy showed no dose- or time-dependency on SB649868 dosing. For details refer to Modular Appendix Pharmacodynamic Figure 12.1, Figure 12.2 and Figure 12.6 and Table 12.1, Table 12.2 and Table 12.6, respectively.

Appetite Visual Analogue Scale (AVAS) to assess appetite.

The Visual Analogue Scale for the evaluation of appetite was assessed on Day –11 (baseline), and pre-/post-meal on Days –7, –2, –1, 7 and 14. Generally, there were no obvious differences upon visual inspection of the data (Modular Appendix: Pharmacodynamic Table 12.7). The SB649868 dose did not seem to have any effect on the appetite of the subjects.

Romberg/ heel-to-toe test

The Romberg Heel-to-Toe test was a simple check of coordinative performance of the subjects for an overall assessment of neurological impairment. There was a mixed picture across all dose groups, including placebo, with the majority of subjects (at least 66% or more) performing well. On Day 14 there were even more subjects in the 30-mg SB649868 groups performing better than the placebo group. Therefore, test gave no evidence of a dose- or time-dependency for which the intake of SB649868 could be made responsible (Modular Appendix: Pharmacodynamic Table 12.8).


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Conclusions:

SB-649868 is an orexin antagonist and is being developed for the treatment of insomnia. Study OXS104092 is part of a group of studies being conducted to allow the progression of the compound into long-term studies in the target patient population. In particular, this study assessed safety and tolerability, and pharmacokinetics of SB-649868 administered for 15 consecutive days. As the compound was shown to both inhibit and induce CYP3A4 in preclinical studies, the effect of SB-649868 on the pharmacokinetic of simvastatin, a CYP3A4 substrate, was also assessed. Finally, the effect of SB-649868 on different pharmacodynamic parameters of sleep/wake and appetite were also assessed at different time-points.

SB-649868 was safe and well tolerated at the doses of 5, 15 and 30 mg/d for 15 consecutive days. Somnolence, fatigue, headache and dry mouth were the AEs most frequently reported. These AEs appeared to be reported more frequently after treatment with SB-649868 but a dose-response was apparent only for somnolence and fatigue. These AEs were expected and have been already observed in previous studies with SB-649868 in both healthy volunteers and patients with primary insomnia. Laboratory tests, vital signs assessments and ECG did not highlight clinically significant changes.

Whatever the dose administered, SB-649868 was absorbed quite rapidly with a median time to peak of 2.5 to 3.0 hours on Days 1, 7 and 14. On Day 14 following the peak, concentrations declined rapidly with a mean terminal half-life of about 3 to 6 hours and were comparable to that measured on Day –7 after single SB-649868 dose (3-5 hours).

Consistently with FTIH results, the increase of AUC across the investigated doses was slightly more than proportional whereas the increase of Cmax behaved almost proportionally.

Repeated administration of SB-649868 was associated with a dose-dependent accumulation. SB-649868 exposure was slightly higher on Day 7 after multiple dosing compared to Day 1. No further accumulation was observed on Day 14 except for the 30-mg dose leading to an overall accumulation compared to Day 1 of 1.2-fold for 5- and 15-mg doses and 1.5-fold for 30-mg dose. This accumulation was slightly higher than that expected from single dose data as shown by time invariance ratios. The deviation from time invariance was more marked after the 30-mg dose. Finally, time to steady state appeared also to be dose-dependent ranging from 4 days at the doses of 5 and 15mg to 7 days at the dose of 30mg.

A dose- and time-dependent effect of co-administered SB-649868 on increase of both simvastatin and β-hydroxy-simvastatin was observed. The increase in simvastatin AUC was less than 1-fold at the 5-mg dose, 3- to 4-fold at the 15-mg dose and 5- to 6-fold at the 30-mg dose, suggesting a moderate CYP3A4 inhibition at SB-649868 15-mg dose and a moderate to strong CYP3A4 inhibition at SB-649868 30-mg dose. Time-dependency was evident when comparing simvastatin and β-hydroxy-simvastatin exposures at Day 1 and Day 4, while the change in simvastatin and β-hydroxy-simvastatin exposures between Day 4 and Day 15 was small Future studies will need to


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be conducted to properly assess the time-dependence of CYP3A4 interaction by SB-649868.

Several pharmacodynamic assessments were performed during the study at different time-points. No significant effects of SB-649868 were observed on scales assessing alertness and sleepiness, such as the Bond & Lader scale and the SSS, at any time-point. These results are unexpected as a significant dose-dependent effect on the “alertness” domain of the Bond & Lader scale was observed in study OXS104096 [Study OXS104096]. A possible explanation is the high placebo response which was observed in the current study; while the effect observed with SB-649868 on the “alertness” domain of the Bond & Lader scale was comparable in the two studies (OXS104092 and OXS104096), the average “alertness” VAS in the placebo group ranged between 40 and 50 mm in the current study, and between 16 and 28 mm in the previous study. The lack of effect on the LSEQ and actigraphy is not unexpected as these assessments were performed during or refer to bedtime, i.e. at least 12 hours after the administration of treatments. The lack of effects on the DSST and VLMT confirmed that SB-649868 is not associated with neurocognitive impairment.

As orexin has been implicated in the control of appetite and food intake, we also assessed the effects of SB-649868 on appetite using a standard appetite scale. No effects were observed at any time-point. These results suggest that SB-649868 administration is not associated with important changes in appetite in male healthy subjects. However, more sophisticated studies in the target patient population should be conducted to assess the potential beneficial effect of SB-649868 in the control of appetite.

Date of Report:

Jun 2008


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