EX-99.2 3 a13-23869_2ex99d2.htm EX-99.2

Exhibit 99.2

POSTER NO. PS272

Ethnic sensitivity assessment of fluticasone furoate (FF)/vilanterol (VI) in asthma patients in Japan and Korea: a pre-specified subgroup analysis

Gross AS(1), Goldfrad C(2), Hozawa S(3), James M(4), Clifton CS(1), Sugiyama Y(5), Jacques L(6)

(1)Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Sydney, Australia; (2)Quantitative Sciences Division, GlaxoSmithKline, Uxbridge, UK; (3)Hiroshima Allergy and Respiratory Clinic, Hiroshima, Japan; (4)Medical Affairs, GlaxoSmithKline K.K., Tokyo, Japan; (5)Medicines Development Respiratory, GlaxoSmithKline K.K., Tokyo, Japan; (6)Respiratory Medicines Discovery and Development, GlaxoSmithKline, Uxbridge, UK

INTRODUCTION

· Inhaled corticosteroid (ICS)/long-acting beta 2-agonist (LABA) combinations are recommended by Japanese(1) and global asthma guidelines(2) for asthma patients uncontrolled on ICS alone.

· FF/VI is a once-daily ICS/LABA combination therapy delivered via the ELLIPTA TM dry powder inhaler, which is effective for 24h.

· Responses to pharmacotherapy can vary across ethnic groups(3),(4) including in Japanese patients.

OBJECTIVES

· To establish whether doses of FF/VI recommended from multinational studies are relevant to asthma patients in Japan.

· To compare the efficacy, safety, PK and PD data for FF/VI in patients from Japan and/or Korea with data from patients not from Japan or Korea

· Patients from Korea were included due to similarities in a range of intrinsic and extrinsic ethnic factors between the populations of Japan and Korea.(5)–(7)

METHODS

· A pre-specified subgroup analysis of multicentre, randomised, double-blind, parallel-group international studies that included asthma patients from Japan and/or Korea.

· Inclusion criteria: >12 years of age, pre-bronchodilator % predicted forced expiratory volume in one second (FEV 1) of 40–90%, FEV 1 reversibility of >12% and >200mL.

· Efficacy results were pooled from three Phase III studies, ranging from 12 to 76 weeks duration, that included patients from Japan (GSK study numbers: HZA106827; HZA106829; HZA106837).

· Change from baseline in trough FEV 1 after 12 weeks with once-daily FF/VI 100/25mcg, once-daily FF 100mcg or placebo was analysed across two studies (HZA106827; HZA106837) and data for once-daily FF/VI 200/25mcg, once-daily FF 200mcg and twice-daily fluticasone propionate (FP) 500mcg were from one study (HZA106829).

· Safety data were pooled from the three studies noted above and an additional three placebo-controlled Phase IIb studies, ranging from 28 days to 8 weeks duration, that included patients from Korea (B2C109575; FFA109685; FFA109687).

· PK data were estimated based on a post-hoc analysis of population PK data for FF(8) and of study DB111207 data for VI(9); PD data, including 24h urinary cortisol excretion, were assessed.

RESULTS

Table 1. Demographic and baseline characteristics

Demographic and baseline characteristics (Efficacy population)

|  | Japan |  | Not-Japan |  | Overall |
|  | N=148 |  | N=3066 |  | N=3214 |
Age(1) (years) |  | 47.5 (14.66) |  | 41.9 (16.63) |  | 42.2 (16.59) |
Male (%) |  | 38 |  | 36 |  | 36 |
Weight(1) (kg) |  | 62.5 (13.63) |  | 76.2 (19.29) |  | 75.5 (19.28) |
Height(1) (cm) |  | 160.7 (8.05) |  | 165.7 (9.98) |  | 165.5 (9.96) |
FEV 1(1) (L) |  | 1.933(2) (0.5481) |  | 2.231(3) (0.6469) |  | 2.218(4) (0.6456) |
% Predicted FEV 1(1) |  | 74.7(2) (11.13) |  | 70.6(3) (11.18) |  | 70.8(4) (11.21) |

Demographic characteristics (Safety population)

|  |  |  | Not- |  |  |
|  | Japan+Korea |  | Japan+Korea |  | Overall |
|  | N=194 |  | N=4037 |  | N=4231 |
Age(1) (years) |  | 46.1 (15.00) |  | 41.3 (16.47) |  | 41.5 (16.44) |
Male (%) |  | 40 |  | 37 |  | 37 |
Weight(1) (kg) |  | 63.5 (13.37) |  | 76.1(5) (19.68) |  | 75.5(6) (19.61) |
Height(1) (cm) |  | 161.6 (8.46) |  | 165.7 (10.21) |  | 165.5 (10.17) |

(1)Mean (SD); (2)n=147; (3)n=3059; (4)n=3206; (5)n=4036; (6)n=4230

Efficacy

· Efficacy data were compared between patients (N=3214) from Japan and ‘Not-Japan’; 85% (N=2739) completed the studies.

· Improvements in trough FEV 1 were reported in all populations for FF/VI 100/25mcg and FF 100mcg versus placebo and for FF/VI 100/25mcg versus FF 100mcg (Table 2)

· There was no evidence of a statistically significant difference in treatment effect between patients from Japan and Not-Japan (p=0.403).

· Changes from baseline in FEV 1 were similar with FF/VI 200/25mcg and FF 200mcg in patients from Japan and the overall population (Figure 1)

· Improvements were greater than with twice-daily FP 500mcg.

Table 2. Comparison of change from baseline in trough FEV 1 at Week 12 between treatment arms (Efficacy population)

|  |  |  | FF/VI |  | FF |
|  |  |  | 100/25mcg |  | 100mcg |
|  | N |  | 1201 |  | 1203 |
|  |  |  | 0.181 |  | 0.105 |
|  | Difference vs. placebo(1) |  | (0.111, 0.252) |  | (0.034, 0.175) |
|  |  |  | p<0.001 |  | p=0.003 |
Overall |  |  |  |  |  |  |
|  |  |  | 0. 077 |  | — |
|  | Difference vs. FF 100mcg |  | (0.045, 0.108) |  |
|  |  |  | p<0.001 |  |
|  | n |  | 46 |  | 46 |
|  |  |  | 0.323 |  | 0.216 |
Japan |  | Difference vs. placebo(2) |  | (0.104, 0.542) |  | (–0.003, 0.436) |
|  | Difference vs. FF 100mcg |  | 0.107 |  | — |
|  |  |  | (–0.056, 0.270) |  |
|  | n |  | 1155 |  | 1157 |
Not-Japan |  | Difference vs. placebo(3) |  | 0.168 |  | 0.093 |
|  |  |  | (0.095, 0.241) |  | (0.020, 0.166) |
|  | Difference vs. FF 100mcg |  | 0.075 |  | — |
|  |  |  | (0.043, 0.108) |  |  |

Least squares mean change (95% confidence interval). Studies included: HZA106827, HZA106837. Data were analysed using a Last Observation Carried Forward Analysis of Covariance model, with terms for baseline FEV 1, region, gender, age, treatment group, study & region by treatment interaction. 1 n=193; 2 n=18, 3 n=175

Figure 1. Box plot of change from baseline in trough FEV 1 at Week 12 by geographic region (Efficacy population)

Safety

· Safety data were compared between patients (N=4231) from Japan/Korea and Not-Japan/Korea; N=3584 (85%) completed the studies.

· In all active treatment groups, a greater proportion of patients from Japan/Korea versus Not-Japan/Korea reported on-treatment adverse events; this trend was also observed in the placebo group, suggesting that this is not related to FF or VI (Table 3).

Table 3. Summary of on-treatment adverse events and serious adverse events (Safety population)

|  |  |  | FF/VI |  | FF/VI |  | FF |  | FF
|  | Placebo |  | 100/25mcg |  | 200/25 mcg |  | 100mcg |  | 200mcg
All on-treatment adverse events |  |  |  |  |  |  |  |  |  |
Japan+Korea |  | 12/29 (41) |  | 37/47 (79)(1) |  | 9/14 (64)(1) |  | 38/55 (69) |  | 16/22 (73)
Not-Japan/Korea |  | 87/375 (23) |  | 658/1163 (57) |  | 83/183 (45) |  | 744/1375 (54) |  | 134/386 (36)
Overall |  | 99/404 (25) |  | 695/1210 (57) |  | 92/197 (47) |  | 782/1430 (55) |  | 150/390 (38)
On-treatment non-fatal serious adverse events |  |  |  |  |  |  |  |  |  |
Japan+Korea |  | 0/29 (0) |  | 1/47 (2)(1) |  | 0/14 (0)(1) |  | 1/55 (2) |  | 0/22 (0)
Overall |  | 0/404 (0) |  | 40/1210 (3) |  | 6/197 (3) |  | 30/1430 (2) |  | 1/390 (<1)
On-treatment fatal adverse events |  |  |  |  |  |  |  |  |  |
Japan+Korea |  | 0/29 (0) |  | 0/47 (0)(1) |  | 0/14 (0)(1) |  | 0/55 (0) |  | 0/22 (0)
Overall |  | 0/404 (0) |  | 1/1210(2) (<1) |  | 0/197 (0) |  | 1/1430 (<1) |  | 0/390 (0)

Data presented as number of patients with an adverse event/number of patients in population group (%);

(1)Only subjects from Japan;

(2)One additional subject (South East Asian) died during follow-up

Safety (cont’d)

· Serious adverse events reported for patients from Japan+Korea (1 FF/VI 100/25mcg, 1 FF 100mcg: both subarachnoid haemorrhage) were not considered drug related.

PK/PD

· Estimated FF AUC(0-24) and VI C max were higher in Japanese versus White/Caucasian patients (Table 4).

PK/PD (cont’d)

· No clinically relevant effects on cortisol concentrations (Figure 2) or heart rate were observed.

· The PK profile of FF at clinical doses (<200mcg) did not differ when administered simultaneously with VI 25mcg compared with FF alone for either Japanese or White/Caucasian patients.

Table 4. Model predicted PK parameters

Race |  | Treatment |  | N |  | C max (pg/mL) |  | AUC (0-24) (pg.h/mL)
Model predicted FF PK parameters |  |  |  |  |  |  |  |
|  |  |  |  |  | 18.0 |  | 348.6
|  | FF/VI 100/25mcg |  | 14 |  | [11.8, 26.1] |  | [214.7, 510.8]
|  |  |  |  |  | 19.9 |  | 304.6
Japanese |  | FF 100mcg |  | 15 |  | [13.2, 27.8] |  | [240.4, 382.6]
|  |  |  |  |  | 42.4 |  | 605.1
|  | FF/VI 200/25mcg |  | 13 |  | [28.2, 59.7] |  | [489.2, 871.8]
|  |  |  |  |  | 34.6 |  | 581.9
|  | FF 200mcg |  | 8 |  | [24.2, 49.8] |  | [374.1, 855.1]
|  | FF/VI 100/25mcg; |  |  |  | 15.2 |  | 232.2
White / |  | FF 100mcg |  | 492 |  | [14.9, 15.6] |  | [226.0, 238.5]
Caucasian |  | FF/VI 200/25mcg; |  |  |  | 30.0 |  | 471.6
|  | FF 200mcg |  | 471 |  | [29.1, 30.8] |  | [459.0, 484.1]
Model predicted VI PK parameters |  |  |  |  |  |  |  |
|  |  |  |  |  | 113.3 |  | 139.1
|  | FF/VI 100/25mcg |  | 14 |  | [38.7, 243.7] |  | [117.2, 159.0]
Japanese |  |  |  |  |  | 144.9 |  | 146.1
|  | FF/VI 200/25mcg |  | 13 |  | [63.4, 236.1] |  | [119.4, 168.0]
White / |  | FF/VI 100/25mcg; |  |  |  | 42.2 |  | 165.7
Caucasian |  | FF/VI 200/25mcg |  | 660 |  | [39.7, 44.9] |  | [160.2, 171.4]

Geometric mean (95% confidence interval); FF data from post-hoc analysis of population PK data(8); VI data from post-hoc analysis of study DB111207(9)

Figure 2. Ratio of 24h urinary cortisol excretion to baseline at the end of treatment (Urinary cortisol population(1))

(1)Urinary cortisol population: subset of patients from Safety population, that were not considered to have confounding factors, and for whom urine samples were available;

(2)Only subjects from Japan

CONCLUSIONS

· The efficacy and safety profile of FF/VI is similar in asthma patients from Japan+Korea and Not-Japan+Korea.

· The FF/VI clinical doses recommended based on global studies are also suitable for asthma patients in Japan.

REFERENCES

(1) Ohta K, et al. Allergol Int. 2011;60:115–45.

(2) Global Initiative for Asthma. Global Burden of Asthma. Available at: http://www.ginasthma.org/ local/uploads/files/GINABurdenReport_1.pdf. Last accessed: 10 Sept 2013.

(3) Bjornsson TD, et al. J Clin Pharmacol 2003;43:943–67.

(4) Huang SM, et al. Clin Pharmacol Ther 2008;84:287–94.

(5) Jin HJ, et al. PLoS ONE 2009;4:1–10.

(6) HUGO Pan-Asian SNP Consortium, et al. Science 2009;326:1541–45.

(7) Chowbay B, et al. Drug Metab Rev 2005;37:327–78.

(8) GSK data on file.

(9) Nakahara N, et al. Int J Clin Pharmacol Ther 2013;51:660–72

ACKNOWLEDEGMENTS

· The presenting author, Yutaro Sugiyama, is employed by GlaxoSmithKline.

· The authors acknowledge the contributions of the following employees of GlaxoSmithKline: Dr Romina Nand, Dr Carol Lee and Dr Ann Allen.

· These studies were funded by GlaxoSmithKline (GSK study codes HZA106827 (cllinicaltrial.gov registration number: NCT01165138); HZA106829 (NCT01134042); HZA106837 (NCT01086384); B2C109575 (NCT00600171); FFA109685 (NCT00603278); FFA109687 (NCT00603382); DB111207 (NCT00964249).

· Editorial support (in the form of writing assistance, assembling tables and figures, collating author comments, grammatical editing and referencing) was provided by Laura Maguire, MChem, at Gardiner-Caldwell Communications (Macclesfield, UK) and was funded by GlaxoSmithKline.

ELLIPTA TM is a trade mark of the GlaxoSmithKline group of companies

Presented at the 18 th Congress of the Asian Pacific Society of Respirology, Yokohama, Japan, 11–14 November 2013