Treatment B: FF (400 µg) and UMEC (250 µg)/vi(100 µg) The indicated dose is the total of four inhalations via the dry powder inhaler.

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Nickolas Walters
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1 GSK Medicine:GSK (Umeclidinium)+ GW6424 (Vilanterol) + GW (Fluticasone furoate) Study Number: Title: An open label, randomised, four-period crossover, single dose study in healthy volunteers to evaluate the pharmacokinetics of FF/UMEC/VI combination administered at dose levels 100/62.5/25 mcg and 100/125/25 mcg and in comparison with FF/VI (100/25 mcg) and UMEC/VI (62.5/25 mcg) Rationale: Study CTT was conducted to evaluate the pharmacokinetics and pharmacodynamics of the individual components administered as FF/UMEC/VI (ICS/LAMA/LABA) combination compared to administration as FF/VI (ICS/LABA), UMEC/VI (LAMA/LABA) and FF/UMEC (ICS/LAMA) dual combinations. Study explored the pharmacokinetics of the components of the FF/UMEC/VI combination at two doses of UMEC (62.5 and 125 mcg). Results from study CTT suggested that the conclusions for VI may have been confounded by inadequate estimation of Cmax. Study further evaluated the pharmacokinetics of the components administered as a fixed dose triple product compared to each of the dual combination products, FF/VI and UMEC/VI. Phase: 1 Study Period: 15Jul Sep2013 Study Design: This was a randomized, open-label, single centre, single dose (four inhalations), four sequence, four period cross over study in healthy male and female subjects to assess the pharmacokinetics (PK) of FF, UMEC and VI. During each treatment period, subjects attended the clinic on Day -1 for standard safety assessments and familiarization with the inhaler. Each subject remained in the clinic until 24 hours after the dose was given on Day 1. PK was assessed by the measurement of plasma concentrations of FF, UMEC and VI at the following time points: predose, 3 min, 5 min, 7min, 10min, 12min, 15min, 30min, 45min, 1h, 1.5h, 2, 4, 6, 8, 12 and 24 hours postdose. A follow-up visit was conducted within 7-21 days after the last dose of study drug. Centres: Parexel International, Early Phase Clinical Unit Harbor Hospital Center, 3001 S. Hanover Street 7th floor Baltimore Maryland United States Indication: COPD Treatment: Treatment A: FF (400 µg) and UMEC (500 µg)/vi(100 µg) Treatment B: FF (400 µg) and UMEC (250 µg)/vi(100 µg) Treatment C: FF (400 µg) and VI (100 µg) Treatment D: UMEC (250 µg) and VI (100 µg) The indicated dose is the total of four inhalations via the dry powder inhaler. Objectives: To assess the systemic exposure of FF and UMEC and VI following single inhaled doses (four inhalations) of FF/UMEC/VI at two different UMEC dose levels. Primary Outcome: To assess the systemic exposure of FF and UMEC and VI following single inhaled doses (four inhalations) of FF/UMEC/VI at two different UMEC dose levels AUC(0- ) [or AUC(0-t') if AUC(0- ) could not be determined] and Cmax for each individual component (UMEC dose-normalised) across treatment groups was estimated using the 1

2 following treatment ratio: FF/UMEC/VI 100mcg/125mcg/25mcg Versus FF/UMEC/VI 100mcg /62.5mcg/25mcg To assess the systemic exposure of FF and UMEC and VI following single inhaled doses (four inhalations) of FF/UMEC/VI 100mcg /62.5mcg /25mcg compared with FF/VI 100mcg /25mcg and UMEC/VI 62.5mcg /25mcg using the following treatment ratios: FF: FF/UMEC/VI versus FF/VI UMEC: FF/UMEC/VI versus UMEC/VI VI: FF/UMEC/VI versus FF/VI VI: FF/UMEC/VI versus UMEC/VI Secondary Outcome: To determine the PK of FF, UMEC and VI following single dose administration via the dry powder inhaler. Derivation of t¹ ₂ and Cmax (tmax). Statistical Methods: This study was designed to estimate the effect of each treatment on primary and secondary parameters of interest. No formal statistical hypotheses were tested. Descriptive statistics were used to assess safety and tolerability objectives. Plasma (FF, UMEC and VI) concentration-time data was analyzed by non-compartmental methods with WinNonlin Professional Version 5.2 or higher. The following statistical analyses were performed to address the primary objectives: Following loge-transformation, AUC(0-t') (AUC(0-4) for FF, AUC(0-2) for UMEC and AUC(0-6) for VI) and Cmax was analysed separately by ANOVA using a mixed effects model, fitting period and treatment as fixed effects, and subject as a random effect. For comparison of the two UMEC dose levels the UMEC PK parameters were dose normalized prior to analysis by dividing the respective PK parameter values by the nominal dose received. The adjusted geometric mean ratios and corresponding 90% confidence intervals for all comparisons were calculated. The ratios were calculated by back-transforming the difference between the LS Means. The 90% confidence intervals for the differences were calculated, using the pooled estimate of variance.the within-subject coefficients of variation (CVw) for AUC(0-t') and Cmax were calculated based on the loge-normal distribution. 2

3 Study Population: Number of Subjects All Treatments Number of subjects planned, N: Number of subjects randomized, N: Number of subjects included in All subjects (safety) population, n (%): (100%) Number of subjects included in PK population, n (%): (100%) Number of subjects completed as planned, n (%): (98%) Number of subjects withdrawn (any reason), n (%): 1 (2%) Number of subjects withdrawn for SAE, n (%): 0 (0%) Number of subjects withdrawn for AE, n (%): 0 (0%) Reasons for subject withdrawal, n (%) Lost to follow-up 0 (0%) Adverse events 0 (0%) Protocol violation 1 (2%) Demographics Age in Years, Mean (SD) 39.1 (12.73) Sex, n (%) Female: 8 (18%) Male: 36 (32%) Ethnicity, n (%) Hispanic or Latino: 5 (11%) Not Hispanic or Latino: 39 (89%) Race, n (%) African American/African Heritage 34 (77%) American Indian or Alaskan Native 1 (2%) Asian East Asian Heritage 0 Asian Japanese Heritage 0 Asian South East Asian Heritage 0 Native Hawaiian or Other Pacific Islander 0 White Arabic/North African Heritage 1 (2%) White White/Caucasian/European Heritage 8 (18%) 3

4 Pharmacokinetic Results: Summary of Fluticasone Furoate Plasma Pharmacokinetic Parameters Parameter AUC(0-4) (hr*pg/ml) Treatment N n Geo. Mean % CI (196.1,229.1) (191.7,232.1) (199.8,238.8) %CVb a AUC(0-t) (554.7,713.4).2 (hr*pg/ml) (525.2,702.2) (565.8,732.1).8 Cmax (pg/ml) (73.27,90.56) (72.19,91.05) (76.62,95.82) 37.6 tlast (hr) b (3.98, 24.10) (6.00, 24.12) (8.00, 24.12) tmax (hr) b (0.05, 2.00) (0.05, 2.00) (0.03, 2.02) a : between subject coefficient of variability b : Median (min, max) n = number of subjects for whom parameter derived : Not Applicable Parameter Treatment comparison Ratio (SE Loge) 90% CI %CVw a AUC(0-4) VS (0.032) (0.951,1.058) 14.9 (hr*pg/ml) VS (0.032) (0.917,1.020) Cmax VS (0.049) (0.927,1.092) 23.1 (pg/ml) VS (0.049) (0.872,1.026) a : Within subject coefficient of variability 4

5 Summary of Umeclidinium Plasma Pharmacokinetic Parameters Parameter Treatment N n Geo. Mean AUC(0-2) (hr*pg/ml) AUC(0-t) (hr*pg/ml) Cmax (pg/ml) tmax (hr) b % CI %CVb a (383.1,466.5) (186.1,225.1) (186.3,222.3) (688.1,862.3) (282.1,368.7) (275.0,349.3) (909.97, ) (4.06,656.86) (462.61,650.52) (0.05,0.17) (0.05,0.12) (0.03,0.20) t1/2 (hr) (2.675,6.165) (1.985,2.608) (2.099,2.577) 27.4 a : Between subject coefficient of variability b : Median (range) n = number of subjects for whom parameter derived Parameter Treatment comparison Ratio (SE loge) 90% CI %CVw a AUC(0-2) VS 1.0 (0.031)* (0.991,1.100) 14.6 (hr*pg/ml) VS (0.031) (0.953,1.058) Cmax (pg/ml) VS (0.048)* (0.960,1.127) 22.7 VS (0.048) (0.908,1.066) a : Within subject coefficient of variability *:Ratio estimates were obtained following dose-normalisation of the data 5

6 Summary of Vilanterol Plasma Pharmacokinetic Parameters Parameter Treatment N n Geo. Mean AUC(0-6) (hr*pg/ml) AUC(0-t) (hr*pg/ml) Cmax (pg/ml) tmax (hr) b % CI %CVb a (401.8,5.2) (379.0,428.3) (383.8,3.1) (347.1,396.4) (464.0, 534.0) (9.4, 530.6) (466.7, 550.6) (398.1, 478.3) (580.17,646.14) (482.37,548.49) (700.55,749.33) (580.99,657.66) (0.08,0.20) (0.08,0.17) (0.08,0.20) (0.10,0.20) t1/2 (hr) (3.505,5.663) (3.627,6.363) (4.014,5.870) (3.577,6.192) a : Between subject coefficient of variability b : median (range) n = number of subjects for whom parameter derived Parameter Treatment comparison Ratio (SE loge) 90% CI %CVw a AUC(0-6) (hr*pg/ml) VS (0.024) (1.010,1.094) VS (0.024) (0.949,1.028) 11.2 VS (0.024) (1.0,1.130) Cmax (pg/ml) VS (0.032) (1.038,1.155) VS (0.032) (1.006,1.120) 15.1 VS (0.032) (1.142,1.271) a: Within subject coefficient of variability 6

7 Safety Results: AEs were collected from the start of Study Treatment and until the follow-up contact. SAEs were collected over the same time period as AEs. However, any SAEs assessed as related to study participation (e.g. study treatment, protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a GSK product were recorded from the time a subject consented to participate in the study up to and including any follow-up contact. All SAEs were recorded and reported to GSK within 24 hours. System organ class preferred term FF/UMEC/VI 400/500/100 (n=) FF/UMEC/VI 400/250/100 (n=) FF/VI 400/100 (n=) UMEC/VI 250/100 (n=) Total * (n=) Any event 2 (5%) 3 (7%) 1 (2%) 0 6 (14%) General disorders and administration site conditions Any event 1 (2%) 2 (5%) 1 (2%) 0 4 (9%) Catheter site bruise 1 (2%) (2%) Catheter site haematoma (2%) 0 1 (2%) Catheter site pain 0 1 (2%) (2%) Infusion site swelling 0 1 (2%) (2%) Injury, poisoning and procedural complications Any event 1 (2%) (2%) Excoriation 1 (2%) (2%) Musculoskeletal and connective tissue disorders Any event 0 1 (2%) (2%) Neck pain 0 1 (2%) (2%) = Total is total no. of subjects experiencing the event not total no. of events. This was a crossover trial so the same subject may appear in more than one treatment column. Serious Adverse Events - On-Therapy There were no SAEs reported during this study. 7

8 Conclusion: Following administration of the triple combination product, FF/UMEC/VI, at two UMEC dose strengths (62.5 and 125mcg) the systemic exposure for UMEC (Cmax and AUC) increased in proportion to the increase in dose. There was no evidence for a difference in systemic exposure and drug delivery to the airways for FF or VI (Cmax or AUC) between the two triple combination products with different UMEC dose strengths. There was no evidence for a difference in the systemic exposure and drug delivery to the airways for FF and VI (AUC and Cmax) following administration of FF/UMEC/VI (100/62.5/25) compared with FF/VI (100/25). There was no evidence for a difference in the systemic exposure and drug delivery to the airways for UMEC (AUC and Cmax) and VI AUC(0-6) following administration of FF/UMEC/VI (100/62.5/25) compared with UMEC/VI (62.5/25). The maximum observed plasma concentration (Cmax) was slightly higher for VI administered as the triple FF/UMEC/VI (100/62.5/25), compared with UMEC/VI (62.5/25) (ratio 1.21, 90% CI 1.14, 1.27). This small PK difference is not considered to be of clinical significance in view of the following: The VI Cmax for UMEC/VI (62.5/25) was marginally below that of FF/UMEC/VI (100/62.5/25); however, this did not appear to arise from a significant difference in delivered dose since the VI AUC values were comparable. Neither is it considered relevant to the efficacy of the VI component of FF/UMEC/VI (100/62.5/25) since the small difference in VI Cmax suggests a marginally greater absorption rate from the lung and hence if pharmacologically relevant would not increase the availability of VI for topical efficacy for FF/UMEC/VI. VI has been shown to result in heart rate increase at supra-therapeutic doses and the relationship between VI Cmax and heart rate increase has been characterized. Model based population predictions indicate that an approximately 3-fold higher VI dose compared with the therapeutic dose (25mcg) in healthy subjects is required to result in a 9 bpm increase in maximum 0-4 hour heart rate compared with placebo and a 6 bpm higher weighted mean 0-4 hour heart rate compared with placebo. VI systemic exposure in subjects with COPD has been shown to be on average 2-3- fold lower than that seen in healthy subjects following administration as FF/VI and UMEC/VI. No clinically significant effect on heart rate has been observed in COPD patients in either the FF/VI or UMEC/VI programmes. Therefore this small difference in VI Cmax when delivered as FF/UMEC/VI compared with UMEC/VI is unlikely to translate into a clinically meaningful increase in heart rate in the COPD population, the target population for this new product. 8

The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not

The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product.