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Lung function effects and safety of fluticasone furoate (FF)/vilanterol (VI) in patients with COPD: low-mid dose assessment Kerwin EM1, Scott-Wilson C2, Sanford L3, Rennard SI4, Agusti A5, Barnes N6, Crim C2 1. Clinical Research Institute of Southern Oregon, Medford, OR, USA; 2. GlaxoSmithKline, Research Triangle Park, NC, USA; 3. GlaxoSmithKline, Stockley Park, London, UK; 4. University of Omaha, Nebraska, OH, USA; 5. Thorax Institute, Hospital Clinic, IDIBAPS, University of Barcelona and FISIB, CIBERES, Mallorca, Spain; 6. Respiratory Medicine, Barts and The London NHS Trust, London, UK

CONFLICT OF INTEREST DISCLOSURE Edward Kerwin, M.D. has served on Advisory Boards for Astra Zeneca, Forest, Ironwood, Mylan, Pearl, Sanofi, Sunovion and Targacept; Speakers Panels for AstraZeneca, Pfizer, Sanofi, and Sunovion; and has received travel reimbursement from Merck, Forest and Novartis. He has conducted clinical trials for multiple pharmaceutical companies, including GlaxoSmithKline

Introduction An inhaled corticosteroid (ICS) combined with a long-acting beta2 agonist (LABA) is an established treatment for COPD patients experiencing impaired airway function or acute exacerbations Fluticasone furoate (FF) and vilanterol (VI) are respectively, a novel ICS and LABA, in development as a once-daily combination therapy for COPD and asthma

Objectives Post-Dose & Trough Lung Function Effects 24-week efficacy of VI Addition of FF to VI Dose Range FF when added to VI Symptoms Safety

FF 100mcg (N=206) VI 25mcg (N=205) FF/VI 50/25mcg (N=206) FF/VI 100/25mcg (N=206) Placebo (N=207) R F S Clinic Visit (Day) 1 (-14 to -17) 2 (1) 3 (2) 4 (7) 5 (14) 6 (28) 7 (56) 8 (84) 9 (112) 10 (140) 11 (168) 12 (169) Phone (176±2) Study design

Endpoints Co-primary Weighted mean FEV1 (0-4hr) post-dose, Day 168 Change from baseline Trough FEV1, Day 169 Secondary CRQ-SAS dyspnoea domain Peak FEV1 (0-4hr) post-dose, Day 1 Time to 100mL (0-4hr) post-dose, Day 1 Safety

VI 25 vs. Placebo FF/VI 100/25 vs. Placebo FF/VI 100/25 vs. FF 100 wmFEV1(0-4hr) Day 168 Trough FEV1 Day 169 VI 25 vs. Placebo FF/VI 100/25 vs. Placebo FF/VI 100/25 vs. VI 25 Co-Primary , FF/VI 100/25 Secondary, FF/VI 100/25 FF/VI 100/25 vs. Placebo for each endpoint FF/VI 50/25 vs. Placebo FF/VI 50/25 vs. Placebo FF/VI 50/25 vs. VI 25 wmFEV1(0-4hr) Day 168 Trough FEV1 Day 169 Co-Primary , FF/VI 50/25 LEVEL 1 LEVEL 2 LEVEL 3 Move to Level 2 if p<0.05 for all Secondary , FF/VI 50/25 FF/VI 50/25 vs. Placebo for each endpoint Move to Level 3 if p<0.05 for all Study power: 80mL for FF/VI vs. VI Trough FEV1 Day 169 100mL for FF/VI vs. Placebo Trough FEV1 Day 169 100mL for FF/VI vs. FF wmFEV1 (0-4hr) Day 168

Characteristics Total (N=1030) Mean Age, yr (SD) 62.7 (9.09) Male Sex, n (%) 685 (67) Mean Post-BD FEV1, L (SD) 1.406 (0.48) Mean Post-BD %pred FEV1, % (SD) 48.3 (12.45) GOLD stage, n (%) II III IV 487 (47) 445 (43) 94 (9) Mean mMRC dyspnoea, score (SD) 2.4 (0.5) Moderate* exacerbations, n (%) 0 1 2 >2 787 (76) 202 (20) 31 (3) 10 (<1) *requiring systemic corticosteroids and/or antibiotics

wmFEV1 (0-4hr): VI vs. PBO Day 168 Test mL (95% CI) p VI – PBO 103 (52, 153) <0.001 0 1 Day wm FEV1 (L), LS mean (95% CI) 1.2 1.3 1.4 1.5 1 14 56 84 168 Placebo VI 25

Trough FEV1: VI vs. PBO Day 169 Test mL (95% CI) p VI – PBO 67 (12, 121) 0.017 -0.05 Day Trough FEV1 (L), LS mean change from baseline (95% CI) 0.00 0.05 0.10 0.15 0.20 0.25 2 7 14 28 56 84 112 140 168 169 Placebo VI 25

wmFEV1 (0-4hr): FF/VI vs. PBO Day 168 Test mL (95% CI) p FF/VI 100/25 – PBO 173 (123, 224) <0.001 FF/VI 50/25 – PBO* 192 (141, 243) - 0 1 Day wm FEV1 (L), LS mean (95% CI) 1.2 1.3 1.4 1.5 1 14 56 84 168 Placebo FF/VI 50/25 FF/VI 100/25 *p-value not shown due to statistical hierarchy; difference is descriptive only

Trough FEV1: FF/VI vs. PBO Day 169 Test mL (95% CI) p FF/VI 100/25 – PBO 115 (60, 169) <0.001 FF/VI 50/25 – PBO* 129 (74, 184) - -0.05 Day Trough FEV1 (L), LS mean change from baseline (95% CI) 0.00 0.05 0.10 0.15 0.20 0.25 2 7 14 28 56 84 112 140 168 169 Placebo FF/VI 50/25 FF/VI 100/25 *p-value not shown due to statistical hierarchy; difference is descriptive only

wmFEV1 (0-4hr): FF/VI vs. FF Day 168 Test mL (95% CI) p FF/VI 100/25 – FF 120 (70, 170) <0.001 0 1 Day wm FEV1 (L), LS mean (95% CI) 1.2 1.3 1.4 1.5 1 14 56 84 168 FF 100 FF/VI 50/25 FF/VI 100/25

Trough FEV1: FF/VI vs. VI Day 169 Test mL (95% CI) p FF/VI 100/25 – VI 48 (-6, 102) 0.082 FF/VI 50/25 – VI* 62 (8, 117) - -0.05 Day Trough FEV1 (L), LS mean change from baseline (95% CI) 0.00 0.05 0.10 0.15 0.20 0.25 2 7 14 28 56 84 112 140 168 169 VI 25 FF/VI 50/25 FF/VI 100/25 *p-value not shown due to statistical hierarchy; difference is descriptive only

CRQ-SAS dyspnoea domain: Day 168 Test Units(95% CI) VI – Placebo 0.14 (-0.10, 0.38) FF 100 – Placebo 0.06 (-0.18, 0.30) FF/VI 50/25 – Placebo 0.19 (-0.05, 0.43) FF/VI 100/25 – Placebo 0.30 (0.06, 0.54) FF/VI 50/25 – VI 25 0.05 (-0.19, 0.29) FF/VI 100/25 – VI 25 0.16 (-0.08, 0.40) FF/VI 100/25 – FF 100 0.24 (0.01, 0.48) Differences are descriptive only due to statistical hierarchy Range: 1 – maximum impairment, 7 – no impairment; MCID > 0.5 Units

Peak FEV1 (0-4hr): Day 1 Test mL(95% CI) VI – Placebo 142 (114, 169) FF 100 – Placebo 12 (-15, 39) FF/VI 50/25 – Placebo 148 (120, 175) FF/VI 100/25 – Placebo 139 (112, 166) FF/VI 50/25 – VI 25 6 (-22, 33) FF/VI 100/25 – VI 25 -3 (-30, 25) FF/VI 100/25 – FF 100 127 (100, 154) Differences are descriptive only due to statistical hierarchy

Time to 100mL (0-4h): Day 1 MEDIAN TIME 100mL Treatment Min Placebo n/a FF 100 n/a VI 25 16 FF/VI 100/25 17 FF/VI 50/25 17 Serial FEV1: Day 1 (0-4h) n/a = not applicable as >50% of patients did not achieve a 100mL improvement by 4hr Placebo FF 100 VI 25 FF/VI 50/25 FF/VI 100/25 Time - Day 1 Change from baseline FEV1 (L) mean (SD) 0.0 0.2 0.4 5min 15min 30min 1hr 2hr 4hr 0.1 0.3

Safety Placebo N=207 FF 100 N=206 VI 25 N=205 FF/VI 50/25 N=206 FF/VI 100/25 N=206 ANY EVENT, n (%) On-Treatment AEs 100 (48) 123 (60) 111 (54) 114 (55) 111 (54) On-Treatment SAEs 11 (5) 16 (8) 15 (7) 6 (3) 11 (5) EVENTS OF SPECIAL INTEREST, n (%) Cardiovascular Effects 16 (8) 18 (9) 15 (7) 15 (7) 11 (5) Local Steroid Effects 7 (3) 13 (6) 6 (3) 24 (12) 16 (8) LRTI excluding pneumonia 8 (4) 8 (4) 6 (3) 3 (1) 5 (2) Pneumonia 3 (1) 4 (2) 5 (2) 3 (1) 5 (2) Hypersensitivity 2 (<1) 5 (2) 3 (1) 1 (<1) 6 (3) Effects on Glucose 1 (<1) 4 (2) 1 (<1) 3 (1) 5 (2) Bone Disorders 4 (2) 2 (<1) 2 (<1) 1 (<1) 1 (<1) Ocular Effects 1 (<1) 2 (<1) 1 (<1) 1 (<1) 1 (<1) Systemic Steroid Effects 2 (<1) 0 0 2 (<1) 1 (<1) Effects on Potassium 1 (<1) 1 (<1) 0 0 0 Tremor 0 1 (<1) 0 0 0

VI 25mcg provides sustained bronchodilation over 24 weeks in moderate-to-severe COPD Addition of FF to VI provides further bronchodilation Additional lung function effect not statistically significantly greater than VI alone VI has a negligible effect on dyspnoea Addition of FF at 100mcg provides a numerical improvement VI provides rapid substantial post-dose bronchodilation from Day 1 onward Addition of FF provides no more rapid or increased bronchodilation FF/VI exhibits a safety profile similar to that of its components and placebo Summary

FF/VI represents a once-daily treatment option for moderate-to-severe COPD which is efficacious and well tolerated Conclusion

A dual – acting muscarinic antagonist, beta 2 – agonist (MABA) molecule (GSK961081) improves lung function in COPD: A randomised trial Pascal Wielders*, Andrea Ludwig-Sengpiel, Nicholas Locantore, Suus Baggen, Robert Chan and John H. Riley * Catharina Hospital Eindhoven, The Netherlands, on behalf of The Investigators The study was registered on the Clinical Trials Register NCT01319019, used the study code MAB115032 and was funded by GlaxoSmithKline. My institution has received grants from GSK, AstraZeneca and Novartis Speakers fee from GSK, AstraZeneca, Boehringer Ingelheim, Novartis

GSK961081 a dual pharmacophore Beta Agonist Muscarinic Antagonist Linker MABA

Study aims To assess the safety and efficacy of GSK961081 in moderate and severe COPD subjects To assess the dose and dosing regimen MAB115032 – Design. A phase IIb multicentre, randomised, double-blind, double-dummy, placebo- and active-controlled, parallel-group, dose-ranging and dose-interval study.

Study design Placebo BID Salmeterol 50mcg BD GSK961081 100mcg BD GSK961081 200mcg BD GSK961081 400mcg BD GSK961081 100mcg OD GSK961081 400mcg OD GSK961081 800mcg OD V1 Day 29 Day 14 Day 7 Day 1 Screen Run - in 7 days Follow-up 7 days V4 Salbutamol prn Day 28 V2 V6 V7 V8 V3 Day 2 V5

Males or females age:  40 years of age COPD Diagnosis: Tobacco Use: Current and former. >10 pack years Severity of Disease: Post-salbutamol FEV1/FVC ratio of < 0.70 Post-salbutamol FEV1 30 and 70%

Asthma: a current diagnosis of asthma or other respiratory disorder Lung Resection: Chest X-Ray: Chest X- ray (or CT scan) with significant abnormalities COPD Medications*: oral corticosteroids or antibiotics 6 weeks prior Hospitalisation: for COPD or pneumonia in 12 weeks prior. Other Disease/Abnormalities: symptomatic (or documented history of) laryngopharyngeal /extraesophageal reflux or posterior laryngitis; previous history of laryngopharyngeal ulcerations and erosions. * ICS was allowed

Patients screened (n=660) Screening or run-in failures (n=223; of whom 210 did not meet entry criteria) ITT Population (n=436)† Placebo (n=81) SAL 50 BD (n=47) ‘081 100 BD (n=52) ‘081 200 BD (n=50) ‘081 400 BD (n=54) ‘081 100 OD (n=50) ‘081 400 OD (n=50) ‘081 800 OD (n=52) Completed: 71 (88%) Withdrew: 10 (12%) Completed: 43 (91%) Withdrew: 4 (9%) Completed: 47 (90%) Withdrew: 5 (10%) Completed: 45 (90%) Withdrew: 5 (10%) Completed: 49 (91%) Withdrew: 5 (9%) Completed: 45 (90%) Withdrew: 5 (10%) Completed: 41 (82%) Withdrew: 9 (18%) Completed: 48 (92%) Withdrew: 4 (8%)

Efficacy Endpoints Primary: Mean change from baseline for Trough FEV1 on Day 29 Others Weighted mean change from baseline FEV1 over 0-12hrs on Day 28 Weighted mean change from baseline FEV1 over 0-24hrs on Day 28 in subjects with overnight visits Serial FEV1 profile on Day 1 and Day 28 FVC Rescue medication use Safety Profile

Treatment SAL 50 100 BD 200 BD 400 BD 100 OD 400 OD 800 OD N 43 47 46 49 45 41 48 LSMean Diff 77mL 173mL 249mL 258mL 155mL 215mL 277mL 95% CI (0, 150) (100, 250) (170, 320) (190, 330) (80, 230) (140, 290) (200, 350) p-value 0.046 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001

Comparison of dosing regimen in Subset at Day 28 PBO ‘081 200mcg BD ‘081 400mcg BD SAL 50mcg ‘081 400mcg OD ‘081 800mcg OD Change from baseline FEV1 (L) 0.5 0.4 0.3 0.2 0.1 0.0 -0.1 -0.2 0 4 8 12 16 20 24 Planned time from day 28 AM dose (h)

Placebo subtracted 12 hour FEVI profile at day 1 ‘081 100mcg BD ‘081 100mcg OD SAL 50mcg ‘081 200mcg BD ‘081 400mcg OD ‘081 400mcg BD ‘081 800mcg OD Difference from place placebo, FEV1 (L) 0.0 0.1 0.2 0.3 0.4 Planned time from Day 1 AM dose (h) 0 4 8 12

Placebo subtracted 12 hour FEVI profile at day 28 ‘081 100mcg BD ‘081 100mcg OD SAL 50mcg ‘081 200mcg BD ‘081 400mcg OD ‘081 400mcg BD ‘081 800mcg OD Difference from placebo, FEV1 (L) 0.0 0.1 0.2 0.3 0.4 Planned time from day AM dose (h) 0 4 8 12

Rescue Med Use, Weeks 1 – 4 (occasion per day) Treatment SAL 50 100 BD 200 BD 400 BD 100 OD 400 OD 800 OD N 43 50 48 52 48 45 51 LSMean Diff -0.39 -0.57 -0.56 -0.74 -0.45 -0.65 -0.62 95% CI (-0.7, -0.1) (-0.9, -0.3) (-0.9, -0.2) (-1.1, -0.4) (-0.8, -0.1) (-1.0, -0.3) (-0.9, 0.3) p-value 0.026 <0.001 <0.001 <0.001 0.007 <0.001 <0.001 Less rescue use Difference from Placebo with 95% Confidence Interval Adjusted Difference from Placebo, Rescue Use (occasions/day), Day 1-28 Treatment 0.15 0.0 -0.15 -0.30 -0.45 -0.60 -0.75 -0.90 -1.05 43 50 48 52 48 45 51 N SAL 50mcg 100mcg BD 200mcg BD 400mcg BD 100mcg OD 400mcg OD 800mcg OD Note: Placebo LSMean Change was -0.29 occasions/day

Safety Results – On – Therapy AE’s (> 3% in any group) AE Preferred Term PBO (n=81) SAL 50 (n=47) 100 BD (n=52) 200 BD (n=50) 400 BD (n=54) 100 OD (n=50) 400 OD (n=50) 800 OD (n=52) Headache 5 (6%) 2 (4%) 2 (4%) 0 5 (9%) 5 (10%) 5 (10%) 2 (4%) Cough 2 (2%) 0 2 (4%) 4 (8%) 1 (2%) 5 (10%) 5 (10%) 4 (8%) Dysgeusia* 0 0 2 (4%) 3 (6%) 4 (8%) 3 (6%) 2 (4%) 1 (2%) Nasopharyngitis 3 (4%) 0 1 (2%) 3 (6%) 0 3 (6%) 1 (2%) 0 Back pain 2 (2%) 0 1 (2%) 0 0 0 2 (4%) 0 Dysphonia 2 (2%) 0 0 0 0 0 1 (2%) 2 (4%) Muscle spasms 0 1 (2%) 1 (2%) 0 2 (4%) 0 0 1 (2%) Nausea 2 (2%) 0 0 0 0 1 (2%) 1 (2%) 0 Myalgia 1 (1%) 1 (2%) 0 0 0 0 2 (4%) 0 Palpitations 0 1 (2%) 0 0 2 (4%) 0 0 0 * - Dysgeusia here combines the preferred terms “Dysgeusia” and “Product taste abnormal”

Safety Results – On – Therapy AE’s Leading to Withdrawal AE Preferred Term PBO (n=81) SAL 50 (n=47) 100 BD (n=52) 200 BD (n=50) 400 BD (n=54) 100 OD (n=50) 400 OD (n=50) 800 OD (n=52) Any event 2 (2%) 0 1 (2%) 2 (4%) 2 (4%) 2 (4%) 0 1 (2%) Placebo Contusion, pain, wheezing 100 BD Tachycardia 200 BD Cough, dysgeusia, Wolff-Parkinson-White syndrome 400 BD Bundle branch block left, dermatitis allergic SAL 50 none 100 OD 1st degree atrioventricular block, 7th nerve paralysis 400 OD none 800 OD Cough

Conclusions GSK961081 is a dual pharmacophore having both muscarinic antagonist and beta 2-agonist activities GSK961081 appears safe and well tolerated GSK961081 provides rapid symptom relief in moderate and severe COPD subjects GSK961081 is a potent bronchodilator in moderate and severe COPD subjects

Acknowledgements The GSK study team including Helen Griffiths, Francis Arkhurst, the medical monitor Dmitriy Galkin and Ginny Norris for Scientific advice. The Subjects for taking part in the trial. The investigators for their collection of subjects and running of the trial: Abdullah I (SA), Arpasova K (RS), Aisanov Z (RU), Bantje T (NL) Bateman E (SA), Bjermer L (SW), Blazhko V (UE), Bruning A (SA), De Munck D (NL), Dzurilla M (RS), Feshchenko Y (UE), Foerster K (GE), Gavrysiuk V (UE), Goossens M (NL), Hajkova M (RS), Hukelova H (RS), Iashyna L (UE), Irusen E (SA), Jogi R (ES), Joubert J (SA), Kornmann O (GE), Kuulpak EM (ES), Leshchenko I (RU), Lindberg A (SW), Linnhoff A (GE), Löfdahl M (SW), Lundback B (SW), Ludwig-Sengpiel A (GE), Mihaescu T (RO), Mihaicuta S (RO), Mostovoy Y (UE), Nemes R (RO), Ogorodova L (RU), Ostrovskyy M (UE), Pertseva T (UE), Pribulova E (RO), Rascu A (RO), Richter (SA), Samaruutel P (ES), Schenkenberger I (GE), Schroeder-Babo W (GE), Sinninghe Damste H(NL), Sooru E (ES), Stallaert R (NL), Sushko V (UE), Trofimov V (RU), Wielders P(NL), Wuerziger J (GE), Zorin V (UE)