Risk of Death and Chronic Obstructive Pulmonary Disease (COPD) Hospitalization Wise R15, Yates J3

Calverley PMA1, Celli BR2, Crim C3, Dransfield MT4, Halpin DMG5, Han MK6, Jones CE7, Kilbride S8, Lange P9,10, Lettis S8, Lipson DA7,11, Martinez FJ12, Morris A3, Newby DE13, Singh D14, Vestbo J14, Risk of Death and Chronic Obstructive Pulmonary Disease (COPD) Hospitalization Wise R15, Yates J3

1University of Liverpool, University Hospital Aintree, Liverpool, UK; 2Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; with Fluticasone Furoate-Containing Therapy: Post Hoc Subgroup Analysis From 3GlaxoSmithKline, Research Triangle Park, NC, USA; 4Lung Health Center, University of Alabama at Birmingham, Birmingham, AL, USA; 5University of Exeter Medical School, University of Exeter, Exeter, UK; 6University of Michigan, Ann Arbor, MI, USA; 7GlaxoSmithKline, Collegeville, PA, USA; 8GlaxoSmithKline, Stockley Park West, Uxbridge, Middlesex, UK; 9University of Copenhagen, Copenhagen, Denmark; 10Herlev-Gentofte the SUMMIT Trial in Patients with COPD and a History of Exacerbation Hospital, Herlev, Denmark; 11Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 12New York-Presbyterian Hospital/Weill Cornell Medical Center, New York, NY, USA; 13University of Edinburgh, Edinburgh, UK; 14The University of Manchester, Manchester Poster No. P1448 University NHS Foundation Trust, Manchester, UK; 15Johns Hopkins University School of Medicine, Baltimore, MD, USA

Introduction Results

● The event-driven SUMMIT trial (NCT01313676) investigated the efficacy of ● The intent-to-treat population in SUMMIT comprised 16,485 patients. Of these, 3428 Figure 1. Risk of on-/off-treatment ACM and severe exacerbations with FF, VI Figure 4. Kaplan–Meier plot of time to on-/off-treatment ACM up to Day 365 fluticasone furoate (FF), an inhaled corticosteroid (ICS) and vilanterol (VI), a met the IMPACT trial exacerbation inclusion criterion and were included in this subgroup and FF/VI vs placebo up to the CED long-acting β2-agonist (LABA), both as monotherapy and in combination, in analysis. Baseline characteristics were similar across treatment arms (Table 1) patients with COPD and with moderate airflow limitation and heightened Patients with an event, 5 ● Up to the CED: n (%) Treatment Reduction in 4.5 p-value cardiovascular (CV) risk. No significant difference in all-cause mortality (ACM) Treatment Placebo Favors Favors comparison risk, % (95% CI) HR (95% CI) p-value Placebo – Risk of on-/off-treatment death was significantly lower in all treatment arms versus n/N (%) n/N (%) was seen with FF/VI, FF or VI treatment compared with placebo in the overall treatment placebo 4 FF vs placebo 23.1 (−28.9, 54.1) 0.320 VI 1 placebo (Figure 1 and Figure 2). Time to on-/off-treatment ACM ITT population. 3.5 VI vs placebo −2.0 (-63.5, 36.4) 0.934 FF vs placebo 54/840 (6.43)89/857 (10.39) 0.64 (0.46, 0.90) 0.010 – CV events were the most common primary cause of death, occurring in 22 (2.6%), 32 FF/VI vs placebo 24.4 (−26.0, 54.6) 0.284 FF/VI ● However, in the 1-year IMPACT trial (NCT02164513), triple therapy with 3 FF (3.7%), 31 (3.6%), and 40 (4.7%) patients in the FF, VI, FF/VI, and placebo treatment VI vs placebo 64/866 (7.39)89/857 (10.39) 0.71 (0.51, 0.98) 0.034 FF/umeclidinium (UMEC)/VI significantly reduced the risk of on-/off-treatment 2.5 2,3 arms, respectively. FF/VI vs placebo 59/865 (6.82)89/857 (10.39) 0.66 (0.47, 0.91) 0.013 ACM in patients with a history of exacerbations compared with UMEC/VI. 2 – Compared with placebo, the risk of severe exacerbation was significantly less in Time to first severe exacerbation ● A history of moderate or severe exacerbations was not an inclusion criterion in FF vs placebo 93/840 (11) 141/857 (16) 0.65 (0.50, 0.85) 0.001 1.5 1 the FF treatment arm, with numerical reductions seen for both the VI and FF/VI the SUMMIT trial, whereas in the IMPACT trial patients with moderate airflow Probability event (%)of arms (Figure 1). VI vs placebo 132/866 (15) 141/857 (16) 0.88 (0.70, 1.12) 0.302 1 limitation were required to have an exacerbation history of ≥2 moderate or ≥1 FF/VI vs placebo 119/865 (14) 141/857 (16) 0.79 (0.62, 1.01) 0.055 severe exacerbation in the prior year.2 We hypothesized that FF-based ● In the analysis of data up to Day 365, no significant differences in on-/off-treatment 0.5 0.2 0.4 0.6 0.8 1.0 1.2 treatments would have had a beneficial effect on ACM in those SUMMIT patients ACM were seen between any treatment and placebo, although numerical reductions 0 HR (95% CI) 0 28 56 84 112 140 168 196 224 252 280 308 336 364 compared with placebo were seen in the FF and FF/VI treatment arms (Figure 3 and with a history of exacerbations. Time to Event (Days) ● This post hoc analysis tested this hypothesis using the ACM and severe Figure 4). Number of Patients at Risk exacerbations data from patients enrolled in SUMMIT who met the exacerbation ● Only FF was associated with a statistically significant reduction in severe Figure 2. Kaplan–Meier plot of time to on-/off-treatment ACM up to the CED Placebo 857 855 853 853 851 844 842 838 833 830 826 825 729 18 775 inclusion criteria of IMPACT. exacerbation risk versus placebo up to Day 365, although numerical reductions were Treatment Reduction in p-value FF 840 838 835 834 832 829 827 826 826 825 821 819 761 721 seen with FF/VI and VI (Figure 3). 16 comparison risk, % (95% CI) Placebo VI 866 863 860 857 855 851 849 847 845 844 839 838 789 738 14 FF vs placebo 35.7 (9.8, 54.1) 0.010 12 FF/VI 865 865 865 864 861 858 854 851 848 846 842 841 795 750 Table 1. SUMMIT baseline patient characteristics in subanalysis population VI vs placebo 29.3 (2.5, 48.7) 0.034 FF/VI Methods 10 VI FF/VI vs placebo 34.2 (8.6, 52.7) 0.013 FF Placebo FF VI FF/VI 8 (N=857) (N=840) (N=866) (N=865) 6 Time to on and off-treatment 4 Randomized Double blind Multicenter death from any cause Age, mean (SD) years 64.6 (8.0) 64.0 (8.40) 64.5 (8.2) 64.5 (8.4)

Probability Probability Death (%) of 2 Primary Primary Study Phase 3 endpoint Conclusions SUMMIT (113782 [NCT01313676]) Male, n (%) 650 (76) 628 (75) 654 (76) 648 (75) 0 Subgroup analyses conducted for: 0 12 24 36 Patients who met IMPACT exacerbation BMI, mean (SD) kg/m2 28.25 (5.98) 27.75 (6.07) 28.26 (6.12) 28.08 (5.74) Time to Event (Months) ● This post hoc analysis showed that in a subpopulation of 40–80 years of age history criterion: Number of Patients at Risk patients with moderate airflow limitation, heightened CV risk Moderate airflow obstruction: FEV Former smoker, n (%) 484 (56) 456 (54) 443 (51) 463 (54) Placebo 857 729 368 82 1 ≥2 moderate or ≥1 severe 50%–70% predicted FF 840 720 360 82 exacerbation in the prior year and a history of exacerbations in the SUMMIT study, risk of % predicted post- VI 866 738 394 89 Post-bronchodilator FEV1/FVC ratio ≤0.70 FF/VI 865 749 370 95 Primary endpoint: on-/off-treatment ACM was significantly lower in patients bronchodilator FEV1 at 58.9 (6.09) 59.2 (6.00) 58.9 (6.09) 58.9 (6.03) Smoking history ≥10 pack-years All-cause mortality on and off-treatment Patients screening, mean (SD) receiving FF, VI and FF/VI at CED and numerically reduced Modified MRC dyspnea scale score ≥2 Additional endpoint: History or elevated risk of CVD On-treatment severe exacerbations Figure 3. Risk of on-/off-treatment ACM and severe exacerbations with FF, VI with FF and FF/VI at Day 365 compared with placebo. Moderate/severe exacerbations Data for both endpoints were reported and FF/VI vs placebo up to Day 365 up to a common end date (CED) and in prior year, n (%) ● Risk of severe exacerbation was significantly lower in 1 year in the selected subpopulation 1 237 (28) 241 (29) 236 (27) 270 (31) Patients with an event, FF/VI Fluticasone furoate 100 mcg n (%) patients receiving FF monotherapy compared with placebo Once-daily Vilanterol 25 mcg Moderate exacerbation: a symptomatic ≥2 620 (72) 599 (71) 630 (73) 595 (69) Treatment Placebo Favors Favors HR (95% CI) p-value deterioration requiring treatment with antibiotic n/N (%) n/N (%) treatment placebo drugs or systemic corticosteroids at CED and Day 365. Numerical reductions were seen in FF Time to on-/off-treatment ACM Fluticasone furoate 100 mcg Severe exacerbation: any exacerbation leading Severe exacerbations in prior

Once daily analysisPost hoc the VI and FF/VI arms at both timepoints to hospitalization or death year, n (%) FF vs placebo 25/840 (2.98) 34/857 (3.97) 0.77 (0.46, 1.29) 0.320 • HR and 95% CI for time to on-/off- VI Vilanterol 25 mcg 0 295 (34) 315 (38) 318 (37) 295 (34) VI vs placebo 35/866 (4.04) 34/857 (3.97) 1.02 (0.64, 1.64) 0.934 Once daily treatment ACM and for time to first 1 487 (57) 462 (55) 476 (55) 493 (57) ● In a subpopulation of patients with COPD at high risk of severe exacerbation were obtained by ≥2 75 (9) 63 (8) 72 (8) 77 (9) FF/VI vs placebo 26/865 (3.01) 34/857 (3.97) 0.76 (0.45, 1.26) 0.284 Treatments fitting a Cox proportional hazards exacerbation, there appears to be a survival benefit with Placebo Placebo Time to first severe exacerbation Once daily model with covariates of treatment FF-containing therapies compared to placebo, in group, age and gender. SGRQ total score, mean (SD) 52.9 (15.9) 52.9 (16.5) 53.2 (17.0) 52.1 (16.3) FF vs placebo 68/840 (8) 94/857 (11) 0.72 (0.52, 0.98) 0.036 Event-driven – • Percentage reduction in risk was VI vs placebo 80/866 (9) 94/857 (11) 0.81 (0.60, 1.10) 0.173 agreement with the results seen in the IMPACT trial. median study exposure 1.8 years calculated as (1-HR)*100 CAT score, mean (SD) 21.1 (6.6) 20.9 (6.2) 21.0 (6.7) 20.3 (6.2) FF/VI vs placebo 80/865 (9) 94/857 (11) 0.80 (0.60, 1.08) 0.149

CVD included coronary artery disease, peripheral artery disease, previous stroke, previous myocardial infarction, and diabetes with BMI, body mass index; CAT, COPD Assessment Test; SD, standard deviation; SGRQ, St George’s Respiratory 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 target organ disease. CV risk was defined as the following: ≥60 years of age and receiving medication for >2 of hypercholesterolemia, Questionnaire HR (95% CI) hypertension, diabetes mellitus, and peripheral artery disease. On and off-treatment deaths are those which occur between study treatment start date and the minimum of the last known contact date, the CED and Day 365 inclusive. CED, common end date;

CI, confidence interval; CVD, cardiovascular disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; HR, hazard ratio; MRC, Medical Research Council.

Disclosures Sciences, The Implementation Group, and Verona. Has ownership interest in HGE fees and non-financial support from the American College of Chest Physicians, Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, GE Healthcare, Hoffman La Technologies. MT Dransfield: received personal fees from AstraZeneca, Boehringer AstraZeneca, Boehringer Ingelheim, Continuing Education, ConCert, Genentech, GSK, Roche, Inositec, Jansen, Medicines Company, Medtronic, Nordic Pharma, Pfizer, Sanofi Acknowledgments ● This study was funded by GlaxoSmithKline (GSK; NCT01313676). ELLIPTA is owned Ingelheim, PneumRx/BTG, Quark Pharmaceuticals and GSK, grant support from the Inova Fairfax Health System, Miller Communications, National Society for Continuing Aventis, Siemens, Toshiba, UCB, Wyeth, Zealand Pharma. D Singh: has received ● Editorial support (in the form of writing assistance, including development by or licensed to the GSK Group of Companies. American Lung Association, Department of Defense, Department of Veterans Affairs, Education, Novartis, Pearl Pharmaceuticals, PeerView Communications, Prime personal fees from GSK, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Genentech, of the initial draft based on author direction, assembling tables and figures, and NIH, and contracted clinical trial support from Boehringer Ingelheim, Novartis, Communications, Puerto Rico Respiratory Society, Chiesi, Roche, Sunovion, Glenmark, Menarini, Mundipharma, Novartis, Peptinnovate, Pfizer, Pulmatrix, Scan the QR code or click on ● On behalf of all authors, an audio recording of this poster was prepared by Peter collating authors’ comments, grammatical editing, and referencing) was Calverley, who did not receive any payment for this recording. AstraZeneca, Yungjin, PneumRx/BTG, Pulmonx, Boston Scientific, Gala, Nuvaira, and Theravance, Potomac, University of Alabama Birmingham, Physicians Education Theravance and Verona, and grant support from AstraZeneca, Boehringer Ingelheim, http://tago.ca/CHEST_3 to access a ● PMA Calverley: received personal fees from GSK, Boehringer Ingelheim, Novartis, GSK. DMG Halpin: received personal fees from AstraZeneca, Boehringer Ingelheim, Resource, Canadian Respiratory Network and Teva, non-financial support from Chiesi, Glenmark, Menarini, Mundipharma, Novartis, Pfizer, Pulmatrix, Theravance and provided Ellen Barker, at Fishawack Indicia Ltd, and was funded by downloadable version of this poster, a Phillips Respironics, Reciharm, and Zambon. BR Celli: received compensation for Chiesi, GSK, Novartis, Pfizer and Sanofi, and non-financial support from Boehringer ProterrixBio, Gilead, Nitto and Zambon, and personal fees from Columbia University, Verona. J Vestbo: has received personal fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline (GSK). Advisory Boards and consultation fees from GSK, Boehringer-Ingelheim, Astra Zeneca, Ingelheim and Novartis. MK Han: has received personal fees from AstraZeneca, GSK, Integritas, MD Magazine, Methodist Hospital Brooklyn, New York University, Unity, Chiesi, GSK and Novartis, and grant support from Boehringer Ingelheim. R Wise: has version that has been formatted for Mylan, and Boehringer Ingelheim and research support from Novartis and Sunovion. UpToDate, WedMD/MedScape, Western Connecticut Health Network, Academic CME, received personal fees from AstraZeneca/MedImmune, Boehringer Ingelheim, Novartis, Pulmonx, Chiesi, Menarini and Bayer. C Crim: employee of GSK and holds References online viewing, and the associated stocks/shares in GSK. GJ Criner: received personal fees from Almirall, Amgen, CE Jones: employee of GSK and holds stocks/shares in GSK. S Kilbride: employee of Patara, PlatformIQ, American Thoracic Society, Rockpointe and France Foundation, ContraFect, Pulmonx, Roche, Spiration, Sunovion, Merck, Circassia, Pneuma, Verona, audio recording AstraZeneca, Boehringer Ingelheim, Broncus Medical, Chiesi, CSA Medical, Eolo, Gala GSK and holds stocks/shares in GSK. P Lange: has received personal fees from GSK, grant support from NIH, Rare Disease Health Communications and ProMedior, and is a Bonti, Denali, Aradigm, Mylan/Theravance, Propeller Health, AbbVie and GSK, and 1. Vestbo J, et al. Lancet. 2016;387:1817–26 Therapeutics, GSK, Helios Medical, Medtronic, Merck, Mereo BioPharma, NGM AstraZeneca, and Boehringer Ingelheim, and grant support from Boehringer Ingelheim member of steering committees for Afferent/Merck, Biogen, Veracyte, Prometic, Bayer grant support from AstraZeneca/MedImmune, Boehringer Ingelheim, Pearl 2. Lipson D, et al. N Engl J Med. 2018;3;378:1671–80. Pharmaceuticals, Novartis, Nuvaira, Olympus, Philips Respironics, Pulmonx, Respivant and GSK. S Lettis: employee of GSK and holds stocks/shares in GSK. DA Lipson: and Bridge Biotherapeutics. A Morris: employee of GSK and holds stocks/shares in Therapeutics, GSK, and Sanofi-Aventis. J Yates: employee of GSK and holds employee of GSK and holds stocks/shares in GSK. FJ Martinez: has received personal GSK. DE Newby: has received personal fees, grants or undertaken trials with GSK, stocks/shares in GSK. 3. Lipson, D et al. Am J Resp Crit Care Med. 2020;201:1508–16. Prepared for the American College of Chest Physicians Congress (2020)