Evidence Summary to support COPD formulary decision making and guideline development

Transcription

1 Evidence Summary to support COPD formulary decision making and guideline development Prescribing and adverse event reporting information can be found on the final pages of this document. Anoro, and Ellipta Trademarks are owned by or licensed to the GSK Group of Companies. 217 GSK Group of Companies or its licensor.

2 Instructions for using this document This document has been designed to allow you to quickly access the information that you require. It may be used in a linear manner by scrolling through the content, or by navigating straight to the section of interest using the links contained within the document. There are six key sections where diverse information has been included these are accessible via the toolbar, which is located at the top of every page. Please see the illustration of the toolbar here: Clicking on the relevant button in the toolbar will take you straight to the first page of that section; from there you will be able to navigate within that section. In certain sections, for example the section, a summary has been provided on the first page of that section and is followed by more detailed information. If at any time you wish to return to your previous page after following a link, you can press Alt + the back arrow key on your keyboard (Alt + ); this will return you to your original place in the document. If in doubt, the button in the toolbar will take you back to the main homepage where all information can be accessed. Anoro Ellipta is part of the Ellipta range of COPD medicines. The other medicines in the chronic obstructive pulmonary disease (COPD) Ellipta portfolio are: Incruse Ellipta (umeclidinium 55 mcg), indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD 1 Relvar Ellipta (fluticasone furoate/vilanterol 92/22 mcg), indicated for the symptomatic treatment of adults with a FEV1 <7% predicted normal (post-bronchodilator) with an exacerbation history despite regular bronchodilator therapy 2 Trelegy Ellipta (fluticasone furoate/umeclidinium/vilanterol 92/55/22 mcg), indicated as a maintenance treatment in adult patients with moderate to severe COPD who are not adequately treated by a combination of an inhaled corticosteroid and a long-acting β2-agonist or a combination of a long-acting muscarinic antagonist and a long-acting β2-agonist 3 For further information please visit UK/UCV/46/17(4) Date of preparation: November 218 2

3 page The Details section provides of Anoro Ellipta, including: Disease area and licensed indication Trade and generic name Drug class and treatment type Strength and dosing Manufacturer Device The section for Anoro Ellipta includes: Status of marketing authorisation Health Technology Assessment (HTA) body information The section provides information that may be of use when considering a formulary application, including: Place in therapy as recommended by HTA bodies Place in therapy as recommended by clinical guidelines The section for Anoro Ellipta includes: Efficacy data Safety data The section for Anoro Ellipta includes: Ellipta device information Inhaler errors data device preference data The section includes: Cost of Anoro Ellipta considerations for Anoro Ellipta 3

4 Details Disease area Chronic Obstructive Pulmonary Disease (COPD) 4 Trade name Anoro Ellipta 4 Generic name Drug class Umeclidinium bromide (UMEC; long-acting muscarinic receptor antagonist [LAMA]) and vilanterol (VI; long-acting β2-agonist [LABA]) combination 4 Respiratory systems; bronchodilators; long-acting β2 agonists/long-acting muscarinic receptor; LAMA/LABA 5 Strength 55/22 mcg 4 Dose One inhalation of Anoro Ellipta 55/22 mcg once daily, at the same time each day 4 Marketing Authorisation Holder Glaxo Group Limited 4 Treatment type Long term 4 Licensed indication(s) Anoro Ellipta is indicated for the maintenance bronchodilator treatment to relieve symptoms in adults patients with chronic obstructive pulmonary disease (COPD) 4 The Anoro Ellipta device is a multi-dose dry powder inhaler (DPI). The inhaler consists of a light grey body, a red mouthpiece cover and a dose counter, packed into a foil laminate tray containing a desiccant packet. The tray is sealed with a peelable foil lid. 4 Device 4

5 Does Anoro Ellipta have UK/EU marketing authorisation? NICE TA recommendation 55/22 mcg 1 x 3 doses [EU/1/14/898/2] 4,6 Consistent with other respiratory medicines prescribed in primary care, Anoro Ellipta did not undergo a National Institute for Health and Care Excellence (NICE) technology appraisal 7 SMC number 978/14 8 AWMSG reference Black triangle This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 4,1 5

6 Indication The clinical trial data for Anoro Ellipta (umeclidinium/vilanterol; UMEC/V) has been assessed and approved by the European s Agency (EMA). 6 This is reflected in the licence for Anoro Ellipta 55/22 mcg. 4 Anoro Ellipta is indicated as a maintenance bronchodilator treatment to relieve symptoms in adults patients with chronic obstructive pulmonary disease (COPD) 4 Place in therapy recommended by relevant bodies NICE SMC AWMSG In line with other respiratory medicines prescribed in primary care, Anoro Ellipta did not undergo a NICE technology appraisal. Instead NICE has published an evidence summary for Anoro Ellipta. 7 SMC advice accepts the use of Anoro Ellipta for use within NHS Scotland: 8 Indication under review: As a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease. Two randomised controlled studies demonstrated that after 24 weeks of treatment, umeclidinium/vilanterol significantly improved lung function compared with an inhaled long-acting muscarinic antagonist in patients with moderate to very severe COPD. Indirect comparisons demonstrated comparable efficacy with other combinations of long acting muscarinic antagonist plus long acting beta agonist. AWMSG advice recommends Anoro Ellipta for the treatment of COPD: Umeclidinium/vilanterol (as trifenatate) (Anoro Ellipta) is recommended as an option for use within NHS Wales as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). 9 6

7 Place in therapy recommended by clinical practice guidelines GOLD Strategy 219 The Global Initiative for Chronic Obstructive Lung Disease (GOLD) 219 suggests that initial pharmacological treatment should be individualised based on symptom severity and exacerbation history. This is evaluated using the ABCD assessment tool shown in figure 1 below 11 s in group B, group C and group D, depending on the individualised assessment of symptoms and exacerbation risk, can be suitable for the LAMA/LABA class of medicines. Anoro Ellipta is indicated for the maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD and therefore could be appropriate for patients in group B. 4 GOLD state for group B patients with severe breathlessness initial therapy with two bronchodilators may be considered. 11 Figure 1: Initial pharmacological treatment GOLD A separate algorithm is provided for follow-up treatment (figure 1.1 below). This is independent to the patients GOLD group at diagnosis; instead treatment options are individualised based on if a patient is presenting with dyspnoea or exacerbations. 1 Figure 1.1. Follow-up Pharmacological Treatment * Figures adapted from Global Initiative for Chronic Obstructive Lung Disease (218). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. 219 Global Initiative for Chronic Obstructive Lung Disease, all rights reserved. Use is by express license from the owner. eos = blood eosinophil count (cells/µl) * Consider if eos 3 or eos 1 AND 2 moderate exacerbations / 1 hospitalization ** Consider de-escalation of ICS or switch if pneumonia, inappropriate original indication or lack of response to ICS 7

8 NICE 218 COPD Guidelines The NICE guideline covers diagnosing and managing COPD. It aims to help people with COPD to receive a diagnosis earlier so that they can benefit from treatments to reduce symptoms, improve quality of life and keep them health for longer. NICE recommend that you should offer a LAMA/LABA as first line maintenance therapy to people who: - Have spirometrically confirmed COPD and - Do not have asthmatic features/features suggesting steroid responsiveness and - Remain breathless or have exacerbations despite: - Having used or been offered treatment for tobacco; optimised non-pharmacological management and relevant vaccinations; and are using a short-acting bronchodilator. Figure 2: Chronic obstructive pulmonary disease in over 16s: non-pharmacological management and use of inhaled therapies 12 NICE * Asthmatic features/features suggesting steroid responsiveness in this context include any previous secure diagnosis of asthma or atopy, a higher blood eosinophil count, substantial variation in FEV1 over time (at least 4 ml) or substantial diurnal variation in peak expiratory flow (at least 2%) Figure adapted from National Guideline Centre. (218) Chronis obstructive pulmonary disease: management of chronic obstructive pulmonary disease in adults in primary and secondary acare. London: National Guideline Centre. NICE 218. All rights reserved. Subject to Notice of rights. 8

9 Anoro Ellipta (UMEC/VI) is a LAMA/LABA with proven efficacy 12,19 Anoro Ellipta (UMEC/VI) delivers significantly superior bronchodilation vs tiotropium* HandiHaler (TIO) and Spiolto Respimat (TIO/OLO) for patients with COPD 13,19 Anoro Ellipta (UMEC/VI) has an adverse event profile comparable to that of tiotropium HandiHaler (TIO) and Spiolto Respimat (TIO/OLO) in clinical studies The Efficacy studies include: Active-comparator studies (UMEC/VI vs OLO/TIO) o Feldman et al., 217 Active-comparator studies (UMEC/VI vs TIO) o Maleki-Yazdi et al., 217 o Kerwin et al., 217 o Decramer et al., 214 Active-comparator studies (UMEC/VI vs TIO + IND) o Kalberg et al., 216 Placebo-controlled study o Donohue et al., 213 The Safety summary includes: A pooled analysis of safety data for Anoro Ellipta A summary of Anoro Ellipta safety data from: o Donohue et al., 214 o Feldman et al., 212 *Details of the blinding process for all tiotropium comparator studies discussed in this Evidence Summary can be found on page 474 in Decramer M et al., Lancet Respir Med. 214 Jun;2: Doi: 1.116/S (14) TIO/OLO: tiotropium/olodaterol; UMEC/VI: UMEC/VI: umeclidinium/vilanterol 9

10 Efficacy study summaries Dosing information Each single inhalation of Anoro Ellipta provides a delivered dose (the dose leaving the mouthpiece) of 65 mcg umeclidinium bromide equivalent to 55 mcg umeclidinium and 22 mcg vilanterol (as trifenatate). This corresponds to a pre-dispensed dose of 74.2 mcg umeclidinium bromide equivalent to 62.5 mcg umeclidinium and 25 mcg vilanterol (as trifenatate). 4 information UMEC 113 mcg, VI 22 mcg, UMEC/VI 5/25 mcg, and UMEC/VI 113/22 mcg included in the Decramer et al., 214 study, Donohue et al., 213 study, Donohue et al., 214 study, and Feldman et al., 212 study are not licensed in the UK. The results have not been included in the efficacy section but have been included in the safety section for transparency purposes. Safety studies with an un-licensed dose have also been included for transparency. Interpreting clinical trial results statistical hierarchy When reviewing the outcomes of clinical trials it is important to understand the relevance of statistical hierarchy and how that impacts the conclusions that can be derived from a study. This concept is explained below. Statistical hierarchy sequentially tests the significance of a number of endpoints in a study programme in a predetermined order. For each endpoint, a determination of significance can only be made if all prior endpoints were also significant. Treatment comparisons for the primary endpoints are required to be statistically significant in order to infer significance for the secondary endpoints. Therefore, if the trial does not meet its primary endpoint, the secondary endpoints cannot be statistically analysed; those results are described as descriptive only. 1

11 Feldman et al., 217 (UMEC/VI vs TIO/OLO) For more detailed information about this study, please see the Anoro Evidence Dossier, or click here to download the publication via PubMed online. This link will take you to a non-gsk website. GSK does not recommend, endorse or accept liability for sites controlled by third-parties. Study objective population Design Treatments Baseline characteristics To compare the efficacy and safety of UMEC/VI 55/22 mcg OD with TIO/OLO 5/5 mcg OD for the treatment of COPD 16,17 Inclusion criteria: 4 years with a diagnosis of COPD Smoking history 1 pack-years Post-bronchodilator FEV1/FVC ratio <.7 Post-bronchodilator FEV1 7% to 5% mmrc dyspnoea score 2 Not receiving ICS-containing therapy at study inclusion An open-label, two-period, 8-week, non-inferiority crossover study 2-week run-in period; two 8-week treatment periods: UMEC/VI 55/22 mcg OD then TIO/OLO 5/5 mcg OD TIO/OLO 5/5 mcg OD then UMEC/VI 55/22 mcg OD ITT population Total (N=236) Age (years), mean ± SD 64.4 ± 8.5 Female sex, n (%) 94 (4) Current smoker, n (%) 125 (53) Mean smoking pack-year history ± SD 5.2 ± 25.5 Mean post-bronchodilator FEV1 (L), % predicted ± SD 59.6 ± 5.6 Primary endpoint results Change from baseline in trough FEV1 at Week 8 UMEC/VI 55/22 mcg 175 ml and TIO/OLO 5/5 mcg 122 ml; difference: 53 ml (95% CI 26, 8; p<.1) The difference exceeded the non-inferiority margin of 5 ml, demonstrating non-inferiority compared with TIO/OLO 5/5 mcg Trough FEV1 superiority assessment at Weeks 4 and 8 UMEC/VI 55/22 mcg vs TIO/OLO 5/5 mcg o Week 4 difference: 48 ml; 95% CI 25, 71; p<.1 o Week 8 difference: 52 ml; 95% CI 28, 77; p<.1 Secondary and other efficacy endpoint results Percentage of FEV1 responders ( 1 ml change from baseline) at Weeks 4 and 8 The percentage of trough FEV1 responders o Week 4: UMEC/VI 55/22 mcg 69%; TIO/OLO 5/5 mcg 51% o Week 8: UMEC/VI 55/22 mcg 66%; TIO/OLO 5/5 mcg 48% The likelihood of achieving trough FEV1 response o Week 4: OR 2.9; 95% CI 1.39, 3.14; p<.1 o Week 8: OR 2.5; 95% CI 1.34, 3.14; p<.1 Trough FVC and IC at Weeks 4 and 8 Trough FVC o Week 4: UMEC/VI 55/22 mcg vs TIO/OLO 5/5 mcg difference: 4 ml; 95% CI 5, 75; p<.5 o Week 8: UMEC/VI 55/22 mcg vs TIO/OLO 5/5 mcg difference: 67 ml; 95% CI 34, 1; p<.1 11

12 IC o o Week 4: UMEC/VI 55/22 mcg vs TIO/OLO 5/5 mcg difference: 52 ml; 95% CI 16, 88; p<.1 Week 8: UMEC/VI 55/22 mcg vs TIO/OLO 5/5 mcg difference: 47 ml; 95% CI 14, 81; p<.1 CAT score and percentage responders at Weeks 4 and 8 CAT score (UMEC/VI 55/22 mcg vs TIO/OLO 5/5 mcg) o Week 4 difference:.59; 95% CI 1.16,.2; p=.42 o Week 8 difference:.11; 95% CI.68,.45; p=.695 CAT responders (UMEC/VI 55/22 mcg vs TIO/OLO 5/5 mcg) o Week 4: OR 1.25; 95% CI.85, 1.82; p=.258 o Week 8: OR 1.5; 95% CI.72, 1.55; p=.798 Rescue medication use and percentage rescue-free days (Weeks 1 8) Puffs/day: UMEC/VI 55/22 mcg vs TIO/OLO 5/5 mcg difference:.25 puffs; 95% CI.37,.41; p<.1) Rescue-free days over Weeks 1 8: UMEC/VI 55/22 mcg vs TIO/OLO 5/5 mcg difference: 1.91; 95% CI.71, 4.53) -reported outcomes Weekly mean E-RSCOPD symptom score Range: UMEC/VI 55/22 mcg: 1.79 to 1.61; TIO/OLO 5/5 mcg: 1.72 to 1.31 Statistically significant difference in favour of UMEC/VI 55/22 mcg at Week 5 (p=.31) Inhaler ease of use (inhaler-naïve population; n=75) 96% of patients rated ELLIPTA as very easy or easy to use compared with 83% of patients using Respimat Significantly more patients rated Ellipta higher than Respimat on: o Overall ease of use (4% vs 11%; p=.1) o Ease of telling the number of doses remaining (53% vs 1%; p<.1) o Ease of learning to use (43% vs 4%; p<.1) o Ease of handling (4% vs 4%; p<.1) o Ease of preparation (49% vs 3%; p<.1) o Ease of holding while using (32% vs 4%; p<.1) More information about patient factors associated with Anoro Ellipta is provided in the section Safety UMEC/VI 55/22 mcg (n=235) TIO/OLO 5/5 mcg (n=23) Any AE, n (%) 59 (25) 71 (31) Most common AE type, n (%) Viral URTI URTI Any AE leading to discontinuation of study medication or withdrawal from study, n (%) 11 (5) 8 (3) 14 (6) 7 (3) Any SAE, n (%) 3 (1) 2 (<1) Any fatal SAE, n (%) 12

13 COPD exacerbations, n (%) 1 2 AEs of special interest, n (%) Cardiovascular Cardiac arrhythmia Cardiac failure Cardiac ischaemia Hypertension Stroke Pneumonia LRTI excluding pneumonia Ocular effects (antimuscarinic) Paradoxical bronchospasm Asthma/bronchospasm Urinary retention 217 (92) 15 (6) 3 (1) 4 (2) 3 (1) about the safety of Anoro Ellipta is provided in the Safety summary 211 (92) 18 (8) 4 (2) 2 (<1) 3 (1) 2 (<1) AE = adverse event; CAT = COPD Assessment Test; COPD = chronic obstructive pulmonary disease; E-RS = Exact Respiratory Symptoms Tool; FEV 1 = forced expiratory volume in 1 second; FVC = forced vital capacity; IC = inspiratory capacity; ICS = inhaled corticosteroid; ITT = intention-to-treat; LRTI = lower respiratory tract infection; mmrc = modified Medical Research Council; NR = not reported; OD = once daily; SAE = serious adverse event; SD = standard deviation; TIO/OLO = tiotropium/olodaterol; UMEC/VI = umeclidinium/vilanterol; URTI = upper respiratory tract infection 13

14 Maleki-Yazdi et al., 217 (UMEC/VI vs TIO) For more detailed information about this study, please see the Anoro Evidence Dossier, or click here to download the publication via PubMed online. This link will take you to a non-gsk website. GSK does not recommend, endorse or accept liability for sites controlled by third-parties. Citation Study objective population Design Treatments Baseline characteristics Primary endpoint results Secondary and other efficacy endpoint results Maleki-Yazdi et al., Assessing short-term deterioration in maintenance-naïve patients with COPD receiving umeclidinium/vilanterol and tiotropium HandiHaler: a pooled analysis of three randomized trials. Advances in Therapy 216; 33: To compare the efficacy of UMEC/VI 55/22 mcg OD with TIO 1 mcg OD in a subgroup of patients in patients with COPD and moderate to severe breathlessness Inclusion criteria: 4 years with a diagnosis of symptomatic COPD Post-bronchodilator FEV1 value of 7% predicted normal FEV1/FVC ratios <.7 mmrc dyspnoea score 2 A post-hoc pooled analysis using three multicentre, randomised, 24-week, parallel-group, blinded, active comparator studies 5 7-day run-in period; 85-day treatment period UMEC/VI 55/22 mcg OD Ellipta inhaler TIO 1 mcg OD HandiHaler Intent to Treat (ITT) population UMEC/VI 55/22 mcg (n=878) TIO 1 mcg (n=869) Maintenance Naive (MN) population UMEC/VI 55/22 mcg (n=275) TIO 1 mcg (n=258) Age (years), mean ± SD 63. ± ± ± ± 8.7 Female sex, n (%) 282 (32) 275 (32) 81 (29) 93 (36) Current smoker, a n (%) 457 (52) 439 (51) 18 (65) 155 (6) Smoking pack-years, b n (%) 45.1 (25.6) 46.1 (27.) 47.1 (25.6) 4.5 (3.1) Reversible to salbutamol, c,d n (%) 243 (28) 248 (29) 94 (34) 77 (3) Mean post-albuterol % predicted FEV1, mean ± SD 47. ± ± ± ± 12.8 LS mean change from baseline in trough FEV1 on Day 169 (MN and ITT populations) UMEC/VI 55/22 mcg vs TIO 1 mcg: MN population: 146 ml; 95% CI 12, 189; p=.1; ITT population: 96 ml; 95% CI 71, 118, p<.1, favouring the UMEC/VI 55/22 mcg treatment group* Deterioration events A lower proportion of patients displayed a short-term CID in the UMEC/VI 55/22 mcg treatment group vs TIO 1 mcg treatment group, in both populations (MN: 41% vs 55%; ITT: 41% vs 56%) Significantly reduced risk of first CID favouring the UMEC/VI 55/22 mcg group in the MN (HR=.66; 95% CI.51,.85; p=.1) and the ITT (HR=.66; 95% CI.54,.71: p<.1) populations Fewer patients demonstrated a sustained CID in the UMEC/VI 55/22 mcg compared with TIO 1 mcg in both the MN (22% vs 3%) and the ITT (21% vs 3%) populations 14

15 Significantly reduced risk of sustained CID favouring the UMEC/VI 55/22 mcg group in the MN (HR=.69; 95% CI.49,.97; p<.5) and the ITT (HR=.64; 95% CI.53,.77; p<.1) populations -reported outcomes Safety UMEC/VI 55/22 mcg vs TIO 1 mcg SGRQ total score and proportion of responders Total SGRQ scores demonstrated significant improvement with UMEC/VI 55/22 mcg in the ITT population on Days 28 and 84, but not on Day 168 o Day 28: 2.25 units; 95% CI 3.26, 1.23; p<.1 o Day 84: 1.63 units; 95% CI 2.76,.49; p=.5 o Day 168:.93 units; 95% CI 2.19,.33; p=.149 Significantly greater odds of being a SGRQ responder at Days 28 and 84: OR 1.3 units at both time points; p=.7 at Day 28; p=.9 at Day 84, but not at Day 168 o No significant differences in the MN population Median percentage of rescue-free days Percentage response favoured the UMEC/VI 55/22 mcg group vs the TIO 1 mcg group in the ITT (46% vs 36% [OR 1.5; 95% CI 1.2, 1.9]) and the MN (47% vs 37% [OR 1.5: 95% CI 1., 2.2]) populations More information about patient factors associated with Anoro Ellipta is provided in the section On-treatment non-fatal SAEs, any event, n (%) UMEC/VI 55/22 mcg (n=878) ITT population TIO 1 mcg (n=869) MN population UMEC/VI 55/22 mcg (n=275) TIO 1 mcg (n=258) 42 (5) 35 (4) 8 (3) 11 (4) Fatal AEs, n (%) 4 (<1) 7 (1) 3 (1) 2 (<1) AEs reported by 3% of patients on any treatment, n (%) Nasopharyngitis Headache Cough URTI AEs of special interest, n (%) CV events (any) Pneumonia 63 (7) 8 (9) 27 (3) 25 (3) 2 (<1) 2 (<1) 62 (7) 55 (6) 28 (3) 26 (3) 2 (<1) 6 (<1) 18 (7) 2 (7) 8 (3) 5 (2) about the safety of Anoro Ellipta is provided in the Safety summary 15 (6) 15 (6) 4 (2) 8 (3) a reclassified as current smoker if smoked within 6 months; b Smoking pack-years = (number of cigarettes smoked per day/2) x number of years smoked; c Reversibility was defined as an increase in FEV 1 12% and 2 ml following administration of albuterol; d ITT population: UMEC/VI 55/22 mcg OD, n=876; TIO 1 mcg OD, n=863 *Anoro Ellipta (n=23) 252mL improvement vs tiotropium HandiHaler (n=216) 17mL improvement at day 169. (Pooled ITT population; Anoro n=878, tiotropium = 869). Details of the blinding process for all tiotropium comparator studies discussed in this Evidence Summary can be found on page 474 in Decramer M et al. Lancet Respir Med. 214 Jun; 2: Doi: 1.116/S (14) AE = adverse event; CI = confidence interval; CID = clinically important deterioration; CV = cardiovascular; FEV 1 = forced expiratory volume in 1 second; FVC = forced vital capacity; HR = hazard ratio; LS = least squares; mmrc = modified Medical Research Council; OD = once daily; OR = odds ratio; SAE = serious adverse event; SD = standard deviation; SGRQ = St George s Respiratory Questionnaire; TIO = tiotropium; UMEC/VI = umeclidinium/vilanterol; URTI = upper respiratory tract infection 15

16 Kerwin et al., 217 (UMEC/VI vs TIO) For more detailed information about this study, please see the Anoro Evidence Dossier, or click here to download the publication via PubMed online. This link will take you to a non-gsk website. GSK does not recommend, endorse or accept liability for sites controlled by third-parties. Citation Study objective population Design Treatments Baseline characteristics Primary endpoint results Kerwin et al. Umeclidinium/vilanterol as step-up therapy from tiotropium HandiHaler in patients with moderate COPD: a randomized, parallel-group, 12-week study. Int J COPD. 217;12: ,18 To evaluate the efficacy and safety of UMEC/VI 62.5/25 mcg OD and TIO 1 mcg OD in patients with moderate COPD Inclusion criteria: 4 years with clinical diagnosis of moderate COPD Post salbutamol FEV1 7% and 5% of normal predicted mmrc dyspnoea score 1 Prescribed TIO for 3 months Phase III, randomised, multicentre, double-blind*, double-dummy, parallel-group, active controlled 12-week lung function study in patients with moderate COPD 4-week run-in period; 12-week treatment period: TIO 1 mcg OD UMEC/VI 55/22 mcg OD UMEC/VI 55/22 mcg (n=247) TIO 1 mcg (n=247) Age (years), mean ± SD 64.5 ± ± 8.7 Female sex, n (%) 84 (44) 87 (45) Mean smoking pack-year history, years ± SD 38.6 ± ± 2.2 Post-salbutamol % predicted FEV1, mean ± SD 59.8 ± ± 5.3 Post-salbutamol FEV1/FVC, mean ± SD 53.1 ± ± 8.4 Trough FEV1 on Day 85 UMEC/VI 55/22 mcg vs TIO 1 mcg: 88 ml; p<.1 FEV1 3h post-dose on Day 84 UMEC/VI 55/22 mcg vs TIO 1 mcg: 73 ml; p<.1 Trough FEV1 from Day 2 onwards UMEC/VI 55/22 mcg vs TIO 1 mcg: greater improvements on all assessments; p<.1 Secondary and other efficacy endpoint results Proportion of patients achieving an increase of.1 L above baseline in trough FEV1 on Day 85 UMEC/VI 55/22 mcg vs TIO 1 mcg: OR 1.89; p<.1 Mean serial FEV1 5 min postdose on Day 1 UMEC/VI 55/22 mcg vs TIO 1 mcg: 5 ml; p<.1 wmfev1 over 3 h post-dose on Day: Day 1: UMEC/VI 55/22 mcg vs TIO 1 mcg: 55 ml; p<.1 Day 28: UMEC/VI 55/22 mcg vs TIO 1 mcg: 8 ml; p<.1 Day 56: UMEC/VI 55/22 mcg vs TIO 1 mcg: 56 ml; p<.5 Day 84: UMEC/VI 55/22 mcg vs TIO 1 mcg: 72 ml; p<.1 16

17 Rescue-free days UMEC/VI 55/22 mcg vs TIO 1 mcg: 2.3; p<.1 Rescue salbutamol use (mean puffs/day) UMEC/VI 55/22 mcg vs TIO 1 mcg:.1; p<.5 -reported outcomes TDI score Day 28: UMEC/VI 55/22 mcg vs TIO 1 mcg:.5; p<.5 Day 56: UMEC/VI 55/22 mcg vs TIO 1 mcg:.1; p=ns Day 84: UMEC/VI 55/22 mcg vs TIO 1 mcg:.4; p=ns Improvements in SGRQ and CAT scores on Days 28 and 84 Similar between groups More information about patient factors associated with Anoro Ellipta is provided in the section UMEC/VI 55/22 mcg (n=247) TIO 1 mcg (n=247) On-treatment AEs, n (%) 75 (3) 77 (31) Any AEs leading to withdrawal or discontinuation of medication, n (%) 5 (2) 4 (2) On-treatment nonfatal SAEs, n (%) 6 (2) 6 (2) On-treatment fatal SAEs, n (%) Most common AE type, n (%) Nasopharyngitis 18 (7) 17 (7) Safety Headache AEs of special interest, n (%) Cardiovascular Cardiac arrhythmias Cardiac failure Ischaemic heart disease CNS haemorrhages and cerebrovascular conditions 16 (6) 4 (2) 2 (<1) 18 (7) 3 (1) 2 (<1) Pneumonia LRTI excluding pneumonia 2 (<1) On-treatment COPD exacerbation, n (%) 2 (<1) 8 (3) about the safety of Anoro Ellipta is provided in the Safety summary AE = adverse event; CAT = COPD Assessment Test; CI = confidence interval; COPD = chronic obstructive pulmonary disease; CV = cardiovascular; FEV 1 = forced expiratory volume in 1 second; FVC = forced vital capacity; ITT = intent-to-treat; LRTI = lower respiratory tract infection; mmrc = modified Medical Research Council; NS = not significant; OD = once daily; OR = odds ratio; SAE = serious adverse event; SD = standard deviation; SGRQ = St George s Respiratory Questionnaire; TDI = Transition Dyspnoea Index; TIO = tiotropium; UMEC = umeclidinium; VI = vilanterol Details of the blinding process for all tiotropium comparator studies discussed in this Evidence Summary can be found on page 474 in Decramer M et al. Lancet Respir Med. 214 Jun; 2: Doi: 1.116/S (14)

18 Decramer et al., 214 (UMEC/VI vs VI and TIO) For more detailed information about this study, please see the Anoro Evidence Dossier, or click here to download the publication via PubMed online. This link will take you to a non-gsk website. GSK does not recommend, endorse or accept liability for sites controlled by third-parties. Citation Study objective population Design Treatments Baseline characteristics Primary endpoint results Decramer et al. Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials. Lancet Respir Med. 214;43: To examine the efficacy and safety of two different doses of inhaled UMEC plus VI* * VI 22 mcg, UMEC 113 mcg and UMEC/VI 113/22 mcg are not licensed in the UK and therefore the results have not been included in the efficacy section but have been included in the safety section Inclusion criteria: 4 years with clinical diagnosis of moderate to very severe COPD Smoking history 1 pack-years Post bronchodilator FEV1/FVC ratio <.7 FEV1 7% predicted MRC dyspnoea score 2 Phase III, randomised, multicentre, double-blind, double-dummy, parallel-group, active controlled 24-week lung function studies in patients with moderate to very severe COPD Study 1: TIO 1 mcg OD VI 22 mcg* OD UMEC/VI 55/22 mcg OD UMEC/VI 113/22 mcg* OD Study 2: TIO 1 mcg OD UMEC 113 mcg* OD UMEC/VI 55/22 mcg OD UMEC/VI 113/22 mcg* OD Study 1 UMEC/VI 55/22 mcg (n=212) TIO 1 mcg (n=28) Age (years), mean ± SD 63. ± ± 9.4 Female sex, n (%) 64 (3) 68 (33) Mean smoking pack-year history, years Post-salbutamol % predicted FEV1, mean ± SD 48. ± ± 13.4 Post-salbutamol FEV1/FVC, mean ± SD 47.7 ± ± 11.9 Study 2 UMEC/VI 55/22 mcg (n=217) TIO 1 mcg (n=215) Age (years), mean ± SD 65. ± ± 8.3 Female sex, n (%) 77 (35) 62 (29) Mean smoking pack-year history, years Post-salbutamol % predicted FEV1, mean ± SD 47.7 ± ± 13.1 Post-salbutamol FEV1/FVC, mean ± SD 46.2 ± ± 11.6 Pre-dose (trough) FEV1 on Day 169 Study 1: UMEC/VI 55/22 mcg vs TIO 1 mcg: 9 ml; p.1 Study 2: UMEC/VI 55/22 mcg vs TIO 1 mcg: 6 ml; p=.182 Pooled analysis: UMEC/VI 55/22 mcg vs TIO 1 mcg: 75 ml; p< 1 18

19 wmfev1 over 6 h post-dose on Day 168 Study 1: UMEC/VI 55/22 mcg vs TIO 1 mcg: 74 ml; p=.52 Study 2: UMEC/VI 55/22 mcg vs TIO 1 mcg: 96 ml; p<.1 Pooled analysis: UMEC/VI 55/22 mcg: 84 ml; p<.1 Peak FEV1 on Day 168 Study 1: UMEC/VI 55/22 mcg vs TIO 1 mcg: 72 ml; p=.18 Study 2: UMEC/VI 55/22 mcg vs TIO 1 mcg: 93 ml; p<.2 Secondary and other efficacy endpoint results Trough FVC on Day 169 Study 1: UMEC/VI 55/22 mcg vs TIO 1 mcg: 68 ml; p=.13 Study 2: UMEC/VI 55/22 mcg vs TIO 1 mcg: 98 ml; p<.143 Proportion of patients achieving an increase in FEV1 of 12% and.2 L above baseline at any time during 6 h post-dose on Day 1 Study 1: UMEC/VI 55/22 mcg vs TIO 1 mcg: OR 2.5; p<.1 Study 2: UMEC/VI 55/22 mcg vs TIO 1 mcg: OR 2.1; p=.2 Proportion of patients achieving an increase of.1 L above baseline in trough FEV1 on Day 169 Study 1: UMEC/VI 55/22 mcg vs TIO 1 mcg: OR 2.1; p=.3 Study 2: UMEC/VI 55/22 mcg vs TIO 1 mcg: OR 1.4; p=.6 Time to first COPD exacerbation** No differences in risk of a COPD exacerbation observed between the UMEC/VI and monotherapy groups TDI focal score and the proportion of TDI responders, defined as patients with a TDI focal score 1 unit at Day 168 Study 1: UMEC/VI 55/22 mcg: 2.3 vs TIO 1 mcg: 2.4; treatment difference.1 (95% CI.7,.5; p=.72) Study 2: UMEC/VI 55/22 mcg: 2.3 vs TIO 1 mcg: 2.1; treatment difference.2 (95% CI.5,.9; p=.55) No significant differences in TDI score or odds of being a TDI responder on Day 168 between UMEC/VI 55/22 mcg and TIO 1 mcg -reported outcomes SOBDA diary score and the proportion of SOBDA responders, defined as a decrease of.1 units from baseline Study 1: UMEC/VI 55/22 mcg:.18 vs TIO 1 mcg:.18 Study 2: UMEC/VI 55/22 mcg:.29 vs TIO 1 mcg:.21 SGRQ score and the proportion of SGRQ responders, defined as a decrease from baseline in SGRQ total score of 4 units Study 1: UMEC/VI 55/22 mcg: 6.87 vs TIO 1 mcg: 7.62 Study 2: UMEC/VI 55/22 mcg: 9.95 vs TIO 1 mcg: 9.78 No significant differences between treatments with respect to change from baseline in SGRQ Device preference (as measured by the COPD device preference questionnaire) ELLIPTA preferred to HandiHaler across the treatment groups More information about patient factors associated with Anoro Ellipta is provided in the section 19

20 Safety Study 1 UMEC/VI 55/22 mcg (n=212) UMEC/VI 113/22 mcg (n=214) VI 22 mcg (n=29) TIO 1 mcg (n=28) On-treatment AEs, n (%) 18 (51) 94 (44) 99 (47) 82 (39) Most common AE type, n (%) Nasopharyngitis Headache URTI Back pain 21 (1) 2 (9) 8 (4) 1 (5) 14 (7) 14 (7) 7 (3) 7 (3) 17 (8) 21 (1) 5 (2) 3 (1) 16 (8) 9 (4) 8 (4) 4 (2) Treatment-related AEs, n (%) 11 (5) 9 (4) 12 (6) 7 (3) AEs leading to discontinuation or study withdrawal, n (%) 1 (5) 15 (7) 1 (5) 9 (4) On-treatment SAEs, n (%) 7 (3) 5 (2) 15 (7) 13 (6) Fatal AEs, n (%) Study 2 UMEC/VI 55/22 mcg (n=217) UMEC/VI 113/22 mcg (n=215) UMEC 113 mcg (n=222) TIO 1 mcg (n=215) On-treatment AEs, n (%) 127 (59) 133 (62) 131 (59) 126 (59) Most common AE type, n (%) Nasopharyngitis Headache URTI Back pain 14 (6) 21 (1) 6 (3) 8 (4) 16 (7) 2 (9) 1 (5) 6 (3) 6 (3) 25 (11) 17 (8) 1 (5) 17 (8) 15 (7) 14 (7) 11 (5) Treatment-related AEs, n (%) 16 (7) 17 (8) 28 (13) 16 (7) AEs leading to discontinuation or study withdrawal, n (%) 2 (9) 15 (7) 17 (8) 11 (5) On-treatment SAEs, n (%) 22 (1) 15 (7) 15 (7) 9 (4) Fatal AEs, n (%) 2 (<1) about the safety of Anoro Ellipta is provided in the Safety summary * VI 22 mcg, UMEC 113 mcg and UMEC/VI 113/22 mcg are not licensed in the UK and therefore the results have not been included in the efficacy section but have been included in the safety section; ** Anoro Ellipta is indicated for the maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD); Includes on-treatment and post-treatment events AE = adverse event; COPD = chronic obstructive pulmonary disease; ECG = electrocardiogram; FEV 1 = forced expiratory volume in 1 second; FVC = forced vital capacity; MRC = medial research council; OD = once daily; OR = odds ratio; RTI = respiratory tract infection; SAE = serious adverse event; SD = standard deviation; SGRQ = St George s Respiratory Questionnaire; SOBDA = shortness of breath with daily activities; TDI = transition dyspnoea index; TIO = tiotropium; UMEC = umeclidinium; URTI = upper respiratory tract infection; VI = vilanterol; wm = weighted mean Details of the blinding process for all tiotropium comparator studies discussed in this Evidence Summary can be found on page 474 in Decramer M et al. Lancet Respir Med. 214 Jun; 2: Doi: 1.116/S (14)

21 Kalberg et al., 216 (UMEC/VI vs TIO + IND) For more detailed information about this study, please see the Anoro Evidence Dossier, or click here to download the publication via PubMed online. This link will take you to a non-gsk website. GSK does not recommend, endorse or accept liability for sites controlled by third-parties. Citation Study objective population Design Treatments Baseline characteristics Primary endpoint results Secondary and other efficacy endpoint results Kalberg et al., Dual bronchodilator therapy with umeclidinium/vilanterol versus tiotropium HandiHaler plus indacaterol in chronic obstructive pulmonary disease: a randomized controlled trial. Drugs in R&D 216; 16: ,2 To compare the efficacy and safety of UMEC/VI 55/22 mcg OD compared with TIO 1 mcg OD + indacaterol (IND) 15 mcg OD in patients with moderate to very severe COPD Inclusion criteria: 4 years with a history of COPD Current or former cigarette smoker with 1 pack-years Pre- and post-bronchodilator FEV1/FVC ratios <.7 mmrc dyspnoea score 2 Corrected QT interval <45 (or <48 for patients with bundle branch block) A 12-week, multicentre, randomised, blinded, triple-dummy, parallel-group, lung function non-inferiority study 5 7-day run-in period; 85-day treatment period UMEC/VI 55/22 mcg OD Ellipta + placebo OD HandiHaler + placebo OD Breezhaler TIO 1 mcg OD HandiHaler + IND 15 mcg OD Breezhaler + placebo OD Ellipta ITT population UMEC/VI 55/22 mcg (n=482) TIO 1 mcg + IND 15 mcg (n=479) Age (years), mean ± SD 64 ± ± 8.4 Female sex, n (%) 127 (26) 138 (29) Current smoker, n (%) 198 (41) 218 (46) Smoking pack-years, a mean ± SD 43.2 ± ± 23.1 Post-salbutamol FEV1 b (L), mean ± SD ± ±.48 Post-salbutamol FEV1/FVC, b mean ± SD 45.7 ± ± 11.1 LS mean change from baseline in trough FEV1 on Day 85 (PP population) UMEC/VI 55/22 mcg vs TIO 1 mcg + IND 15 mcg: 1 ml; 95% CI 29, 3; p=.964; non-inferiority margin of 5 ml met wmfev1 6 hours post-dose on Days 1 and 84 (ITT population) Day 1: UMEC/VI 55/22 mcg vs TIO 1 mcg + IND 15 mcg: 1 ml; 95% CI: 2, 18, p=.98 Day 84: UMEC/VI 55/22 mcg vs TIO 1 mcg + IND 15 mcg: 23 ml; 95% CI 54, 8, p=.145 Trough FEV1 on Days 28 and 56 (ITT population) Day 28: UMEC/VI 55/22 mcg vs TIO 1 mcg + IND 15 mcg: 4 ml; p=.774 Day 56: UMEC/VI 55/22 mcg vs TIO 1 mcg + IND 15 mcg: 11 ml; p=

22 Serial FEV1 at Days 1 and 84 Day 1: UMEC/VI 55/22 mcg vs TIO 1 mcg + IND 15 mcg: 7 ml; 95% CI 23, 31; p=.5 Day 84: UMEC/VI 55/22 mcg vs TIO 1 mcg + IND 15 mcg: 3 ml; 95% CI 17, 4; p=.784 -reported outcomes Serial and trough FVC Day 2: UMEC/VI 55/22 mcg vs TIO 1 mcg + IND 15 mcg: 16 ml; 95% CI 25, 57; p=.437; p=.437 Day 85: UMEC/VI 55/22 mcg vs TIO 1 mcg + IND 15 mcg: 2 ml; 95% CI 29, 68; p=.433 Similar improvements in TDI and SGRQ scores in UMEC/VI 55/22 mcg and TIO 1 mcg + IND 15 mcg treatment groups, respectively, at Day 84 TDI focal scores that exceeded the MCID of 1 unit: 2.32 vs 2.62 Similar improvements in SGRQ score: 4.93 and 5.1 TDI responders: o Day 28 (OR 1.1; 95% CI.77, 1.33; p=.927) o Day 56 (OR.95; 95% CI.73, 1.25; p=.72) o Day 84 (OR.88; 95% CI.67, 1.16; p=.364) SGRQ responders o Day 28 (OR 1.19; 95% CI.92, 1.55; p=.19) o Day 56 (OR 1.4; 95% CI.8, 1.35; p=.764) o Day 84 (OR 1.5; 95% CI.81, 1.37; p=.69) LS mean change from baseline in rescue medication use over Days 1 84 Overall difference between treatment groups (.1 puffs/day) (95% CI.1,.3) Median percentage of rescue-free days No differences between treatment groups (. puffs/day) (95% CI, 2.6; p=.265) preference for inhaler device and ease of use Overall 65% of users across both treatment groups reported a preference for the Ellipta inhaler vs Breezhaler or Handihaler, stating the reason as ease of use More information about patient factors associated with Anoro Ellipta is provided in the section Safety UMEC/VI 55/22 mcg (n=482) TIO 1 mcg + IND 15 mcg (n=479) On-treatment AE, n (%) 22 (42) 186 (39) Drug-related AE, n (%) 3 (6) 37 (8) AEs leading to discontinuation, n (%) 12 (2) 8 (2) AEs reported in 3% of patients, n (%) Nasopharyngitis Headache Cough 36 (7) 32 (7) 16 (3) 28 (6) 27 (6) 17 (4) On-treatment nonfatal SAE, n (%) 17 (4) 15 (3) On-treatment fatal SAE, n (%) 4 (<1) s experiencing COPD exacerbation, n (%) 48 (1) 49 (1) 22

23 AEs of special interest, n (%) Cardiovascular effects Cardiac arrhythmias Cardiac failure Ischaemic heart disease CNS haemorrhages and cerebrovascular conditions Pneumonia LRTI excluding pneumonia 11 (2) 7 (1) 4 (<1) 2 (<1) 4 (<1) 7 (1) about the safety of Anoro Ellipta is provided in the Safety summary 9 (2) 3 (<1) 3 (<1) 4 (<1) a Smoking pack-years = (number of cigarettes smoked per day/2) x number of years of smoking; b n = 479 in UMEC/VI 55/22 mcg OD, n = 477 in TIO 1 mcg OD + IND 15 mcg OD 2 (<1) 9 (2) AE = adverse event; CI = confidence interval; CNS = central nervous system; COPD = chronic obstructive pulmonary disease; FEV 1 = forced expiratory volume in 1 second; FVC = forced vital capacity; IND = indacaterol; ITT = intent-to-treat; LRTI = lower respiratory tract infection; LS = least squares; MCID = minimal clinically important difference; mmrc = modified medial research council; OD = once daily; PP = per-protocol; SD = standard deviation; SGRQ = St George s Respiratory Questionnaire; TIO = tiotropium; TDI = Transition Dyspnoea Index; UMEC/VI = umeclidinium/vilanterol Details of the blinding process for all tiotropium comparator studies discussed in this Evidence Summary can be found on page 474 in Decramer M et al. Lancet Respir Med. 214 Jun; 2: Doi: 1.116/S (14)

24 Donohue et al., 213 (UMEC/VI PLACEBO-CONTROLLED vs MONOTHERAPIES) For more detailed information about this study, please see the Anoro Evidence Dossier, or click here to download the publication via PubMed online. This link will take you to a non-gsk website. GSK does not recommend, endorse or accept liability for sites controlled by third-parties. Citation Study objective population Design Treatments Baseline characteristics Primary endpoint results Secondary and other efficacy endpoint results Donohue et al., Efficacy and safety of once daily umeclidinium/vilanterol 62.5/25 mcg in COPD. Resp Med. 213;17: To examine the efficacy and safety of UMEC/VI 55/22 mcg OD compared with UMEC 55 mcg OD, VI* 22 mcg OD and placebo in patients with COPD * VI 22 mcg is not licensed in the UK and therefore the results have not been included in the efficacy section but have been included in the safety section Inclusion criteria: 4 years with clinical history of COPD Smoking history 1 pack-years Post-salbutamol FEV1/FVC ratio <.7 Post-salbutamol FEV1 7% MRC dyspnoea score 2 Phase III, randomised, multicentre, double-blind, placebo-controlled parallel-group 24- week study 7 14-day run-in period; 24-week treatment period: Placebo UMEC 55 mcg OD VI 22 mcg* OD UMEC/VI 55/22 mcg OD Placebo (n=28) UMEC 55 mcg (n=418) UMEC/VI 55/22 mcg (n=413) Mean age, years ± SD 62.2 ± ± ± 8.7 Female sex, n (%) 85 (3) 12 (29) 18 (26) Smoking pack-year history, years ± SD 47.2 ± ± ± 25.8 Post-salbutamol % predicted FEV1, mean ± SD 46.7 ± ± ± 13.2 Post-salbutamol FEV1/FVC, mean ± SD 47.1 ± ± ± 11.4 LS mean difference in trough FEV1 at Day 169 UMEC 55 mcg vs placebo: 115mL; p<.1 UMEC/VI 55/22 mcg vs placebo: 167 ml; p<.1 UMEC/VI 55/22 mcg vs UMEC 55 mcg: 52 ml; p=.4 wmfev1 over 6h post-dose at Day 168 UMEC 55 mcg vs placebo: 15mL; p<.1 UMEC/VI 55/22 mcg vs placebo: 242 ml; p<.1 UMEC/VI 55/22 mcg vs UMEC 55 mcg: 92 ml; p<.1 Serial FEV1 assessments at Day 168 (24 hour population) Improvements with UMEC/VI 55/22 mcg compared with UMEC 55 mcg, and placebo for the majority of timepoints Median time to onset during 6h post-dose at Day 1 UMEC 55 mcg: 56 minutes UMEC/VI 55/22 mcg: 27 minutes 24

25 Odds of achieving an increase in FEV1 of 12% and.2 L above baseline at any time during 6h post-dose at Day 1 UMEC 55 mcg vs placebo: OR 5.9; 95% CI 4., 8.6; p.1 UMEC/VI 55/22 mcg vs placebo: OR 9.; 95% CI 6.1, 13.2; p.1 UMEC/VI 55/22 mcg vs UMEC 55 mcg: OR 1.5; 95% CI 1.2, 2.; p.5 Odds of achieving an increase of.1 L above baseline in trough FEV1 at Day 169 UMEC 55 mcg vs placebo: OR 3.2; 95% CI 2.2, 4.5; p.1 UMEC/VI 55/22 mcg vs placebo: OR 4.1; 95% CI 2.9, 5.9; p.1 UMEC/VI 55/22 mcg vs UMEC 55 mcg: OR 1.3; 95% CI 1., 1.7 Peak FEV1 increases from baseline (LS mean) at Day 168 UMEC 55 mcg vs placebo: 13 ml; p<.1 UMEC/VI 55/22 mcg vs placebo: 224 ml; p<.1 Trough FVC increases from baseline (LS mean) at Day 169 UMEC 55 mcg vs placebo: 175 ml; p=.2 UMEC/VI 55/22 mcg vs placebo: 248 ml; p.2 UMEC/VI 55/22 mcg vs UMEC 55 mcg: 74 ml; p=.12 Proportion of responders according to TDI score at Day 168 Placebo: 41% UMEC 55 mcg: 53%; OR vs placebo = 1.6 (1.2, 2.3); p.1 UMEC/VI 55/22 mcg: 58%; OR vs placebo = 2. (1.5, 2.8); p.1 Time to first COPD exacerbation** UMEC 55 mcg vs placebo: HR.6 (.4, 1.); p=.35 UMEC/VI 55/22 mcg vs placebo: HR.5 (.3,.8); p=4 LS mean change in SGRQ total score at Day 168 UMEC 55 mcg vs placebo: 4.69; p<.1 UMEC/VI 55/22 mcg vs placebo: 5.51; p<.1 UMEC/VI 55/22 mcg vs UMEC 55 mcg:.82; p=.441 Rescue salbutamol use UMEC 55 mcg vs placebo:.3 puffs/day UMEC/VI 55/22 mcg vs placebo:.8 puffs/day; p.1 UMEC/VI 55/22 mcg vs UMEC 55 mcg OD:.6 puffs/day, p<.5 -reported outcomes Difference in LS mean TDI focal scores at Day 168 UMEC 55 mcg vs placebo: 1.; p.1 UMEC/VI 55/22 mcg vs placebo: 1.2; p.1 UMEC/VI 55/22 mcg vs UMEC 55 mcg:.3 Difference in LS mean SOBDA focal scores at Week 24 UMEC 55 mcg vs placebo:.1; p=.43 UMEC/VI 55/22 mcg vs placebo:.17; p<.1 UMEC/VI 55/22 mcg vs UMEC 55 mcg:.8; p=.68 More information about patient factors associated with Anoro Ellipta is provided in the section 25

26 Safety Placebo (n=28) UMEC 55 mcg (n=418) VI 22 mcg (n=421) UMEC/VI 55/22 mcg (n=413) On-treatment AE, n (%) 13 (46) 216 (52) 24 (48) 212 (51) AEs leading to permanent discontinuation of study drug or withdrawal from study, n (%) 9 (3) 34 (8) 24 (6) 23 (6) On-treatment SAE, n (%) 9 (3) 27 (6) 24 (6) 21 (5) Fatal SAE, n (%) 3 (<1) 3 (<1) 3 (<1) Most common AE type, n (%) Headache Nasopharyngitis AEs of special interest, n (%) Cardiovascular Acquired long QT Cardiac arrhythmias Cardiac failure Cardiac ischaemia Hypertension Sudden death Stroke Effects on glucose Effects on potassium Tremor Urinary retention Ocular effects Gallbladder disorders Pneumonia Intestinal obstruction Anticholinergic syndrome 26 (9) 16 (6) 26 (9) 12 (4) 5 (2) 3 (1) 6 (2) 2 (<1) 2 (<1) 2 (<1) 8 (3) 32 (8) 29 (7) 41 (1) 2 (5) 7 (2) 7 (2) 12 (3) 7 (2) 3 (<1) 3 (<1) 3 (<1) 6 (1) 18 (4) 25 (6) 26 (6) 31 (7) 18 (4) 3 (<1) 3 (<1) 7 (2) 2 (<1) 7 (2) 2 (<1) 2 (<1) 4 (<1) 14 (3) about the safety of Anoro Ellipta is provided in the Safety summary 35 (8) 39 (9) 33 (8) 18 (2) 3 (<1) 7 (2) 15 (4) 6 (1) 4 (<1) 8 (2) 1 (2) * VI 22 mcg is not licensed in the UK and therefore the results have not been included in the efficacy section but have been included in the safety section ** Anoro Ellipta is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD); Includes both on-treatment and post-treatment AEs AE = adverse event; COPD = chronic obstructive pulmonary disease; FEV 1 = forced expiratory volume in 1 second; FVC = forced vital capacity; HR = hazard ratio; LS = least squares; MRC = medial research council; OD = once daily; OR = odds ratio; SGRQ = St George s Respiratory Questionnaire; SAE = serious adverse events; SOBDA = Shortness Of Breath With Daily Activity; TDI = transitional dyspnoea index; UMEC = umeclidinium; VI = vilanterol; wm = weighted mean 26

27 Safety summary Please consult the full Summary of Product Characteristics (SPC) for Anoro Ellipta before prescribing. 4 The safety profile of Anoro is based on safety experience with UMEC/VI and the individual components from the clinical development program comprising of 6,855 patients with COPD and from spontaneous reporting. The clinical development programme included 2,354 patients who received UMEC/VI OD in the Phase III clinical studies of 24 weeks or more, of whom 1,296 patients received the recommended dose of 55/22 mcg in 24-week studies; 832 patients received a higher dose of 113/22 mcg in 24-week studies and 226 patients received 113/22 mcg in a 12-month study. 4 The frequencies assigned to the adverse reactions identified in Table 1 include crude incidence rates observed in the integration of five 24-week studies and in the 12-month safety study. Table 1: Summary of adverse reaction with UMEC/VI 55/22 mcg 4 System organ class Adverse reactions Frequency Infections and infestations Immune system disorders Nervous system disorders Eye disorders Cardiac disorders Respiratory, thoracic and mediastinal disorders Gastrointestinal disorders Skin and subcutaneous tissue disorders Renal and urinary disorders Urinary tract infection Sinusitis Nasopharyngitis Pharyngitis Upper respiratory tract infection Hypersensitivity reactions including: Rash Anaphylaxis, angioedema and urticaria Headache Tremor Dysgeusia Vision blurred Glaucoma Intraocular pressure increased Atrial fibrillation Supraventricular tachycardia Rhythm idioventricular Tachycardia Supraventricular extrasystoles Palpitations Cough Oropharyngeal pain Dysphonia Paradoxical bronchospasm Constipation Dry mouth Rash Urinary retention Dysuria Bladder outlet obstruction Common Common Common Common Common Uncommon Rare Common Uncommon Uncommon Rare Rare Rare Uncommon Uncommon Uncommon Uncommon Uncommon Uncommon Common Common Uncommon Rare Common Common Uncommon The frequency of adverse reactions is defined using the following convention: very common ( 1/1); common ( 1/1 to <1/1); uncommon ( 1/1, to <1/1); rare ( 1/1, to <1/1,); very rare (<1/1,) and not known (cannot be estimated from available data) Rare Rare Rare 27

28 Donohue et al., 214 (UMEC SAFETY PROFILE) For more detailed information about this study, please see the Incruse Evidence Dossier, or click here to download the publication via PubMed online. This link will take you to a non-gsk website. GSK does not recommend, endorse or accept liability for sites controlled by third-parties. This safety study was done with unlicensed doses but has been included in the Evidence Summary for safety transparency purposes. Citation Study objective population Design Treatments Baseline characteristics Donohue et al., Safety and tolerability of once-daily umeclidinium/vilanterol 125/25 mcg* and umeclidinium 125 mcg* in patients with chronic obstructive pulmonary disease: results from a 52-week, randomised, double-blind, placebo-controlled study. Respir Res. 214; 15: ,23 To assess the safety and tolerability of UMEC 113 mcg* OD and UMEC/VI 113/22 mcg* OD over 52 weeks compared with placebo in patients with COPD * UMEC 113 mcg and UMEC/VI 113/22 mcg are not licensed in the UK therefore the results have not been included in the efficacy section but have been included in the safety section Inclusion criteria: Current or former smoker with a smoking history of 1 pack-years 4 years of age history of COPD Post-salbutamol FEV1/FVC ratio <.7 Post-salbutamol FEV1 35% and 8% of predicted values Phase III, randomised, multicentre, double-blind, placebo-controlled, parallel-group, 52- week study 7 1-day run-in period; 52-week treatment period: UMEC 113 mcg* OD UMEC/VI 113/22 mcg* OD UMEC 113 mg (n=227) UMEC/VI 113/22 mg (n=226) Placebo (n=19) Mean age, years ± SD 61.7 ± ± ± 8.3 Female sex, n (%) 82 (36) 7 (31) 36 (33) Smoking pack-years, mean ± SD 39.2 ± ± ± 24.7 Current medical condition, n (%) 196 (86) 19 (84) 88 (81) Pre-bronchodilator FEV1 (ml), mean ± SD 1,432 ±.51 n=225 1,498 ±.53 n=225 1,579 ±.57 n=18 Post-salbutamol % predicted FEV1 (ml), mean ± SD 54.2 ± 11.8 n= ± 12.1 n= ± 11.7 n=19 28

29 Safety UMEC 113 mg (n=227) UMEC/VI 113/22 mg (n=226) Placebo (n=19) On-treatment AE, n (%) 132 (58) 12 (53) 57 (52) On-treatment SAE, n (%) 17 (7) 14 (6) 7 (6) Most common AEs reported by 4% patients, n (%) Headache 25 (11) 2 (9) 9 (8) Nasopharyngitis 2 (9) 11 (5) 5 (5) Ventricular extrasystoles 12 (5) 11 (5) 5 (5) Extrasystoles 1 (4) 1 (4) 4 (4) Back pain 9 (4) 1 (4) 3 (3) Hypertension 4 (2) 8 (4) 5 (5) Sinusitis 6 (3) 8 (4) 3 (3) Influenza 5 (2) 6 (3) 5 (5) Upper respiratory tract infection 8 (4) 2 (<1) 3 (3) Ventricular tachycardia 3 (1) 4 (2) 4 (4) Most common SAEs reported by 1% patients, n (%) COPD 4 (2) 2 (<1) 3 (3) Pneumonia 3 (1) AE of special interest reported by 2% patients, n (%) Cardiovascular 49 (22) 34 (15) 25 (23) Pneumonia 11 (5) 5 (2) 2 (2) Anticholinergic syndrome 5 (2) 5 (2) 2 (2) Effects on glucose 8 (4) Proportion of patients with one or more abnormal, clinically significant ECG interpretation At any time post baseline 26% 24% 23% Proportion of patients with one or more abnormal, clinically significant 24-hour Holter ECG interpretation At any time post baseline 55% 55% 52% COPD exacerbations Proportion of patients reporting 15% 13% 24% Proportion resulting in hospitalisation HR vs placebo (time to first exacerbation) 7% 6% 12%.4; 95% CI:.3,.8; RR = 6%.6; 95% CI:.3, 1.; RR = 4% * UMEC 113 mcg and UMEC/VI 113/22 mcg are not licensed in the UK therefore the results have not been included in the efficacy section but have been included in the safety section; Anoro Ellipta is indicated for the maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). 24 AE = adverse event; COPD = chronic obstructive pulmonary disease; ECG = electrocardiogram; FEV 1 = forced expiratory volume in 1 second; FVC = forced vital capacity; HR = hazard ratio; OD = once daily; SAE = serious adverse event; SD = standard deviation; UMEC = umeclidinium; UMEC/VI = umeclidinium/vilanterol - 29

30 Feldman et al., 212 For more detailed information about this study, please see the Anoro Evidence Dossier. You can also request further information by contacting This safety study was done with unlicensed doses but has been included in the Evidence Summary for safety transparency purposes. Citation Study objective population Design Treatments Baseline characteristics Primary endpoint results Safety Feldman et al., 28-Day safety and tolerability of umeclidinium in combination with vilanterol in COPD: A randomized placebo-controlled trial. Pulmonary Pharmacology & Therapeutics 212; 25: To assess the 28-day safety, tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of repeat inhaled doses of UMEC/VI 5/25 mcg* in patients with COPD * UMEC/VI 5/25 mcg is not licensed in the UK therefore the results have not been included in the efficacy section but have been included in the safety section Inclusion criteria: 4 years of age history of COPD Smoking history of 1 pack-years Post-salbutamol FEV1/FVC ratio <.7 Post-salbutamol FEV1 8% of predicted values A multicentre, double-blind, placebo-controlled, parallel group study 5 8-day run-in period; 52-week treatment period: UMEC/VI 5/25 mcg* Placebo UMEC/VI 5/25 mcg (n=42) Placebo (n=9) Age (years), mean ± SD 59.2 ± ± 9.8 Female sex, n (%) 18 (43) 2 (22) Smoking pack-years, mean ± SD 58.4 ± ± 44.7 Pre-bronchodilator FEV1, mean ± SD ± ±.46 Post-bronchodilator % predicted FEV1, mean ± SD 48.4 ± ± 15.6 Change from baseline in wm pulse rate during 6h post-dose on Day 28 UMEC/VI 5/25 mcg vs placebo: difference.5 bpm, 95% CI 5.5, 4.5 wm pulse rate during 6h post-dose on Days 1 and 14 Day 1: UMEC/VI 5/25 mcg.6 bpm, placebo 1.2 bpm; difference:.6 bpm, 95% CI 3.9, 5.2 Day 14: UMEC/VI 5/25 mcg 3.1 bpm, placebo 1.7 bpm; difference: 4.8 bpm, 95% CI 1.2, 1.9 Maximum pulse rate during 6h post-dose on Days 1, 14 and 28 Day 1: UMEC/VI 5/25 mcg vs placebo, difference 2. bpm, 95% CI 3.7, 7.6 Day 14: UMEC/VI 5/25 mcg vs placebo, difference 4.8 bpm, 95% CI 1.8, 11.3 Day 28: UMEC/VI 5/25 mcg vs placebo, difference 1.3 bpm, 95% CI 6.9, 4.3 Minimum pulse rate during 6h post-dose on Days 1, 14 and 28 Day 1: UMEC/VI 5/25 mcg vs placebo, difference.3 bpm, 95% CI 4.3, 5. Day 14: UMEC/VI 5/25 mcg vs placebo, difference 4. bpm, 95% CI 2.3, 1.2 Day 28: UMEC/VI 5/25 mcg vs placebo, difference 1.7 bpm, 95% CI 3.6, 7.1 3

31 wm systolic/diastolic blood pressure 6h post-dose on Days 1, 14 and 28 Placebo: 13.8/79.2, 131./79.3 and 134.6/81.3 mmhg UMEC/VI 5/25 mcg: 134./8.1, 131.1/78.7 and 13.9/77.8 mmhg The adjusted mean changes in maximum systolic blood pressure from baseline on Days 1, 14 and 28 Placebo: 138.1, and mmhg UMEC/VI 5/25 mcg: 143.9, and 14.6 mmhg The adjusted mean changes in minimum diastolic blood pressure from baseline on Days 1, 14 and 28 Placebo: 73.7, 73.2 and 75.7 mmhg UMEC/VI 5/25 mcg: 73.7, 71.4 and 7.6 mmhg 24-h Holter ECG parameters at screening and Day 28 11% of patients in each group had clinically significant unfavourable changes The proportion of patients who had a clinically significant unfavourable change from baseline in the 12-lead ECG at any time post-baseline was similar between UMEC/VI 5/25 mcg (29%) and placebo (22%) Maximum QTc with interval corrected by Fridericia s method (QTcF) (during 6h postdose) on Days 1, 14 and 28 (measured using 12-lead ECG) UMEC/VI 5/25 mcg vs placebo: o Day 1, 3. ms, 95% CI 5.2, 11.2 o Day 14, 1.4 ms, 95% CI 9.9, 12.8 o Day 28, 2.6 ms, 95% CI 8.9, 14 Changes in haematological and clinical chemistry parameters from baseline on Days 14 and 29 No clinically relevant changes Incidence of AEs and SAEs throughout the 28-day treatment period and follow-up On-treatment AEs: UMEC/VI 5/25 mcg 26% vs placebo 11% No single AE was reported by any more than one patient No deaths or SAEs were reported Incidence of COPD exacerbations Three patients (UMEC/VI 5/25 mcg) had a COPD exacerbation 31

32 Plasma concentrations and derived PK (maximum plasma concentration [Cmax], time to maximum plasma concentration [tmax], area under the curve [AUC] for UMEC and VI parameters) UMEC and VI were rapidly absorbed (median tmax ~6 min) with a higher Cmax on Day 14 vs Day 1 The observed mean accumulation of Cmax for Day 14 vs Day 1 was 38% (9% CI 6%, 8%) for UMEC and 31% (9% CI 5%, 63%) for VI. No further accumulation was seen on Day 28 No differences in AUC for either drug on Day 1, 14 and 28, ratios range.8.9 for both comparisons (Day 14/Day 1 and Day 28/Day 1). PK data on both days showed high variability with a large percent coefficient of variance No obvious trends for either UMEC or VI in individual steady-state Cmax and change from baseline in pulse rate on Day 28; changes from baseline were similar to that observed with placebo * UMEC/VI 5/25 mcg is not licensed in the UK therefore the results have not been included in the efficacy section but have been included in the safety section Anoro Ellipta is indicated for the maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). 24 AE = adverse event; AUC = area under the curve; CI = confidence interval; COPD = chronic obstructive pulmonary disease; ECG = electrocardiogram; FEV 1 = forced expiratory volume in 1 second; FVC = forced vital capacity; OD = once daily; PD = pharmacodynamics; PK = pharmacokinetics; SAE = serious adverse event; SD = standard deviation; UMEC = umeclidinium; VI = vilanterol; wm = weighted mean 32

33 However efficacious an inhaled medication is, if it is not delivered optimally it will not work as effectively. 26 Incorrect inhaler use is associated with increased risk of hospitalisation and emergency room visits, and inhaler handling errors impact the effectiveness of clinical control. 27 When patients are prescribed an inhaler, the choice should in part be based on how easy an inhaler is to use, and training to minimise errors in the use of the device is essential to achieve the desired drug effect. 28 The GOLD Strategy indicates that when a treatment is given via an inhaled device, the importance of education and training in inhaler device technique cannot be overemphasized. 11 How to use Anoro Ellipta 95% of patients with COPD used Ellipta correctly first time after initial demonstration. 29 With just three steps, patients simply: Open, inhale, close. 3 The Ellipta portfolio for COPD Ellipta is the only inhaler that enables device continuity for patients with COPD requiring a maintenance therapy. 3 With Ellipta, significantly fewer patients with COPD made critical errors compared to other commonly used inhalers after reading the patient information leaflet. 31* * Critical error defined as an error that is most likely to result in no, minimal or significantly reduced medication being delivered to the lungs

34 Van der Palen et al., 216 (CRITICAL ERRORS) Device study summaries For more detailed information about this study, please see the Anoro Evidence Dossier, or click here to download the publication via PubMed online. This link will take you to a non-gsk website. GSK does not recommend, endorse or accept liability for sites controlled by third-parties. Citation Study objective population Design Treatments Baseline characteristics Primary endpoints/results Secondary endpoints/results Van der Palen et al., A randomised open-label cross-over study of inhaler errors, preference and time to achieve correct inhaler use in patients with COPD or asthma: comparison of Ellipta with other inhaler devices. NPJ Prim Care Respir Med. 216;26: ,32 To compare the Ellipta inhaler with other devices The information below focuses only on COPD studies; asthma results are not presented Inclusion criteria: 18 years with a physician diagnosis of COPD and currently receiving treatment for COPD Naïve to Ellipta and other inhaler Multicentre, single-visit, randomised, open-label, cross-over study s with COPD were assigned to one of five groups: Ellipta vs Accuhaler Ellipta vs MDI Ellipta vs Turbohaler Ellipta vs HandiHaler Ellipta vs Breezhaler Mean age, years Female sex, n (%) COPD history, n (%) 6 m 1 y 1 25 y 25 y Total (N=567) Ellipta vs Accuhaler (n=171) Ellipta vs MDI (n=8) Ellipta vs Turbohaler (n=1) Ellipta vs HandiHaler (n=118) Ellipta vs Breezhaler (n=98) (4) 68 (4) 27 (34) 33 (33) 46 (39) 51 (52) 422 (74) 123 (22) 22 (4) 135 (79) 29 (17) 7 (4) 59 (74) 18 (22) 3 (4) 62 (62) 32 (32) 6 (6) 92 (78) 23 (19) 3 (3) 74 (76) 21 (21) 3 (3) Number of patients with at least one critical error* after reading the patient information leaflet (PIL), n (%): Ellipta vs Accuhaler: 9 (5) vs 75 (44); p<.1 Ellipta vs MDI: 1 (13) vs 48 (6); p<.1 Ellipta vs Turbohaler: 8 (8) vs 44 (44); p<.1 Ellipta vs HandiHaler: 17 (14) vs 57 (48); p<.1 Ellipta vs Breezhaler: 13 (13) vs 45 (46); p<.1 Number of patients with at least one overall error after reading the PIL, n (%): Ellipta vs Accuhaler: 52 (3) vs 112 (65); p<.1 Ellipta vs MDI: 25 (31) vs 68 (85); p<.1 Ellipta vs Turbohaler: 31 (31) vs 71 (71); p<.1 Ellipta vs HandiHaler: 51 (43) vs 73 (62); p<.1 34

35 Ellipta vs Breezhaler: 3 (31) vs 55 (56); p<.1 Percentage of patients making no errors after reading the PIL and thus not requiring instruction from trained respiratory nurse: Ellipta vs Accuhaler: 7% (n=119) vs 35% (n=59) Ellipta vs MDI: 69% (n=55) vs 15% (n=12) Ellipta vs Turbohaler: 69% (n=69) vs 29% (n=29) Ellipta vs HandiHaler: 57% (n=67) vs 38% (n=45) Ellipta vs Breezhaler: 69% (n=68) vs 44% (n=43) Percentage of patients requiring instruction from trained respiratory nurse after reading PIL: Ellipta vs Accuhaler: 3% (n=52) vs 65% (n=68) Ellipta vs MDI: 31% (n=25) vs 85% (n=68) Ellipta vs Turbohaler: 31% (n=31) vs 71% (n=8) Ellipta vs HandiHaler: 43% (n=51) vs 62% (n=73) Ellipta vs Breezhaler: 31% (n=3) vs 56% (n=56) Percentage of patients who rated the ease of use of the device as very easy or easy: Ellipta vs Accuhaler: 97% (n=165) vs 6% (n=14) Ellipta vs MDI: 92% (n=73) vs 44% (n=35) Ellipta vs Turbohaler: 96% (n=96) vs 55% (n=55) Ellipta vs HandiHaler: 98% (n=115) vs 38% (n=38) Ellipta vs Breezhaler: 94% (n=92) vs 55% (n=54) preference - the majority of patients preferred Ellipta overall compared with: Ellipta vs Accuhaler: 74% (n=126) vs 11% (n=19); p<.1 Ellipta vs MDI: 75% (n=6) vs 19% (n=15); p<.1 Ellipta vs Turbohaler: 86% (n=86) vs 6% (n=6); p<.1 Ellipta vs HandiHaler: 87% (n=13) vs 11% (n=13); p<.1 Ellipta vs Breezhaler: 72% (n=71) vs 19% (n=19); p<.1 s preferred the Ellipta inhaler for most individual criteria: Number of steps for correct use, time taken to use, size of device, dose counter, comfort of mouthpiece and ease of opening (p<.1) with some exceptions where there was no difference (listed below) Criteria for which there was no difference in patient preference between devices: Size of the inhaler, % patients preferring: o Ellipta: 39% or MDI: 33% o Ellipta: 44% or Turbohaler: 38% o Ellipta: 41% or Breezhaler: 44% Comfort of mouthpiece, % patients preferring: o Ellipta: 33% or HandiHaler: 31% o Ellipta: 4% or Breezhaler: 37% Safety No adverse events were reported throughout the study * Critical error was defined as an error that is most likely to results in no, minimal or significantly reduced medication being delivered to the lungs 29 COPD = chronic obstructive pulmonary disease; m = months; MDI = metered-dose inhaler; PIL = patient information leaflet; SD = standard deviation; y = years 35

36 Financial Impact The 3-day cost for Anoro Ellipta is Anoro Ellipta is cost neutral within the LAMA/LABA class. However, Anoro Ellipta has demonstrated significantly superior bronchodilation compared to both tiotropium HandiHaler (LAMA) and Spiolto Respimat within LAMA/LABA class. 11,14 Anoro Ellipta is also part of the Ellipta range of medicines which are competitively priced and can enable maintenance therapy device continuity for patients with COPD. To access the most current cost comparison chart of maintenance therapies for the treatment of COPD follow the link to the GSK healthcare professional website (GSKpro.com) Demonstrate affordability and potential cost-savings A GSK Health Outcomes Consultant can demonstrate potential cost savings that Anoro Ellipta and the wider Ellipta range of medicines can offer your local health economy or health care system. To arrange an appointment with a Health Outcomes Consultant to discuss, please either: uk.hoc-on-demand@gsk.com Live Chat: GSKpro.co.uk An appointment may be arranged to suit your preference - either in person, telephone or video call. NHS list price 36

37 Impact When considering respiratory medicine optimisation, in addition to the clinical, patient and financial impact, it is also important to consider the environmental sustainability of inhalers. GSK and the NHS are bound by the targets set out in the Climate Change Act (28). A key milestone within the 28 act is for companies bound by this act, such as GSK and the NHS, to achieve a 25% reduction in their entire CO2 footprint by Healthcare procurement, which accounts for 61% of the NHS total carbon footprint, offers several significant opportunities for carbon footprint reduction. 34 Within healthcare procurement, 35% of emissions are attributed to pharmaceuticals, from which carbon footprint is calculated from aspects such as manufacturing, distribution and use phase. 34 Each year around 73 million inhalers are prescribed for asthma and COPD in the UK. 35 Approximately 7% of these inhalers are pmdis (pressurised Metered Dose Inhalers) containing greenhouse gases, such as HFA (hydrofluoroalkane) propellants, that are either discharged into the local environment during use by patients or put into household waste. 36 UK emissions of HFAs from inhalers are equivalent to 8% of the NHS entire carbon footprint. 36 Dry Powder Inhalers (DPIs) that do not contain greenhouse gases are available as an alternative to pmdis. Devices used for the delivery of bronchodilators and steroids can be equally efficacious and may be equally appropriate For example, the Ellipta inhaler (DPI), has a carbon footprint 24 times smaller than Evohaler (Figure 3; NB. Evohaler is not licensed in COPD). 39 The British Thoracic Society (BTS) are now advocating change: 4 Complete elimination of pmdis may not be possible due to patient preference and the need to generate sufficient inspiratory flow to activate the DPIs. However, BTS encourages all prescribers and patients to consider switching pmdis to DPIs whenever they are likely to be equally effective. Figure 3: Carbon footprint associated with Evohaler MDI and Ellipta DPI Figure for illustrative purposes only; Evohaler MDI is not indicated for the treatment of COPD. KgCO2e values include all emissions for the full life cycle of each product (from raw material production to consumer use and disposal) and are reflective of values for maintenance inhalers only. GSK have an inhaler recycling and recovery scheme for all respiratory inhalers. By working together with patients, pharmacies and healthcare professionals, we aim to reduce waste and greenhouse gas emissions, moving towards a more environmentally sustainable treatment of respiratory disease. To find out more information about how decreasing your reliance on MDIs may help your local health economy to meet their carbon emission reduction target by 22, contact uk.hoc-on-demand@gsk.com. 37