NEWER BRONCHODILATORS

Dr R Lakshmi Narasimhan SR Pulmonary Medicine Topics to be covered

• Ultra LABA (+/-ICS) • Newer LAMA • LAMA + LABA • Novel Bronchodilators Why the need for newer BD?

• OD dosing convenient and hence improves compliance and adherence

• BDs that provide rapid relief provide patients with reassurance after first dose and thus also improve compliance

• BDs with rapid onset of action also suitable for asthma

• Once-daily agents may also affect stability of airway tone, with reduced fluctuations in airway patency leading to increased morning FEV1

Murphy et al. Turning a Molecule into a Medicine: the Development of Indacaterol as a Novel Once-Daily Bronchodilator Treatment for Patients with COPD. Drugs (2014) 74:1635–1657 Ultra long acting Beta 2 Agonists

• Indacaterol • Vilanterol • Olodaterol • Carmoterol • Milveterol • Abediterol • GSK-642444 • PF-610355 Indacaterol

• QAB-149 • First once daily ultra-LABA to be developed • Approved for COPD in Europe in 2009, US and Japan in 2011, and China in 2012 Pharmacology

• Fast onset of action* • Sustained bronchodilation (~24 hrs)** – Lipophilic – remains membrane bound – High intrinsic affinity to Beta2 receptors • Delivered via Breezhaler® single dose DPI device • 150, 300 mcg capsules *Balint B et al. INSURE Trial. Int J Chron Obstruct Pulmon Dis. 2010;5:311–8. **Laforce C et al. INTEGRAL study. Pulm Pharmacol Ther. 011;24(1):162–8.

Other potential mechanisms

• Anti-inflammatory effect • Anti-tumour effect • May inhibit NF-kB activity and MMP-9 pathway preventing lung damag • Improves airway responsiveness to SABAs The INERGIZE programme

• INERGIZE = INdacaterol: Empowerment, bReathlessness relief and lunG function optimIZed for patiEnts with COPD • 4 ‘pivotal’ phase III double-blind RCTs – INVOLVE – INHANCE (stage 1 and 2) – INLIGHT 1 – INLIGHT 2 • 9 other RCTs also done • INHANCE stage 1 dose finding study for other trials – 150, 300 mcg selected Inclusion criteria

• Age > 40 yrs • Post BDR FEV1/FVC < 0.7 • > 10 pack-years h/o smoking • Moderate-Severe COPD (GOLD) • 80% > FEV1 > 30% predicted • Concomitant ICS use allowed wherever indicated • Asthma/other lung diseases excluded Study N Comparator Dose Duration 1o and 2o Endpoints Result INHANCE 1683 Placebo, 150, 26 wks 24 hr post dose Both doses better than Stage2 Tiotropium 300 trough FEV1 at 12 placebo & superior to Donohue et al. 18 mcg dpi wks, TDI score, tiotropium at 12 wks 2010 od SGRQ score FEV1 and SABA use Double blind, (p<0.01), 300 mcg dose double dummy better TDI score than tio, parallel grp RCT SGRQ same as Tio INLIGHT-1 416 Placebo 150 12 wks 24 hr post dose Safety and efficacy Feldman et al. trough FEV1 after 1st confirmed when 2010 dose, and after 12 compared to placebo Double blind, wks, days of poor parallel grp RCT COPD control INLIGHT-2 1002 Placebo, 150 26 wks 24 hr post dose Superior to Salmeterol Kornmann Salmeterol trough FEV1, days of w.r.t FEV1 at all times, et al. 2011 50 mcg dpi poor COPD control, days free from SABA use Double blind, bd SGRQ, TDI and TDI, SGRQ at wk 12 parallel grp RCT INVOLVE 1732 Placebo, 300, 52 wks 24 hr post dose Superior to Formoterol in Dahl et al. 2010 Formoterol 600 trough FEV1, mMRC, FEV1 at all times, SABA Double blind, 12 mcg dpi BODE, SGRQ, use, TDI at wk 12. Double dummy bd 6MWT, Form and Ind (600 mcg) RCT exacerbations had lesser exacerbation rates than placebo but no diff b/w them Study N Comparator Dose Duration 1o and 2o Endpoints Result INDORSE 415 Placebo 150, 26 wks 24 hr post dose Safety confirmed, Chapman 300 (Total 52 trough FEV1 at 26 Significant improvement et al. 2011 wks) wks, TDI score, in FEV1, SGRQ. Trend (contd from SGRQ score, toward lesser INHANCE) exacerbations exacerbations in both doses but not sig. INPUT 96 Placebo, 300 3 x 14 d 24 hr post dose No difference in morning Magnussen Salmeterol mcg trough FEV1 on day vs evening dosing (8-11 et al. 2010 50 mcg dpi AM 14 am/pm) (Crossover) bd vs PM INSIST Korn 1123 Salmeterol 150 12 wks 24 hr post dose Superior across all et al. 2011 50 mcg dpi trough FEV1, SABA subgroups, no diff in ADR bd use, TDI INSURE 89 Salbutamol 150, Single 5 min post dose Onset of action as rapid Balint et al. 200 mcg, 300 doses FEV1 as salbutamol and faster 2010 salmeterol/ than salmeterol fluticasone (Crossover) 50/500 mcg, Placebo INTEGRAL 68 Placebo, 300 3 x 14 d 24-h post-dose Superiority vs placebo LaForce Salmeterol trough FEV1 on Day for FEV1 at each et al. 2011 50 mcg dpi 14 scheduled time-point (Crossover, bd post-dose, and vs Salm in open label) 24 hr trough FEV1 Study N Compara Dose Duration 1o and 2o Endpoints Result tor INTENSITY 1593 Tiotropiu 150 12 wks 24 hr post dose Non-inferior to Buhl et al. m 18 mcg trough FEV1 at 12 tiotropium in FEV1, 2011 dpi od wks, TDI score, better than tio in SGRQ, SGRQ score TDI, SABA use INTIME 169 Placebo, 150, 14 d 24 hr post dose Both doses Non-inferior Vogelmeier Tiotropiu 300 trough FEV1 at day to tiotropium, 150 mcg et al. 2010 m 18 mcg 14 dose better than (crossover) dpi od tiotropium INTRUST- 1134 Placebo + Ind 150 12 wks 24 hr post dose Combination superior to 1/2 Mahler 1142 Tio 18 mcg + trough FEV1, SABA Tio alone in FEV1(60-90 et al. 2012 mcg dpi Tio 18 use, SGRQ, TDI ml) and symptom scores, od mcg od SABA use

INVIGORATE 3444 Tiotropiu 150 52 wks 24 hr post dose Non-inferior to Decramer m 18 mcg trough FEV1, TDI, tiotropium in FEV1, et al. 2013 dpi od SGRQ, SGRQ but Significantly exacerbations more exacerbations with Indacaterol Summary

• Indacaterol is an effective ultra long acting BD • Rapid onset and sustained bronchodilation • Benefits shown in Symptom scores, Quality of Life*, lung function* and exercise tolerance** • But not effective as LAMA in preventing exacerbations *Efficacy of indacaterol on quality of life and pulmonary function in patients with COPD and inhaler device preferences. International Journal of COPD 2014:9 107–114 ** Indacaterol improves daily physical activity in patients with chronic obstructive pulmonary disease. International Journal of COPD 2013:8 1–5 Olodaterol

• BI 1744 CL • Rapid onset of action • Long duration of action ~ 24 hrs • Dose 5-10 mcg via Respimat® breath actuated inhaler • May also have anti-inflammatory and anti- fibrotic effects Study N Compar Dose Duration 1o and 2o Endpoints Result ator Ferguson 1266 (2 Placebo 5, 10 48 wks 24 hr post dose Both doses equally et al. studies trough FEV1 at superior to placebo 2014 combined) 12/24/48 wks, PGR, SABA use Feldman 199 (2 Placebo, 5, 10 6 wks 24 hr post dose Both doses Non-inferior et al. 2014 studies Formote trough FEV1 at 6 to formoterol combined) rol 12 wks mcg bd

Koch 906 Placebo, 5, 10 48 wks FEV10-3 AUC, 24 hr Both doses Non-inferior et al. 2014 937 Formote post dose trough to formoterol, rol 12 FEV1, SABA use, Better than formoterol in mcg bd SGRQ, TDI, SGRQ, TDI no diff in exacerbations exacerbations Lange 230 Placebo, 150 6 wks 24 hr post dose Non-inferior to et al. 2014 Tiotropi trough FEV1 tiotropium in FEV1 um 18 mcg

• GOLD 2-4 included in studies Summary

• Olodaterol non-inferior to formoterol in long term • But more long term data in comparison with Tiotropium required Vilanterol

• Approved in combination with Fluticasone furoate • Dose = 100 mcg Fluticasone + 25 mcg Vilanterol • ELLIPTA® DPI device • Rapid onset, ultra long acting • May be used both in Asthma or COPD as once daily medication Study N Dose Comparator Duratio 1o and 2o Endpoints Result (COPD) n Dransfiel 1622 FF+Vil Vilanterol 52 wks Rate of exacerbations All combination arms d et al. 50/25, 25 mcg better than Vil arm, 2013 100/25, but most benefit in 200/25 100/25, 200/25 arms Martinez 1224 FF+Vil Vil 25mcg, 24 wks Trough FEV1 at 24 Both doses of FF+Vil et al. 200/25, FF 50, FF wks, SABA use, SGRQ, and Vil alone superior 2013 100/25 100, TDI to placebo but only Placebo higher dose combn superior to FF 100 Kerwin 1030 FF+Vil Vil 25mcg, 24 wks Trough FEV1 at 24 FF+Vil (100/25) et al. 50/25, FF 100mcg, wks, SABA use, SGRQ, superior to individual 2013 100/25 Placebo TDI components, Both doses of combn and Vil alone superior to placebo Agusti 528 Salmeterol/ 12 wks 24 hr post dose trough Trend to favour FF/Vil et al. Fluticasone FEV1, Change in FEV1 but not statistically 2014 (50/250) bd from baseline, SGRQ, significant SABA use Dransfiel 1860 Salmeterol/ 12 wks 24 hr post dose trough Significant d et al. Fluticasone FEV1, Change in FEV1 improvement in FEV1, 2014 (50/250) bd from baseline, SABA no difference in use rescuer use FF + Vilanterol in asthma

Study N Dose Comparator Duratio 1o and 2o Endpoints Result n Bateman 2019 FF+Vil FF 100 mcg 24-78 Rate of exacerbations, Combination better et al. 100/25 wks Trough FEV1 than FF alone 2014 (330 events) Woodcock 806 FF+Vil Salmeterol/ 24 wks Trough FEV1 at 24 No difference between et al. 2013 100/25 Fluticasone wks, SABA use, AQLQ, the 2 arms (50/250) bd exacerbations

O’Byrne 586 FF+Vil FF 200mcg 24 wks Trough FEV1 at 24 FF+Vil better than FF et al. 2014 200/25 od, FP wks, SABA use, AQLQ, or FP in FEV1 and 500mcgbd exacerbations rescuer use, no difference in AQLQ Bleecker 609 FF+Vil Placebo, FF 12 wks 24 hr post dose trough Both treatments et al. 2014 100/25 100mcg od FEV1, Change in FEV1 superior to placebo, from baseline, SABA B/w them trend to use favour FF/Vil but not statistically significant Summary

• Flu + Vil comparable in efficacy to Salmeterol + FP in both asthma and COPD • Convenient once daily dosing and rapid onset of action make it an attractive option in both diseases • Studies comparing them with LAMA are required Carmoterol

• CHF-4226, TA-2005 • Rapid onset, ulta-long acting BA • Dose 2 mcg od • Was found to be non=inferior to formoterol in asthma • Further trials withheld by the manufacturer after phase 2 and early phase 3 trials as it was not found to be “competitive” Milveterol

• GSK-159797, TD-3327 • Currently undergoing phase 3 trials in asthma and COPD Newer LAMA

• Aclidinium bromide • Glycopyrronium bromide • Umeclidinium bromide • CHF-5407 • TD-4208 • AZD8683 • V-0162 Aclidinium bromide

• Aclidinium is a quaternary ammonium derivative of a (3R)-quinuclidinol ester  Hence low systemic exposure • Maybe used od or bd • Dose 400 mcg bd approved by FDA • Delivered via Genuair® DPI • Rapid onset of action compared to tiotropium

Glycopyrronium

• NVA 237 • Used 50 mcg od • Delivered via Breezhaler® DPI device • 3 major trials – GLOW 1, 2, 3 Study N Dose Comparator Duratio 1o and 2o Endpoints Result n D’Urzo et 817 Glyco Placebo 26 wks FEV1, VC, TDI, SGRQ Better than placebo al GLOW1. 50 mcg 2011 od Kerwin 792 Glyco Placebo, 52 wks FEV1, VC, TDI, SGRQ Better than tiotropium et al 50 mcg Tiotropium at 26 wks but not at 52 GLOW2. od 18 mcg od wks, No diff in TDI or 2012 SGRQ Beeh 108 Glyco Placebo 26 wks FEV1, VC, TDI, SGRQ Better than placebo et al. 2013 50 mcg od Umeclidinium

• Novel LAMA with strong affinity to M3 receptors • Faster and longer acting compared to Tiotropium • Approved in combination with Vilanterol as DPI (125/25 mcg or 62.5/25 mcg) Study N Dose Comparato Duratio 1o and 2o Endpoints Result r n Donohue et 1532 62.5/25 Umec 62.5 24 wks Trough FEV1, symptom Improvement in FEV1 al. 2013 Vil 25 scores, Rescue SABA when compared with Placebo use monotherapies for both Celli et al. 1493 125/25 Umec 125 24 wks Trough FEV1, symptom doses. 2014 Vil 25 scores, Rescue SABA No difference in Placebo use exacerbation rates or dyspnea scores/SGRQ. Anzueto 843 125/25 Vil 25 mcg, 24 wks Trough FEV1, symptom et al. 2014 62.5/25 Tiotropium scores, Rescue SABA 18 mcg od use

Decramer 1141 125/25 Vil 25 mcg, 24 wks Trough FEV1, symptom et al. 2014 1191 62.5/25 Tiotropium scores, Rescue SABA 18 mcg od, use Umec 125 mcg MABA therapy

• Combination of LABA and LAMA in a single fixed dose system • Synergistic effect as they act via diff pathways QVA 149

• Fixed dose combination of 110 μg indacaterol + 50 μg glycopyrronium • DPI administered od via Breezhaler® • Series of 8 Phase III trials done as part of IGNITE program • Approved in Europe, FDA approval pending Study N Dose Comparator Duratio 1o and 2o Endpoints Result n Dahl et al. 193 110/50 Ind 150 mcg 4 wks Trough FEV1, symptom Non-inferior in all BEACON mcg od + Glyco 50 scores, Rescue SABA aspects 2013 mcg od use Dahl et al. 339 110/50 Placebo 52 wks Safety, Trough FEV1, Better than placebo in ENLIGHTEN mcg od symptom scores, all, safe 2013 Rescue SABA use Mahler 247 110/50 Placebo, 6 wks x BDI/TDI score, FEV1, Better than both et al BLAZE mcg od Tiotropium 3 FVC tiotropium and placebo 2014 18 mcg od (crossover) Beeh et al. 85 110/50 Placebo, 3 wks x Exercise tolerance, Better than placebo in BRIGHT mcg od Tiotropium 3 FEV1, VC, Lung all, Better than tio in 2014 18 mcg od volumes, SABA use FEV1, VC, SABA use (crossover) Asai et al. 160 110/50 Tiotropium 52 wks FEV1, FVC, symptom Better than tiotropium ARISE 2013 mcg od 18 mcg od scores, rescue SABA in all (open label) use Study N Dose Comparator Durati 1o and 2o Endpoints Result on Vogelmeier 259 110/50 Salmeterol/ 26 FEV1, FVC, SGRQ, TDI QVA149 significantly et al. mcg od Fluticasone wks rescue SABA use, better in all except ILLUMINATE 50/500 mcg exacerbations SGRQ, no diff in 2013 bd exacerbations, ADR Bateman et 2144 110/50 Placebo, 26 Safety, Trough FEV1, Better than placebo in al. SHINE mcg od Ind 150 mcg, wks symptom scores, all, safe 2013 Glyco 50mcg, Rescue SABA use Tiotropium 18 mcg od Wedzicha 2224 110/50 Glyco 50mcg 64 Rate of exacerbations, QVA vs Glyco et al SPARK mcg od od, wks FEV1, symptom scores, Mild: 0.85 (p=0.0072) 2013* Tiotropium Rescue SABA use Mod- 18 mcg od severe: 0.88 (p=0.038) All: 0.85 (p=0.0012) SGRQ and FEV1 better QVA vs Tio Mild: 0.84 (p=0.0052) All: 0.86 (p=0.0017) SGRQ and FEV1 better Glyco vs Tio Severe: 1.43 (p=0.025) *Included patients with Severe/V.severe COPD (GOLD 3/4), FEV1 < 50 %, at least 1 exacerbation in past 1 yr Summary of Results

• No significant increase in cardiac AEs • LAMA+LABA produces significantly more bronchodilatation than individual drugs (60-90 ml improvement in FEV1) • Significant improvement in dyspnea also seen • QVA149 better in reducing exacerbations than Glycopyrronium/Tiotropium alone, but similar to LABA+ICS Novel Bronchodilator targets