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New Drugs and Novel Devices A Breath of Fresh Air? Karen Dahri, PharmD September/2015 Disclosures I have no conflicts of interest to declare. Learning ObjecKves By the end of the presentaKon the learner should be able to: 1. Describe the treatment algorithm recommended for the management of COPD. 2. IdenKfy the new pharmacotherapy opKons for COPD and describe their place in therapy. 3. Demonstrate the proper inhaler techniques for the new devices available. 4. Make evidenced based recommendaKons for specific paKents to improve their pharmacotherapeuKc management of their COPD. Outline • Drug Development • New InhalaKon Devices • Guideline RecommendaKons • New Pharmacological Agents • Controversies with New Therapies Drug Development 1956 • Metered Dose Inhalers 1967 • First dry powder inhaler 1974 • CFCs depleKng the ozone 1987 • Montreal Protocol 1995 • HFA AAPS PharmSciTech 2015; 16(3): 479-‐490. Inhaler Device Scramble Basic Principles of InhalaKon Therapy EMJ Respir 2013; 1: 64-‐71. Dry Powder Inhalers • Single-‐Unit Dose Devices – Drug supplied individually • MulK-‐dose Devices – Reservoir • Bulk supply of drug – MulK-‐unit • Individually prepared and sealed doses of drug EMJ Respir 2013; 1: 64-‐71.; Int J Clin Pract 2007; 61(6): 1022-‐1036. Dry Powder Inhalers Medical Devices: Evidence and Research 2015; 8: 131-‐139. Genuair Tudorza Genuair Product Monograph Breezhaler AAPS PharmSciTech 2015; 16(3): 479-‐490. Ellipta Breo Ellipta GSK Drug InformaKon MulK-‐dose Liquid Inhaler • Combo of advantages of pMDIs and nebulizers • Slowly aerosolizes propellant free-‐drug soluKons as a sof mist • Decreases chance for oropharyngeal deposiKon Medical Devices: Evidence and Research 2015; 8: 131-‐139. Respimat Spiriva Respimat Product Monograph COPD Step-‐Wise Approach LAMA + LABA LAMA or LABA SABA + SAMA SABA prn or SAMA prn • Salbutamol/ Ipratropium Respimat • LABA • Indacaterol • LAMA • Aclidinium • Glycopyrronium • Tiotropium Respimat • Umeclidinium • Aclidinium/ formoterol • Glycopyrronium/ Indacaterol • Tiotropium/ olodaterol • Umeclidinium/ Vilanterol ICS/LABA + LAMA • ICS/LABA • FluKcasone/ Vilanterol Global Strategy for Diagnosis, Management and Prevention of COPD Manage Stable COPD: Goals of Therapy • Relieve symptoms • Improve exercise tolerance • Improve health status • Prevent disease progression • Prevent and treat exacerbaKons • Reduce mortality © 2015 Global IniKaKve for Chronic ObstrucKve Lung Disease Reduce symptoms Reduce risk Summary of Efficacy SABA Symptoms Spirometry/lung funcKon ✔ SAAC LABA LAMA ICS ✔ ✔ ✔ ✔ ✔ ✔ ✔ ✔ ✔ ✔ ✔ ✔ Exercise tolerance ICS/LABA ICS/LABA/LAMA Theophylline Roflumilast ✔ ✔ Quality of life ✔ ✔ ✔ ✔ ExacerbaKons ✔ ✔ ✔ ✔ HospitalizaKons ✔ ✔ ✔ ✔ Disease progression Mortality 18 Study Features Korn S Respiratory Medicine 2011 Indacaterol Comparator Outcome Results MC, RCT, DB, 12 Indacaterol 150 wks μg/d 1123 pts 62.8yrs, 70% M Salmeterol 50 μg BID Spirometry Indacaterol > salmeterol Kornmann O Eur Respir J 2011 MC, RCT, DB, 6 mos 1002 pts Indacaterol 150 μg/d Salmeterol 50 μg BID + Placebo Spirometry @ 12 wks Comparisons vs placebo Dahl R Thorax 2010 MC, RCT, DB, 1 year; 1732 pts 68-‐77% completed study Indacaterol 300 μg/d OR 600 μg/d Formoterol 12 μg Spirometry vs BID placebo @ 12 OR wks Placebo Comparisons vs placebo Buhl Eur Respir J 2011 MC, RCT, DB 797 pts; 12 wks Indacaterol 150 μg/d Tiotropium 18 μg/d (HandiHaler) Non-‐inferiority on trough FEV1 @ 12 wks Indacaterol = Kotropium for spirometry Donohue Am J Respir Crit Care Med 2010 26 wks; 1683 Indacaterol 150 pts randomized, μg/d 77% completed OR Indacaterol 300 μg/d Tiotropium 18 μg/d (HandiHaler) Trough FEV1 @ 12 wks Indacaterol > Kotropium Tiotropium 18 μg/d (HandiHaler) Trough FEV1 @ 12 wks Indacaterol non-‐ inferior to Kotropium Decramer Lancet 52 weeks, RCT, Respir Med 2013 DB, DD, MC; 3444 pts Interven>on Indacaterol 150 μg/d Indacaterol NEJM 2011; 365(24): 2247-‐49. New LAMAs • Aclidinium • Glycopyrronium • Tiotropium Respimat • Umeclidinium LAMAs Bioavailability Half-‐life Elimina>on Time to Peak Aclidinium ~6% 5-‐8 hrs 10 mins Glycopyrronium ~40% 13-‐22 hrs 5 mins Tiotropium 2-‐3% 34 hrs 5-‐7 mins 11 hrs 5-‐15 mins Umeclidinium Lexi Drugs; Spiriva Respimat Monograph Am J Health-‐Syst Pharm 2014; 71: 386-‐93. Aclidinium bromide for stable chronic obstruc>ve pulmonary disease The Cochrane Library, Copyright 2015, The Cochrane CollaboraKon. 2 Aclidinium bromide for stable chronic obstruc>ve pulmonary disease The Cochrane Library, Copyright 2015, The Cochrane CollaboraKon. 3 Glycopyrronium Seminars in Respiratory and CriKcal Care Medicine 2015; 36(4): 523-‐42. BMJ 2011; 342: d3215 doi: 10.1136/bmj.d3215 Tiotropium Respimat NEJM 2013; 369: 1491-‐501. Umeclidinium • Improvement in FEV1 • vs placebo – Dyspnea – SGRQ – Time to first exacerbaKon Seminars in Respiratory and CriKcal Care Medicine 2015; 36(4): 523-‐42.; Incruse Ellipta Monograph Combo LAMA + LABA • Aclidinium/formoterol • Glycopyrronium/Indacaterol • Tiotropium/olodaterol • Umeclidinium/Vilanterol OpKmal Pharmacotherapy – Canadian Guidelines 34 Tiotropium + LABA • Comparison of a Combination of Tiotropium + Formoterol to Salmeterol + Fluticasone in Moderate COPD Chest 2008; 134: 255-262. – Tiotropium/Formoterol > Salmeterol/Fluticasone • Effects of Tiotropium With and Without Formoterol on Airflow Obstruction & Resting Hyperinflation in Pts w/ COPD Chest 2006; 129: 509-517. – Combo > effect in spirometry outcomes Long-‐acKng beta2-‐agonist in addiKon to Kotropium versus either Kotropium or long-‐acKng beta2-‐agonist alone for chronic obstrucKve pulmonary disease. Cochrane Databse Syst Rev.; 4: CD008989.doi: 10.1002/14651858.CD008989.pub2 36 Global Strategy for Diagnosis, Management and Prevention of COPD GOLD 4 D ICS + LABA or LAMA GOLD 3 ICS + LABA and/or LAMA A GOLD 2 GOLD 1 B SAMA prn or SABA prn LABA or LAMA CAT < 10 CAT > 10 mMRC 0-‐1 mMRC > 2 IniKaKve for Chronic ObstrucKve Lung Disease © 2015 Global 2 or more or > 1 leading to hospital admission 1 (not leading to hospital admission) 0 C ExacerbaKons per year Manage Stable COPD: Pharmacologic Therapy RECOMMENDED FIRST CHOICE Global Strategy for Diagnosis, Management and Prevention of COPD Manage Stable COPD: Pharmacologic Therapy ALTERNATIVE CHOICE D GOLD 4 GOLD 3 ICS + LABA and LAMA or ICS + LABA and PDE4-‐inh or LAMA and LABA or LAMA and PDE4-‐inh. A GOLD 2 GOLD 1 LAMA or LABA or SABA and SAMA B LAMA and LABA CAT < 10 CAT > 10 mMRC 0-‐1 mMRC > 2 IniKaKve for Chronic ObstrucKve Lung Disease © 2014 Global 2 or more or > 1 leading to hospital admission 1 (not leading to hospital admission) 0 LAMA and LABA or LAMA and PDE4-‐inh or LABA and PDE4-‐inh ExacerbaKons per year C Aclidinium bromide and formoterol fumarate as a fixed-‐dose combinaKon in COPD: pooled analysis of symptoms and exacerbaKons from two six-‐month, mulKcentre, randomised studies (ACLIFORM & AUGMENT) • +ve effect on lung funcKon as measured by spirometry • TDI Score clinically significant difference vs placebo • Prolonged Kme to first exacerbaKon in comparison vs placebo Respiratory Research 2015; 16(92): DOI 10.1186/s1293-‐015-‐0250-‐2. Effiacy and Safety of a Fixed-‐Dose CombinaKon of Indacaterol and Glycopyrronium for the Treatment of COPD Chest 2014; 146(2): 309-‐317. Effiacy and Safety of a Fixed-‐Dose CombinaKon of Indacaterol and Glycopyrronium for the Treatment of COPD • vs Tiotropium – FEV1, TDI (%), SGRQ (%), exacerbaKon • vs Glycopyrronium – FEV1, SGRQ (%), exacerbaKons • Vs Indacaterol (1 trial) – FEV1 Chest 2014; 146(2): 309-‐317. Tiotropium and olodaterol fixed-‐dose combinaKon versus mono-‐components in COPD (GOLD 2-‐4) Eur Respir J 2015; 45: 869-‐871 A SystemaKc Review of the Efficacy and Safety of a Fixed-‐Dose CombinaKon of Umeclidinium and Vilanterol for the Treatment of COPD Chest 2015; 148(2): 397-‐407 A SystemaKc Review of the Efficacy and Safety of a Fixed-‐Dose CombinaKon of Umeclidinium and Vilanterol for the Treatment of COPD • vs Umeclidinium – FEV1, TDI (%), SGRQ (%), ExacerbaKons • vs Vilanterol – FEV1, TDI (%), ExacerbaKons • vs Tiotropium – FEV1 Chest 2015; 148(2): 397-‐407 Seminars in Respiratory and CriKcal Care Medicine 2015; 36(4): 523-‐42. COPD Step-‐Wise Approach LAMA + LABA LAMA or LABA SABA + SAMA SABA prn or SAMA prn • Salbutamol/ Ipratropium Respimat • LABA • Indacaterol • LAMA • Aclidinium • Glycopyrronium • Tiotropium Respimat • Umeclidinium • Aclidinium/ formoterol • Glycopyrronium/ Indacaterol • Tiotropium/ olodaterol • Umeclidinium/ Vilanterol ICS/LABA + LAMA • ICS/LABA • FluKcasone/ Vilanterol Assessment of SymptomaKc Response • Have you noKced a difference since starKng this treatment? • If you are bexer: – Are you less breathless? – Can you do more? – Can you sleep bexer? – Describe what difference it has made to you. • Is that change worthwhile to you? Gold 2015 Guidelines References AgusK A, de Teresa L, De Backer W et al. A comparison of the efficacy and safety of once-‐daily fluKcasone furoate/vilanterol with twice-‐daily fluKcasone propionate/salmeterol in moderate to very severe COPD. Eur Respir J 2014; 43: 763-‐772. DOI: 10.1183/09031936.00054213 Anoro Ellipta Drug Monograph Bateman ED, Chapman KR, Singh D et al. Aclidinium bromide and formoterol fumarate as a fixed-‐dose combinaKon in COPD: pooled analysis of symptoms and exacerbaKons from two six-‐month mulKcenter, randomized studies (ACLIFORM and AUGMENT). Respiratory Research 2015; 16(92): DOI 10.1186/s12931-‐015-‐0250-‐2 Berkenfeld K, Lamprecht A, McConville JT. Devices for Dry Powder Drug Delivery to the Lung. AAPS PharmSciTech 2015; 16(3): 479 – 490. Breo Ellipta Drug Monograph Buhl R, Dunn LJ, Disdier C et al. Blinded 12-‐week comparison of once-‐daily indacaterol and Kotropium in COPD. Eur Respir J 2011; 38: 797-‐803. Buhl R, Maltais F, Abrahams R et al. Tiotropium and olodaterol fixed-‐dose combinaKon versus mono-‐components in COPD (GOLD 2-‐4). Eur Respir J 2015; 45: 969-‐979. Calverley P, Vlies B. New PharmacotherapeuKc Approaches for Chronic ObstrucKve Pulmonary Disease. Semin Respir Crit Care Med 2015; 36: 523-‐542. Chowdhury BA, Seymour SM, Michele TM et al. The Risks and Benefits of Indacaterol – The FDA’s Review. N Engl J Med 2011; 365(24): 2247-‐49. Chapman KR, Beeh KM, Beier J et al. A blinded evaluaKon of the efficacy and safety of glycopyrronium, a once-‐daily long-‐acKng muscarinic antagonist, versus Kotropium, in paKents with COPD: the GLOW5 study. BMC Pulmonary Medicine 2014; 14:4 Dahl R, Chung KF, Buhl R et al. Efficacy of a new once-‐daily long-‐acKng inhaled β2-‐agonist indacaterol versus twice-‐daily formoterol in COPD. Thorax 2010; 65: 473-‐479. doi: 10.1136/thx. 2009.125435. Decramer ML, Chapman KR, Dahl R et al. Once-‐daily indacaterol versus Kotropium for paKents with severe chronic obstrucKve pulmonary disease (INVIGORATE): a randomized, blinded, parallel-‐ group study. Lancet Respir Med 2013; 1(7): 524-‐33. Donohue JF, Fogart C, Lovtall J et al. Once-‐daily Bronchodilators for Chronic ObstrucKve Pulmonary Disease. Indacaterol versus Tiotropium. Am J Respir Crit Care Med 2010; 182: 155-‐162. D’Urzo A, Kerwin E, Overend T et al. Once daily glycopyrronium for the treatment of COPD: pooled analysis of the GLOW1 and GLOW2 studies. Current Medical Research and Opinion, 30:3, 493-‐508, DOI: 10.1185/03007995.2013.858618. Global IniKaKve for Chronic ObstrucKve Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevenKon of COPD, 2015. hxp://www.goldcopd.org/guidelines-‐global-‐strategy-‐for -‐diagnosis-‐management.html. References Ibrahim M, Verma R, Garcia-‐Contreras L. InhalaKon drug delivery devices: technology update. Medical Devices: Evidence and Research 2015; 8: 131-‐139. Incruse Ellipta Monograph Inspiolto Respimat Monograph Karner C, Cates CJ. Long-‐acKng beta2-‐agonist in addiKon to Kotropium versus either Kotropium or long-‐acKng beta2-‐agonist alone for chronic obstrucKve pulmonary disease. Cochrane Database Syst Rev; 4: CD008989.doi: 10.1002/14651858.CD008989.pub2 Kim JS, Park J, Lim SY Comparison of Clinical Efficacy and Safety between Indacaterol and Tiotropium in COPD: Meta-‐analysis of Randomized Controlled Trials. PLOS ONE. DOI: 10.1371/ journal.pone.0119948. Korn S, Kerwin E, AKs S et al. Indacaterol once-‐daily provides superior efficacy to salmeterol twice-‐daily in COPD: A 12-‐week study. Respiratory Medicine 2011; 105: 719-‐726. Kornmann O, Dahl R, Centanni S et al. Once-‐daily indacaterol versus twice-‐daily salmeterol for COPD: a placebo-‐controlled comparison. Eur Respir J 2011; 37: 273-‐279. Ni H, et al. Aclidinium bromide for stable chronic obstrucKve pulmonary disease. Cochrane Database Syst Rev 2014; (9): CD010509. Roche N, Chrystyn H, Lavorini F et al. EffecKveness of Inhaler Devices in Adult Asthma and COPD. EMJ Respir 2013; 1: 64-‐71. Rodrigo GJ, Plaza V. Effiacy and Safety of a Fixed-‐Dose CombinaKon of Indacaterol and Glycopyrronium for the Treatment of COPD. Chest 2014; 146(2): 309-‐317. Rodrigo GJ, Neffen H. A SystemaKc Review of the Efficacy and Safety of a Fixed-‐Dose CombinaKon of Umeclidinium and Vilanterol for the Treatment of COPD. Chest 2015; 148(2): 397-‐407. Singh S, Loke YK, Enright PL et al. Mortality associated with Kotropium mist inhaler in paKents with chronic obstrucKve pulmonary disease: systemaKc review and meta-‐analysis of randomized controlled trials. BMJ 2011; 342: d3215 doi: 10.1136/bmj.d3215. Spiriva Drug Monograph Stone LE, Skelley JW, Kyle JA et al. Aclidinium bromide for the treatment of chronic obstrucKve pulmonary disease. American J of Health-‐System Pharmacy 2014; 71(5): 386-‐393. Tudorza Drug Monograph UlKbro Breezhaler Drug Monograph Wise RA, Anzueto A, Coxon D et al. Tiotropium Respimat Inhaler and the Risk of Death in COPD. N Engl J Med 2013; 369: 1491-‐501.
