Literature Model for FEV1 in COPD Trials Separating the Dynamic - PowerPoint PPT Presentation

Literature Model for FEV1 in COPD Trials Separating the Dynamic Components of Placebo Effect, Disease Progression and Interacting Drug Effects Jakob Ribbing, Christine Falcoz, Itzela Correa and Steven W Martin 21 st PAGE meeting, Venice (Italy) 6 th June 2012 Global Pharmacometrics

Acknowledgements • Lutz Harnisch • Margherita Bennetts • Tracy Higgins • Thomas Kerbusch • John C Lukas 2

The FEV1 biomarker in COPD • Chronic obstructive pulmonary disease (COPD) – Third leading cause of death in US and projected to increase world-wide due to projected to increase world wide due to smoking • Forced expiratory volume in one second (FEV1) – Important endpoint for diagnosis and the primary biomarker for dose selection in ph2b – Ph3 need to show reduced exacerbations 3

Example of how literature analysis aids internal development at Pfizer Internal Data Literature Data Model prediction of Model prediction of FEV1 comparison to FEV1-treatment effects FEV1 Drugs X/Y Dose- competitor drugs (MDI) across published Response in FEV1 compounds Model prediction of Model prediction of Exacerbation rate (ER) Drugs X/Y Dose- FEV1-ER relation across Response in ER published compounds Predicted efficacy in ER across published ER comparison to compounds competitor drugs (MDI) 4

Drug Class of interest in COPD • Long-acting bronchodilators (inhaled) – Long-acting β 2 agonists ( LABA ) – Long-acting anticholinergics ( LAAC ) L ti ti h li i ( LAAC ) • Anti-inflammatory therapy – Inhaled corticosteroids ( ICS ) – PDE4-inhibitors ( PDE4i ) 5

Literature FEV1 in COPD Change from baseline trough FEV1 (up to wk 26) by treatment class ICS ICS LABA ICS LABA LAAC LAAC Absolute 0.2 FEV1 is 0.1 analysed, but FB (L) displayed as displayed as 0.0 Trough FEV1 CF change from baseline, due LABA LABA LAAC PBO PDE4i to 0.2 dominating 0.1 variability in baseline! 0.0 0 5 10 15 20 25 0 5 10 15 20 25 6 Time (weeks)

Linear disease progression Disease modifying effects? Pauwels (1999) Tashkin (2008) NCT00144339 Ref=637 Trial ID=43 N=1277 Post-BD Ref=661 Trial ID=75 N=5993 Pre-BD 1 0.0 1 1 1 1 1 1 0.1 1 1 1 1 1 1 1 1 -0.1 1 1 1 1 1 1 0.0 1 1 -0.2 UPLIFT study y -0.1 - CFB in FEV1(L) -0.3 Budesonide 800 UG/DAY 1 Tiotropium 18 UG/DAY 1 PBO PBO -0.2 0 50 100 150 0 50 100 150 200 CFB FEV1 (L) CFB FEV1 (L) CFB FEV1 (L) CFB FEV1 (L) Celli (2008) NCT00268216, SCO30003 UNK (2000) Ref=663 Trial ID=81 N=6112 Post-BD Ref=741 Trial ID=60 N=1116 Pre-BD 1 0.1 0.0 1 1 1 2 1 1 3 2 1 1 3 2 1 3 1 -0.1 0.0 2 1 3 2 1 3 2 3 1 2 3 1 1 -0.2 -0.1 TORCH study 1 Salmeterol 100 UG/DAY 3 -0.3 -0.2 Fluticasone 1000 UG/DAY 2 Fluticasone/Salmeterol 1000/100 UG/DAY 1 Triamcinolone 1200 UG/DAY 1 7 PBO PBO 0 50 100 150 0 50 100 150 200 Week Time (weeks) Time (weeks) Time (weeks) Time (weeks) 48 / LIKE COPD 110621 l / f 1 19 / 04J 2012

Illustration of ISV in placebo effect at typical disease progression FEV1 active = Baseline + Eff placebo + Progression disease Legend 95% Conf. Int. Pre-SABA/SAAC Placebo Short study duration Long study duration Graph illustrates gradual placebo gradual placebo 1.22 1.20 response, but 1.21 mixture component 1.15 allowed immediate FEV1 (L) 1.20 placebo response as well 1.10 1.19 1.05 1.18 0 1 2 3 4 5 6 0 1 2 3 4 8 Week Year

Placebo, Salmeterol (LABA) and Fluticasone (ICS) FEV1 active = Baseline + Eff placebo + Progression disease + Eff drug Legend Pre-SABA/SAAC Placebo Salmeterol 50 mcg BID Fluticasone 250 mcg BID Short study duration Long study duration 1.4 1.40 1.35 1.3 FEV1 (L) 1.30 1.2 1.25 1.1 1.20 0 1 2 3 4 5 6 0 1 2 3 4 9 Week Year

Salmeterol interaction with FEV1 post-SABA/SAAC FEV1 active = Baseline + Eff placebo + Progression disease + Eff drug Legend Post-SABA/SAAC Pre-SABA/SAAC Placebo Salmeterol 50 mcg BID Fluticasone 250 mcg BID Short study duration Long study duration 1.4 1.40 1.35 1.3 FEV1 (L) 1.30 1.2 1.25 1.1 1.20 0 1 2 3 4 5 6 0 1 2 3 4 10 Week Year

Covariates • Pre-specified – baseline parameter, based on inclusion criteria: • Min/max disease severity:mild/moderate/severe/v. severe • Restricted medical history limits more severe patients • min/max #exacerbations in previous year (no, any#, ≥ 1, ≥ 2) – Disease prog. proportional to (ipred) baseline untreated • Selected at p<0.001: – Baseline decline with Age – Baseline < 1.2 L: Linear decline in anti-inflammatory efficacy 11

η -diagnostics: Base model Baseline affects drug response 1.0 1.5 2.0 typical efficacy ETA on AI efficacy ETA on BD efficacy 1.4 1.2 Ratio: ipred efficacy over 1.0 0.8 0.6 0.4 1.0 1.5 2.0 Untreated study baseline (L) 12

η -diagnostics: Base model Baseline affects drug response 1.0 1.5 2.0 typical efficacy ETA on AI efficacy ETA on BD efficacy 1.4 648 fluticasone trials salmeterol trials budesonide trials formoterol trials 261 roflumilast trials tiotropium trials 599 714 165 1.2 308 637 indacaterol trials 577 684 663 668 693 490 668 573 573 353 353 Ratio: ipred efficacy over 653 653 639 494 573 676 714 765 536 807 807 455 648 779684 694 577 509 678 750 488 609 663 668 673 673 668 1.0 536 492 776 328 656 656 609 686 690 690 687 709 778 779 779 288 288 1 667 658767 659 659 798 610261 706 662 605 647 647 493 762 164 661 708 621 621 607 660 660 308 790 251 251 706 695 695 664 664 664 649 666 270 664 683 695 708 679 657 0.8 649 786 785 679 647 0.6 657 0.4 1.0 1.5 2.0 Untreated study baseline (L) 13

ETA diagnostics: Final model 1.0 1.5 2.0 typical efficacy ETA on AI efficacy ETA on BD efficacy 1.15 fluticasone trials 490 693 salmeterol trials budesonide trials formoterol trials 573 1.10 roflumilast trials tiotropium trials 353 639 663 indacaterol trials 649 684 653 653 494 648 536 1 05 1.05 261 261 676 676 765 765 714 714 807 807 807 807 Ratio: ipred efficacy over 694 509 455 684 714 165 666 637 678 573 488 536 492 776 668 599 686 673 673 577 663 668 656 656 668 328 308 577 709 609 1.00 690 690 288 288 687 750 667 779 609 1 779 779 798 695 659 659 778 261 786 647 647 706 605 767 762 662 493 649 661 706 621 621 164 658 610 679 708 695 695 664 0.95 647 648 251 251 790 708 660 660 785 308 607 664 664 664 0.90 270 657 683 679 0.85 657 1.0 1.5 2.0 Untreated study baseline (L) 14

Efficacy in moderate COPD Pre-SABA/SAAC LABA + ICS same 154 ml SXFP 50/250 mcg BID efficacy as the sum SX 50mcg BID and 162 ml Spiriva 18 mcg QD of the two mono indacaterol 149 ml components 75 mcg QD formoterol 86 ml 9 mcg BID salmeterol 92 ml 50 mcg BID Respimat 116 ml 5 mcg QD Spiriva 128 ml 18 mcg QD Fluticasone 61 ml 250 mcg BID budesonide 36 ml 400/320 mcg BID roflumilast 83 ml 500 mcg QD 0.05 0.10 0.15 15 Placebo-corrected FEV1 (L)

Efficacy in moderate COPD Pre-SABA/SAAC LABA+LAAC 154 ml SXFP 50/250 mcg BID interaction estimated SX 50mcg BID and 162 ml Spiriva 18 mcg QD as a relative reduction indacaterol 149 ml in LABA effect 75 mcg QD formoterol 86 ml 9 mcg BID salmeterol 92 ml 50 mcg BID Respimat 116 ml 5 mcg QD Spiriva 128 ml 18 mcg QD Fluticasone 61 ml 250 mcg BID budesonide 36 ml 400/320 mcg BID roflumilast 83 ml 500 mcg QD 0.05 0.10 0.15 16 Placebo-corrected FEV1 (L)

Efficacy in moderate COPD 95% CI excluding treatment heterogeneity Pre-SABA/SAAC 154 ml 95% CI: 136-171 ml SXFP 50/250 mcg BID Indacaterol (QD) has superior SX 50mcg BID and 162 ml 95% CI: 135-195 ml trough efficacy in comparison Spiriva 18 mcg QD to the two BID LABAs. indacaterol 149 ml 95% CI: 131-167 ml 75 mcg QD formoterol 86 ml 95% CI: 68-106 ml 9 mcg BID salmeterol 92 ml 95% CI: 80-106 ml 50 mcg BID Respimat 116 ml 95% CI: 101-131 ml 5 mcg QD Spiriva 128 ml 95% CI: 117-139 ml 18 mcg QD Several large studies indicating Fluticasone 61 ml 95% CI: 48-72 ml 250 mcg BID poor efficacy for budesonide. budesonide 36 ml Due to protocol/study conduct 95% CI: 22-51 ml 400/320 mcg BID or compound? roflumilast 83 ml 95% CI: 71-97 ml 500 mcg QD 0.05 0.10 0.15 17 Placebo-corrected FEV1 (L)

Efficacy in moderate COPD 95% CI including treatment heterogeneity (ISV Emax) Pre-SABA/SAAC 95% CI: 115-187 ml 154 ml SXFP 50/250 mcg BID 95% CI: 112-224 m SX 50mcg BID and 162 ml Spiriva 18 mcg QD 95% CI: 100-196 ml indacaterol 149 ml 75 mcg QD 95% CI: 57-123 ml formoterol 86 ml 9 mcg BID 95% CI: 65-127 ml salmeterol 92 ml 50 mcg BID 95% CI: 78-154 ml Respimat 116 ml 5 mcg QD 95% CI: 87-167 ml Spiriva 128 ml 18 mcg QD 95% CI: 38-77 ml Fluticasone 61 ml 250 mcg BID 95% CI: 20-57 ml budesonide 36 ml 400/320 mcg BID 95% CI: 57-113 ml roflumilast 83 ml 500 mcg QD 0.05 0.10 0.15 0.20 18 Placebo-corrected FEV1 (L)