Ponencia realizada por el Profesor Ronald Dahl.Desarrolo clínico del Indacaterol.
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Ponencia realizada por el Profesor Ronald Dahl.Desarrolo clínico del Indacaterol.

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Ponencia realizada por el Profesor Ronald Dahl sobre el desarrollo clínico del Indacaterol. Ponencia realizada el pasado septiembre en Amsterdam dentro del Symposium "Hacia un tratamiento más ...

Ponencia realizada por el Profesor Ronald Dahl sobre el desarrollo clínico del Indacaterol. Ponencia realizada el pasado septiembre en Amsterdam dentro del Symposium "Hacia un tratamiento más personalizado de la EPOC" Organizado por el Grupo Ferrer.

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  • Speaker notes: PK and PD steady state are reached by Day 15Where available, data are LOCF. Day 1, Day 15 and Week 12 data are from the extended ITT dataset in Study B2335S; Week 26 data are from the B2335S ITT dataset; Week 52 data are from B2335SEExt ITT: Table 3-24_fdaB2335S: PTT 14.2-3.1B2335SE: PTT 14.2-1.1
  • Superiority of indacaterol plus tiotropium versus tiotropium alone was demonstrated for FEV1 AUC5 min–8 h at Week 12 in both studies, with differences of 130 and 120 mL (both p<0.001). Changes from baseline in trough FEV1 at Week 12 (raw means) were 230 mL (22%) and 190 mL (20%) with indacaterol plus tiotropium, and 150 mL (15%) and 110 mL (12%) with tiotropium monotherapy.ReferenceMahler et al. Combining once-daily bronchodilators in COPD: Indacaterol plus tiotropium versus tiotropium alone. Presented at ATS 2011.
  • Significant between-treatment differences in FEV1 (p<0.001) occurred at each time point after dosing at Week 12. ReferenceMahler et al. Combining once-daily bronchodilators in COPD: Indacaterol plus tiotropium versus tiotropium alone. Presented at ATS 2011.

Ponencia realizada por el Profesor Ronald Dahl.Desarrolo clínico del Indacaterol. Presentation Transcript

  • 1. Indacaterol – Desarrollo clínico Prof. Ronald Dahl Aarhus University Hospital Dinamarca
  • 2. Desarrollo tecnológico En biologia:el desarollo es un proceso por el que un organismo evoluciona desde su origen hasta alcanzar la condición de adulto.The development and documentation of the new ultra long acting beta2agonist; Indacaterol (Oslif®) - a summary.
  • 3. Airflow limitation includes irreversible and partially reversible components Irreversible components include1,2 – loss of elastic recoil due to alveolar destruction – destruction of alveolar attachments which support and maintain patency of small airways – small airway fibrosis Partially reversible components include1,2 – accumulation of mucus – smooth muscle hypertrophy and bronchoconstriction2 – inflammatory infiltrate in airway mucosa 1. GOLD 2009; 2. Brusasco Eur Respir Rev 2006
  • 4. Can we improve on current bronchodilator therapy?
  • 5. As new bronchodilators are introduced therehave been more consistent improvements in outcomes for patients with COPD Improvement in outcome Duration of action Lung Exercise Quality (hours)1 function2–8 Breathlessness2–8 endurance*1,2 of life1–14 Exacerbations1–3,5,7–14Albuterol 4–6    NA NAIpratropiumbromide 6–8     Salmeterol ≥12    (‡) Formoterol ≥12     †Tiotropium 24    (‡) (‡)evidence of effectiveness; evidence of effectiveness over SABA or SAMA; evidence of effectiveness over LABA*Outcome demonstrated by all bronchodilators, lack of evidence of significant differences between them†Equivocal evidence depending on formulation;5,10,11 ‡Evidence of numerical improvements over shorter acting comparator4,8NA = evidence not available 1. GOLD 2009; 2. Celli et al. ERJ 2004; 3. Mahler et al. Chest 1999; 4. Rennard et al. AJRCCM 2001 5. Dahl et al. AJRCCM 2001; 6. Wadbo et al. ERJ 2002; 7. Vincken et al. ERJ 2002; 8. Brusasco et al. Thorax 2003 9. Rutten van-Molken et al. Eur J Health Econ 2007; 10. Szafranski et al. ERJ 2003; 11. Calverley et al. ERJ 2003 12. Calverley et al. NEJM 2007; 13. Niewoehner et al. Ann Intern Med 2005; 14. Tashkin et al. NEJM 2008
  • 6. Dose Response: Indacaterol and ComparatorsF12=Formoterol 12 µg BID S50=Salmeterol 50 µg BID T18=Tiotropium 18 µg
  • 7. COPD Pooled Study-level Analysis: Predicted Response at Each Dose LevelTreatment comparisonIndacaterol 600 µg QDIndacaterol 300 µg QDIndacaterol 150 µg QDIndacaterol 75 µg QDTiotropium 18 µg QDSalmeterol 50 µg BIDIndacaterol 37.5 µg QDFormoterol 12 µg BIDIndacaterol 18.75 µg QD 40 60 80 100 120 140 160 180 200 Trough FEV1 – difference from placebo (mL)
  • 8. Lack of Tachyphylaxis over 52 Weeks Study B2335S/SE 75 µg 150 µg 300 µg 250difference from placebo (mL) 200 Trough FEV1 – 150 100 50 0 After 1 day Day 15 Week 12 Week 26 Week 52 All p<0.001 vs placebo Dotted line shows prespecified 120 mL level of clinically important difference Trough FEV1 = mean of measurements at 23 h 10 min and 23 h 45 min post-dose
  • 9. Safety over Dose Range – Mortality Relative risks (to placebo) adjusted for time on treatment COPD safety population ExposureTreatment comparison (total pt-yr)Pooled Indacaterol 2096Indacaterol 600 µg QD 394Indacaterol 300 µg QD 737Indacaterol 150 µg QD 860Indacaterol 75 µg QD No death 105Tiotropium 18 µg QD 356Salmeterol 50 µg BID 275Formoterol 12 µg BID 396 0.0 0.5 1.0 1.5 2.0 2.5 3.0 8.5 Relative risk of death
  • 10. Tiotropium comparator studies: blinding procedures INHANCE1 – open-label tiotropium as comparator INTIME2 – indacaterol and matching placebo were identical – an exact physical match to tiotropium was not available, so full blinding was achieved by third-party blinding procedures – study drug was prepared and provided to the patient each morning, either at home or in the clinic, by persons independent of other clinical trial processes INTENSITY3 – placebo tiotropium manufactured to be matching in size and colour; no manufacturer’s logo – medication dispensed by a third party with no other involvement in study 1. Donohue et al. Am J Respir Crit Care Med 2010; 2. Vogelmeier et al. Respir Res 2010; 3. Buhl et al. ERJ 2011, in press
  • 11. IntensityBlinded 12 week comparison of once dailyindacaterol and tiotropium in COPD
  • 12. Design Randomized, double-dummy, blinded, parallel-group study Indacaterol 150 μg od via SDDPI*+ placebo via HandiHaler® (n=794) Run-in Tiotropium 18 μg od via HandiHaler® + placebo via SDDPI* (n=799) Week 12 2 weeks Baseline Trough FEV1 FEV1 (primary endpoint)*SDDPI = single-dose dry powder inhaler Buhl et al. ERJ 2011. online as doi: 10.1183/09031936.00191810
  • 13. Patient demographics and baseline characteristics Indacaterol TiotropiumCharacteristics n=794 n=799Age (years) 63.6 (8.60) 63.4 (8.29)Sex (%) (Male/Female) 70/30 67/33Duration of COPD (years) 7.0 (6.01) 7.0 (6.32)ICS use (%) 54 56Ex-smoker/smoker (%) 55/45 56/44Smoking history (pack-years) 43.2 (20.87) 41.8 (19.81)FEV1 post-bronchodilator (L) 1.53 (0.459) 1.52 (0.447)FEV1 reversibility (%) 14.1 (12.63) 13.7 (13.44)FEV1 % predicted (post-bronchodilator) 54.6 (12.80) 54.3 (12.81)FEV1/FVC post-bronchodilator 51.0 (9.38) 51.2 (9.42)Use of as-needed salbutamol (puffs/day) 3.8 (3.74) 3.6 (3.51)BDI score 6.8 (2.2) 6.8 (2.23)SGRQ score 42.3 (17.60) 42.7 (18.04)Data are mean (standard deviation) unless otherwise stated.BDI = baseline dyspnoea index; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity;ICS = inhaled corticosteroids; SGRQ = St George’s Respiratory Questionnaire;pack years = total years of smoking multiplied by cigarette packs smoked per day Buhl et al. ERJ 2011. online as doi: 10.1183/09031936.00191810
  • 14. Indacaterol and tiotropium both demonstrated spirometric efficacy, as measured by trough FEV1 at Week 12 Indacaterol Tiotropium 150 μg o.d. 18 μg o.d. Trough FEV1 1.44 L 1.43 L p<0.001 for non-inferiority Trough FEV1 130 mL 120 mL change from baseline Buhl et al. ERJ 2011. online as doi: 10.1183/09031936.00191810
  • 15. Indacaterol provided significant improvements in dyspnea score compared with tiotropium at 12 weeks Patients (%) with clinically important TDI total score change (≥1 point) in TDI total score Tiotropium 18 µg o.d. Indacaterol 150 µg o.d. 2,5 Difference 60 0.58 (p<0.001) 57.9% IMPROVEMENT 2.01 2 55 Odds ratio 1.49 1,5 1.43 (p<0.001) 50.1% 50 1 45 0,5 0 40TDI = Transition Dyspnea Index Buhl et al. ERJ 2011. online as doi: 10.1183/09031936.00191810
  • 16. Indacaterol provided significant improvements in quality of life vs tiotropium at 12 weeks SGRQ total score Patients (%) with clinically important change (≥4 units) in SGRQ score Tiotropium 18 µg o.d. Indacaterol 150 µg o.d. 40 55 39.2 Difference –2.1 (p<0.001) 50.5% 39 Improvement 50 Odds ratio 1.43 38 (p<0.001) 45 37.1 37 42.5% 40 36 35 35 Changes from baseline in SGRQ total score (unadjusted means) were −5.1 (indacaterol) and −3.0 (tiotropium)SGRQ = St George’s Respiratory Questionnaire Buhl et al. ERJ 2011. online as doi: 10.1183/09031936.00191810
  • 17. Intime3rd party blinded
  • 18. INTIME: 14-day, 3rd party blinded, cross-over study Indacaterol Indacaterol Placebo 150 µg o.d. 300 µg o.d. Indacaterol Indacaterol Tiotropium 300 µg o.d. 150 µg o.d. 18 µg o.d. n=169 Tiotropium Indacaterol Placebo 18 µg o.d. 150 µg o.d. Tiotropium Indacaterol Placebo 18 µg o.d. 300 µg o.d. 14 days 14 days 14 days 14 days 14 days 14 days Run-in and Treatment 1 Wash-out and Treatment 2 Wash-out and Treatment 3randomisation cross-over cross-over Vogelmeier et al. Respir Res 2010; 11: 135-142
  • 19. Indacaterol 150 μg and 300 μg provided superior bronchodilation, compared with placebo 250 Trough FEV1 difference versus placebo 200 *** 150 *** (mL) *** MCID 100 50 0 Tiotropium Indacaterol Indacaterol 18 µg o.d. 150 µg o.d. 300 µg o.d.***p<0.001 vs placeboThe dotted line represents the 120 mL minimal clinically important difference (MCID)vs placebo. Data are LSM with 97.5% confidence intervals (CI) (indacaterol vsplacebo) or 95% CI (tiotropium vs placebo) Vogelmeier et al. Respir Res 2010; 11: 135-142
  • 20.  Pooled analysis on various efficacy and safety outcomes in trials with Indacaterol and comparitors
  • 21. Demographic characteristics of patients in the indacaterol pivotal registration studies Placebo Open-label Tiotropium Formoterol Indacaterol 150 µg Indacaterol 300 µg 80 70 60Patients (%) 50 40 30 20 10 0 <65 years Male Mild to ICS user Current moderate smoker COPD Novartis data on file
  • 22. Indacaterol in the presence of concomitant ICS
  • 23. POOLED ANALYSIS Pooled analysis: indacaterol provides clinically significant bronchodilation on Day 1 compared with placebo regardless of ICS use Placebo Open-label Tiotropium Formoterol Indacaterol 150 µg o.d. Indacaterol 300 µg o.d. Change in trough FEV1 from baseline (mL) 200 ICS non-users ICS users 180 160 140 Prespecified level of 120 clinically 100 relevant effect 80 60 40 20 0Data are unadjusted means and standard errorsICS = inhaled corticosteroid Decramer et al. ERS 2010
  • 24. POOLED ANALYSIS 3-month safety profile by ICS use Indacaterol Indacaterol Open-label 150 µg 300 µg Formoterol Tiotropium PlaceboICS non-users Any AE 190 (46.7) 216 (47.5) 112 (40.6) 139 (51.5) 281 (47.2) COPD worsening 25 (6.1) 39 (8.6) 30 (10.9) 26 (9.6) 75 (12.6) Cough 23 (5.7) 28 (6.2) 6 (2.2) 10 (3.7) 31 (5.2) URTI 22 (5.4) 13 (2.9) 5 (1.8) 11 (4.1) 16 (2.7) Nasopharyngitis 13 (3.2) 26 (5.7) 17 (6.2) 19 (7.0) 28 (4.7) Any SAE 18 (4.4) 16 (3.5) 13 (4.7) 15 (5.6) 21 (3.5) COPD worsening 2 (0.5) 3 (0.7) 5 (1.8) 5 (1.6) 6 (1.0)ICS users Any AE 134 (60.9) 203 (51.0) 134 (47.9) 90 (62.1) 207 (45.1) COPD worsening 39 (17.7) 62 (15.6) 41 (14.6) 28 (19.3) 84 (18.3) Nasopharyngitis 17 (7.7) 23 (5.6) 14 (5.0) 11 (7.6) 33 (7.2) Headache 12 (5.5) 12 (3.0) 9 (3.2) 8 (5.5) 15 (3.3) Muscle spasms 12 (5.5) 8 (2.0) 6 (2.1) 0 4 (0.9) URTI 11 (5.0) 17 (4.3) 3 (1.1) 11 (7.6) 11 (2.4) LRTI 9 (4.1) 12 (3.0) 5 (1.8) 8 (5.5) 11 (2.4) Any SAE 12 (5.5) 17 (4.3) 8 (2.9) 6 (4.1) 26 (5.7) COPD worsening 6 (2.7) 2 (0.5) 4 (1.4) 1 (0.7) 11 (2.4)URTI = upper respiratory tract infection; LRTI = lower respiratory tract infection; SAE = serious adverse event Decramer et al. ERS 2010
  • 25. Indacaterol efficacy and safety by age
  • 26. POOLED ANALYSIS Pooled analysis: indacaterol provides clinically significant bronchodilation on Day 1 compared with placebo regardless of age Placebo Open-label Formoterol Indacaterol 150 µg Indacaterol 300 µg tiotropium Change in trough FEV1 from baseline (mL) 200 180 160 140 Prespecified level of 120 clinically 100 relevant effect 80 60 40 20 0 Age <65 years Age ≥65 yearsData are unadjusted means and standard errors Buhl et al. ERS 2010
  • 27. POOLED ANALYSIS 3-month safety profile by age Indacaterol Indacaterol Open-label 150 µg 300 µg Formoterol Tiotropium PlaceboAge <65 years (n=331) (n=450) (n=282) (n=215) (n=573)Any AE 51.7 48.2 44.7 52.1 47.0 COPD worsening 12.4 13.1 13.5 11.2 15.5 Headache 6.0 2.9 3.9 4.7 2.8 URTI 5.1 5.1 1.8 4.7 2.6 Cough 4.5 4.2 3.2 3.7 4.9 Nasopharyngitis 3.9 6.2 6.0 7.4 5.1Age ≥65 years (n=296) (n=403) (n=274) (n=200) (n=482)Any AE 51.7 50.1 43.8 58.5 45.4 COPD worsening 7.8 10.4 12.0 15.0 14.5 Cough 6.1 6.0 2.2 4.0 3.5 Nasopharyngitis 5.7 5.2 5.1 7.0 6.6 URTI 5.4 1.7 1.1 6.0 2.5 Headache 2.7 2.7 1.8 4.0 2.1 Dyspnoea 2.7 2.5 1.5 3.5 3.5 LTRI 1.4 2.7 2.2 4.0 1.9 Dry mouth 0.7 0.3 0 5.0 0.6URTI = upper respiratory tract infection; LRTI = lower respiratory tract infection Buhl et al. ERS 2010
  • 28. Rates of COPD exacerbations over 3 months of treatment 3-month pooled data Open-label tiotropium (n=415) Indacaterol 150 µg (n=627) Formoterol (n=522) Indacaterol 300 µg (n=821) 1.2 Rate of ratios vs placebo for COPD 1.0 exacerbations 0.8 * ** 0.6 0.4 0.2 0*p<0.05, **p<0.01 vs placeboData are from Poisson regression analysis of rates of COPDexacerbations with 95% CI Siler et al. ATS 2010
  • 29. INHANCE Indacaterol provides clinically significantbronchodilation at Week 12 compared with placebo regardless of SABA reversibility Difference in trough FEV1 versus placebo (mL) 300 Open-label tiotropium Indacaterol 150 µg Indacaterol 300 µg 250 *** *** 200 *** 150 *** *** *** *** *** *** Prespecified level of clinically relevant effect1 100 Published threshold of MCID1 50 0 >12% ≤12% ≤5% Baseline SABA reversibility at screening***p<0.001 vs placebo 1. Kleerup et al. ERS 2010;Data are LSM with 95% CI 2. Donohue et al. 2005MCID = minimal clinically important difference
  • 30. Indacaterol provides clinically significant INHANCE bronchodilation at Week 12 compared with placebo regardless of SAMA reversibility Difference in trough FEV1 versus placebo (mL) 300 Open-label tiotropium Indacaterol 150 µg Indacaterol 300 µg 250 *** *** 200 *** *** Prespecified level of 150 *** clinically relevant effect1 *** ** ** 100 Published threshold * of MCID2 50 0 >12% ≤12% ≤5% Baseline SAMA reversibility at screening*p<0.05, **p<0.01, ***p<0.001 vs placeboData are LSM with 95% CIs 1. Kleerup et al. ERS 2010;MCID = minimal clinically important difference 2. Donohue et al. 2005
  • 31. Indacaterol provided significant and clinically relevant improvements in breathlessness over 6 months (pooled analysis) OR vs placebo: 1.49* 2.02* 1.79* 1.91* 2.69* increase in TDI score from baseline 70 65.9 Patients with clinically relevant 60.5 60 57.8 54.3 54.1 60 45.3 50 (%) 40 30 20 20 0 Placebo Open-label Formoterol Salmeterol Indacaterol Indacaterol Tiotropium 150 µg o.d. 300 µg o.d.Plotted data are unadjusted means. *p<0.05 vs placebo for odds ratio (OR)Difference of ≥1 = clinically important improvement in the TDI total scoreTDI = Transition Dyspnea Index. Kleerup et al. ATS 2010
  • 32. Indacaterol improved quality of life (SGRQ Total Score) over 6 months (pooled analysis) Open-label Indacaterol Indacaterol Placebo Tiotropium Formoterol Salmeterol 150 µg o.d. 300 µg o.d. 0 Change in SGRQ total score –1 –2 from baseline (%) Improvement –3 –2.7 –4 –5 –4.5 –5.2 –5.3 –6 –6.2 –7 –6.9 –8Plotted data are unadjusted means Kleerup et al. ATS 2010
  • 33. Summary: symptoms Phase III clinical data showed that all active treatments resulted in symptom improvement Improvements in spirometry with indacaterol were associated with significant clinical outcomes for patients: – breathlessness ■ significant improvements compared with tiotropium, formoterol (300 µg) and salmeterol (150 µg) – health related quality of life ■ significant and clinically relevant improvements in SGRQ Total Score compared with placebo ■ significant improvements in the SGRQ Total Score compared with tiotropium and salmeterol and numerical improvements vs formoterol – reduction in need for rescue medication compared with tiotropium, salmeterol, formoterol and placebo – significant reduction in COPD exacerbations, compared with placebo
  • 34. INDORSE Cardiovascular safety profile of indacaterol: 52-week safety study Indacaterol Indacaterol 150 µg o.d. 300 µg o.d. Placebo (N=144) (N=146) (N=124) n (%) n (%) n (%)Pulse rate – higha 0 1 (0.7) 0Systolic blood pressure – highb 1 (0.7) 2 (1.4) 2 (1.6)Diastolic blood pressure – highc 1 (0.7) 0 2 (1.6)QTc >450/470 ms (males/females)d 10 (6.9) 9 (6.2) 11 (8.9) Increase 30–60 ms 28 (19.4) 30 (20.5) 30 (24.4) Increase >60 ms 1 (0.7) 1 (0.7) 1 (0.8)a>130bpm, or ≥120 bpm and ≥15 bpm increase; b>200 mmHg, or ≥180 mmHg and≥20 mmHg increase; c>115 mmHg, or ≥105 mmHg and ≥15 mmHg increasedNo patient had value >500 ms Chapman et al. Chest 2011 (accepted)
  • 35. Cough following inhalation 17–20% of patients experienced a sporadic cough within 15 seconds following inhalation of indacaterol – short-lasting, typically 5 seconds (10 seconds in current smokers) – higher frequency among females vs males and current smokers versus ex-smokers Only 6.8% of patients reported cough as an AE in clinical trials Generally well tolerated Cough following inhalation did not lead to any patient discontinuing from clinical studies at the recommended doses No evidence of an association with bronchospasm, exacerbations, deteriorations of disease or loss of efficacy Novartis Data (SmPC)
  • 36. Summary: Safety Once-daily indacaterol was shown to have an acceptable safety profile The overall incidence and pattern of adverse events and serious adverse events were similar to placebo and the active comparators tiotropium, salmeterol and formoterol in patients with moderate-to- severe COPD
  • 37. Combining bronchodilators in COPD Current guidelines recommend adding a second bronchodilator to therapy in moderate COPD in order to optimize the symptom benefit for patients1 Combining bronchodilators of different pharmacologic classes may improve efficacy and decrease the risk of side effects compared with increasing the dose of a single bronchodilator1 As airflow obstruction becomes more severe, a LAMA plus a LABA combination has been advocated2 1. GOLD 2010; 2. Tashkin and Cooper. Chest 2004
  • 38. INTRUST 1 and INTRUST 2(Studies B2341 and B2351)
  • 39. INTRUST 1/2 key findings In previous studies, indacaterol as monotherapy has consistently demonstrated 24-h bronchodilator efficacy Concurrent use of indacaterol and tiotropium significantly improves bronchodilation compared with tiotropium alone – Indacaterol plus tiotropium provides significant improvements in FEV1 AUC5 min−8 h and trough FEV1 – Significant between-treatment differences are seen at each time point after dosing Indacaterol plus tiotropium significantly improves lung deflation (indicated by increased IC) compared with tiotropium alone Indacaterol plus tiotropium is well tolerated and has an acceptable cardiovascular profile
  • 40. COPD Phase III SDDPI INTRUST 1/2: Efficacy and safety of indacaterol plus tiotropium vs tiotropium alone over 12 weeks Patients Male or female, age ≥40 years, moderate-to-severe COPD FEV1 ≤65% and ≥30% predicted; FEV1/FVC <70% (post-bronchodilator) Number 1134 randomized in INTRUST1 1142 randomized in INTRUST2 Device Single-dose dry-powder inhaler (SDDPI) Indacaterol dose 150 µg o.d. added to tiotropium 18 µg o.d. Comparator Tiotropium 18 µg o.d. + placebo Main objective Efficacy of indacaterol + tiotropium versus tiotropium + placebo (standardized area under the curve of FEV1 from 5 min to 8 h post-dose [FEV1 AUC5 min−8 h]) at Week 12 Mahler et al. (ATS poster) 2011NB: doses of indacaterol approved in Europe are 150 and 300 μg via SDDPI (Studies B2341 and B2351)
  • 41. COPD Phase III SDDPI INTRUST 1/2 : 12-week efficacy and safety Study design Double-blind, randomized, placebo-controlled, parallel-group studies in male and female patients with COPD Indacaterol 150 μg o.d. + tiotropium* 18 μg o.d. n=570 INTRUST 1 B2341 Placebo + tiotropium* 18 μg o.d. n=561 INTRUST 2 Indacaterol 150 μg o.d. + tiotropium* 18 μg o.d. n=572 B2351 Placebo + tiotropium* 18 μg o.d. n=570 Baseline FEV1 12 weeks FEV1*Open-label tiotropium Mahler et al. (ATS poster) 2011NB: doses of indacaterol approved in Europe are 150 and 300 μg via SDDPI (Studies B2341 and B2351)
  • 42. COPD Phase III SDDPI INTRUST 1/2: Indacaterol plus tiotropium significantly improves bronchodilation vs tiotropium alone (1) FEV1 AUC5 min–8 h and trough FEV1 at Week 12 160 INTRUST 1 140 FEV1 treatment difference (mL) INTRUST 2 *** 120 *** 100 80 *** *** 60 40 20 0 FEV1 AUC5 min–8 h Trough FEV1 (primary endpoint) (key secondary endpoint)Data are LSM and 95% CI for the treatment difference between indacaterol plus tiotropium and tiotropium alone***p<0.001 for indacaterol plus tiotropium versus tiotropium alone Mahler et al. (ATS poster) 2011NB: doses of indacaterol approved in Europe are 150 and 300 μg via SDDPI (Studies B2341 and B2351)
  • 43. COPD Phase III SDDPI INTRUST 1/2: Indacaterol plus tiotropium significantly improves bronchodilation vs tiotropium alone (2) FEV1 at serial timepoints post-dose at Week 12 180 INTRUST 1 INTRUST 2 FEV1 treatment difference (mL) 160 140 120 100 80 60 40 20 Study drug inhalation 0 –1 0 1 2 3 4 5 6 7 8 Trough Time (h) (24 h post-dose)Data are LSM and 95% CI for the treatment difference between indacaterol plus tiotropium and tiotropium aloneAll differences for indacaterol plus tiotropium versus tiotropium alone significant at p<0.001 Mahler et al. (ATS poster) 2011NB: doses of indacaterol approved in Europe are 150 and 300 μg via SDDPI (Studies B2341 and B2351)
  • 44. QVA149
  • 45. Significant improvement in trough FEV1 versus indacaterol and placebo (Day 7) 1.6 *# 1.5 FEV1 (L) 1.4 * * 1.3 1.2 QVA149 Indacaterol Indacaterol Placebo 300/50 μg 300 μg 600 μg (n=136) (n=140) (n=138) (n=140)Randomized, double-blind, placebo controlled, four-period crossover studyStudy A2204; data are LSM ± SE; *p<0.0001 vs placebo; #p<0.0001 vsindacaterol 300 μg and 600 μgLSM = least squares mean; SE = standard error Van Noord et al. Thorax 2010
  • 46. QVA149 had a rapid onset of action with sustained bronchodilation over 24 hours (Day 7) Placebo (n=140) Indacaterol 300 µg (n=140) Indacaterol 600 µg (n=142) QVA149 300/50 (n=142) 1.7 1.6 FEV1 (L) 1.5 1.4 1.3 1.2 –2 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (hours)Randomized, double-blind, placebo controlled, four-period crossover studyStudy 2204; data are LSM. QVA149 300/50 µg statistically superior (p<0.05)to indacaterol 300 µg, 600 µg and placebo at all post-baseline timepointsLSM = least squares mean Van Noord et al. Thorax 2010
  • 47. No significant difference* in 24-hour mean heart rate versus placebo or indacaterol (Day 14) 6 5 4 Treatment contrast in 3 heart rate (bpm) 2 1 0 –1 –2 –3 –4 –5 –6 QVA149 QVA149 QVA149 Indacaterol QVA149 QVA149 QVA149 600/100 μg 300/100 μg 150/100 μg 300 μg 600/100 μg 300/100 μg 150/100 μg versus placebo versus indacaterol 300 μgRandomized, double-blind, placebo-controlled, parallel-group, 14-day study; n=257Study A2203; *None of the CIs crossed the pre-specified equivalence margin of +5 and –5 bpm.Data are LSM and the corresponding 95% Cls; safety populationCI = confidence interval; LSM = least squares mean Van de Maele et al. COPD 2010
  • 48. QVA149 safety summary (A2203) Once-daily QVA149 600/100 µg, 300/100 µg and 150/100 µg produced no significant effect on 24-hour mean heart rate after 14 days of treatment All QVA149 doses were well tolerated, with overall AE rates similar to placebo and indacaterol 300 μg The effect of QVA149 on other cardiovascular assessments, including Fridericia’s QTc interval, appeared to be minimal with a profile similar to placebo The overall incidence of abnormal vital signs was similar between treatment groups Van de Maele et al. COPD 2010
  • 49. THANK YOU FOR YOUR ATTENTION