Post on 06-Apr-2018
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
1/49
Indacaterol Desarrollo clnico
Prof. Ronald Dahl
Aarhus University Hospital
Dinamarca
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
2/49
Desarrollo tecnolgico
En biologia:el desarollo es un proceso por el que un organismo
evoluciona desde su origen hasta alcanzar la condicinde adulto.
The development and documentation of the new ultra longacting beta2agonist; Indacaterol (Oslif) - a summary.
http://es.wikipedia.org/wiki/Desarrollo_tecnol%C3%B3gicohttp://es.wikipedia.org/wiki/Desarrollo_tecnol%C3%B3gicohttp://es.wikipedia.org/wiki/Desarrollo_tecnol%C3%B3gicohttp://es.wikipedia.org/wiki/Desarrollo_tecnol%C3%B3gico8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
3/49
Airflow limitation includes irreversible andpartially reversible components
Irreversible components include
1,2
loss of elastic recoil due to alveolar destruction
destruction of alveolar attachments which supportand maintain patency of small airways
small airway fibrosis
Partially reversible components include1,2
accumulation of mucus
smooth muscle hypertrophy andbronchoconstriction2
inflammatory infiltrate in airway mucosa
1. GOLD 2009; 2. Brusasco Eur Respir Rev 2006
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
4/49
Can we improve on current bronchodilatortherapy?
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
5/49
As new bronchodilators are introduced therehave been more consistent improvements in outcomes for
patients with COPD
12Formoterol
()12Salmeterol
()()24Tiotropium
Improvement in outcome
68
Ipratropium
bromide
NANA46Albuterol
Exacerbations13,5,714Quality
of life114Exercise
endurance*1,2Breathlessness28Lung
function28
Duration ofaction
(hours)1
*Outcome demonstrated by all bronchodilators, lack of evidence of significant differences between themEquivocal evidence depending on formulation;5,10,11Evidence 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 20015. 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 200312. Calverley et al. NEJM 2007; 13. Niewoehner et al. Ann Intern Med 2005; 14. Tashkin et al. NEJM 2008
evidence of effectiveness; evidence of effectiveness over SABA or SAMA; evidence of effectiveness over LABA
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
6/49
Dose Response: Indacaterol and Comparators
F12=Formoterol 12 g BID S50=Salmeterol 50 g BID T18=Tiotropium 18 g
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
7/49
COPD Pooled Study-level Analysis:Predicted Response at Each Dose Level
40 60 80 100 120 140 160 180 200
Indacaterol 600 g QD
Indacaterol 300 g QD
Indacaterol 150 g QD
Indacaterol 75 g QD
Tiotropium 18 g QD
Salmeterol 50 g BID
Indacaterol 37.5 g QD
Formoterol 12 g BID
Indacaterol 18.75 g QD
Treatment comparison
Trough FEV1
difference from placebo (mL)
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
8/49
Lack of Tachyphylaxis over 52 WeeksStudy B2335S/SE
0
50
100
150
200
250
TroughFE
V1
dif
ferencefromp
lacebo(mL)
75 g 150 g 300 g
All p
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
9/49
Safety over Dose Range MortalityRelative risks (to placebo) adjusted for time on treatment
COPD safety population
0.0 0.5 1.0 1.5 2.0 2.5 3.0
Pooled Indacaterol
Indacaterol 600 g QD
Indacaterol 300 g QD
Indacaterol 150 g QD
Indacaterol 75 g QD
Tiotropium 18 g QD
Salmeterol 50 g BID
Formoterol 12 g BID
Treatment comparison
Relative risk of death
Exposure(total pt-yr)
2096
394
737
860
105
356
275
396
No death
8.5
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
10/49
Tiotropium comparator studies: blindingprocedures
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 wasachieved by third-party blinding procedures
study drug was prepared and provided to the patient each morning, either athome or in the clinic, by persons independent of other clinical trial processes
INTENSITY3
placebo tiotropium manufactured to be matching in size and colour; nomanufacturers 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
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
11/49
Intensity
Blinded 12 week comparison of once dailyindacaterol and tiotropium in COPD
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
12/49
Indacaterol 150 g od via SDDPI*+ placebo via HandiHaler(n=794)
Tiotropium 18 g od via HandiHaler+ placebo via SDDPI* (n=799)
Run-in
*SDDPI = single-dose dry powder inhaler
Design
Randomized, double-dummy, blinded, parallel-group study
2 weeks BaselineFEV1
Trough FEV1(primaryendpoint)
Week 12
Buhl et al. ERJ 2011. online as doi: 10.1183/09031936.00191810
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
13/49
Patient demographics and baseline characteristics
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 Georges Respiratory Questionnaire;
pack years = total years of smoking multiplied by cigarette packs smoked per day
Characteristics
Indacaterol
n=794
Tiotropium
n=799
Age (years) 63.6 (8.60) 63.4 (8.29)
Sex (%) (Male/Female) 70/30 67/33
Duration of COPD (years) 7.0 (6.01) 7.0 (6.32)
ICS use (%) 54 56
Ex-smoker/smoker (%) 55/45 56/44
Smoking 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)
Buhl et al. ERJ 2011. online as doi: 10.1183/09031936.00191810
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
14/49
Indacaterol and tiotropium both demonstrated spirometricefficacy, as measured by trough FEV1 at Week 12
Indacaterol150 g o.d.
Tiotropium18 g o.d.
Trough FEV1 1.44 L 1.43 L p
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
15/49
Indacaterol provided significant improvements in dyspneascore compared with tiotropium at 12 weeks
0
0,5
1
1,5
2
2,5
TDI total score
Difference0.58 (p
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
16/49
Indacaterol provided significant improvements in qualityof life vs tiotropium at 12 weeks
35
36
37
38
39
40
Difference2.1 (p
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
17/49
Intime
3rd party blinded
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
18/49
INTIME: 14-day, 3rd party blinded, cross-over study
Indacaterol150 g o.d.
Indacaterol300 g o.d.
Tiotropium18 g o.d.
Placebo
Indacaterol150 g o.d.
Indacaterol300 g o.d.
Tiotropium18 g o.d.
Placebo
Indacaterol150 g o.d.
Indacaterol300 g o.d.
Tiotropium18 g o.d.
Placebo
Run-in andrandomisation
Wash-out andcross-over
Wash-out andcross-over
14 days 14 days 14 days 14 days 14 days 14 days
Vogelmeier et al. Respir Res 2010; 11: 135-142
Treatment 1 Treatment 2 Treatment 3
n=169
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
19/49
Indacaterol 150 g and 300 g provided superiorbronchodilation, compared with placebo
0
50
100
150
200
250
Tiotropium18 g o.d.
Indacaterol150 g o.d.
Indacaterol300 g o.d.
***
***
***
***p
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
20/49
Pooled analysis on various efficacy and safetyoutcomes in trials with Indacaterol and comparitors
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
21/49
Demographic characteristics of patientsin the indacaterol pivotal registration studies
0
10
20
30
40
50
60
70
80
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
22/49
Indacaterol in the presence ofconcomitant ICS
POOLED ANALYSIS
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
23/49
Pooled analysis: indacaterol provides clinicallysignificant bronchodilation on Day 1 compared with
placebo regardless of ICS use
0
20
40
60
80
100
120
140
160
180
200 ICS non-users ICS users
Data are unadjusted means and standard errors
Changein
troughFEV1fromb
aseline(mL)
Prespecifiedlevel ofclinicallyrelevant effect
ICS = inhaled corticosteroid
Open-label TiotropiumFormoterol Indacaterol 150 g o.d. Indacaterol 300 g o.d.Placebo
Decramer et al. ERS 2010
POOLED ANALYSIS
POOLED ANALYSIS
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
24/49
3-month safety profile by ICS use
Indacaterol150 g
Indacaterol300 g Formoterol
Open-labelTiotropium Placebo
ICS 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)
Decramer et al. ERS 2010
URTI = upper respiratory tract infection; LRTI = lower respiratory tract infection; SAE = serious adverse event
POOLED ANALYSIS
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
25/49
Indacaterol efficacy and safety by age
POOLED ANALYSIS
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
26/49
Pooled analysis: indacaterol provides clinically significantbronchodilation on Day 1 compared with placebo
regardless of age
0
20
40
60
80
100
120
140
160
180
200
Data are unadjusted means and standard errors
Changein
troughFEV1fromb
aseline(mL)
Open-labeltiotropium
Formoterol Indacaterol 150 g Indacaterol 300 gPlacebo
Prespecifiedlevel ofclinicallyrelevant effect
Age
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
27/49
3-month safety profile by ageIndacaterol
150 g
Indacaterol
300 g Formoterol
Open-label
Tiotropium Placebo
Age
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
28/49
Indacaterol 150 g (n=627)
Indacaterol 300 g (n=821)
Rateofratiosvsplacebofo
rCOPD
exacerbations
0
0.2
0.4
0.6
0.8
1.0
1.2
*p
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
29/49
*** ***
*** ***
******
0
50
100
150
200
250
300
>12%
Prespecified level ofclinically relevant effect1
Differenc
eintroughFEV1ve
rsusplacebo(mL)
******
***
12% 5%
INHANCE
***p
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
30/49
1. Kleerup et al. ERS 2010;
2. Donohue et al. 2005
***
***
*** ***
******
0
50
100
150
200
250
300
>12%
Prespecified level ofclinically relevant effect1
*p
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
31/49
Kleerup et al. ATS 2010
0
70
20
30
40
50
60
Plotted data are unadjusted means. *p
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
32/49
Kleerup et al. ATS 2010
8
0
6
4
3
2
1
ChangeinSGRQtotals
core
fr
ombaseline(%)
2.7
4.5
5.3
6.9
6.2
Open-labelTiotropium Formoterol
Indacaterol150 g o.d.
Indacaterol300 g o.d.Placebo
5.2
Salmeterol
5
7
Improvement
Plotted data are unadjusted means
Indacaterol improved quality of life(SGRQ Total Score) over 6 months (pooled analysis)
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
33/49
Summary: symptoms Phase III clinical data showed that all active treatments resulted in
symptom improvement
Improvements in spirometry with indacaterol were associated withsignificant clinical outcomes for patients:
breathlessness
significant improvements compared with tiotropium, formoterol
(300 g) and salmeterol (150 g) health related quality of life
significant and clinically relevant improvements in SGRQ TotalScore compared with placebo
significant improvements in the SGRQ Total Score compared withtiotropium and salmeterol and numerical improvements vsformoterol
reduction in need for rescue medication compared with tiotropium,salmeterol, formoterol and placebo
significant reduction in COPD exacerbations, compared with placebo
INDORSE
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
34/49
Indacaterol150 g o.d.
(N=144)n (%)
Indacaterol300 g o.d.
(N=146)n (%)
Placebo(N=124)
n (%)
Pulse rate higha 0 1 (0.7) 0
Systolic 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 3060 ms 28 (19.4) 30 (20.5) 30 (24.4)
Increase >60 ms 1 (0.7) 1 (0.7) 1 (0.8)
a>130 bpm, or 120 bpm and 15 bpm increase; b>200 mmHg, or 180 mmHg and20 mmHg increase; c>115 mmHg, or 105 mmHg and 15 mmHg increasedNo patient had value >500 ms
Cardiovascular safety profile of indacaterol:52-week safety study
Chapman et al. Chest 2011 (accepted)
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
35/49
Cough following inhalation
1720% of patients experienced a sporadic cough within15 seconds following inhalation of indacaterol
short-lasting, typically 5 seconds (10 seconds in currentsmokers)
higher frequency among females vs males and current smokersversus ex-smokers
Only 6.8% of patients reported cough as an AEin 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)
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
36/49
Summary: Safety
Once-daily indacaterol was shown to have an acceptable safetyprofile
The overall incidence and pattern of adverse events and seriousadverse events were similar to placebo and the active comparatorstiotropium, salmeterol and formoterol in patients with moderate-to-severe COPD
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
37/49
Combining bronchodilators in COPD
Current guidelines recommend adding a secondbronchodilator to therapy in moderate COPD in order tooptimize the symptom benefit for patients1
Combining bronchodilators of different pharmacologic
classes may improve efficacy and decrease the risk ofside effects compared with increasing the dose of asingle bronchodilator1
As airflow obstruction becomes more severe, a LAMAplus a LABA combination has been advocated2
1. GOLD 2010; 2. Tashkin and Cooper. Chest 2004
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
38/49
INTRUST 1 and INTRUST 2
(Studies B2341 and B2351)
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
39/49
INTRUST 1/2 key findings
In previous studies, indacaterol as monotherapy has consistentlydemonstrated 24-h bronchodilator efficacy
Concurrent use of indacaterol and tiotropium significantlyimproves bronchodilation compared with tiotropium alone
Indacaterol plus tiotropium provides significant improvementsin FEV1 AUC5 min8 h and trough FEV1
Significant between-treatment differences are seen at each timepoint 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 acceptablecardiovascular profile
INTRUST 1/2 Efficac and safet ofSDDPICOPD
Phase III
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
40/49
INTRUST 1/2: Efficacy and safety ofindacaterol 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
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
41/49
INTRUST 1/2 : 12-week efficacy and safetyStudy design
12 weeks
Indacaterol 150 g o.d. + tiotropium* 18 g o.d. n=570
Placebo + tiotropium* 18 g o.d. n=561
Double-blind, randomized, placebo-controlled, parallel-group studiesin male and female patients with COPD
Baseline FEV1 FEV1
COPD SDDPI
NB: doses of indacaterol approved in Europe are 150 and 300 g via SDDPI
Indacaterol 150 g o.d. + tiotropium* 18 g o.d. n=572
Placebo + tiotropium* 18 g o.d. n=570
INTRUST 1B2341
Mahler et al. (ATS poster) 2011(Studies B2341 and B2351)
INTRUST 2
B2351
*Open-label tiotropium
Phase III
SDDPICOPD Phase III
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
42/49
INTRUST 1/2: Indacaterol plus tiotropium significantlyimproves bronchodilation vs tiotropium alone (1)
SDDPI
NB: doses of indacaterol approved in Europe are 150 and 300 g via SDDPI
Data are LSM and 95% CI for the treatment difference between indacaterol plus tiotropium and tiotropium alone***p
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
43/49
NB: doses of indacaterol approved in Europe are 150 and 300 g via SDDPI
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
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
44/49
QVA149
Si ifi t i t i t h FEV
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
45/49
Significant improvement in trough FEV1 versusindacaterol and placebo (Day 7)
Randomized, double-blind, placebo controlled, four-period crossover studyStudy A2204; data are LSM SE; *p
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
46/49
QVA149 had a rapid onset of action withsustained bronchodilation over 24 hours (Day 7)
1.7
1.6
1.5
1.4
1.3
1.2
2 0 2 4 6 8 10 12 14 16 18 20 22 24
Time (hours)
FEV
1
(L)
Van Noord et al. Thorax 2010
Indacaterol 300 g (n=140)QVA149 300/50 (n=142)
Placebo (n=140)Indacaterol 600 g (n=142)
Randomized, double-blind, placebo controlled, four-period crossover studyStudy 2204; data are LSM. QVA149 300/50 g statistically superior (p
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
47/49
Randomized, double-blind, placebo-controlled, parallel-group, 14-day study; n=257Study A2203; *None of the CIs crossed the pre-specified equivalence margin of +5 and5 bpm.Data are LSM and the corresponding 95% Cls; safety population
Treatmen
tcontrastin
heartrate(bpm)
654
32
10
12
3456
QVA149600/100 g
versus placebo
QVA149300/100 g
QVA149150/100 g
Indacaterol300 g
QVA149600/100 g
QVA149300/100 g
QVA149150/100 g
versus indacaterol 300 g
No significant difference* in 24-hour meanheart rate versus placebo or indacaterol (Day 14)
Van de Maele et al. COPD 2010CI = confidence interval; LSM = least squares mean
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
48/49
QVA149 safety summary (A2203)
Once-daily QVA149 600/100 g, 300/100 g and150/100 g produced no significant effect on 24-hourmean heart rate after 14 days of treatment
All QVA149 doses were well tolerated, with overall AE
rates similar to placebo and indacaterol 300 g
The effect of QVA149 on other cardiovascularassessments, including Fridericias QTc interval,appeared to be minimal with a profile similar to placebo
The overall incidence of abnormal vital signs wassimilar between treatment groups
Van de Maele et al. COPD 2010
8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam
49/49
THANK YOU FOR YOUR
ATTENTION