ponencia del profesor ronald dalh realizada en amsterdam

8/2/2019 Ponencia del Profesor Ronald Dalh realizada en Amsterdam

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Indacaterol Desarrollo clnico

Prof. Ronald Dahl

Aarhus University Hospital

Dinamarca


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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%B3gico


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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


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Can we improve on current bronchodilatortherapy?


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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


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Dose Response: Indacaterol and Comparators

F12=Formoterol 12 g BID S50=Salmeterol 50 g BID T18=Tiotropium 18 g


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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 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)


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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


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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 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


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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


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Intensity

Blinded 12 week comparison of once dailyindacaterol and tiotropium in COPD


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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


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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


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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


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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


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Indacaterol provided significant improvements in qualityof life vs tiotropium at 12 weeks

35

36

37

38

39

40

Difference2.1 (p


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Intime

3rd party blinded


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INTIME: 14-day, 3rd party blinded, cross-over study



Tiotropium18 g o.d.

Placebo



Tiotropium18 g o.d.

Placebo



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


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Indacaterol 150 g and 300 g provided superiorbronchodilation, compared with placebo

0

50

100

150

200

250

Tiotropium18 g o.d.



***

***

***

***p


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Pooled analysis on various efficacy and safetyoutcomes in trials with Indacaterol and comparitors


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Demographic characteristics of patientsin the indacaterol pivotal registration studies

0

10

20

30

40

50

60

70

80


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Indacaterol in the presence ofconcomitant ICS

POOLED ANALYSIS


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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


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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


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Indacaterol efficacy and safety by age

POOLED ANALYSIS


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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


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3-month safety profile by ageIndacaterol

150 g

Indacaterol

300 g Formoterol

Open-label

Tiotropium Placebo

Age


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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


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*** ***

*** ***

******

0

50

100

150

200

250

300

>12%

Prespecified level ofclinically relevant effect1

Differenc

eintroughFEV1ve

rsusplacebo(mL)

******

***

12% 5%

INHANCE

***p


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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


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Kleerup et al. ATS 2010

0

70

20

30

40

50

60

Plotted data are unadjusted means. *p


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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


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)


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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


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(N=144)n (%)


(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)


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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)


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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


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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


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INTRUST 1 and INTRUST 2

(Studies B2341 and B2351)


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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


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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


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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


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INTRUST 1/2: Indacaterol plus tiotropium significantlyimproves bronchodilation vs tiotropium alone (1)

SDDPI


Data are LSM and 95% CI for the treatment difference between indacaterol plus tiotropium and tiotropium alone***p


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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


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QVA149

Si ifi t i t i t h FEV


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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


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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


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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


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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


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ATTENTION

ponencia del profesor ronald dalh realizada en amsterdam

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