120323-bakris et al talking paper slides

EU/AZI-010002 Date of preparation: 01/11/2011

The comparative effects of azilsartan medoxomil and

olmesartan on ambulatory and clinic blood pressure

Bakris GL, Sica D, Weber M, White WB,

Roberts A, Perez AP, Cao C, Kupfer SJ Clin Hypertens. 2011;13:81-88

Prescribing information can be obtained from your Takeda representative

Disclosures

Grants, Consultancy and Speaker honoraria received by

Takeda Pharma

2EU/AZI-010002

Hypertension has been identified as the leading risk factor

for mortality worldwide1

• Hypertension affects approximately 44% of people aged 35-64 years and

remains poorly controlled3

• For every 20mmHg increase in clinical SBP or 10mmHg clinical DBP, the risk

of vascular mortality doubles4

• Cardiovascular disease costs Europe an estimated €169 billion each year2,

with hypertension a major modifiable risk factor

• Modest reductions in SBP can substantially reduce morbidity and mortality of

vascular events5

1. Ezzati et al. Lancet. 2002;360:1347–60. 2. Leal J, et al. Eur Heart J 2006;27:1610-19. 3. Wolf-Maier K, et al. JAMA 2003;289:2363-2369. 4. Lewington S, et al. Lancet. 2002;360:1903–1913. 5. Whelton PK, et al. JAMA 2002;288:1882-1888.

SBP = systolic blood pressure; DBP=diastolic blood pressure; CHD=coronary heart disease

% Reduction in mortality

Reduction in SBP (mmHg) Stroke CHD Total

2 -6 -4 -3

3 -8 -5 -4

5 -14 -9 -7

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Azilsartan medoxomil: a new-generation ARB for the

treatment of essential hypertension

• ARBs are effective in reducing BP and

are better tolerated than other classes

of antihypertensive1

• Azilsartan medoxomil (AZL-M): 2

• Prodrug, rapidly hydrolysed to azilsartan

– a highly selective angiotensin receptor

blocker

• Once-daily dosing

• Estimated bioavailability – 60%

• Elimination half-life – 12 hours

4

N

NN NH

OOOCH2CH3

OOC

O O

O

H3C

N

NN NH

OOOCH2CH3

HOOC

TAK-491 MW=606.62

TAK-536 MW=456.46

Hyd

roly

sis

1. Veronesi M, et al. Vasc Health Risk Manag 2007;3:999-1005 2. Bakris GL, et al. J Clin Hypertens 2011;13:81-88.

EU/AZI-010002

Washout

Study design and treatments

Bakris GL, et al. J Clin Hypertens 2011;13:81-88.

AZL-M = azilsartan medoxomil, OLM-M = olmesartan medoxomil

Single-blind placebo run-in phase

AZL-M 40 mg(n=283)

AZL-M 80 mg(n=285)

OLM-M 40 mg(n=282)

AZL-M 20 mg(n=283)

PLACEBO(n=142)

6 weeks

ABPM at final visit

1 week 2 weeks

Screening

Baseline ABPM and randomisation

(N=1,275)

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Inclusion and exclusion criteria

Inclusion criteria:

• Age ≥18 years

• Primary hypertension

• Clinic SBP 150–180 mmHg

• 24-hour mean SBP 130–170 mmHg

Key exclusion criteria:

• Sitting clinic DBP >114 mmHg

• History of major CV events

• Cardiac conduction defects

• Secondary hypertension

• Severe renal impairment or

known/suspected renal artery stenosis

• Type 1 or poorly controlled type 2 diabetes

• Significant hepatic abnormalities

• Hyperkalaemia

CVD = cardiovascular disease, SBP = systolic blood pressure, DBP = diastolic blood pressure


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Study endpoints

Primary endpoint:

• Mean change in 24-hour mean SBP (by ABPM)

at 6 weeks

Key secondary endpoints:

• Mean change in trough sitting clinic SBP at 6 weeks

Other:

• Mean change in 24-hour DBP by ABPM

• Mean change in trough sitting clinic DBP

• Day-time mean (6 am–10 pm), night-time mean

(12 am–6 am), mean at 0-12 hours after dosing, mean

trough (22 – 24 hours after dosing) SBP and DBP

• Proportion of responders*

Safety endpoints:

• Adverse events

• Laboratory tests

• ECG

• Vital signs

7

*Response defined as clinic SBP <140 mmHg and/or reduction ≥20 mmHg from baseline


EU/AZI-010002

Statistical analysis

• Changes in 24-hour mean SBP and clinic SBP were analysed by a step-wise testing

procedure (ANCOVA)

• if the treatments failed to meet significance at one step, then analysis of the remaining steps

became invalid

• Other secondary variables used similar ANCOVA model without step-wise testing

Step 6: AZL-M 80 mg vs OLM-M

Superiority analysis




Non-inferiority (1.5 mmHg margin)



Step 1: AZL-M 80 mg vs placebo








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Placebo AZL-M 20 mg AZL-M 40 mg AZL-M 80 mg OLM-M 40 mg

n 142 283 283 285 282

Mean age (SD), years 59.4 (10.5) 57.1 (11.0) 57.4 (9.6) 58.1 (11.6) 58.9 (11.6)

Mean weight (SD), kg 83.4 (19.0) 84.2 (21.5) 84.6 (20.4) 83.5 (19.6) 82.9 (19.6)

Mean BMI (SD), kg/m2 30.0 (4.9) 30.4 (5.7) 30.6 (5.9) 30.0 (5.5) 29.8 (5.3)

Gender, n (%)

Male 76 (53.5) 133 (47.0) 142 (50.2) 149 (52.3) 140 (49.6)

Female 66 (46.5) 150 (53.0) 141 (49.8) 136 (47.7) 142 (50.4)

Ethnicity, n (%)*

Caucasian 103 (72.5) 202 (71.4) 205 (72.4) 209 (73.3) 209 (74.1)

Black/African-American 16 (11.3) 32 (11.3) 31 (11.0) 31 (10.9) 31 (11.0)

American Indian/Alaska Native 29 (20.4) 51 (18.0) 49 (17.3) 52 (18.2) 50 (17.7)

Patient demographics were similar across

treatment groups

* Rest Asian or multiracial; patients may have chosen more than one category for race

Bakris GL, et al. J Clin Hypertens 2011;13:81-88.9EU/AZI-010002

Placebo AZL-M 20 mg AZL-M 40 mg AZL-M 80 mgOLM-M 40

mg

24-hour mean BP, mmHg/n 142 282 281 282 282

SBP (SD) 146.0 (12.5) 145.6 (9.7) 146.2 (10.2) 146.3 (9.9) 146.3 (9.8)

DBP (SD) 87.2 (9.4) 87.6 (9.2) 88.0 (9.2) 87.7 (8.8) 87.5 (9.8)

Clinic BP, mmHg/n 142 283 281 284 282

SBP (SD) 158.7 (11.4) 158.7 (11.6) 158.5 (12.2) 159.4 (12.0) 159.2 (12.1)

DBP (SD) 91.3 (10.4) 92.4 (10.4) 92.2 (11.2) 92.1 (10.3) 91.4 (10.7)

Baseline blood pressure was similar across

treatment groups

TPEU Data on file EU/AZI-010024

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Significantly greater reduction in 24-hour mean SBP at

Week 6 with AZL-M 80 mg vs OLM-M 40 mg

-1.4

-12.2*-13.5*

-14.6*

-12.6*

-18

-14

-10

-6

-2

2

Placebo AZL-M 20mg AZL-M 40mg AZL-M 80mg OLM-M 40mg

*p<0.001 vs placebo p=0.038 vs OLM-M

Baseline:146.3 mmHg

N=120 Baseline:145.4 mmHg

N=241

Baseline:146.0 mmHg

N=244

Baseline:146.2 mmHg

N=243

Baseline:146.5 mmHg

N=250


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Greater numerical reduction in trough clinic SBP at Week 6

with AZL-M 80 mg vs OLM-M 40 mg

-2.1

-14.3* -14.5*

-17.6*†

-14.9*

-20

-16

-12

-8

-4

0

Placebo AZL-M 20mg AZL-M 40mg AZL-M 80mg OLM-M 40mg

*p<0.001 vs placebo; †Superiority of AZL-N 80 mg vs OLM-M 40 mg could not be claimed because prior step in sequential testing was not statistically significant.

Baseline:158.7mmHg

N=140 Baseline:158.5mmHg

N=274

Baseline:158.5mmHg

N=276

Baseline:159.4mmHg

N=279

Baseline:159.2mHg

N=280


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p=0.043 (NS) † vs OLM-M

Bakris GL, et al. J Clin Hypertens 2011;13:81-88.13

126 18 240

5

0

-5

-10

-15

-20

Placebo

AZL-M 20 mg

AZL-M 40 mg

AZL-M 80 mg

OLM-M 40 mg

Ch

ange

in S

BP

(m

m H

g) b

y A

BP

M

Reductions in ambulatory SBP were sustained throughout

the 24-hour monitoring period

Hour after dosing

EU/AZI-010002

Efficacy results: mean change in diastolic

BP at week 6

24 hr mean DBP

-0.7

-7.5*

-8.4* -8.6*

-7.7*

-10

-6

-2

Placebo AZL-M 20 mg AZL-M 40 mg

AZL-M 80 mg OLM-M 40mg

Trough clinic DBP

0.2

-6.8* -6.9*

-8.4*

-6.9*

-10

-6

-2

2

Placebo AZL-M 20 mg AZL-M 40 mg

AZL-M 80 mg OLM-M 40mg

*P<0.001 vs placebo

P=0.172 vs OLM-M

TPEU Data on file EU/AZI-010025 Adapted from Bakris G L, et al. J Clin Hypertens 2011; 13:81-88

*P<0.001 vs placebo

P=0.044 vs OLM-M

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N=142 N=283 N=281 N=284 N=282

N=142N=283 N=281 N=284 N=282

EU/AZI-010002

Response rate was similar between treatments

47.8 50.4

56.653.2

0

10

20

30

40

50

60

Re

spo

nd

ers

* (%

)

AZL-M 20mg AZL-M 40mg AZL-M 80mg OLM 40mg

*Reduction in clinic SBP to <140 mmHg and/or ≥20 mmHg decrease from baseline


15

N=283N=281

N=284

N=282

EU/AZI-010002

Placebo (n=142)

AZL-M20 mg(n=283)

AZL-M40 mg(n=281)

AZL-M80 mg(n=284)

OLM-M40 mg(n=282)

Any AE, N (%) 51 (35.9) 109 (38.5) 101 (35.9) 117 (41.2) 107 (37.9)

AE leading to discontinuation, N (%)

6 (4.2) 11 (3.9) 3 (1.1) 6 (2.1) 4 (1.4)

Serious AEs, N (%) 3 (2.1) 8 (2.8) 0 1 (0.4) 2 (0.7)

Death, N (%) 0 1 (0.4)* 0 0 0

Most common AEs, N (%)HeadacheDyslipidaemiaDizziness

10 (7.0)3 (2.1)4 (2.8)

13 (4.6)10 (3.5)8 (2.8)

9 (3.2)11 (3.9)6 (2.1)

16 (5.6)16 (5.6)8 (2.8)

9 (3.2)10 (3.5)10 (3.5)

AZL-M has a similar tolerability to OLM-M


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* Due to gastrointestinal haemorrhage and shock. Not related to treatment

Study summary

• Efficacy (at Week 6)

• AZL-M 80 mg lowered 24-hour mean SBP to a significantly greater

extent than OLM-M 40 mg (-14.6 mmHg vs -12.6 mmHg; p=0.038)

• AZL-M 40 mg was non-inferior to OLM-M 40 mg

• Safety (at Week 6)

• AZL-M had a similar safety and tolerability profile to placebo and

OLM-M (most common AEs: headache, dyslipidaemia, dizziness)


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Implications for hypertension management

“An important aspect of this trial is the use of ABPM to

establish the primary end point. ABPM provides more reliable

predictive data on cardiovascular outcomes than

conventional office readings”1

...Data from this study suggest that AZL-M 80 mg is more

effective in reducing SBP than the highest approved dose of

OLM-M, which is considered to be more effective than others

in the ARB class2,3”

1. Bakris GL, et al. J Clin Hypertens 2011;13:81-88. 2. Zannad F, et al. Fundam Clin Pharmacol 2007;21:181-190. 3. Oparil S, et al. J Clin Hypertens 2001;3:283-291.

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This study was funded by Takeda Global

Research and Development

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120323-bakris et al talking paper slides

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