Transcript ALiskiren - Moodle Lille 2

Josselin Courselle – Julien Maurin – Thomas Patard
 What is high blood pressure?
 Its impact on cardiovascular risk
 Actual treatments
 The Renin Angiotensin Aldosterone System (RAAS)
 Choice criteria of a drug to treat hypertension
 Aliskiren: discover and mechanism of action
 Efficacy of aliskiren
 Pharmacokinetics of Aliskiren
 Safety/Tolerability
 Combinations
 End-organ protection
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 Medical condition in which the blood pressure is chronically elevated
 High blood pressure: > 140/90 mmHg
 2 types of hypertension:
Primary (essential) hypertension (90-95%)
no known cause
highly heritable and polygenic
(1),(2)
Secondary hypertension (~10%)
renovascular hypertension
renal disorders
endocrine disorders
other causes
(1) Johnson JA, Turner ST (June 2005). "Hypertension pharmacogenomics: current status and future directions". Current Opinion
in Molecular Therapy 7 (3): 218–225.
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(2) Hideo Izawa; Yoshiji Yamada et al (May 2003). "Prediction of Genetic Risk for Hypertension". Hypertension .
More than a quarter of the world's adult population (972 millions)
1.56 billion by 2025, a 60% increase over the current figure.
Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J, « Global Burden of hypertension : analysis of worldwide
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data », The Lancet, 15th January, 2005, Vol. 365, No 9455, 217-23.
Hypertension: major risk factor for cardiovascular diseases such as stroke,
myocardial infarction, and congestive heart failure
2007 Guidelines for the management of arterial hypertension - European Society of Cardiology and European Society 5of
Hypertension
8x
8
7
Cardiovascular
Mortality
Risk
6
5
4
3
2
1
4x
2x
0
115/75
135/85
155/95
SBP/DBP (mm Hg)
175/105
A 2 mmHg reduction in systolic blood pressure is associated with a 7% risk
reduction in coronary heart disease mortality and a 10% risk reduction in stroke
mortality*
Chobanian AV, Bakris GL, Black HR, et al (December 2003). « Seventh report of the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure » - Hypertension 42 (6): 1206–52
* Lewington S, Clarke R, Qizilbash N, Peto R, Collins Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis
of individual data for one million adults in 61 prospective studies. Lancet 2002;360:1903-13.
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Once-a-day administration
Presence of subclinical
organ damage
Side effects
Possibility of
interactions
Cost
European Society of Cardiology Clinical Practice Guidelines (2007)
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Lifestyle Modifications
Not at Goal Blood Pressure
Initial drug choices
Without Compelling
Indications
Stage 1 Hypertension
Stage 2 Hypertension
(SBP 140–159 or DBP 90–99 mmHg)
Thiazide-type diuretics for most.
May consider ACEI, ARB, BB, CCB,
or combination.
(SBP >160 or DBP >100 mmHg)
2-drug combination for most (usually
thiazide-type diuretic and
ACEI, or ARB, or BB, or CCB)
With Compelling
Indications
Drug(s) for the compelling
indications
Other antihypertensive drugs
(diuretics, ACEI, ARB, BB, CCB)
as needed.
Not at Goal Blood Pressure
Optimize dosages or add additional drugs
until goal blood pressure is achieved.
Consider consultation with hypertension specialist.
European Society of Cardiology Clinical Practice Guidelines (2007)
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« Management of adults with essential hypertension » - Clinical practice guidelines from French « Haute Autorité de
Santé »
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For Individuals With:
Hypertension
(No diabetes or renal disease)
BP Goal:
< 140/90 mmHg
Diabetes Mellitus
< 130/80 mmHg
Renal Disease
< 135/85 mmHg
with proteinuria >1 g/24h or
diabetic kidney disease
<125/75 mmHg
Chobanian AV et al. JAMA. 2003;289:2560–2571.
American Diabetes Association. Diabetes Care. 2002;25:134–147.
National Kidney Foundatrion. Am J Kidn Dis. 2002;39(suppl 1):S1–S266.
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11
Ang II
production
Peripheral
vasoconstriction
& hypertension
PRA
ARBs / ACEIs
BP
Stimulation of
RAS & SNS
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 First new treatment for hypertension in over 10 years
 Double digit drops in blood pressure as monotherapy
 Additional benefits in combination with other antihypertensives
 Blood pressure control beyond 24 hours
 Placebo-like safety and tolerability
 Potential for end-organ protection
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 First new treatment for hypertension in over 10 years
 Double digit drops in blood pressure as monotherapy
 Additional benefits in combination with other antihypertensives
 Blood pressure control beyond 24 hours
 Placebo-like safety and tolerability
 Potential for end-organ protection
15
16
natural substrate
pseudopeptide
IC50≈ nM
No oral bioavailability
17
Elimination of peptidic skeleton
Loss of interactions to compensate …
18
Identification of an
unexpected pocket
Optimisations
S3sp
Aliskiren
IC50≈ nM
Oral bioavailability: 3%
19
Renin: first enzyme in RAAS
Renin cleaves angiotensinogen to
angiotensin I, which is converted by ACE
to angiotensin II
“Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin” - J. Rahuel , V.
Rasetti , J. Maibaum , R. Göschke, N-C. Cohen , S. Stutz , F. Cumin, W. Fuhrer, J.M. Wood and M.G. Grütter
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Aliskiren binds to the S3sp
S3sp is a binding subpocket of renin
essential for its activity
“Structure-based drug design: the discovery of novel nonpeptide orally active inhibitors of human renin” - J. Rahuel , V.
Rasetti , J. Maibaum , R. Göschke, N-C. Cohen , S. Stutz , F. Cumin, W. Fuhrer, J.M. Wood and M.G. Grütter
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 First new treatment for hypertension in over 10 years
 Double digit drops in blood pressure as monotherapy
 Additional benefits in combination with other antihypertensives
 Blood pressure control beyond 24 hours
 Placebo-like safety and tolerability
 Potential for end-organ protection
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Placebo
Aliskiren Placebo
Aliskiren Placebo
-2
Placebo
Aliskiren
Placebo
Aliskiren
systolic
sys
0
Aliskiren
-4
-6
-8
-10
‡
-12
*
-18
n=130
Study 2201
‡
§
*
n=130
**
§
-14
-16
†
n=176
n=175
Study 2203
†
**
n=115
n=113
Study 1201
n=163
n=166
Study 2308
n=192
n=180
Study 2204
Systolic
*: p<0.05 vs. placebo for study 2201; § : p<0.05 vs. placebo for study 2203; ‡ : p<0.0001 vs. placebo for study 1201
†:p<0.0001 vs. placebo for study 2308; ** : p<0.05 vs. placebo for study 2204
Source:
Studies Novartis A2201, A2203, A1201, A2308 and A2204
Diastolic
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 First new treatment for hypertension in over 10 years
 Double digit drops in blood pressure as monotherapy
 Additional benefits in combination with other antihypertensives
 Blood pressure control beyond 24 hours
 Placebo-like safety and tolerability
 Potential for end-organ protection
24
Randomization
Aliskiren 75 mg n=183
Aliskiren 150 mg n=183
Aliskiren 300 mg n= 180
HCTZ 6,25 mg n=188
Washout
Placebo
HCTZ 12,5 mg n=188
HCTZ 25 mg
n=188
Aliskiren 75 mg + HCTZ 6,25 mg n=187
Aliskiren 150 mg + HCTZ 12,5 mg n=184
Aliskiren 300 mg + HCTZ 25 mg n=173
Placebo n= 192
1 week 2 weeks
Oparil S, et al. Lancet 2007.
8 weeks
25
-9
*
-10
*
(3)
n = 184
n = 173
n = 176
(2)
*
*
-13
-15
(1)
*
-12
-14
25 mg
*
*
*
-11
n = 188
6,25 12,5
Combination
n = 187
HCTZ
n = 194
150 300 mg
n = 180
-8
75
n = 183
-7
n = 195
0
Aliskiren
n = 183
Placebo
* : p<0.001 vs. Placebo for Novartis study 2204
(1) = Aliskiren 75 mg + HCTZ 6.25 mg
(2) = Aliskiren 150 mg + HCTZ 12.5 mg
(3) = Aliskiren 300 mg + HCTZ 25 mg
Data on file: Novartis Study A2204
*
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Ang II
production
Peripheral
vasoconstriction
& hypertension
Compensatory
response mechanism
blocked by DRI
PRA
Further
lowering of
BP
ARBs / ACEis
BP
Complementary
mechanism
DRI
Stimulation of
RAS & SNS
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Randomized, double-blind, parallel group, dose escalation study in
837 patients with hypertension and diabetes
Washout
2 weeks
Placebo
2–4 weeks
Uresin Y, et al. 2006 (Study 2307)
Aliskiren 150 mg
Aliskiren 300 mg
n = 282
Ramipril 5mg
Ramipril 10mg
n =278
Aliskiren 150mg +
Ramipril 5mg
Aliskiren 300mg+
Ramipril 10mg
n = 277
4 weeks
4 weeks
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Ramipril 10 mg
n = 278
Aliskiren 300 mg
n = 282
Combination
n = 277
0
dia
sys
dia
sys
dia
sys
-2
-4
mmHg
-6
-8
-10
-12
-10.7
-11.3
-12.0
-12.8
-14
*
-14.7
-16
-16.6
-18
Responder rate* (%)
*
** : p<0.001 vs ramipril alone
* : p< 0.05 vs ramipril alone
**
65.8
73.1
74.1
proportion of patients with mean diastolic pressure <90 mmHg and/or a >10 mmHg decrease from baseline
Uresin Y, Renin Angiotensin Aldosterone Syst 2007; 8; 190 (Study 2307)
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Randomization
Washout
1–2 weeks
Aliskiren 150 mg
n = 437
Aliskiren 300 mg
Aliskiren/valsartan
150/160 mg n = 446
Aliskiren/valsartan
300/320 mg
Valsartan 160 mg
n = 455
Valsartan 320 mg
Placebo
n = 459
Placebo
Placebo
3–4 weeks
Oparil S, et al. Lancet 2007.
4 weeks
4 weeks
Week 8
Endpoint
Change in DBP
(mm Hg)
Change in SBP
(mm Hg)
BP Control Rate
(%)
Aliskiren
Valsartan
Aliskiren +
Valsartan
Placebo
300 mg
n=437
320 mg
n=455
300/320 mg
n=446
n=459
-9.0*†
-9.7*†
-12.2*
-4.1
-13.0*†
-12.8*†
-17.2*
-4.6
37.4 *†
33.8 *†
49.3*
16.5
*p<0.0001 vs. placebo
†p<0.001 vs. aliskiren/valsartan
ACC 2007
Following once-daily treatment with amlodipine 5 mg for 4 weeks, patients whose
hypertension responded inadequately to therapy (mean sitting diastolic blood
pressure [DBP] 90-109 mmHg) were randomized to 6 weeks of double-blind
treatment
Randomization n=545
Aliskiren/amlodipine 150/5 mg
n = 187
Amlodipine 5mg
Amlodipine 10 mg
n = 178
Amlodipine 5mg
n = 180
4 weeks
6 weeks
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Amlodipine
5 mg
Amlodipine
10 mg
Aliskiren 150 mg
+ amlodipine 5 mg
n = 180
n = 178
n = 187
0
dia
sys
dia
-5.0
sys
-5
dia
sys
-4
-4.8
-6
-7
-8
-8.0*
-9
-8.5*
-10
-9.6*
*
-11
**
: p<0.0001 vs. Amlodipine 5 mg
: p<0.0005 vs. Amlodipine 10 mg
-11.0*
Peripheral edema (%)
Novartis Study 2305
3.4
11.2
2.1 **
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 First new treatment for hypertension in over 10 years
 Double digit drops in blood pressure as monotherapy
 Additional benefits in combination with other antihypertensives
 Blood pressure control beyond 24 hours
 Placebo-like safety and tolerability
 Potential for end-organ protection
34
Blood Pressure Lowering in Essential Hypertension With an Oral Renin Inhibitor, Aliskiren - Alice Stanton; Chris Jensen; Juerg
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Nussberger; Eoin O'Brien Hypertension Dec 2003
Aliskiren 75 mg
Aliskiren 150 mg
Aliskiren 300 mg
Losartan 100 mg
0
-0.6
-2
-4
-6
-3.5
-4.7
-5.7
-8
-8.2
-10
-12
-9.4
-10.5
-14
-14.1
-16
Change SBP
Change DBP
Blood Pressure Lowering in Essential Hypertension With an Oral Renin Inhibitor, Aliskiren - Alice Stanton; Chris Jensen
Juerg Nussberger; Eoin O'Brien Hypertension Dec 2003
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100%
n= 56
Trough/peak ratio
Proportion of BP
lowering at the end of
the 24-hour period
(trough) versus the
effect at the peak after
dosing (2hours)
n= 130
80
Study 2308
60
Study 2201
40
20
0
Aliskiren 300mg
2308 data from ambulatory blood-pressure monitoring
2201 peak values taken at 2 hours post-dose
Source: Novartis Study A2308/2201
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 First new treatment for hypertension in over 10 years
 Double digit drops in blood pressure as monotherapy
 Additional benefits in combination with other antihypertensives
 Blood pressure control beyond 24 hours
 Placebo-like safety and tolerability
 Potential for end-organ protection
38
Pharmacokinetics
Bioavailability
2,6%
Half-life
About 40 hours
Steady state
After 7 days
Difference created by
polymorphism
Minimal
Metabolisation
Not metabolised by Cyt P
450
Elimination
Fecal
In Urine 0,6%
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Common
About
1/100
• Gastro-Intestinal
disorders: diarrhoea
40
Type of population
Recommandation
Renal impairment
From mild to several impairment
No adjustment of the initial dose is
required
Hepatic impairment
From mild to several impairment
No adjustment of the initial dose is
required
Elderly patients
( over 65 years )
No adjustment of the initial dose is
required
Pediatric patients
( below 18 years )
Lack of data on safety and efficacy
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 First new treatment for hypertension in over 10 years
 Double digit drops in blood pressure as monotherapy
 Additional benefits in combination with other antihypertensives
 Blood pressure control beyond 24 hours
 Placebo-like safety and tolerability
 Potential for end-organ protection
42
Damage to
circulatory
system
Enlarged
heart
Heart and
blood
vessel
injury
Blood vessel
and kidney malfunction
Heart failure,
kidney failure
and stroke
End-stage
organ failure
Abnormal blood
vessel function
Risk factors:
diabetes,
high blood pressure
Organ
damage
Renin
System
Death
43
Adapted from: Dzau V, et al. Am Heart J 1991;121:1244–63
Ang II
production
Peripheral
vasoconstriction
& hypertension
Compensatory
response mechanism
blocked by DRI
PRA
Potential
end-organ
protection
ARBs / ACEIs
BP
Complementary
mechanism
DRI
Stimulation of
RAS & SNS
44
Plasma Ang II
(pg/mL)
80
PRA
(ng/mL/h)
80
60
60
40
40
20
20
0
0
0 6 12
24
Time (hours)
Azizi et al. J AM Soc Nephrol 2004.
48
Aliskiren 300 mg
Valsartan 160 mg
Aliskiren 150 mg
+ valsartan 80 mg
Placebo
0 6 12
24 30
Time (hours)
48
45
 PRA indicates the capacity of circulating renin to form Ang I
 PRA is associated with the occurrence of cardiovascular
disease among hypertensive patients1
 A 25% increase in the risk of myocardial infarction for every
2 ng/mL/h increase in PRA1
 Increased PRA activates the RAAS leading to increased
generation of Ang II. Ang II is important in the generation of
hypertension and both the short-term and long-term effects
leading to organ damage
1.
2.
Alderman MH, et al. 1997
Burnier M, et al. 2000
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ALLAY
ALOFT
AVOID
ALiskiren in
Left
ventriculAr
hypertrophY
ALiskiren
Observation of
heart Failure
Treatment
Aliskiren in the
eValuation of
prOteinuria In
Diabetes
Aliskiren vs losartan
vs. Combo
Aliskiren vs placebo
added to optimal heart
failure treatment
Aliskiren vs placebo
added to losartan
Primary endpoint:
Left ventricular mass
(and structure) by
magnetic resonance
imaging
Primary endpoint:
Primary endpoint:
Reduction in brain
natriuretic peptide
% reduction urinary
albumin/creatinine
ratio
47
(ALiskiren in Left ventriculAr hypertrophY)
 Primary objective
• Combination of aliskiren and losartan versus losartan
monotherapy in reducing LV mass index in hypertensive
overweight patients
 Key secondary objectives
• Evaluate whether aliskiren monotherapy was non-inferior to
losartan monotherapy in reducing LV mass index
• Safety and tolerability of study treatments
48
Randomized, multicenter (77 centers in 9 countries), double-blind, active-controlled
trial in overweight patients with HT and LV hypertrophy
Randomization
Prior ACEi /ARB
treatment
12 weeks
No prior ACEi /ARB
treatment
2 weeks
Aliskiren 150 mg
Aliskiren 300 mg
Losartan 50 mg
Losartan 100 mg
Aliskiren/Losartan
150/50 mg
Aliskiren/Losartan 300/100 mg
+
Addition of diuretics, and CCBs, -blockers
and/or vasodilators as necessary*
Screening &
washout phases
2 or 12 weeks
Titration phase
2 weeks
Maintenance phase
34 weeks
* To achieve BP target of < 140/90 mmHg (< 130/80 mmHg for patients with diabetes)
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1104 patients were
screened
465 patients were
randomized
Aliskiren
Losartan
Aliskiren/Losartan
n = 154
n = 152
n = 154
• 14 (9.1%) patients
discontinued
• Safety, 4 (2.6%)
• Other, 10 (6.5%)
133 (90.9%) completed
CMR* assessments
• 21 (13.8%) patients
discontinued
• Safety, 10 (6.6%)
• Other, 11 (7.2%)
• 12 (7.8%) patients
discontinued
• Safety, 5 (3.2%)
• Other, 7 (4.6%)
129 (84.9%) completed
CMR * assessments
138 (89.6%) completed
CMR * assessments
* CMR= Cardiac Magnetic Resonance
50
Change in LV Mass Index (g/m2)
0
Aliskiren
Losartan
Combination
n = 132
n = 123
n = 136
-1
-2
All
p < 0.0001
vs baseline
-3
-4
-5
-6
-7
-4.9 ± 1 (-5.4%)
-4.8 ± 1 (-4.7%)
(non-inferiority)
p < 0.0001
-5.8 ± 0.9 (-6.4%)
(superiority)
p = 0.52
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 Aliskiren was as effective as losartan in reducing LV mass over 36
weeks of treatment
 The reduction in LV mass with the combination was not significantly
greater than with losartan alone.
 Aliskiren alone or combined with an ARB was safe and well tolerated
 This study demonstrates that aliskiren is an effective and safe
treatment option in patients with LV hypertrophy.
52
(Aliskiren in the eValuation of prOteinuria
In Diabetes)
Urinary Albumin Creatinine Ratio (UACR) is a Predictor Of kidney
Events Diabetic mellitus
 Continuous relationship between UACR and diabetic
nephropathy
 Suppression of albuminuria is correlated with kidney events in
outcome trials
53
Randomization
Aliskiren 150 mg
Aliskiren 300 mg
n = 301
Placebo
Placebo
n = 298
+
Losartan 100 mg + optimal antihypertensive therapy
Open-label
12–14 weeks
Double-blind
12 weeks
12 weeks
• All patients continue to receive open-label
• All treatments administered once daily
losartan 100 mg and optimal antihypertensive • Patients force-titrated after 12 weeks
therapy during the double-blind period
Parving et al. 2007
54
55
5
+2%
n = 289
0
n = 287
-5
-10
-15
Aliskiren
-20
-18%
New England Journal of Medicine - 358;23 www.nejm.org june 5, 2008
Placebo
n~8,600 patients with CVD and/or diabetic nephropathy
Randomization
Aliskiren
150 mg
Aliskiren 300 mg once daily
Placebo
Conventional treatment
4 – 12 weeks
*ALTITUDE
4 weeks
Composite primary
endpoint (first event)
• CV death
• Resuscitated sudden
death
• Non-fatal MI
• Non-fatal stroke
• Hospitalization for CHF
• Doubling of baseline
serum creatinine
• Onset of ESRD* or
renal death
total follow-up ~4 years*
is an event driven study and will conclude when ~1628 patients meet the primary endpoint
Data on File, Study FIR 2012, Novartis 2007
58
Regional Drug and Therapeutics Centre NEWDRUG EVALUATION No.88 February 2008
59
First new treatment for hypertension in over 10 years
2007: The first-in-class in renin inhibition Tekturna® (aliskiren) is approved by
FDA
The recommanded dose is 150 mg or 300 mg once-daily
Tekturna® (aliskiren) is indicated for the treatment of essential hypertension. It
may be used alone or in combination with other antihypertensive agents.
Hypertension insufficiently
controlled
Therapeutic escape after sustained
use of ACE inhibitors or ARBs
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Special thanks to : Philippe Marboeuf
Helene Gras-Masse
61