nouvelles molécules anti-hypertensives · cinod naproxcinod phase iii nicox * development stopped...
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Stéphane LAURENT, MD, PhD, FESCPharmacology Department, Hôpital Européen Georges P ompidou, Paris Cardiovascular Research Center (P.A.R.C.C.), INSERM U970 Université Paris Descartes, Assistance Publique-Hôp itaux de Paris
Nouvelles molécules anti-hypertensives
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Stéphane LAURENT, MD, PhD
DISCLOSURE
Drug companies
ASTRA-ZENECABAYER-SCHERINGBOEHRINGER-INGELHEIMCHIESIDAICHII-SANKYOESTEVEMENARINIMSDNEGMANOVARTISPFIZERRECORDATISERVIER
ManufacturersALAM MEDICALATCORAXELIFEESAOTE-PIE MEDICALFUKUDA-DENSHIHEMO SAPIENSOMRONTENSIOMED
Potential conflict of interest: Research grant, advisory board, honorarium as speak er or chairman
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Kotchen T. Hypertension 2011
Rate of discovery of antihypertensive agents… a peak during the 1970’s
BBCentrally actingα1 blockersACEICCB
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The 1980’s and 1990’s: two decades of novel ACEIs a nd ARBs
ARB, n=7
1980 20001990
losartancandesartan
eprosartanirbesartan
valsartantelmisartan
olmesartan
ACEI, n=13captopril
enalaprilperindoprillisinopril
ramiprilquinapril
benazeprilcilazapril
fosinopril
zofenopril
trandolapril
moexipril
Date of market authorization in Europe
imidapril
2010
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No novel anti-HT drug during the last 15 years…
…except aliskiren, a renin-inhibitor
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Kotchen T. Hypertension 2011
Still using « old » antihypertensive agents
Thiazides
Spironolactine
BB
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New vasodilators: the pipeline
• Systemic hypertension
• Heart failure
• Pulmonary hypertension
• Chronic kidney disease
• Migraine
• Spasm of cerebral artery after
subarachnoid hemorrage
• Raynaud phenomenon
• ...
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Pharmacological class Drug Pre-clinical stage
Phase I-III Pharmaceutical industry
RERB (renin/prorenin blocker) �
ACE2 activator �
AT2-receptor agonist, non peptide C21 � No anti-HT effectTissue protection
Vicore Pharma
Aminopeptidase A (APA) inhibitor QGC001 � Quantum Genomics Corp.
Vaccine Ang I vaccine PMD3117 Phase II Protherics Inc.
Ang II vaccine Cyt006-AngQb Phase II Cytos Biotechnology AG
Dual AT1R/ETA antagonist (DARAs) PS-433540 Phase II Ligand Pharmaceuticals
Novel dual ARB/partial PPAR γ agonist �
AGE breaker Alagebrium (ALT-711)
Phase II* Synvista Therapeutics
* Development stopped
New drugs for hypertension: most of them target the RAAS (I)Laurent S et al. Lancet 2012
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Pharmacological class Drug Pre-clinical stage
Phase I-III Pharmaceutical industry
Dual vasopeptidase inhibitor
1. Dual NEP/ACE inhibitor Ilepatril – AVE7688 Phase III Sanofi-Aventis
2. Dual NEP/ECE inhibitor Daglutril- SLV306 Phase II* S olvay Pharmaceuticals
Dual ARNI (Dual NEPI/ARB) LCZ696 Phase III Novartis Pharmaceuticals
Aldosterone synthase inhibitor
LCI699 Phase II * Novartis Pharmaceuticals
Endothelin antagonist Bosentan Phase II Actelion Pharmaceuticals
Darusentan Phase III * Gilead Sciences
NO donor NO-releasing drugs
Nitrosyl-cobinamide �
NO-releasing hybrids
NO-losartanNO-telmisartan
�
�
Cayman Chemicals
CINOD Naproxcinod Phase III NicOx
* Development stopped
Laurent S et al. Lancet 2012
New drugs for hypertension: most of them target the RAAS (II)
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Pharmacological class Drug Pre-clinical stage
Phase I-III Pharmaceutical industry
Dual vasopeptidase inhibitor
1. Dual NEP/ACE inhibitor Ilepatril – AVE7688 Phase III Sanofi-Aventis
2. Dual NEP/ECE inhibitor Daglutril- SLV306 Phase II* S olvay Pharmaceuticals
Dual ARNI (Dual NEPI/ARB) LCZ696 Phase III Novartis Pharmaceuticals
Aldosterone synthase inhibitor
LCI699 Phase II * Novartis Pharmaceuticals
Endothelin antagonist Bosentan Phase II Actelion Pharmaceuticals
Darusentan Phase III * Gilead Sciences
NO donor NO-releasing drugs
Nitrosyl-cobinamide �
NO-releasing hybrids
NO-losartanNO-telmisartan
�
�
Cayman Chemicals
CINOD Naproxcinod Phase III NicOx
* Development stopped
New drugs for hypertension (II)
Laurent S et al. Lancet 2012
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Pure and dual NEP inhibitors
Pure NEP inhibitors
candoxatril Pfizer
ecadotril Bioprojet
thiorphan Bioprojet
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Vasopeptidase inhibitors (VPI) Dual NEP/ACE inhibitors
Metabolites
� vasodilatation� Na excretion� antihypertrophic effect� antifibrotic effect
� vasoconstriction � Na retention� pro-hypertrophic effect� pro-fibrotic effect
� Ang II� Ang II <
Synergistic effect on BP loweringand reduction of target organ damage
Risk of angioedema
Ang I
ACE inhibitionNEP inhibition
NEP ACE
O� Natriuretic peptides
(ANP, BNP,…)
Ang II
Counter-regulation with pure NEP inhibitors
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Vasopeptidase inhibitors (VPI) Dual NEP/ACE inhibitors
Metabolites
� vasodilatation� Na excretion� antihypertrophic effect� antifibrotic effect
� vasoconstriction � Na retention� pro-hypertrophic effect� pro-fibrotic effect
� Ang II� Ang II <
Synergistic effect on BP loweringand reduction of target organ damage
Risk of angioedema
Ang I
ACE inhibitionNEP inhibition
NEP ACE
O� Natriuretic peptides
(ANP, BNP,…)�
Ang II
Weak antihypertensive effectand protection of target organs
� Ang II� SNS� ET-1
Counter-regulation with pure NEP inhibitors
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Vasopeptidase inhibitors (VPI) Dual NEP/ACE inhibitors
Metabolites
� vasodilatation� Na excretion� antihypertrophic effect� antifibrotic effect
� vasoconstriction � Na retention� pro-hypertrophic effect� pro-fibrotic effect
� Ang II� Ang II <
Synergistic effect on BP loweringand reduction of target organ damage
Risk of angioedema
Ang I
ACE inhibitionNEP inhibition
NEP ACE
O� Natriuretic peptides
(ANP, BNP,…)�
Ang II
� Ang II
Counter-regulation with pure NEP inhibitors
Inhibition of ANB/BNP-induced intracellular signaling
Weak antihypertensive effectand protection of target organs
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Pure and dual NEP inhibitors
Pure NEP inhibitors
candoxatril Pfizer
ecadotril Bioprojet
thiorphan Bioprojet
Dual NEP/ACE inhibitors
omapatrilat BMS
Ki NEP 8.9 nM , Ki ECA 6.0 nM
fasidotril, alatriopril BioprojetKi NEP 5.1 nM , Ki ACE 9.8 nM
sampatrilat Pfizer
Also: BMS-SanofiMerrel-DowNovartisScheringZambon
Neprilysin
ACE
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Dual NEP/ACE inhibitors
Metabolites
� vasodilatation� Na excretion� antihypertrophic effect� antifibrotic effect
� vasoconstriction � Na retention� pro-hypertrophic effect� pro-fibrotic effect
� Ang II� Ang II� Natriuretic peptides(ANP, BNP,…)
<
Synergistic effect on BP loweringand reduction of target organ damage
Risk of angioedema
Ang I
ACE inhibitionNEP inhibition
� Bradykinin
NEP
Metabolites
ACE
Metabolites
Vasopeptidase inhibitors (VPI) Dual NEP/ACE inhibitors
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Antihypertensive effects of fasidotrilin low - and high-renin hypertension in rat
Model HypertensionGoldblatt 2K-1Clip renin-dependentDOCA-sel volume-dependentSHR renin > volume
Laurent S et al. Hypertension 2000
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• Dual NEP/ACE inhibitorACE Ki = 6 nMNEP Ki = 9 nM
• Orally active
• Antagonises the BP response
to Ang I in rats
• Enhances the natriuretic effectof ANP in rats
• Lowers BP in different animal modelsof hypertension independently
of the renin status
• Increases urine ANP concentrations inhumans dose-dependently
Omapatrilat
*
HS
O
NH O
N
HS
CO2H
*
-32
-28
-24
-20
-16
-12
-8
-4
0
placebo Oma 10mg
Oma 20mg
Oma 40mg
DBPSBPPP
Changes in trough BP at week 9 (mmHg)
*
* **
*
Larochelle et al. Am J Hypertens. 2003
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Dual NEP/ACE inhibitors
Vasopeptidase inhibitors (VPI) Dual NEP/ACE inhibitors
Metabolites
� vasodilatation� Na excretion� antihypertrophic effect� antifibrotic effect
� vasoconstriction � Na retention� pro-hypertrophic effect� pro-fibrotic effect
� Ang II� Ang II� Natriuretic peptides(ANP, BNP,…)
<
Synergistic effect on BP loweringand reduction of target organ damage
Risk of angioedema
Ang I
ACE inhibitionNEP inhibition
� Bradykinin
O
NEP
Metabolites
ACE
Metabolites
↘ kininase II↘ NEP
↘ aminopeptidase P
� Bradykinine
O
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Omapatrilat(n=12,609)
Enalapril(n=12,557)
Absolute difference
No treatment, or treated with antihistamines only
162 (1.28%) 65 (0.52%) 0.76%
Treated with epinephrine or steroids; no airway compromise
110 (0.87%) 21 (0.17%) 0.71%
Airway compromise 2 0 _
TOTAL 274 86 _
OCTAVE: Severity of angioedema
Kostis JB et al. Am J Hypertens. 2004
Double-blind, randomized, multicenter, parallel groups, 6 months
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In vitro inhibitory effects of AVE 7688 (Ilepatril)
and omapatrilat on ACE and NEP
AVE 7688 IC50 ACE 0.052 nM(Ilapatril) IC 50 NEP 5 nM
ratio ACE/NEP 0.01
Omapatrilat Ki ACE 6 nMKi NEP 8.9 nM
ratio ACE/NEP 0.67
Ilepatril, AVE 7688
Adam et al., 2004
Omapatrilat
AVE 7688(AVE8048)
6 100 000 nM
IC50
66 nM
human aminopeptidase P (APP)
Apstatin(a specific APP inhibitor)
2 300 nM
M100240(MDL100,173)
18 000 nM
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Ilepatril: intensity and duration of ACE inhibition by comparison to other ACEIs or VPI
0 1 2 4 6 9 12 24
0
20
40
60
80
100
AVE25
F20-2
O 40O 80
O 10
E10E20
Cushman assay
AVE25 LS
AVE5
R10
Time (h)
AC
E a
ctiv
ity (
mU
/ml)
Azizi M et al. Unpublished data
Azizi M et al. Clin Pharm Ther 2006
AVE = IlepatrilO= Omapatrilat
EnalaprilRamipril
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Ilepatril: intensity and duration of ACE inhibition by comparison to other ACEIs or VPI
0 1 2 4 6 9 12 24
0
20
40
60
80
100
AVE25
F20-2
O 40O 80
O 10
E10E20
Cushman assay
AVE25 LS
AVE5
R10
Time (h)
AC
E a
ctiv
ity (
mU
/ml)
Azizi M et al. Unpublished data
Azizi M et al. Clin Pharm Ther 2006
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Pharmacological class Drug Pre-clinical stage
Phase I-III Pharmaceutical industry
Pure NEP inhibitor
Dual vasopeptidase inhibitor
1. Dual NEP/ACE inhibitor Ilepatril – AVE7688 Phase III * Sanofi-Aventis
2. Dual NEP/ECE inhibitor Daglutril- SLV306 Phase II* S olvay Pharmaceuticals
Dual ARNI (Dual NEPI/ARB) LCZ696 Phase IV Novartis Pharmaceuticals
Aldosterone synthase inhibitor LCI699 Phase II * Novartis Pharmaceuticals
Endothelin antagonist Bosentan Phase II Actelion Pharmaceuticals
Darusentan Phase III * Gilead Sciences
NO donor NO-releasing drugs
Nitrosyl-cobinamide
�
NO-relasing hybrids
NO-losartanNO-telmisartan
�
�
Cayman Chemicals
CINOD Naproxcinod Phase III NicOx* Development stopped
3 pharmacological classes around NEP inhibitionLaurent S et al. Lancet 2012
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LCZ696: a dual-acting inhibitor of the angiotensin II receptor and neprilysin (dual ARNi)
Single molecule in which the molecular moieties of valsartan and the
molecular moieties of the NEP inhibitor prodrug AHU377 are present in
a 1:1 molar ratio.
Gu J et al. J Clin Pharmacol, 2010
Valsartan + Sacubitril (AHU377, prodrug of LBQ657)Valsartan
AHU377
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� vasoconstriction � Na retention� pro-hypertrophic effect� pro-fibrotic effect
� vasodilatation� Na excretion� antihypertrophic effect� antifibrotic effect
Synergistic effects on BP lowering
and reduction of target organ damage
� Natriuretic peptides(ANP, BNP,…) AT1R
LCZ696: a dual-acting inhibitor of the Angiotensin II Receptorand Neprilysin (dual ARNi)
AT1R blockadeNEP inhibition
Dual Acting ARNi
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Effects of AHU377 and LCZ696 on SBP in 1085 mild to moderate hypertensive patients
Ruilope LM et al. Lancet 2010
Phase III, randomised, parallel-group, double-blind multicenter trial
Grade I-II hypertensionn=1328Age 18-75
Office BP
Equipotent ARB doses
AHU 200 mg # LCZ 400 mgfor NEPI
Duration 8 weeks
AHU200
LCZ400
Vals320
LCZ200
Vals160
LCZ100
Vals80
Pla
ceb
o-c
orr
ect
ed
ch
an
ge
in
SB
P (
mm
Hg
)
Placebo-corrected change in SBP (mmHg)
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Dual ARNi vs dual NEP/ACE inhibitorsLess increase in BK � less risk of angioedema
↘ NEP
� Bradykinine
↘ aminopeptidase P
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www.clinicaltrials.org
LCZ696: RCTs (March 2017)
n= 51 RCTs
n= 18 hypertensionincluding 5 in Asia/Japan
n= 24 completed
n= 1 hypertension
n= 27 ongoing
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Pbo AHU377 LCZ696 LCZ696 LCZ696 Vals. Vals. Vals.
100 mg 200 mg 400 mg 80 mg 160 mg 320 mg
Any AE 49 (28%) 45 (27%) 36 (23%) 40 (24%) 50 (29%) 36 (22%) 34 (20%) 38 (23%)
Diarrhoea 3 (2%) 3 (2%) 2 (1%) 0 5 (3%) 1 (1%) 1 (1%) 3 (2%)
Back pain 2 (1%) 3 (2%) 1 (1%) 1 (1%) 4 (2%) 3 (2%) 1 (1%) 1 (1%)
Bronchitis 4 (2%) 2 (1%) 1 (1%) 0 4 (2%) 3 (2%) 4 (2%) 1 (1%)
Cough 2 (1%) 2 (1%) 1 (1%) 2 (1%) 4 (2%) 2 (1%) 0 1 (1%)
Dizziness 2 (1%) 0 1 (1%) 1 (1%) 1 (1%) 0 1 (1%) 3 (2%)
Dyspepsia 0 0 1 (1%) 0 3 (2%) 1 (1%) 0 0
Headache 13 (8%) 5 (3%) 4 (3%) 4 (2%) 4 (2%) 5 (3%) 4 (2%) 3 (2%)
Influenza 3 (2%) 1 (1%) 3 (2%) 2 (1%) 3 (2%) 2 (1%) 1 (1%) 4 (2%)
Nasopharyngitis 3 (2%) 3 (2%) 5 (3%) 2 (1%) 2 (1%) 3 (2%) 2 (1%) 2 (1%)
Pruritus 0 2 (1%) 0 4 (2%) 1 (1%) 2 (1%) 0 0
Pharyngitis 4 (2%) 1 (1%) 2 (1%) 1 (1%) 0 0 0 1 (1%)
Sinusitis 2 (1%) 2 (1%) 3 (2%) 0 1 (1%) 2 (1%) 1 (1%) 2 (1%)
URTI 0 2 (1%) 2 (1%) 0 1 (1%) 2 (1%) 3 (2%) 2 (1%)
GI 0 1 (1%) 0 1 (1%) 3 (2%) 1 (1%) 1 (1%) 1 (1%)
No episode of angioedema …but n=3 expected at a rate of 0.5%
Safety of AHU377 and LCZ696in 1085 mild to moderate hypertensive patients
Ruilope LM et al. Lancet 2010
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Antihypertensive efficacy of LCZ696in 389 mild to moderate Asian hypertensive patients
Kario K et al. Hypertension 2014
Phase III, randomised, parallel-group, double-blindmulticenter trial
Grade I-II hypertensionn=389Age 18-75
ABPM
Asian populationJapan, China, Korea, Taiwan, Thailand
Duration 8 weeks
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www.clinicaltrials.org
LCZ696: RCTs (March 2017)
n= 51 RCTs
n= 18 hypertensionincluding 5 in Asia/Japan
n= 1 HFpEF
n= 2 HFrEF
n= 2 aortic stiffness
n= 24 completed
n= 1 hypertension
n= 3 CHF, HeFPef
n= 16 HFrEF
n= 27 ongoing
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Volpe et al. Eur Heart J 2014
The system of natriuretic peptides as an emerging t arget
for the treatment of heart failure and hypertension
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PARAMOUNT
Lancet 2012
Phase II, randomised, parallel-group, double-blindmulticenter trial
Proof of concept in HFpEF
NYHA class II-III heart failure+ LVEF > 45%+ NT-proBNP > 400 pg/ml
n= 149, LCZ696 up to 200 mg bid
n=152, valsartan up to 160 mg bid
Equipotent ARB doses
Duration 36 weeks (9M)
NT-proBNP, surrogate for HF
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PARAMOUNT
Lancet 2012
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PARAGON-HF Experimental design (clinicaltrials.gov)
Phase III, randomised, parallel-group, double-blind multicenter trial
End point study in HFpEF
Age > 55 yrsNYHA class II-IV heart failure with Preserved Ejection Fraction (LVEF > 45%)
Total number of patients 4300
LCZ696 100 mg bidValsartan 80 mg bid
FU up to 57 months
Primary end-pointCV death + hosp. for CHF
Expected primary completion : May 2019
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HR=0.80, P<0.001
Primary end-point
PARADIGM-HF
McMurray JJV et al. NEJM 2014
Phase III, randomised, parallel-group, double-blind multicenter trial
End point study in HFrEF
NYHA class II-IV heart failureLVEF < 40% and then < 35%NT-proNBP > 600 pg/ml
n = 4187 LCZ696 200 mg bidn = 4212 Enalapril 10 mg bid
Median FU 27 months
Primary end-pointCV death + hosp. for CHF
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HR=0.80, P<0.001 HR=0.80, P<0.001
Primary end-point Death from CV cause
PARADIGM-HF
McMurray JJV et al. NEJM 2014
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McMurray JJV et al. NEJM 2014
PARADIGM-HF
HR=0.79, P<0.001 HR=0.84, P<0.001
Hospitalization for heart failure Death from any cause
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PARADIGM-HF
Adverse effects
>>
<
<<
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PARADIGM-HF
Adverse effects and angioedema: no significant diff erence
n=19 n=10
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PARADIGM-HF
Adverse effects and angioedema: no significant diff erence
n=19 n=10
The benefit / risk ratio is very much in favor
of the benefit in very high risk patients
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NEP inhibitors
- 30 years of research and development until the PARADIGM study …
- Effective when combined with an angiotensin II AT1-R antagonist
- A promising novel pharmacological class for heart failure
- Angioedema remain a matter of concern and require a close follow-up in hypertensive patients
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Pharmacological class Drug Pre-clinical stage
Phase I-III Pharmaceutical industry
RERB (renin/prorenin blocker) �
ACE2 activator �
AT2-receptor agonist, non peptide C21 � No anti-HT effectTissue protection
Vicore Pharma
Aminopeptidase A (APA) inhibitor QGC001 � Quantum Genomics Corp.
Vaccine Ang I vaccine PMD3117 Phase II Protherics Inc.
Ang II vaccine Cyt006-AngQb Phase II Cytos Biotechnology AG
Dual AT1R/ETA antagonist (DARAs) PS-433540 Phase II Ligand Pharmaceuticals
Novel dual ARB/partial PPAR γ agonist �
AGE breaker Alagebrium (ALT-711)
Phase II* Synvista Therapeutics
Additional novel drugs for hypertension (II)
* Development stopped
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Non peptide agonists and antagonists of the angiotensin II AT1 and AT2 receptors
L-163,491AT1-R agonist
LosartanAT1-R antagonist
Compound 21AT2-R agonist
PD 123,319AT2-R antagonist
AT1-R AT1-R AT2-R AT2-R
+ +- -
Wan et al. J Med Chem 2004
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Compound 21 = first non peptide selective
angiotensin II AT2 receptor agonist
Ki value = 0.4 nM for the AT2 receptor
Ki >10 µM for the AT1 receptor
Oral bioavailability = 20-30%
Half-life # 4 h in rat
Compound 21, a selective agonist of angiotensin AT2 receptors
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AT2-R mediated molecular pathways involved in tissu e injurySteckeling UM et al. Curr Hypertens Rep 2014
AT2-receptor stimulation - prevents hypertensive end-organ damage- improves neurological outcome after stroke - prevents pulmonary hypertension in a pulmonary fibrosis model
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C21, an AT2-R agonist, is not a BP lowering drugPaulis L, … Steckeling UM. Hypertension 2012
L-NAME + Olmesartan
L-NAME + C21
L-NAME = inhibitor of constitutive NO synthase (NOS)
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Effects of AT2-R stimulation on the rat aortaPaulis L, … Steckeling UM, Hypertension 2012
* Disproprotionate to the reduction in MBP
*
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Effects of AT2-R stimulation on the rat aortaPaulis L, … Steckeling UM, Hypertension 2012
LNAME LN+C21 LN+Olm+C21
* Disproprotionate to the reduction in MBP
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AT2-R mediated molecular pathways involved in tissu e injurySteckeling UM et al. Curr Hypertens Rep 2014
AT2-receptor stimulation - prevents hypertensive end-organ damage- improves neurological outcome after stroke - prevents pulmonary hypertension in a pulmonary fibrosis model
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Pharmacological class Drug Pre-clinical stage
Phase I-III Pharmaceutical industry
RERB (renin/prorenin blocker) �
ACE2 activator �
AT2-receptor agonist, non peptide C21 � No anti-HT effectTissue protection
Vicore Pharma
Aminopeptidase A (APA) inhibitor QGC001 � Quantum Genomics Corp.
Vaccine Ang I vaccine PMD3117 Phase II Protherics Inc.
Ang II vaccine Cyt006-AngQb Phase II Cytos Biotechnology AG
Dual AT1R/ETA antagonist (DARAs) PS-433540 Phase II Ligand Pharmaceuticals
Novel dual ARB/partial PPAR γ agonist �
AGE breaker Alagebrium (ALT-711)
Phase II* Synvista Therapeutics
Additional novel drugs for hypertension (II)
* Development stopped
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Gao J et al, Clinical Science 2014
Aminopeptidase A (APA)
- membrane bound zinc metalloprotease
- involved in the metabolism of Ang II ad Ang III
- can be blocked in vivo (PNAS 1999)
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Brain Renin-Angiotensin System
Gao J et al, Clinical Science 2014
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Gao J et al, Clinical Science 2014
XQGC001
APA �Baroreflex ?
�Sympathetic tone to arterioles and heart
�Vasopressine release
� Diuresis� Blood pressure
QGC001, an orally active APA inhibitor (BAPAi),
is a centrally acting antiHT
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Orally active QGC001 is a pro-drug, generating 2 ac tive
molecules of APA inhibitor (EC33)
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Change in BP in conscious SHR after oral RB150 or e nalapril
Marc Y et al, Hypertension 2012
• RB150 (= QGC001) does not modify the systemic RAS activity• RB150 (= QGC001) might be used in combination with classic RAS blockers
to improve BP control
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Phase I study: Single oral administration of QGC001 on supine BP
Balavoine F et al, Clin Pharmacokinet 2014
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www.clinicaltrials.org
QGC001, APA inhibitor: ongoing RCTs (March 2016)
n= 3 RCTs
n= 2 completed
Phase I, healthy volunteers
n= 1 ongoing
Phase IIa, essential hypertension
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New drugs for hypertension: conclusion
• The pipeline is not dry….
• Several novel pharmacological classes are in development, with first-in-class molecules reachingphase II and III
• …but the development of some promising novel drugs has been stopped
• A gap of few years is expected before leading compounds of novel pharmacological classes are marketed
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New drugs for hypertension: conclusion
• The pipeline is not dry….
• Several novel pharmacological classes are in development, with first-in-class molecules reachingphase II and III
• …but the development of some promising novel drugs has been stopped
• A gap of few years is expected before leading compounds of novel pharmacological classes are marketed
• Huge efforts have been made to synthesize novel molecules either combining the beneficial effects of known pharmacological classes or addressing an entirely novel mechanism of action
• These efforts may not only benefit to hypertensive patients …
• …but also to patients suffering from other disease (Pulmonary Hypertension,
CHF, Cushing syndrome)
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Merci !