Acute Heart Failure , Ularitide this time it is different.

1. Emerging Therapies in AHF:
Ularitide
Stefan D. Anker
Innovative Clinical Trials, University Medicine Göttingen (UMG)
at Göttingen, Germany
s.anker@cachexia.de
Sevilla, 23 May, 2015
Conflict of Interest:
Consultancy, honoraria for speaking and/or research grants from
Bayer, BG Medicine, BioVentrix, Brahms GmbH, Cardiorentis,
LonestarHeart, Novartis, Vifor.

2. ASCEND-HF: Death from any cause or
rehospitalization for HF at 30 days
O’Connor et al. NEJM 2011

3. Native natriuretic peptides
First generation
chimeric peptides
Ularitide

4. Synthesis Sites of the Natriuretic Peptides
DR I
M
K
R
G
SSS
S
G
L
GF
C CS S
G
SGQVM
K V LRR
H
KPS
NH2
HOOC-
Thr
Ala
ProArgSer
Leu
Arg
Arg
Tyr
Arg
Phe
Ser
Asn
Cys
Gly
Leu
GlySerGin
Ala
Gly
IIe
Arg
Asp
MetArgGly
Gly
Phe
Cys
Ser
Ser
S
S
NH2N-
COOH-
NH2N-Ser
Leu
Arg
Arg
Ser
SerCys
Phe
Gly
Gly Arg
Cys
Gly
Arg
Tyr
Asn
Phe
Ser
Gly
Leu
SerGin
Ala
Gly
IIe
Arg
Asp
Met
COOH-
S
S
ANP
BNP
Urodilatin

5. Urodilatin is synthesized in
the distal tubulus cells

is luminally secreted

binds downstream in
inner medullar-collecting
duct to NPR-A and acts
via cGMP

and inhibits
Na-reabsorption
Physiology of Urodilatin (INN: Ularitide)
NPR-A
Natriuresis
Diuresis

6. Summary of the Pharmacological
Effects of Ularitide
Hemodynamic (vasodilation)
• veins
• arteries
Neurohumoral
¯RAAldosterone
¯Endothelin
diuresis
natriuresis
Renal


Thr
Ala
Pro
Arg Ser
Leu
Arg
Arg
Tyr
Arg
Phe
Ser
Asn
Cys
Gly
Leu
Gly Ser Gin
Ala
Gly
IIe
Arg
Asp
Met
ArgGly
Gly
Phe
Cys
Ser
Ser
S
S
NH2
Bronchodilation
Flüge T, Regul.Pept.
1995;59:357-70.
Carstens JT, Clin Sci. 1997;92:397-407
Bestle, MH, Am J Physiol, 1999, R684-R695
Carstens JT, Clin Sci.
1997;92:397-407
Bestle, MH, Am J Physiol,
1999, R684-R695
Carstens JT, Clin Sci. 1997;92:397-407
Bestle, MH, Am J Physiol, 1999, R684-R695

7. SIRIUS I Trial – Study Design
Design:
• In total, 24 patients with decompensated heart failure requiring
hospitalisation as well as right heart catheterisation were included into the
study (6 pts in each group)
• Infusion of Ularitide 7.5, 15, and 30 ng/kg body weight/min, or placebo
over 24 hours
Main Inclusion Criteria
• Symptomatic, decompensated chronic heart failure
• Dyspnea at rest or during minimal activity
• PCWP  18 mmHg, CI  2.5 l/min/m2
Primary Endpoints:
• Change in PCWP at 6 hrs compared to placebo
• Change in patient-assessed dyspnea at 6 hrs compared to placebo
Mitrovic et al, Am Heart J, 2005, 150: 1239
Am Heart J 2005; 150:1239.e1-1239.e8

8. SIRIUS I – PCWP is ReducedPCWPChangefronBaseline(mmHg)
Time (h)
control
30 ng/kg/min
15 ng/kg/min
7,5 ng/kg/min
PCWP = pulmonary capillary wedge pressure
Primary
Endpoint at 6
hours
(n=6 per group)
Am Heart J 2005; 150:1239.e1-1239.e8

9. SIRIUS II Trial – Study Endpoints
Design:
• Infusion of Ularitide 7.5, 15, and 30 ng/kg body weight/min, or placebo
over 24 hours
• In total, 221 patients with decompensated heart failure requiring
hospitalisation as well as right heart catheterisation were included into the
study (6 pts in each group)
Main Inclusion Criteria:
• Symptomatic, decompensated chronic heart failure
• Dyspnea at rest or during minimal activity
• PCWP  18 mmHg, CI  2.5 l/min/m2
Primary Endpoints:
• Change in PCWP at 6 hrs compared to placebo
• Change in patient-assessed dyspnea at 6 hrs compared to placebo
Placebo: 53 pts 7.5 ng: 60 pts 15 ng: 53 pts 30 ng: 55 pts
EHJ 2006; 27:2823–2832

10. Baseline Characteristics
SIRIUS II
N=221
LIDO
N=203
VMAC
N=204
Age (yrs) 60 58 62
Male (%) 70 91 73
PCWP (mmHg) 26 25 28
CI (L min-1m-2) 1.9 1.9 2.2
RAP (mmHg) 10.0 10.4 15
Syst. BP (mmHg) 125 112 120
PCWP = pulmonary capillary wedge pressure
CI = cardiac index
RAP = right atrial pressure
Sys BP= systolic blood pressure
EHJ 2006; 27:2823–2832

11. *p<0.05 vs placebo
24 hrs
6 hrs
%Patients
0
10
20
30
40
50
60
70
Placebo
*
* *
*
*
*
7.5
ng/kg/min
15
ng/kg/min
30
ng/kg/min
SIRIUS II Trial – Patient-Assessed Dyspnea
Proportion Moderately or Markedly Better
PCWP = pulmonary capillary wedge pressureEHJ 2006; 27:2823–2832

12. Ularitide improves the Cardiac Index
Time (Hours)
-1 0 1 2 4 6 8 24 26
1.8
2.0
2.2
2.4
CI(l/min/m2)
*
*
* *
*
*
**
† †
† Placebo
7.5 ng /kg/min
15 ng /kg/min
30 ng /kg/min
Ularitide Decreases Myocardial Consumption (Change from BL)
Placebo
7.5 ng /kg/min
15 ng /kg/min
30 ng /kg/min
EHJ 2006; 27:2823–2832

13. SIRIUS II Trial – Ularitide Reduces PCWP
Primary Endpoint at 6 hours
Placebo
7.5 ng /kg/min
15 ng /kg/min
30ng /kg/min
* p<0.01 vs Placebo
*
*
*
*
*
*
*
*
*
*
*
*
†
† p<0.05 vs Placebo
- 12
- 10
- 8
- 6
- 4
- 2
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time (Hours)
PCWP(mmHg)
†
†
†
PCWP = pulmonary capillary wedge pressure
EHJ 2006; 27:2823–2832

14. Ularitide does not worsen renal function
– analyses through 72 hours –
1000
1200
1400
1600
1800
2000
2200
2400
ml/24h
Placebo 7.5 15 30
Urine Output / 24 h
-8
-7
-6
-5
-4
-3
-2
-1
0
1
2
ml/min
 Creatinine Clearance
Placebo 7.5 ng 15 ng 30 ng
24 h
48 h
72 h
Total Incidences of
Creatinine Increases (> 25%)
%Patients
0
5
10
15
20
25
30
Placebo 7.5 ng 15 ng 30 ng
 Serum Creatinine
-0.10
-0.05
0.00
0.05
0.10
0.15
0.20
Placebo 7.5 15 30
mg/dL
EHJ 2006; 27:2823–2832

15. SIRIUS-II – Safety Results
30 d Mortality
13.2
3.3 3.8
1.8
0
5
10
15
%ofpatients
Placebo 7.15 15 30
Ularitide, ng/kg/min
Serious adverse events
up to 30 d
17
8.3
9.4
10.9
0
5
10
15
20
%ofpatients
Placebo 7.15 15 30
Ularitide, ng/kg/min
EHJ 2006; 27:2823–2832

16. The TRUE-AHF programme:
Ularitide in patients with AHF
shifting a paradigm

17. • Multicenter, randomized, double blind, placebo-controlled trial, to evaluate the
efficacy and safety of intravenous (IV) ularitide in patients suffering from AHF
• Patient enrolment has started across approximately 190 centres in the US,
Europe and Canada
• Treatment: placebo or ularitide (15 ng/kg/min), 48 hrs. on top of standard care
• Patients: up to 4,304 patients with AHF, randomisation 1:1
• Screening: AHF, symptoms at rest, congestion, SBP ≥116mmHg, BNP ≥500 or
NT-BNP ≥2000 pg/mL, GFR ≥30, Furosemide i.v. bolus ≥40mg
Placebo i.v. (n=1,076–2,152)
Ularitide i.v. (n=1,076–2,152)

18. TRUE-AHF – Key Efficacy Measures
Primary
Endpoint
Secondary
Endpoint
2,157 patients recruited as off 20th May, 2015

19. TRUE-AHF
finished
recruitment

20. Thank you !