serelaxin in acute heart failure

John R. Teerlink, MD FACC, FAHA, FESC, FRCP(UK)

Professor of Medicine, University of California San Francisco

Director, Heart Failure and Director, Echocardiography

San Francisco VA Medical Center

16.March, 2015

San Diego, CA

UC SF

Treatment Strategies for Hospitalized Heart Failure Patients:

Should We All RELAX?

Serelaxin in Acute Heart Failure

Treatment Strategies for Hospitalized

Heart Failure Patients

Improve Cardiac Performance without Serious

Adverse Effects

• Nitroxyl donors (CXL-1427)1

• Cardiac myosin activators (Omecamtiv mecarbil)2

1 Sabbah HN, et al. Circ Heart Fail. 2013;6:1250-58. Gheorghiade M, et al. Eur J Heart Fail. 2013;15:679–89. 2 Teerlink JR, et al. Lancet. 2011;378: 667–75. Cleland JGF, et al. Lancet. 2011;378: 676–83.

Treatment Strategies for Hospitalized

Heart Failure Patients

Vasodilators with Demonstrated Clinical Benefits

• TRV027: Angiotensin Type 1 receptor biased-ligand 1

• Ularitide: synthetic urodilatin 2

• Serelaxin: recombinant human relaxin-2

(Pre-RELAX-AHF; RELAX-AHF) 3

1 Soergel D, et al. J Clin Pharmacol. 2013;53:892-9. 2 Mitrovic V, et al. Am Heart J. 2005;150:1239. Mitrovic V, et al. Eur Heart J. 2006; 27:2823–32. 3 Teerlink JR, et al. Lancet. 2009; 373: 1429–39. Teerlink JR, et al. Lancet. 2013;381:29-39.

• Insulin-like protein

• Naturally-occurring peptide

• Found in men and women

• Normal hormone of pregnancy

• Women “exposed” for 9 months to

increased plasma concentrations:

0.8-1.6 ng/ml pregnancy*

• Benign safety profile

Relaxin

*Szlachter et al. Obstet & Gynecol 1982;59:167-70; Stewart et al. J Clin Endocrinol Metab 1990;70:1771-3.

Relaxin

• Onset of hemodynamic changes coincident with relaxin-2 elevation during 1st trimester of pregnancy;

similar but smaller changes observed during the luteal phase of menstrual cycle

• Systemic and renal vasodilation occur in parallel, a unique facet of pregnancy

• Systemic and renal hemodynamics recapitulated in rodent models using serelaxin and similar effects

observed in human studies

Maternal Hemodynamic Adaptations to Pregnancy PARAMETER PREGNANCY

Systemic vascular resistance (dyn.s.cm2) 30%

Cardiac output (L/min) 20%

Global arterial compliance (mL/mm Hg) 30%

Renal vascular resistance (dyn.s.cm2) 20%

Renal blood flow (mL/min/1.73m2) 50-85%

Creatinine clearance (mL/min/1.73m2) 40-65%

(Baylis, C. Am J Kid Dis 1999; Schrier, RW, et al. Am J Kid Dis 1987; Jeyabalan, A, et al. Adv Exp Med Biol 2007)

*Selective dilation of pre-constricted vessels; AHF=acute heart failure; ECM=extracellular matrix; ET-1=endothelin-1; GFR=glomerular filtration rate; NO=nitric oxide; RBF=renal blood flow; SVR-systemic vascular resistance

Serelaxin has potential multi-mechanistic effects which may address

the pathophysiology of AHF

Serelaxin

Adapted from Du et al. Nat Rev Cardiol 2010;7:48–58

Remodeling

↓ Fibrosis

↑ ECM remodeling 3

↑ Matrix

metalloproteinases

↓ Vessel stiffness

↓ Collagen synthesis

↑ Collagen breakdown

↑Tissue healing

↓ Inflammation

↑ Cell survival

↑ Cell preservation 2

↓ Inflammatory cell

infiltration

↓ Oxidative stress

↑ Angiogenesis

↑ Stem cell survival

↓ Oxidative stress

↓ Apoptosis

↓ Ca2+ overload

↓ Infarct size

Vasorelaxation*

↓ Myocardial overload; ↑

Renal function 1

↑ Endothelial NO*

↓ SVR, ↑ RBF, ↑ GFR

↓ ET-1

Volume redistribution

Pre-RELAX-AHF: Main Conclusions • 234 patient, dose finding Phase II study

• With optimal dose across multiple clinical outcome

domains was 30mcg/kg/d serelaxin had trends to:

Teerlink JR, et al. Lancet 2009;373:1429–1432.

- Improved dyspnea relief/

clinical course

- Decreased congestion

- Reduced diuretic use

- Less worsening heart failure

- Shorter length of stay

- Reduced days alive out of

hospital

- ??? Improved cardiovascular

and all-cause survival

• No significant adverse events

• No hypotension SAEs; Hypotension AEs similar to placebo

*p=0.04 vs placebo

*

Pre-RELAX-AHF:

CV Deaths to Day 180 Serelaxin 30 μg/kg/d*

Serelaxin 10 μg/kg/d



Placebo

Teerlink JR, et al. Lancet 2009;373:1429–1432.

Post-discharge evaluation period

Placebo (n=580)

Serelaxin 30 µg/kg/d (n=581)

0 6 12 24 48 h 5 d 14 d 60 d 180 d

48 h study drug

infusion period

Screening

Double-blind, randomized treatment and follow up period

Presentation <16 h

1,161 patients

hospitalized for AHF

RELAX-AHF: Study design

Teerlink JR, et al. Lancet 2013; 381:29-39.

Standard HF therapy

During study investigators free to use any concomitant medications incl. nitrates according to clinical judgment

Entry Criteria:

• Dyspnea, Congestion on CXR,

Elevated BNP/ nt-ProBNP

• SBP >125 mmHg

• eGFR 30-75 ml/min 1.73m2

• ≥40 mg IV furosemide

Excluded:

• Acute Coronary Syndrome

• High dose nitrates

Visual Analog Scale

• Absolute assessment of dyspnea & WHF/ death

• Endpoint: AUC over 5 days 100 = Best breathing

90

80

70

60

50

40

30

20

10

0 = Worst breathing

Likert Scale

3 = Markedly better

2 = Moderately better

1 = Minimally better

0 = No change

-1 = Minimally worse

-2 = Moderately worse

-3 = Markedly worse

• Relative assessment of dyspnea

• Endpoint: moderate/marked improvement at each of 6,12, and 24h

1°Endpoint: VAS and Likert Instruments


0

10

20

30

40

50

60

70

80

6 hr 12 hr 24 hr 6, 12, and 24 hr

PlaceboSerelaxin

p=0.086

p=0.051

p=0.113

p=0.702

n=150 n=156 n=205 n=180 n=256 n=288 n=362 n=389

Proportion of subjects with moderately or markedly better dyspnea by Likert by time point

p value by Chi-square test

1°Endpoint: Dyspnea Relief (Likert)


0.0

0.5

1.0

1.5

2.0

2.5

Dyspnea Assessment by Likert:

Time to Moderately/ Markedly Improved Dyspnea

p = 0.002

n=580 n=581

Placebo Serelaxin

1.91

(1.74, 2.08)*#

1.53

(1.38, 1.68)*#

Mea

n T

ime

to M

od

erat

e o

r M

arke

dly

Imp

rove

d D

ysp

nea

th

rou

gh

Day

5

(Day

s)

*p-value is based on a Wilcoxon rank test; # Mean (95% CI)

Visual Analog Scale

• Absolute assessment of dyspnea & WHF/ death

• Endpoint: AUC over 5 days 100 = Best breathing

90

80

70

60

50

40

30

20

10

0 = Worst breathing

Likert Scale

3 = Markedly better

2 = Moderately better

1 = Minimally better

0 = No change

-1 = Minimally worse

-2 = Moderately worse

-3 = Markedly worse

• Relative assessment of dyspnea

• Endpoint: moderate/marked improvement at each of 6,12, and 24h

1°Endpoint: VAS and Likert Instruments


Clinical events supersede symptoms at the time of their occurrence

Visual Analog Scale Area Under the Curve:

Dyspnea Clinical Composite

Death In-hospital

worsening heart failure

Change in dyspnea score

Visual Analog Scale Area Under Curve Visual Analog Scale AUC With Worst Score

Assignment

Moderate or marked

worsening of symptoms at

any planned assessment

Unresponsive or worsening heart failure requiring

IV or mechanical interventions

Worsening heart failure requiring IV or mechanical

interventions

Death Death

Visual Analog Scale

Area Under Curve

No dyspnea

Severe dyspnea

Numerical scores over time

Worst score

0

5

10

15

20

25

30

35

0 1 2 3 4 5

AUC with placebo, 2308 ± 3082

AUC with serelaxin, 2756 ± 2588

p=0.0075

Ch

ang

e fr

om

bas

elin

e (m

m)

19.4% increase in AUC with serelaxin

from baseline through day 5

(Mean difference of 448 mm-hr)

Days 6

Serelaxin Placebo

12 hrs

1° Endpoint: Visual Analog Scale Area Under the Curve Composite


**HR 0.7 (0.51, 0.96); p=0.024

Cumulative proportion of worsening heart failure

to Day 5 (%)

Worsening of Heart Failure

0

2

4

6

8

10

12

14

16

18

6 hr 12 hr Day 1 Day 2 Day 3 Day 4 Day 5

Placebo (N=573)

Serelaxin (N=570)

Kaplan-Meier estimate D14

for time to WHF (%)

11 3 16 4 31 10 44 17 57 25 64 69 37 36 0

2

4

6

8

10

12

14

16

18

Day 5 Day 14

573 570

(Numbers of subjects with WHF shown for each time point)

Worsening Heart Failure (WHF) was defined as worsening signs and/or symptoms of HF that required an intensification of IV therapy for

heart failure or mechanical ventilatory or circulatory support.

n= 573 570

*p<0.001 through Day 5

*p value by Wilcoxon test; **p value by log rank test for Serelaxin vs. Placebo; HR estimate by Cox model

18


Placebo (N=580)

Serelaxin (N=581)

Patients with WHF event included in the analysis of the 5-day primary endpoint

69 37

Patients who died or who experienced WHF leading to rehospitalization within 5 days

5 4

Patients with WHF within 5 days treated with IV positive inotropic drug or mechanical intervention

17 6

Patients with WHF within 5 days treated with new IV nitrates or IV nitroprusside

13 7

Patients with WHF within 5 days treated with reinitiation or doubling of daily dose of IV diuretic

14 7

Total 49 24

Worsening Heart Failure Events

With More Intensive Rescue Intervention

P=0.003

Primary Endpoint Sensitivity Analyses

Based on Clinically Ranked Outcomes

P value

Analysis of clinically ranked outcomes

All worsening heart failure events assigned same rank

0.0190

Earlier worsening heart failure events assigned worse rank than later events* 0.0110

Recurrent worsening events assigned worse rank than single events 0.0150

Aggressive interventions ranked worse than IV vasodilators, ranked worse than IV diuretics

0.0183

Prespecified primary efficacy analysis 0.0075

Observed VAS scores and log rank test used; Modified from Finkelstein & Schoenfeld (1999) and Felker (2010)

Fewer Serelaxin Treated Patients Required IV

Diuretics, Vasodilators, Inotropes and Mechanical Support

0

50

100

150

200

250

N=572 N=570 IV d

iure

tics

use

(cum

ulat

ive

to

tal d

ose

from

day

1-5

[mg]

)

*p=0.006

Placebo Serelaxin

24% difference

Less use of IV diuretics in serelaxin

group

0

20

40

60

80

100

N=580 N=581

Pat

ient

s tr

eate

d w

ith IV

vas

odila

tors

, In

otro

pes

or M

echa

nica

l Sup

port

(n)

*p=0.017

Placebo Serelaxin

30% difference

16.4%

11.5%

Less use of IV Vasodilators, Inotropes and

Mechanical Support in serelaxin group

P value by Wilcoxon rank sum test (death assigned longest length of stay plus 1 day)

Length of Stay in Hospital and ICU/CCU

Index Hospitalization ICU/CCU

0

1

2

3

4

5

Placebo Serelaxin

0

2

4

6

8

10

12

Placebo Serelaxin

P=0.039

n=578 n=574

P=0.029

n=580 n=581

0.9 days less than placebo

0.3 days less than placebo

Len

gth

of

Sta

y (D

ays)

ICU

/CC

U S

tay

(Day

s)


Dyspnea Relief (VAS AUC Day 5) CV Death Through 180 Days

Metra M, et al. Eur Heart J 34:3128-36.

Early changes from baseline in laboratory values

*p 0.05, **p 0.005, and ***p 0.001 by repeated-measures ANOVA with adjustment for baseline value.

27.2

16.5

0

5

10

15

20

25

30

Placebo Serelaxin

Percent of patients with hs-cTnT increase

p = 0.0001

Metra M, et al. J Am Coll Cardiol 2013;61:196-206.

23.2

16

0

5

10

15

20

25

Placebo Serelaxin

Percent of patients with >0.3 Cys-C increase

p = 0.0027




58

69

0

20

40

60

80

100

Placebo Serelaxin

Percent of patients with NT-proBNP decrease ≥30%

p = 0.0002




Risk for death by early changes in markers of organ function, damage, and congestion


All-cause mortality in the RELAX-AHF program 1.00

0.98

0.96

0.94

0.92

0.90

0.88

0.86

0.84

0.82

Sur

viva

l pro

babi

lity

0 20 40 60 80 100 120 140 160 180

Study Day

Pre-RELAX-AHF: Placebo Pre-RELAX-AHF: Serelaxin RELAX-AHF: Placebo RELAX-AHF: Serelaxin Combined: Placebo Combined: Serelaxin

HR (95%CI), P value

• Pre-RELAX: 0.53 (0.22,1.30), p = 0.16

• RELAX-AHF: 0.63 (CI 0.43, 0.93); p=0.020

• Combined: 0.62 (0.43-0.88), p=0.0076


Serelaxin Trial Program

• RELAX-AHF-2 (NCT01870778): ~6,800 pts with AHF;

1° endpoint: CV Death, Worsening Heart Failure

• RELAX-AHF-ASIA (NCT02007720): ~1520 pts with AHF;

1° endpoint: Trichotomous clinical composite

• RELAX-Repeat (NCT01982292): ~300 pts with CHF;

repeat administration q 4 wks for 3 doses;

Safety and tolerability, efficacy

No time to relax!

Kanu Chatterjee, MBBS, FRCP

(London and Edin), FCCP, FACC, MACP

March 1, 1934-March 4, 2015

“Quiet, modest, and endlessly proud of

the many young physicians he had

inspired and trained, he changed the

practice of cardiology in the world.”

San Francisco Veterans Affairs Medical Center

Thank you!

serelaxin in acute heart failure

Healthcare