Serelaxin.

Acute heart failure: Novel therapies on the horizon

SerelaxinJohn R. Teerlink, MDFACC, FAHA, FESC, FRCP(UK)Professor of Medicine,

University of California San Francisco Director, Heart Failure and Director, Echocardiography

San Francisco VA Medical Center23.May, 2015Sevilla, Spain

• Financial Disclosure– J.R. Teerlink has received research grants

and/or consulting fees from Amgen, Cytokinetics, Janssen, Medtronic, Novartis, St. Jude, Takeda, and Trevena.

• Unlabeled/unapproved uses disclosure– I will be discussing investigational therapies

that are not approved by the FDA or EMA.

UCSF

Presenter Disclosure Information:Heart Failure 2015

Acute heart failure: Novel therapies on the horizon

Lippicky RJ and Packer M. J Am Coll Cardiol 1993;22(4 Suppl A):179A-184A.

“To be of clinical value in the treatment of heart failure, a drug must permit patients either to feel better or to live longer, or both.”

• 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

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

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 d48 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 therapyDuring 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 furosemideExcluded:• Acute Coronary

Syndrome• High dose nitrates

Clinical events supersede symptoms at the time of their occurrenceClinical events supersede symptoms at the time of their occurrence

Visual Analog Scale Area Under the Curve:Dyspnea Clinical Composite

DeathDeathIn-hospital In-hospital

worsening worsening heart heart failurefailure

Change in Change in dyspnea scoredyspnea score

Visual Analog Scale Area Under Curve

Visual Analog Scale AUC With Worst Score Assignment

Moderate or markedworsening of symptoms atany planned assessment

Unresponsive or worsening heart failure requiring IV or mechanical interventions

Worsening heart failure requiring IV or mechanical

interventionsDeath Death

Visual Analog ScaleArea Under Curve

No dyspnea

Severe dyspnea

Numerical scoresover time

Worst score

5432100

5

10

15

20

25

30

35

AUC with placebo, 2308 ± 3082AUC with serelaxin, 2756 ± 2588p=0.0075

Cha

nge

from

bas

elin

e (m

m)

19.4% increase in AUC with serelaxin from baseline through day 5 (Mean difference of 448 mm-hr)

Days6

SerelaxinPlacebo

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 failureto Day 5 (%)

Worsening of Heart Failure

6 hr 12 hr Day 1 Day 2 Day 3 Day 4 Day 50

2

4

6

8

10

12

14

16

18Placebo (N=573)

Serelaxin (N=570)

Kaplan-Meier estimate D14for time to WHF (%)

11 3 16 4 31 10 44 17 5725 64 69 3736

Day 5 Day 140

2

4

6

8

10

12

14

16

18

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

10


Placebo(N=580)

Serelaxin(N=581)

Patients with WHF event included in the analysisof the 5-day primary endpoint 69 37

Patients who died or who experienced WHFleading to rehospitalization within 5 days 5 4

Patients with WHF within 5 days treated withIV 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=0.003Teerlink JR, et al. ESC 2014 Clinical Trial Update Hotline

Primary Endpoint Sensitivity Analyses Based on Clinically Ranked Outcomes

PP valuevalueAnalysis of clinically ranked outcomes

All worsening heart failure events assignedsame 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)

Teerlink JR, et al. ESC 2014 Clinical Trial Update Hotline

Fewer Serelaxin Treated Patients Required IV Diuretics, Vasodilators, Inotropes and Mechanical Support

0

50

100

150

200

250

N=572 N=570IV d

iure

tics

use

(cum

ulat

ive

tota

l dos

e fro

m d

ay 1

-5 [m

g]) *p=0.006

Placebo Serelaxin

24%difference

Less use of IV diuretics in serelaxin group

0102030405060708090

100

N=580 N=581

Pat

ient

s tre

ated

with

IV v

asod

ilato

rs,

Inot

rope

s or

Mec

hani

cal S

uppo

rt (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

Placebo Serelaxin0

1

2

3

4

5

Placebo Serelaxin0

2

4

6

8

10

12 P=0.039

n=578 n=574

P=0.029

n=580 n=581

0.9 daysless than placebo

0.3 daysless thanplacebo

Leng

th o

f Sta

y (D

ays)

ICU

/CC

U S

tay

(Day

s)


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: PlaceboPre-RELAX-AHF: SerelaxinRELAX-AHF: PlaceboRELAX-AHF: SerelaxinCombined: PlaceboCombined: 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

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

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

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

Cardiovascular mortality in Patients with HFpEF in RELAX-AHF

Filippatos G, et al. Eur Heart J 2014;35:1041-1050.

Hemodynamic Effects of Serelaxin in Patients with Acute Heart Failure

18v Study objective: To evaluate the hemodynamic effects of serelaxin in 71 patients

with AHF at a dose rate of 30 µg/kg/day

Swan-Ganz catheter inserted ≥ 1 h prior to randomization

4h post-infusion

30 d20 h study drug infusion

Placebo

Serelaxin 30 µg/kg/d

Double-blind, randomized treatment period



Patients hospitalized with AHF, mean PCWP ≥18 mmHg,SBP ≥115 mmHg, and estimated glomerular filtration rate ≥30 ml/min/1.73m2

Screening

≤48 hPresentation

Randomized 1:1

0 h 8 h 20 h 24 hSafety evaluation

Washout

Washout

Ponikowski P, et al. Eur Heart J 2014;35:431-441.

Hemodynamic Effects of Serelaxin in Patients with Acute Heart Failure

Ponikowski P, et al. Eur Heart J 2014;35:431-441.

*

**

** *

* * **

Renal Hemodynamic Effects of Serelaxin in Patients with Chronic Heart Failure

*Measured by plasma clearance of PAH and IOTH. CHF, chronic heart failure; GFR, glomerular filtration rate; IOTH, iothalamate; i.v., intravenous; PAH, para-amino-hippuric acid; RPF, renal plasma flow

v Study objectives: To assess the renal hemodynamic effects of 24 h i.v. infusion of serelaxin, as determined by RPF and GFR in CHF patients*

8 10 11 13 15 17 19 23 3 7 11 13 15Day -21 to -1 Day 1 Day 2

11:30

–3 –1 0 2 4 6 8 12 16 20 22 23 24 26 28 24.5

Time of day:

Wash-out

Wash-out

Furosemide infusion

IOTH/PAH

Urine collection

Screening

RandomizationPlacebo

Serelaxin 30 µg/kg/day i.v. infusion

0:10

0:30

20

Chronic HFNHHA II-IIILVEF ≤45%BNP ≥100 pg/mL

or NT-proBNP ≥400 pg/mL

Worsening sx within 3 mo

SBP≥110 mmHg

Voors AA, et al. Circ Heart Fail 2014;7:994-1002.

Renal Hemodynamic Effects of Serelaxin in Patients with Chronic Heart Failure

21

Time-weighted average change from baseline

Serelaxin(n = 28)

Placebo(n = 37)

Treatment difference†

(95% CI)p-value

0–24 h 1.31 (1.05) 1.13 (1.04) 1.16 (1.05, 1.28) 0.0042

8–24 h 1.29 (1.05) 1.14 (1.05) 1.13 (1.01, 1.27) 0.0386

24–28 h 1.35 (1.05) 1.16 (1.05) 1.16 (1.03, 1.30) 0.0115

CI, confidence interval; SE, standard errorData presented as least squares geometric mean ratio to baseline (standard error). †Ratio of least squares geometric mean ratios

*p≤0.05 vs. placebo

282422

600

500

400

300

700

0200

SerelaxinPlacebo

2 4 6 8 20 26

Geo

mea

n (±

SE) r

enal

pla

sma

flow

(mL/

min

)

Hours post-dose

** *

* * *

Voors AA, et al. Circ Heart Fail 2014;7:994-1002.

*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

remodeling3

↑ Matrix metalloproteinases↓ Vessel stiffness

↓ Collagen synthesis↑ Collagen breakdown

↑Tissue healing

↓ Inflammation

↑ Cell survival

↑ Cell preservation2

↓ Inflammatory cellinfiltration

↓ Oxidative stress

↑ Angiogenesis↑ Stem cell survival

↓ Oxidative stress↓ Apoptosis

↓ Ca2+ overload↓ Infarct size

Vasorelaxation*

↓ Myocardial overload; ↑ Renal function1

↑ Endothelial NO*↓ SVR, ↑ RBF, ↑ GFR

↓ ET-1Volume redistribution

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

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

Significant Improvements in Biomarkers

*p 0.05, **p 0.005, and ***p 0.001 by repeated-measures ANOVA with adjustment for baseline value.Metra M, et al. J Am Coll Cardiol 2013;61:196-206.

27.2

16.5

Percent of patients with hs-cTnT increase

Placebo Serelaxin

0

5

10

15

20

25

30p = 0.0001

23.2

16

Percent of patients with >0.3 Cys-C increase

Placebo Serelaxin

0

5

10

15

20

25p = 0.0027

5869

Percent of patients with NT-proBNP decrease ≥30%

Placebo Serelaxin0

20

40

60

80

100p = 0.0002

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!

San Francisco Veterans Affairs Medical Center

Thank you!

Kanu Chatterjee, MBBS, FRCP, FCCP, FACC, MACPMarch 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.”

In honor and memory of…

Serelaxin.

Healthcare

Transcript of Serelaxin.