Prof John R Teerlink MD a , Gad Cotter MD b, Beth A Davison PhD b, G Michael Felker MD c, Prof Gerasimos Filippatos MD d,Prof Barry H Greenberg MD e, Prof Piotr Ponikowski MD f, Elaine Unemori PhD g, Prof Adriaan A Voors MD h, Kirkwood F Adams MDi, Prof Maria I Dorobantu MD j, Liliana R Grinfeld MD k, Prof Guillaume Jondeau MD l, Prof Alon Marmor MD m, Prof Josep MasipMD n, Peter S Pang MD o, Prof Karl Werdan MD p, Sam L Teichman MD g, Angelo Trapani PhD q, Christopher A Bush PhD q, Rajnish Saini MD q, Christoph Schumacher PhD r, Thomas M Severin MD r, Prof Marco Metra MD s, for the RELAXin in Acute Heart Failure (RELAX-AHF) Investigators

Presenter Disclosure Information

John R. Teerlink, M.D., F.A.C.C., F.A.H.A., F.E.S.C. Professor of Clinical Medicine, University of California, San Francisco Director of Heart Failure, San Francisco Veterans Affairs Medical CenterThe following relationships exist related to this presentation:Consulting Fees and Grants Corthera, Inc. Significant Level

Background

Serelaxin, recombinant human relaxin-2, is a vasoactive peptide hormone with many biological and haemodynamic effects. In a pilot study, serelaxin was safe and well tolerated with positive clinical outcome signals in patients with acute heart failure. The RELAX-AHF trial tested the hypothesis that serelaxin-treated patients would have greater dyspnoea relief compared with patients treated with standard care and placebo.

Relaxin

Peptide hormoneSimilar in size and shape to

insulin (MW 5963)Found in men and womenNormal hormone of pregnancyWomen “exposed” for 9

months to increased plasma concentrations:0.8-1.6 ng/ml pregnancy*

Benign safety profile

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

Relaxin

Relaxin Mechanisms of ActionVasodilation

NO, cGMP effectors Induction of NOS II/III Upregulation of endothelial

endothelin type B receptor, which mediates vasodilation

Preferential dilation of constricted vessels Relaxin-upregulated ETB

receptors act as vasodilating ET-1 sink

Anti-inflammatory Down-modulation of

inflammatory cytokines linked to outcome in HF (TNF-, TGF-)

Other: Anti-ischemic, Anti-apoptotic, Anti-fibrotic

Relaxin Receptor LGR7

Teichman, SL, et al. Heart Fail Rev 2009; Dschietzig, T, et al. Pharmacol Therap 2006

Acute Heart Failure SyndromesHospitalizations over 1.1 million annually in

U.S.and have tripled in last 3 decades

Post-discharge mortality (10-20%) and rehospitalization (20-30%) within 3-6 months

Approximately 75-90% of patients have normal or elevated blood pressure on presentation

Approximately 90% present with dyspneaCentral role of vasoconstriction

(arterial, venous; systemic, pulmonary and renal)

Neurohormonal activation/ InflammationMyocardial (subendocardial) ischemia

Gheorghiade M, Pang P. J Am Coll Cardiol 2009;53:557–73.

RELAX-AHF was an international, double-blind, placebo-controlled trial, enrolling patients admitted to hospital for acute heart failure who were randomly assigned (1:1) via a central randomisation scheme blocked by study centre to standard care plus 48-h intravenous infusions of placebo or serelaxin (30 μg/kg per day) within 16 h from presentation.

All patients had dyspnoea, congestion on chest radiograph, increased brain natriuretic peptide (BNP) or N-terminal prohormone of BNP, mild-to-moderate renal insufficiency, and systolic blood pressure greater than 125 mm Hg. Patients, personnel administering study drug, and those undertaking study-related assessments were masked to treatment assignment.

The primary endpoints evaluating dyspnoea improvement were change from baseline in the visual analogue scale area under the curve (VAS AUC) to day 5 and the proportion of patients with moderate or marked dyspnoea improvement measured by Likert scale during the first 24 h, both analysed by intention to treat. 

Enrollment:1161Study Start Date:October 2007Study Completion Date:September 2012Primary Completion Date:September 2012

(Final data collection date for primary outcome measure)

Inclusion Criteria

Hospitalized for acute heart failureDyspnea at rest or with minimal exertionPulmonary congestionAble to provide informed consentSystolic blood pressure > 125 mmHgImpaired renal function defined as an eGFR

of 30-75 mL/min/1.73m2

Exclusion Criteria:

Use of other IV therapies for acute heart failure

Fever or sepsisRecent major neurologic eventRecent major surgeryRecent acute coronary syndromeOther recent investigational drug use

1161 patients were randomly assigned to serelaxin (n=581) or placebo (n=580). Serelaxin improved the VAS AUC primary dyspnoea endpoint (448 mm × h, 95% CI 120—775; p=0·007) compared with placebo, but had no significant effect on the other primary endpoint (Likert scale; placebo, 150 patients [26%]; serelaxin, 156 [27%]; p=0·70

No significant effects were recorded for the secondary endpoints of cardiovascular death or readmission to hospital for heart failure or renal failure (placebo, 75 events [60-day Kaplan-Meier estimate, 13·0%]; serelaxin, 76 events [13·2%]; hazard ratio [HR] 1·02 [0·74—1·41], p=0·89] or days alive out of the hospital up to day 60 (placebo, 47·7 [SD 12·1] days; serelaxin, 48·3 [11·6]; p=0·37).

Serelaxin treatment was associated with significant reductions of other prespecified additional endpoints, including fewer deaths at day 180 (placebo, 65 deaths; serelaxin, 42; HR 0·63, 95% CI 0·42—0·93; p=0·019).

Cardiovascular Deaths to Day 180

0.8

0.85

0.9

0.95

1

0 30 60 90 120 150 180

Kap

lan-

Mei

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vent

-fre

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%)

Days

Placebo

Relaxin 10 mcg/kg/d

Relaxin 100 mcg/kg/d

Relaxin 250 mcg/kg/d

Relaxin 30 mcg/kg/d(p<0.05)

The FDA has granted "breakthrough therapy" designation to serelaxin (Novartis Pharmaceuticals), the novel recombinant form of human relaxin 2 that has demonstrated promising clinical findings in acute heart failure (AHF).