Dear Colleagues, Thank you for taking the time to review our presentation for the up-coming ACC Late-breaking Clinical trial Session. As you know, analyses and interpretations of these data continue given the relative “freshness” of the data and consequently, these slides may change to some minor extent (especially since there are way too many right now!). However, the main data and points will remain. I may be up-dating the slides on-line periodically, and would be happy to notify you of if/when I make any changes. You may contact me by email (john.teerlink@ucsf.edu), if you so desire. Additionally, if you note obvious errors or information that you feel would assist in the evaluation of this study, I would be happy to do my best to incorporate it into the presentation. Thanks again and I look forward to seeing you on Sunday!

Sincerely, John

Relaxin, A Novel Treatment for Acute Heart Failure-The Pre-RELAX-AHF Study

John R. Teerlink, Marco Metra, G. Michael Felker, Adriaan A. Voors,

Piotr Ponikowski, Beth D. Weatherley, Elaine Unemori, Sam L.Teichman, and Gad Cotter, on behalf of the

Pre-RELAX-AHF Investigators & Patients

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 Center

The following relationships exist related to this presentation:Consulting Fees and Grants Corthera, Inc. Significant Level

Relaxin

• Peptide hormone• Similar in size and shape to insulin

(MW 5963)• 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

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

Relaxin

Relaxin Mechanisms of Action• Vasodilation

– 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 Syndromes• Hospitalizations 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 dyspnea• Central role of vasoconstriction

(arterial, venous; systemic, pulmonary and renal)• Neurohormonal activation/ Inflammation• Myocardial (subendocardial) ischemia

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

Time (hours)

1 4 8 9 12 16 17 20 24 25 26 27 28 32 48

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apill

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Open-label, pilot study of relaxin in 16 patients with stable HF

Dschietzig T, et al. J Card Failure 2009; in press.

Hemodynamic Response to Relaxin in Chronic Heart Failure

• Safe and well-tolerated at all doses tested (10-960 mcg/kg/d)

• PCWP reduced• Systemic vasodilation• Improved renal

function• Further study in AHF

was warranted

Shaded bars=dosing; open bars=recovery

Pre-RELAX-AHF: Phase 2 Study Objectives

• Evaluate the impact of IV relaxin compared to placebo on symptom relief and other clinical endpoints in patients with AHF and normal or elevated blood pressure

• Evaluate the dose response to relaxin in these patients in order to select the most efficacious dose for further study in subsequent clinical trials

• Assess the safety of relaxin in these patients

Pre-RELAX-AHF: Study Organization

• Co-PIs: M Metra (IT), JR Teerlink (US) • Executive Committee

– GM Felker (US), AA Voors (NL), P Ponikowski (PL), B Greenberg (US), BD Weatherley (US), SL Teichman (US), E Unemori (USA), G Cotter (US)

• DSMB– BM Massie-Chair (US), S Goldstein (US),

M Bohm (GER), G Francis (USA), E Davis (US)• Sponsor: Corthera, Inc. • Coordinating Center: Momentum Research, Inc.• National Regulatory and Local Ethics Approvals

Phase 2 Study Design• Design: Phase 2/3, Multicenter, Randomized, Double-

Blind, Placebo-Controlled, Parallel-Group, International Study• Part A: Phase 2 Dose-ranging, symptom-relief pilot for Phase 3• Part B: Phase 3 Confirmatory study of best dose from Phase 2

• Study Drug: In addition to standard treatment for AHF:• 48 h infusion of placebo or relaxin at 10, 30, 100 or 250

mcg/kg/d

Inclusion Criteria• Admitted for Acute heart failure (all):

– Dyspnea at rest or with minimal exertion– Congestion on chest-X-ray– BNP ≥ 350 or NT-pro-BNP ≥ 1400 pg/mL

• Baseline BP > 125 mmHg• Renal dysfunction (CrCl 30-75 mL/min)• Randomized within 16h of presentation • Received at least 40 mg iv Furosemide

prior to screening

Exclusion Criteria• Fever (t> 38°C)• Acute contrast-induced

nephropathy or recent administration of contrast

• Ongoing/planned IV inotropes, vasopressors, vasodilators (except low dose IV nitrates), or mechanical circulatory/ respiratory support

• Severe pulmonary disease

• Significant stenotic cardiac valvular disease

• Current/planned organ transplantation

• Clinical diagnosis of ACS within 45 days

• Major surgery within 30 d • Hct< 25%• Major neurologic event

within 45 days • Troponin level > 3 xULN• Non-cardiac pulmonary

edema• Significant liver disease.

How to select a dose in Contemporary AHF Phase 2 Studies?

• Patients, physicians and regulators (FDA/EMEA) emphasize symptom-relief and improved outcomes

• Hemodynamics and other surrogates have not been reliable predictors of change in symptoms or outcomes (nesiritide, tezosentan, levosimendan…)

• Phase 2 studies are underpowered, by definition, to assess single clinical outcome

• How to select dose and evaluate Phase 2 data?• Pre-RELAX-AHF approach: Pre-specify areas of

clinical importance and evaluate dose(s) on totality of data

Pre-RELAX-AHF Endpoints• Dyspnea relief: Patient-reported

– 7-point Likert Dyspnea Scale– 100-mm Visual Analog Scale

• In-hospital– Resolution of Signs and symptoms of CHF– Worsening heart failure: Physician-assessed– Length of hospital stay– Change in renal function

• Post-discharge– Day 60: Days alive and out-of-hospital– Day 60: Cardiovascular mortality and

rehospitalization due to heart or renal failure (K-M)– Day 180: Cardiovascular failure (K-M estimate)

Study Conduct and Patient Disposition

• 234 patients enrolled– Safety population

• 230 patients received study drug– Modified Intent-to-Treat Population

• 229 patients received study drug without major protocol violations

– Randomized 3:2:2:2:2 to 48 hrs of therapy (Placebo; Relaxin 10, 30, 100, 250 µg/kg/d)

• Mean duration of infusion– Placebo group: 44 hours– Relaxin 10-250 mcg/kg/d groups: 39-42 hours

• Timing– Mean time from presenting to randomization:

8.4±5.4 hrs [median 6.6 hrs (Q1-Q3: 4.0-13.4)] – Mean time to treatment: 1.0±1.8 hrs from randomization

Baseline CharacteristicsPlacebo 10 30 100 250

# Subjects 61 40 42 37 49Age (yr) 68.4 72.2 71.6 69.2 70.7

% Hosp for HF in Previous Year 29.5% 32.5% 38.1% 42.3% 30.6%

Ejection fraction <40% 44.2% 48.4% 53.6% 68% 55.6%

NYHA III/IV 57.4% 55% 73.8% 72.9% 73.5%

NT Pro-BNP>2000 75.4% 70% 83.3% 70.3% 73.2%

Hypertension history 82% 87.5% 90.5% 81.1% 87.8%

Mitral regurgitation 23% 30% 31% 32.4% 36.7%

Atrial fibrillation/flutter 42.6% 60% 42.9% 56.8% 38.8%

Diabetes Mellitus 49.2% 32.5% 52.4% 32.4% 40.8%

Troponin “leak” 23% 18% 10% 14% 17%

SBP (mmHg) at randomization 148 145 150 146 146

CrCl (mL/min) 57 64 54 54 61

BUN (mg/dL) 28 25 28 26 27

Sodium 141 140 140 141 140

Vasodilator effect of RelaxinVasodilator effect of

Relaxin effect partially balanced by:

• Increased NTG and diuretics in Placebo

• Stopping rules for BP reduction to avoid Hypotension

• Selective vasodilation by Relaxin

• U-shaped dose-response of Relaxin

-20

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PL 10 30 100 250Relaxin (mcg/kg/d)

Dyspnea Relief: Patient-Reported Dyspnea Scales

• Likert Scale

+3 Markedly better+2 Moderately better+1 Mildly better0 No change-1 Mildly worse-2 Moderately worse-3 Markedly worse

• Visual Analog Scale

5 10 15 20 25 30 35 40 45 50

0

55 60 65 70 75 80 85 90 95 100

= Worst imaginable health state

= Best imaginable health state

Rapid Dyspnea Improvement through 24 hours (Likert Scale)

Proportion of Patients with Moderate/Marked Improvement in Dyspnea at 6, 12 and 24 hr

Placebo 10 30 100 2500

5

10

15

20

25

30

35

40

45

50

Patie

nts

(%)

Relaxin (mcg/kg/d)

p = 0.04

Sustained Dyspnea Improvement through Day 14 (Visual Analog

Scale)

Day 5 Day 14

0

1000

2000

3000

4000

5000

6000

7000

8000

9000

10000

Dys

pnea

(AU

C; m

m*h

r)

p=0.11

p=0.05p=0.06

Placebo 10 30 100 250Relaxin (mcg/kg/d)

Placebo 10 30 100 250Relaxin (mcg/kg/d)

p=0.16

p=0.16p=0.15

In-hospital Endpoints

Relaxin (mcg/kg/d) Placebo 10 30 100 250 Number of Subjects in

Efficacy population 61 40 42 37 49

Subjects (%) at Day 5 with: No edema 47.5 55.0 64.3   51.4 * 61.2   No rales 67.2 65.0 76.2 70.3 71.4 JVP <6 cm 67.2 72.5 78.6 + 73.0 76.6 +

Change in BW to Day 14 [kg; median (Q1;Q3)]

-2.0 (-4.2-0.0)

-2.0 (-4.5-0.0)

-3.0 (-5.0-0.0)

-2.5 (-4.7-0.8)

-2.0 (-4.0-0.0)

Subjects (%) on NTG or SNP through Day 5 26.2 17.5 11.9 16.2 8.2

Total IV diuretic dose through Day 5 [mg; median (Q1-Q3)]

170 (80-300)

100 (40-200)

100 (60-360)

90 + (40-200)

140 (60-340)

Length of Stay (d) 12.0 ± 7.3 10.9 ± 8.5 10.2 ± 6.1+ 11.1 ± 6.6 10.6 ± 6.6+

†, p<0.001; *, 0.001≤p≤0.05; +, 0.05<p≤0.20

0

5

10

15

20

25

6, 12 hr 24 hr 48 hr Day 3 Day 4 Day 5

PLRLX 10RLX 30RLX 100RLX 250

% Subjects with Worsening Heart Failure

%

Worsening Heart Failure (Physician-Assessed)

Days Alive and Out of Hospital to Day 60

Placebo 10 30 100 25040

41

42

43

44

45

46

47

48

49

50D

ays

Relaxin (mcg/kg/d)

p=0.05p=0.16

CV Death or Heart/Renal Failure Re-hospitalizations to Day 60

0.8

0.85

0.9

0.95

1

0 10 20 30 40 50 60

Kap

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Placebo

Relaxin 10 mcg/kg/d

Relaxin 100 mcg/kg/d

Relaxin 250 mcg/kg/d

Relaxin 30 mcg/kg/d(p=0·05)

Cardiovascular Deaths to Day 180

0.8

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Relaxin 10 mcg/kg/dRelaxin 100 mcg/kg/d

Relaxin 250 mcg/kg/d

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

Pre-RELAX-AHF Safety

• Overall safety and tolerability– SAEs and AEs

• Blood pressure• Renal safety

Adverse Events

Relaxin (mcg/kg/d) Group Placebo 10 30 100 250 Subjects in Safety (n) 61 40 42 38 49

SAEs to Day 30 Patients with any SAEs to Day 30, n (%)

10 (16.4%)

7 (17.5%)

7 (16.7%)

3 (7.9%)

8 (16.3%)

Cardiac failure, n (%) 5 (8.2%) 2 (5.0%) 1 (2.4%) 0 2 (6.1%) Ventr icular fibrillation, n (%) 0 1 (2.5%) 0 0 0 Hypotension, n (%) 0 0 0 0 2 (4.1%) Bronchitis, n (%) 0 0 1 (2.4%) 0 1 (2.0%) Stroke, n (%) 1 (1.6%) 0 2 (4.8%) 0 0 Renal failure, n (%) 1 (1.6%) 0 1 (2.4%) 0 0 Urinary retention, n (%) 0 0 0 2 (5.3%) 0 AEs to Day 30 Patients with any adverse events to Day 30, n (%)

45 (73.8%)

32 (80.0%)

25 (59.5%)

24 (63.2%)

25 (51.0%)

Change in SBP during study drug infusion

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Drug effect on Systolic Blood Pressure over time by baseline SBP

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Baseline Systolic BP ≤ 140 mmHg Baseline Systolic BP > 140 mmHg

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B BB

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Renal Safety

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Renal impairment on Day 5>0.3 mg/dL increase from baseline >25% increase from baseline

Renal impairment at Day 5 and 14>0.3 mg/dL increase from baseline

Dose Selection Relaxin (mcg/kg/d) 10 30 100 250

Dyspnea through 24 hours (Likert) p=0.54 p=0.04 p=0.28 p=0.86

Dyspnea AUC at Day 5 (VAS) p=0.15 p=0.11 p=0.16 p=0.31

Dyspnea AUC at Day 14 (VAS) p=0.37 p=0.05 p=0.06 p=0.16

Worsening HF to Day 5 p=0.75 p=0.29 p=0.40 p=0.15

Short-term Outcomes:

Length of Stay p=0.36 p=0.18 p=0.75 p=0.20

Day 60 Outcomes

Days alive out of hospital p=0.40 p=0.16 p=0.40 p=0.05

Cardiovascular death or Rehospitalization (KM%)

p=0.32 p=0.05 p=0.23 p=0.08

Renal Safety

Persistent renal impairment p=0.87 p=0.90 p=0.47 p=0.19

= p <0.05 = 0.05 ≤ p <0.20 = p<0.20 against

Conclusions• In selected patients with AHF, early treatment

with relaxin for 48 h produced consistently favorable trends in multiple AHF endpoints, including: – Symptom relief: VAS and Likert Scales– In-hospital measures of AHF signs and symptoms– Post-discharge clinical outcomes to Day 60/180

• Relaxin use in AHF was safe• A dose of 30 mcg/kg/d showed the greatest

effects and will be studied further– RELAX-AHF-1: An international Phase 3 study

Pre-RELAX-AHF Investigators• Russia: S. Boldueva, V. Moiseev, Z. Shogenov,

M. Ruda, A. Vishnevsky, M. Boyarkin, V. Simanenkov, S. Tereschenko, Y. Shwartz, O. Orlikova, M. Arkhipov, I. Libov, R. Sardinov, A. Suvorov

• Israel: A. Marmor, A. Katz, R Zimlichman, M. Omary, R. Hershcoviz, S. Goland, A. Keren, D. Aronson

• Poland: P. Ponikowski, J. Grzybowski, W. Musial• Hungary: D. Apró, G. Lupkovics• Italy: M. Metra• Romania: C. Stamate, A. Salajan, A. Matei• USA: P. Levy, P. Pang, S. Collins, D. Gupta• Belgium: W. Van Mieghem, L. Muylderman,

G. Vervoort