Biased Ligand Approaches for Acute Heart Failure

G. Michael Felker, MD, MHS, FACC, FAHAProfessor of Medicine

Chief, Heart Failure SectionDuke University School of Medicine

Disclosures

• Grant Support and/or Consulting– NIH/NHLBI– Novartis– Amgen– Trevena– Roche Diagnostics– Otsuka– Celladon– Medtronic– Stealth Peptides– Singulex

State of the Art ADHF Therapy

• Diuretics• Vasodilators• Oxygen• Consider inotropic

therapy

Ramirez and Abelmann, New Engl J Med, 1974

Fonarow,GC et al. AHJ 2007

20071974

History of Drug Development in Acute HF

Milrinone

Tezosentan

Rolofylline

Levosmimendan?

Nesiritide?

Myocardial Renal Vascular Neurohormonal

Congestion

• Diastolic dysfunction

• Decreased CO• Myocyte

ischemia/injury• Mitral

regurgitation• Ventricular

interdependence• Tachycardia

End organ dysfunction

• Sodium and volume retention

• Acute kidney injury• RAAS/SNS

activation• Abnormal

intrarenal hemodynamics

• Vasoconstriction• Volume redistribution• Afterload contractility

mismatch• Endothelial

dysfunction• Increased arterial

stiffness• Capillary leakiness

• RAAS activation• SNS activation• Oxidative stress• Inflammation

Substrate Normal Structural Heart Disease Chronic HF

Amplifying Mechanisms

Triggers Hypertension, ACS, arrhythmias, infections, renal dysfunction, nonadherence, medications

Felker, GM and Teerlink, JR. Braunwald’s Heart Disease, 10th edition

25 Years of Progress in Chronic HF

Mentz, Felker, Mann. Heart Failure, a Companion to Braunwald’s Heart Disease. 2014

Modulating the Renin-Angiotensin System in HF

Can We Build a Better

Mousetrap?

Historical function of RAAS

In case of severe blood loss:• RAAS activation• vasoconstriction• fluid and salt retention• maintaining/increasing

intravascular plasma volume

Life saving

Pathophysiological effects of RAAS

In case of heart failure:• RAAS activation• vasoconstriction• fluid and salt retention• maintaining/increasing

intravascular plasma volume

Life threatening

Adverse effect Placebo (%) Enalapril (%) p value*

All effects reported 70 74 <0.001

Angina pectoris 15.2 14.4 NS

Hypotension (at any time)

9.6 25.3 <0.001

Heart failure 28.0 25.1 0.012

Increased serum creatinine

1.0 2.4 <0.001

Diarrhoea 0 1.5 0.024

Cough 3.1 6.8 <0.001

Adverse effects of therapy

*NS denotes not significant

Swedberg et al. New Engl J Med 1992;327:678–84

12

8

4

00 30 60 90 120 150 180

Study day

Kaplan-Meier life-table mortality curves for the placebo and enalapril groups

Mor

talit

y (%

)

Enalapril (3044)

Placebo (3046)

p=0.26

Duke Cardiologist Wins 2012 Nobel Prize

Angiotensin receptor activation in AHF is both maladaptive and beneficial

5/23/2015

AngII

Cardiac contractility

Support perfusion but maladaptive

Na+ & fluid retentionVasoconstriction

GRKb-arrestin

AT1R

Ga

Full AT1R antagonism

5/23/2015

ARB

Cardiac contractility

↓cardiac output

Na+ & fluid retention

↓fluid retention

Vasoconstriction

↓blood pressure

GRK

b-arrestin

AT1R

Ga

Selective B-arrestin biased ligand

5/23/2015

GRKGa

b-arrestin

TRV027

AT1R

Cardiac contractility

preserve cardiac output

Na+ & fluid retention

↓fluid retention

Vasoconstriction

↓blood pressure

GRKGa

b-arrestin

Response Response

b-arrestin biased ligand(TRV027)

[ TRV027 ]

TRV027: a selective b-arrestin biased ligand

GRKGa

b-arrestin

Response Response

Full agonist(Angiotensin II - AngII)

GRKGa

b-arrestin

Response Response

Full antagonist(Valsartan)

GRKGa

b-arrestin

Response Response

GRKGa

b-arrestin

Response Response

GRKGa

b-arrestin

Response Response

Sustained, reversible reduction in MAP by TRV027 in high PRA subjects

5/23/2015

Changes in MAP during and after study drug infusion

0 2 4 6 8 10 12 14 16 18

70

80

90

100

PBO (n=8) normal PRA (n=13)high PRA (n=11)

doseescalation

steadystate infusion washout

TRV027 treated

Time (hours)

MAP

(mm

Hg)

Soergel, D et al. ACC 2013

Dose response on MAP in high PRA subjects

* both high PRA subjects from Cohort 3 had dosing or sampling irregularities and were excluded

“high PRA” = PRA > 5.8

TRV027 exposure-response curve

0 200 400 60070

75

80

85

90

95

8001200

High PRA (n = 4-5)Normal PRA (n = 2-7)

*

Plasma TRV027 (ng/ml)

MA

P

TRV027 dose-response curve

0 1 2 3 470

75

80

85

90

95

5 10

normal PRA (n = 2-7)high PRA (n = 4-5) *

TRV027 dose (ug/kg/min)

MA

P

Soergel, D et al. ACC 2013

Felker GM et al, JACC-HF 2015

TRV027: BLAST-AHF

AHF Pa ent

Randomiza on

-16 hours 48-96 hours

Placebo

TRV027 @1 mg/hr

TRV027 @5 mg/hr

TRV027 @25 mg/hr

Day 5 visit

Day 30 visit

End of Infusion

Follow up

Day 180 call

Evalua on of primary composite endpoint

E qua

l

al

loca

o n

≥40mg furosemide 1 hr before randomization

Each arm added to standard AHF therapy

Felker et al. JACC HF2015

BLAST-AHF Endpoint

• Novel approach to Phase II endpoints• Uses average Z-score across multiple domains on

interest– Death (day 30)– HF rehospitalization (day 30)– Dyspnea by VAS (D5)– Worsening HF (D5)– Length of stay of index hospitalization

Conclusions

• AHF remains major public health problem with few new therapies

• Modulation of effective chronic therapies to augment benefits and mitigate potential adverse effects may be an effective strategy for new drug development

• Biased ligands represent an intriguing approach to AHF therapy currently being studied in the Phase IIb BLAST-HF study

“The rumors of the death of acute heart failure research have been greatly exaggerated.”