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.”
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