eugene braunwald, md - american college of cardiology/media/non-clinical/files-pdfs-excel-ms-word...
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Eugene Braunwald, MD
Paul Dudley White LectureNew York Cardiovascular Symposium
December 13, 2015
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Relevant disclosures
• Research grants (through the Brigham and
Women's Hospital) from AstraZeneca, Daiichi-
Sankyo, Merck, and Glaxo Smith Kline
• Personal fees for consultancies/lectures from
Genyzme, Medicines Co, Theravance, and Sanofi-
Aventis
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Paul Dudley White (1886-1973)
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Dual Goals
� To present the history of the physiologic and clinical advances that led to the development of the first angiotensin-receptor blocker-neprilysin inhibitor (ARNi)
� To use this achievement as a “case study” that demonstrates the necessity of devoting efforts of both academia and industry to advance science and improve medical care.
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2014;371:993
AI
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Sudden Death Pump Failure
Desai AS, et al.
Eur Heart J 2015;36:1990
Cardiovascular Deaths in PARADIGM-HF
AI
__________________
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The consistent benefits of LCZ696
on all outcomes in HF
Compared with enalapril, pts on LCZ696 are LESS LIKELY TO:
� die of a cardiovascular cause or any cause
� die suddenly
� be hospitalized for HF or for any reason
� visit the ER
� be admitted to the ICU
� need iv inotropic therapy
� require devices/surgery for worsening/end-stage HF
� show deterioration in renal function
� show biomarker evidence of continuing myocyte injury
AI
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Robert Adolf Armand Tigerstedt (ca 1910)
A
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Experiment 1B, November 8, 1896“A [rabbit] kidney was pulverized with 21 ml of water. Injection into
jugular vein. Within 80 s, there is a rise in mean arterial pressure
from 62-67 mmHg to 100 mmHg, i.e. an increase by ca. 50%.”
Tigerstedt and Bergman, Niere und Kreislauf
Skand. Arch. Physiol. 8: 223-271, 1898
A
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Harry Goldblatt (1891 - 1977)
A
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_________________
J Exp Med 1934;59:347
A
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Br J Pharmacol 1965;24:163
A
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Bradykinin potentiating factor, the crude extract
of peptides from snake venom, also inhibits
the peptidase which converts angiotensin I to
angiotensin II, both in vitro and in vivo.
SH Ferreira, LJ Greene, VA Alabaster, YS Bakhle, JR Vane
Nature 1970;225:379
A
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Science 1977;196:441
I
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1987;316:1429
AI
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Adolfo J. De BoldA
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Heart Atria Granularity Effects of Changes in Water-Electrolyte Balance
A.J DeBold
_________________
Life Sci 1981;28:89
_________________
Exper Biol Med 1979;161:508
_________________
J Histochem Cytochem 1978;26:1094
A
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Biochem J 1974;137:477
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Biochem J 1987;243:183
A
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Nature 1980;288:286
The First Neprilysin Inhibitor
A
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Natriuretic Peptide System
Heart Failure
Atrial Distension
Release of ANPNEP
Neutral
endopeptidaseVasodilation
Diuresis, Natriuresis
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NEP
Neutral
endopeptidase
Natriuretic Peptide System
Heart Failure
Atrial Distension
Release of ANP
Vasodilation
Diuresis, Natriuresis
NEPi
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Circ Res 1992;71:1501
“It may be necessary to coadminister converting enzyme inhibitors or Ang II antagonists to gain optimum benefit from the use of endopeptidase inhibition in heart failure and hypertension.”
Neprilysin Inhibition Increases Ang II Levels
A
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J Med Chem 1997;40:1570
I
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Omapatrilat
� A combined inhibitor of ACE and NEP
� Extremely effective at lowering blood
pressure
� Developed mainly as an anti-hypertensive
I
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Omapatrilat: angioedema
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I
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LCZ696 – X-ray: Sodium, Oxygen, and Water Coordination
grey =
carbon
atom;
blue =
nitrogen
atom;
red =
oxygen
atom of
active
moieties;
green =
oxygen
atom of
water;
violet =
sodium
atom
LCZ696 is a novel crystalline complex consisting of the molecular moieties of valsartan and sacubitril in
an equimolar ratio
I
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Complementary Blood Pressure Lowering with NEP inhibition and ARB
_________________
Ruillope LM et al
Lancet 2010;375:1255
AI
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Hypothesis-Generating Rationale for Outcomes Trial
___________________________
Solomon SD et al.
Lancet 2012;380:1387
AI
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Solomon SD et al.
Lancet 2012;380:1387
HFpEF - LCZ 696 vs. Valsartan
AI
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Target patient population: ∼4,300 patients with symptomatic HF (NYHA Class II–IV) and LVEF ≥45%
up to 2 weeks ~240 weeks
Valsartan 160 mg BID
LCZ696 200 mg BID
LCZ696
100 mg BID
On top of optimal background medications for co-morbidities (excluding ACEIs and ARBs)
Primary outcome: CV death and total (first and recurrent) HF hospitalizations (anticipated ~1,721 primary events)
Valsartan
80 mg BID*Screening
3–8 weeks
Active run-in period
Double-blind treatment periodRandomization 1:1
Steering Cmt: S. Solomon, co-Chair, J. McMurray, Co-Chair, I. Anand, F. Zannad, A. Maggioni, M. Packer, M. Zile,
B. Pieske, J. Rouleau, M. Redfield, C. Lam, D. Van Veldhuisen, F. Martinez, J. Ge, H. Krum, M. Pfeffer
AIAI
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First oral ARB
ACE isolated
First oral ACEi
NEPi characterized
1980
1990 2000 2010
ANP discovered
HF mortality
Omapatrilat synthesized
Patent for ARNi
PARADIGM
NEP isolated
190019401960 1920
renin discovered angiotensin
1970
Academic
Industrial
isolated
↓ ACEi -HF
Path to PARADIGM HF
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Academic-Industry Contributions to ARNi
ACADEMIC
Creativity and experimental
excellence leading to the
discovery of two important
physiologic systems and
elucidation of their function
in health and disease
� Both components required for the development of Entresto
� The whole is much greater than the sum of its parts
INDUSTRY
Ingenuity and resources
for the development
and application of the most
advanced technology to
develop safe drugs for altering
their function