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TRANSCRIPT
9/2/2015
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Ryan T. Whitney, MD FACC
Bryan Heart Fall Conference 2015
PCSK9 InhibitorsCurrent Status
• I own no stock in the companies mentioned in this talk.
• I am not a speaker, consultant or hired gun for any device or pharmaceutical company.
• I am the co-founder of Together+Clinic, a local healthcare IT company. We can help you better optimize patient management and capture CCM revenue. Stop by our booth to learn more. (Yes, that was a shameless plug)
Disclosures, Conflicts, and Nefarious Connections
• Plays a pivotal role in LDL metabolism
• Promotes the degradation of the LDL receptor and prevents it from recycling to the membrane
Proprotein convertasesubtilisin/kexin type 9 (PCSK9)
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• Alirocumab (Praluent)
– Sanofi, Regeneron
• Evolocumab (Repatha)
– Amgen
• Bococizumab
– Pfizer
Current PCSK9 Inhibitors
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• “…as adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL-C.”
Alirocumab (Praluent) Indications
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• “Indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic CVD, who require additional lowering of LDL-C.”
• “Indicated as an adjunct to diet and other LDL-lowering therapies (eg, statins, ezetimibe, LDL apheresis) for the treatment ofpatients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C”
Evolocumab (Repatha) Indications
• Alirocumab (Praluent)
– 75 mg SC q2weeks
– 150 mg SC q2weeks
Dosing• Evolocumab (Repatha)
– Primary hyperlipidemia:
140 mg SC q2weeks
420 mg SC once monthly
– HoFH
420 mg SC once monthly
• Alirocumab (Praluent)
$14,600
• Evolocumab (Repatha)
$14,100
Yearly Cost
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• Approximately 25 million
statin users
• Indication creep
–10 million users
• Most initial estimates closer to $20 billion
CVS: Costs Could Potentially Reach $150 Billion Annually
FOURIER
SPIRE-1
SPIRE-2
Research at Bryan Heart
A Double-blind, Randomized, Placebo-controlled, Multicenter Study Assessing the Impact of Additional LDL-
Cholesterol Reduction on Major Cardiovascular Events When AMG 145 is Used in Combination With Statin Therapy In Patients with Clinically Evident Cardiovascular Disease
Further Cardiovascular Outcomes Research with PCSK9 Inhibition in
Subjects With Elevated Risk (FOURIER)
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• Inclusion Criteria:
– Male or female ≥ 40 to ≤ 80 years of age
– History of clinically evident cardiovascular disease at high risk for a
recurrent event
– Fasting LDL-C ≥ 70 mg/dL or non-HDL-C ≥ 100 mg/dL
– Fasting triglycerides ≤ 400 mg/dL
• Exclusion Criteria:
– NYHA class III or IV, or last known EF < 30%
– Uncontrolled HTN, VT, hyper/hypothyroidism
– HoFH
– LDL or plasma apheresis
FOURIER Criteria
• Evolocumab q2wk or qmonth with atorvastatin 20 – 80mg
Vs
• Placebo q2wk or qmonth with atorvastatin 20 – 80mg
FOURIER Arms
• Primary Outcome Measures:
– Time to cardiovascular death, myocardial infarction,
hospitalization for unstable angina, stroke, or coronary
revascularization
• Secondary Outcome Measures:
– Time to cardiovascular death, myocardial infarction, or stroke
– Time to death by any cause
– Time to cardiovascular death or hospitalization for worsening heart
failure
– Time to ischemic fatal or non-fatal stroke or TIA
Outcomes (5 years)
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The Evaluation of Bococizumabin Reducing the Occurrence of Major Cardiovascular Events in High Risk Subjects
SPIRE-1 and SPIRE-2
• Inclusion Criteria:
– Must be on background lipid lowering treatment.
– Must be at high risk of a CV event.
– Must have an LDL C >=70 mg/dL and < 100 mg/dL or non-HDL-C >= 100 mg/dL
and < 130 mg/dL.
• Exclusion Criteria:
– An LDL C < 70 mg/dL or >= 100 mg/dL or non HDL-C < 100 mg/dL or >=130 mg/dL.
– Planned coronary (PCI or CABG) or other arterial revascularization.
– New York Heart Association Class IV congestive heart failure or left ventricular
ejection fraction < 25% by cardiac imaging.
– Chronic renal insufficiency with creatinine clearance of <30 or with end state renal disease on dialysis.
– History of hemorrhagic stroke.
– Prior exposure to bococizumab or other investigational PCSK9 inhibitor.
SPIRE-1 (Bococizumab)
• Inclusion Criteria:
– Must be on background lipid lowering treatment.
– Must be at high risk of a CV event.
– Must have an LDL C >=100 mg/dL OR non HDL C >=130 .
• Exclusion Criteria:
– An LDL C <100 mg/dL or non HDL C <130 mg/dL.
– Planned coronary (PCI or CABG) or other arterial revascularization.
– New York Heart Association Class IV congestive heart failure or left ventricular ejection fraction < 25% by cardiac imaging.
– Chronic renal insufficiency with creatinine clearance of <30 or with end state renal disease on dialysis.
– History of hemorrhagic stroke.
– Prior exposure to bococizumab or other investigational PCSK9 inhibitor.
SPIRE-2 (Bococizumab)
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A Subcutaneously Administered Investigational
RNAi Therapeutic (ALN-PCSsc), Targeting PCSK9
for the Treatment of Hypercholesterolemia: Initial
Phase 1 Study Results
Kevin Fitzgerald, PhD
Co-authors:
Amy Simon1, Suellen White1, Anna Borodovsky1, Nirav Patel1, Brian Bettencourt1, Valerie Clausen1, Jay Horton3, Peter
Wijngaard2 , Robert Kauffman1, David Kallend2
1 – Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142 USA
2 – The Medicines Company, 8 Sylvan Way, Parsippany, NJ 07054 USA
3 – Universityof Texas South Western, 5323 Harry Hines Blvd, Dallas, TX 75390 USA
Declaration of Interest: Employees of Alnylam Pharmaceuticals1
Employees of The Medicines Company2
August 30, 2015: European Society of Cardiology (ESC)
3939
PCSK9 Therapeutic Hypothesis
PCSK9 mRNA
PCSK9
synthesis
LDLR
synthesis
PCSK9
LDL
Lysosomal
degradation
Endosome
Nucleus
ALN-PCS
Anti-PCSK9
Mabs Transiently block
PCSK9 binding
To LDL receptor
(LDLR)
PCSK9
Synthesis
InhibitorsDurably block PCSK9
synthesis and all
intracellular and
extracellular PCSK9
functions
LDLR
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40
Initial ALN-PCSsc Phase 1 Study Results SAD PCSK9 Knockdown Relative to Baseline
Data in database as of 04 August 2015
Day/Treatment combinations where N=1 not displayed
100
80
60
40
20
0
-20
-40
0 1 2 3 4 5
Months
Me
an
(S
EM
) %
PC
SK
9 K
no
ck
do
wn
(Ch
an
ge
fro
m B
as
elin
e)
Placebo
25 mg
100 mg
300 mg
500 mg
800 mg
Treatment
41
Initial ALN-PCSsc Phase 1 Study Results SAD LDL-C Lowering Relative to Baseline
Data in database as of 04 August 2015
Days/Treatments where N=1 not displayed
LDL-C analyzed by Beta-Quantification
80
60
40
20
0
Me
an
(S
EM
) %
LD
L-C
Lo
we
rin
g
(Ch
an
ge
fro
m B
as
elin
e)
0 1 2 3 4 5
Months
Placebo
25 mg
100 mg
300 mg
500 mg
800 mg
Treatment
4242
Initial ALN-PCSsc Phase 1 Study ResultsMD PCSK9 Knockdown Relative to Baseline
S ^ =On stable dose of statin
Two subjects excluded from all MD analyses:
One placebo subject elected to discontinue;
One subject in 300 mg statin group was incarcerated on Day 14
Data in database as of 04 August 2015
100
80
60
40
20
0
-20
-40
-60
0 1 2 3 4 5
Months
Me
an
(S
EM
) %
PC
SK
9 K
no
ck
do
wn
(Ch
an
ge
fro
m B
as
elin
e)
Placebo
125 mg qWX4
250 mg q2WX2
300 mg qMX2
300 mg S^qMX2
500 mg qMX2
Treatment
500 mg S^qMX2
qW, q2W, or qM
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Initial ALN-PCSsc Phase 1 Study Results MD LDL-C Lowering Relative to Baseline
Data in database as of 04 August 2015
S ^ =On a stable dose of statins
Two subjects excluded from all MD analyses:One placebo subject elected to discontinue;
One subject in 300 mg statin group was incarcerated on Day 14
60
40
20
0
0 1 2 3 4 5
Month
Me
an
(S
EM
) %
LD
L-C
Lo
we
rin
g
(Ch
an
ge
fro
m B
as
elin
e)
80
qW, q2W, or qM
Placebo
125 mg qWX4
250 mg q2WX2
300 mg qMX2
300 mg S ^ qMX2
500 mg qMX2
Treatment
500 mg S ^ qMX2
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Ryan T. Whitney, MD FACC
Bryan Heart Fall Conference 2015
PCSK9 InhibitorsCurrent Status