PCSK9 - Dres Meeting 2016

LDL Lowering and HDL Infusion on the
Brink of Clinical Implementation
The Start of a New Era in
Cardiovascular Prevention?
Prof. John J.P. Kastelein, MD PhD FESC
Dept. of Vascular Medicine
Academic Medical Center / University of Amsterdam
The Netherlands
Disclosures
Dr. Kastelein consults with and speaks for biotechnological
as well as pharmaceutical companies that develop
molecules that influence lipoprotein metabolism and / or
inflammation to prevent CVD, including Regeneron,
Sanofi, Amgen, Pfizer, Eli Lilly, Ionis, AstraZeneca, CSL Behring,
Cerenis, Esperion, Catabasis, The Medicines Company,
Gemphire, HDL Therapeutics
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PCSK9: Protein and Function
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PCSK9: The Enzyme
Proprotein Convertase Subtilisin Kexin type 9
H
N
S
Lambert et al. (2009) Atherosclerosis
PCSK9: The Chaperone
(Binds to the LDLR)
PCSK9
LDLR
Catalytic
domain
EGFA
domain
CHRD
Prodomain
Endocytosis
Seidah et al. (2014) Circ Res
PCSK9: Genetics and
Consequences
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GOF and LOF in the PCSK9 gene
Davignon, J et al. 2010 Curr. Athero Reports 12: 308-315
PCSK9: Gain of Function
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PCSK9: Gain of Function Mutations
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PCSK9 Gain of Function Mutations:
Clinical Phenotype
FH caused by PCSK9 GOF mutations leads to a
clinical phenotype similar to that due to
mutations in the LDL-R and ApoB genes
 ● FH-associated pathognomonic clinical signs
 ● Coronary artery disease
 ● Premature myocardial infarction
 ● Stroke
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PCSK9: Loss of Function
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PCSK9 Loss of Function Mutations:
Clinical Phenotype
Cohen et al. NEJM 2006;354:1264-7212
PCSK9 Loss of Function Mutations and
very low LDL-C from Birth
AJHG 2006;79:514-23
32 yo woman
Compound heterozygote for 2 LOF alleles in PCSK9
LDL-C 0.36 mmol/L
Fertile, college educated, physically coordinated
(fitness instructor)
Atherosclerosis 2007;193:445-8
African woman
Homozygous C679X
LDL-C 0.40 mmol/L
Healthy with children
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PCSK9: Target for
Pharmacotherapy?
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PCSK9 Monoclonal Antibody (mAB)
Indications Approved by FDA 2015
 Alirocumab & Evolocumab
Use as an adjunct to diet and maximally tolerated statin therapy
in patients who require additional LDL-C lowering:
* Adults with heterozygous familial hypercholesterolemia
* Adults with clinical cardiovascular disease
 Evolocumab
Patients with homozygous familial hypercholesterolemia on
statins, ezetimibe, and/or LDL apheresis
The FDA further noted as a limitation of use that the effect of
alirocumab or evolocumab on cardiovascular morbidity and
mortality has not yet been determined.
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LDL-Lowering Efficacy of PCSK9 mAB’s
Background Statin Therapy
Praluent® prescribing information, July 2015. https://www.praluenthcp.com/ Accessed 10/29/15.
Repatha® prescribing information, September 2015. pi.amgen.com/united_states/repatha/repatha_pi_hcp. Accessed 10/29/15;
Kereiakes D, et al. Am J Cardiol 2015;169:906-915; Robinson JG, et al. NEJM 2015;372:1489-1499.
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Safety of PCSK9 mAB’s
Robinson JG, et al. N Engl J Med 2015;372:1489-1499; Blom DJ, et al. N Engl J Med 2014; 370: 1809-1819; Sabatine MS, et al. N Engl J
Med 2015;372:1500-1509.
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PCSK9 mAB’s: Preliminary Data
CVD Event Reduction
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Ongoing PCSK9 mAB CV Outcome Trials
https://clinicaltrials.gov/ct2/show/NCT01663402?term=ODYSSEY-+Outcomes&rank=1 Accessed November 2015.
https://clinicaltrials.gov/ct2/show/NCT01764633?term=FOURIER&rank=1 Accessed November 2015
https://clinicaltrials.gov/ct2/show/NCT01975376?term=SPIRE&rank=10 Accessed November 2015
https://clinicaltrials.gov/ct2/show/NCT01975389?term=SPIRE&rank=12 Accessed November 2015
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New Approaches for Raising HDL
What is in development?
• Cholesterol Ester Transfer Protein (CETP) inhibitors
• ER-Niacin / Laropiprant combination
• ApoA1 based strategies
• LCAT replacement strategies
• ABCA1 agonists / miR-33 inhibition
• LCAT agonists
• Bile-acid based strategies
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Novel Strategies for the Management of Acute
Coronary Syndromes
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Measuring Steps of Reverse
Cholesterol Transport in Humans
Bile
A-I
FC
CE
SR-BI
FC LCAT
CE
A-I
ABCG1
FC
ABCA1
Liver
Macrophage
ApoA1 Based Therapies
 CER-001, Cerenis Therapeutics
 RVX-208, as developed by Resverlogix
 CSL-112, CSL Behring
 ApoA1 Milano MDCO216, The Medicines Company
 Pre-Beta HDL, as generated by delipidation, HDL Therapeutics Inc.
 Fx-5A, as developed by Kinemed Inc.
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CER-001
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CHI-SQUARE Study Design
Core IVUS Lab
Montreal Heart
Up to 1000 Subjects
Screened w/
Baseline IVUS
following
Acute ACS Event
504 Subjects
Randomized
50 Sites
Canada, US, France,
Netherlands
Screen Period
2 weeks
Therapy Period
5 weeks
IVUS Visit
Screening
Infusion Visits
N = 126
Placebo
N = 126
3 mg/kg
N = 126
6 mg/kg
N = 126
12 mg/kg
Observation Period
2 to 5 weeks
Interim
Visit
Follow-Up
IVUS Visit
Long Term
Follow-up
6 months
Follow-Up
Visit
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CHI-SQUARE Study Results
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Tardif, EHJ 2014
CARAT
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ApoA1-Milano
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Percent Change in Atheroma Volume with IVUS
LDL-C Reduction vs. HDL-C Increasing Therapy
REVERSAL
ASTEROID
ApoA1Milano
-0.8
-4.2
P=0.02
Median change in TAV (%)
4
4
2.7*
2
-0.3†
0
-2
Prava 40 mg
18 months
Atorva 80 mg
18 months
Rosuva 40 mg
24 months
-4
ApoA-1 Milano
5 weeks
Progression
From no change to regression
Nissen SE et al. JAMA. 2003 and 2004
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ApoA1 Milano
 Manufacturing changes (new and more efficient process)
required a full re-start of the development of MDCO-216 (=
ApoA1 Milano)
 Toxicology program has been completed
 Clinical development of MDCO-216 has finished phase I (data
presented at AHA 2014)
 At the present time, a Phase IIb dose-range finding IVUS trial
(MILANO-DRIVE) is in construction and expected to start
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MILANO PILOT
MILANO DRIVE
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Delipidation
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IVUS clinical trial using
selective delipidated HDL
•
•
•
Step 1
Step 2
Step 3
Collected~1 litre
of plasma
Plasma enriched
through process
Re-infused preβ
enriched plasma
Used patients own HDL
Cholesterol removed from
αHDL to yield preβ-HDL
Preβ enriched plasma is
re-infused into patient
Walksman R, et al. J Am Coll Cardiol 2010; 55 : 2727-35.
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Conversion of alpha HDL to Preβ HDL by
Selective HDL Delipidation
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Results of the IVUS Clinical Trial
Using Selective Delipidated HDL:
NEXT: HALO
Change in atheroma volume (mm3)
4
2.8
2
0
-2
-1.73
-4
-6
-6.24
-8
Preβ-HDL infusion
-10
Control infusion
-12
-12.18
-14
Change in total
atheroma volume
Waksman R, et al. J Am Coll Cardiol 2010; 55 : 2727-35.
Change in 10mm most
diseased segment
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CSL-112
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CSL112 (in phase 2) contains human apoA-I and
resembles nascent HDL
CSL112 represents a homogenous population of disc-shaped particles which
resemble nascent HDL
CSL112, a reconstituted HDL, rapidly enhances cholesterol efflux capacity of plasma
following infusion. S. Diditchenko, M. Spycher, M. Waelchli, M. Imboden, S. Schenk, I. Pragst
and S.D. Wright. Presented Wednesday
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AEGIS I and AEGIS II
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New Approaches for Raising HDL
 Exciting times for HDL infusion / delipidation
 CARAT, AEGIS-1, MILANO-PILOT, MILANO-DRIVE, HALO
all poised to run in 2015
 All 4 therapies promote cholesterol efflux
 Cholesterol efflux predicts incident CV events
 Development of Fx-5A and LCAT infusion is eagerly awaited
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