Robert S. Rosenson, MD, FACC 1 Colin Hislop, MD 2 Daniel McConnell, Ph.D 3 Michael Elliott, MA 2
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Transcript of Robert S. Rosenson, MD, FACC 1 Colin Hislop, MD 2 Daniel McConnell, Ph.D 3 Michael Elliott, MA 2
Effects of a Selective Inhibitor of Secretory Phospholipase A2 on Low Density Lipoproteins
and Inflammatory Pathways
Robert S. Rosenson, MD, FACC1
Colin Hislop, MD2
Daniel McConnell, Ph.D3
Michael Elliott, MA2
Yuri Stasiv, Ph.D2
David Waters, MD4
For the PLASMA Investigators
1 Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI2 Anthera Pharmaceuticals, San Mateo, CA
3 Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI4 Division of Cardiology, San Francisco General Hospital, San Francisco, CA
Robert S. Rosenson, M.D. – Consultant/Advisor: Anthera, modest level; Equity Interests/Stock Options: LipoScience, Inc., significant level;Colin Hislop, M.D. – Equity Interests/Stock Options: Anthera, significant level;
Employment: Anthera, significant level;Daniel McConnell, Ph.D. – No DisclosuresMichael Elliott, M.A. –
Equity Interests/Stock Options: Anthera, significant level;Employment: Anthera, significant level;
Yuri Stasiv, Ph.D. – Equity Interests/Stock Options: Anthera, modest level;Employment: Anthera, significant level;
David Waters, M.D. – David Waters, M.D. – Consultant/Advisor: Merck Schering Plough, Atherogenic,
modest level; Pfizer, significant level; Equity Interests/Stock Options: Anthera, modest level; Lecture Fees: Pfizer, significant level;
Disclosure Information
Atherosclerosis, sPLA2 and Inflammation
Macrophage/Foam Cell
Smooth muscle cells Cytokines
Lyso-PC
Small LDLModified LDL
sPLA2
sPLA2
LDL
sPLA2
OX-LDL
Circulating sPLA2
Foam Cells
Monocyte Adhesion
Plaque
Circulating HDL
NEFA
Ox-NEFA
LDL Aggregates
Arachidonic Acid
PLASMA: PLASMA: PPhospholipase hospholipase LLevels evels AAnd nd SSerological erological MMarkers of Atherosclerosis arkers of Atherosclerosis
((PLASMA: PLASMA: NCT00455546))
Varespladib 50 mg BID
Varespladib 100 mg BID
Varespladib 250 mg BID
Varespladib 500 mg BID
Placebo BID
8-week double-blind treatment period
Primary End Point• sPLA2 -IIA mass
Secondary End Points• Lipids• Lipoprotein subclasses• Apo B• Ox-LDL• hs-CRP• Safety in CHD patients
396 Patients• Stable CHD
12wk post MI 6wk post UA
•Therapeutic standard care
(n=79)
(n=77)
(n=78)
(n=80)
(n=79)
Varespladib (A-002), Anthera Pharmaceutical, San Mateo, CA, USAVarespladib (A-002), Anthera Pharmaceutical, San Mateo, CA, USA
Inclusion/Exclusion Criteria
Inclusion
• Men and women > 18 years of age
• Written informed consent from the subject
• Stable CAD
• Stable medical condition, will be compliant and able to comply with the requirements of the protocol
Exclusion
• Active inflammatory disease and drugs to modulate the inflammatory response
MethodsMethods
• sPLAsPLA2 2 mass mass was analyzed by a quantitative two- was analyzed by a quantitative two-
site using a monoclonal antibody specific for site using a monoclonal antibody specific for sPLAsPLA22-Group IIA EIA (Cayman Chemical, Ann -Group IIA EIA (Cayman Chemical, Ann
Arbor, MI). Arbor, MI). • LipoproteinLipoprotein subclassessubclasses were measured by NMR were measured by NMR
spectroscopic assay (LipoScience, Inc., Raleigh, spectroscopic assay (LipoScience, Inc., Raleigh, NC, USA).NC, USA).
• Oxidized LDLOxidized LDL was measured by ELISA using the was measured by ELISA using the specific antibody 4E6 (Mercodia, Uppsula specific antibody 4E6 (Mercodia, Uppsula Sweden).Sweden).
• CRPCRP with a high-sensitivity assay (Dade Behring with a high-sensitivity assay (Dade Behring Nephelometer II, Quest Diagnostics, Van Nuys, Nephelometer II, Quest Diagnostics, Van Nuys, CA, USA).CA, USA).
Demographic and Baseline CharacteristicsDemographic and Baseline CharacteristicsVariableVariable VarespladibVarespladib
50 mg 50 mg (n=79)(n=79)
VarespladibVarespladib
100 mg 100 mg (n=80)(n=80)
VarespladibVarespladib
250 mg 250 mg (n=78)(n=78)
VarespladibVarespladib
500 mg 500 mg (n=77)(n=77)
VarespladibVarespladib
Overall Overall (n=314)(n=314)
PlaceboPlacebo
(n=79)(n=79)
Age (y)Age (y) 62 62 ++ 10 10 64 64 ++ 10 10 63 63 ++ 10 10 61 61 ++ 11 11 62 62 ++ 10 10 62 62 ++ 11 11
Sex (%M/F)Sex (%M/F) 78.5/21.578.5/21.5 72.5/27.572.5/27.5 83.3/16.783.3/16.7 81.8/18.281.8/18.2 79.0/21.079.0/21.0 75.9/24.175.9/24.1
Race (% Caucasian)*Race (% Caucasian)* 100100 7575 94.994.9 98.798.7 97.197.1 94.994.9
BMI (kg/mBMI (kg/m2)2) 30.4 30.4 ++ 5.9 5.9 30.6 30.6 ++ 6.3 6.3 29.9 29.9 ++ 5.4 5.4 30.4 30.4 ++ 5.1 5.1 30.3 30.3 ++ 5.7 5.7 30.5 30.5 ++ 5.3 5.3
MI (%)MI (%) 52 (66)52 (66) 54 (68)54 (68) 47 (60)47 (60) 54 (70)54 (70) 207 (66)207 (66) 53 (67)53 (67)
CABG (%)CABG (%) 54 (68)54 (68) 56 (70)56 (70) 55 (70) 55 (70) 53 (69)53 (69) 218 (69)218 (69) 52 (66)52 (66)
HTN (%)HTN (%) 70 (89)70 (89) 64 (80)64 (80) 67 (86)67 (86) 61 (79)61 (79) 262 (83)262 (83) 57 (72)57 (72)
Diabetes (%)Diabetes (%) 16 (20)16 (20) 28 (35)28 (35) 20 (26)20 (26) 18 (23)18 (23) 82 (26)82 (26) 20 (25)20 (25)
Aspirin (%)Aspirin (%) 74 (94)74 (94) 74 (92)74 (92) 68 (87)68 (87) 72 (94)72 (94) 288 (92)288 (92) 67 (85)67 (85)
Thienopyridine (%)Thienopyridine (%) 20 (25)20 (25) 12 (15)12 (15) 26 (32)26 (32) 29 (38)29 (38) 86 (27)86 (27) 22 (28)22 (28)
Beta Blockers (%)Beta Blockers (%) 52 (66)52 (66) 66 (82)66 (82) 60 (77)60 (77) 54 (70)54 (70) 232 (74)232 (74) 47 (59)47 (59)
ACE/ARB (%)ACE/ARB (%) 45 (57)45 (57) 42 (53)42 (53) 47 (60)47 (60) 41 (53)41 (53) 175 (56) 175 (56) 43 (54)43 (54)
Statin (%)Statin (%) 49 (62)49 (62) 54 (68)54 (68) 53 (68)53 (68) 52 (68)52 (68) 207 (66)207 (66) 51 (65)51 (65)
Data are expressed as means Data are expressed as means ++ standard deviations standard deviations* Race was determined by the investigator* Race was determined by the investigator
VariableVariable VarespladibVarespladib
50 mg 50 mg
(n=79)(n=79)
VarespladibVarespladib
100 mg 100 mg
(n=80)(n=80)
VarespladibVarespladib
250 mg (n=78)250 mg (n=78)
VarespladibVarespladib
500 mg (n=77)500 mg (n=77)
VarespladibVarespladib
Overall Overall (n=314)(n=314)
PlaceboPlacebo
(n=79)(n=79)
sPLAsPLA22 Mass Mass
(ng/mL)*(ng/mL)*
2.10 2.10
(0.2-8.80)(0.2-8.80)
2.20 2.20
(0.05-(0.05-22.30)22.30)
2.00 2.00
(0.20-6.00)(0.20-6.00)
2.402.40
(0.40-5.40)(0.40-5.40)
2.20 2.20
(0.05-22.30)(0.05-22.30)
2.202.20
(0.08-6.80)(0.08-6.80)
TC (mg/dL)TC (mg/dL) 175 175 ++ 6.0 6.0 178 178 ++ 5.7 5.7 173 173 ++ 5.1 5.1 178 178 ++ 6.6 6.6 176 176 ++ 2.9 2.9 174 174 ++ 5.9 5.9
LDL-C (mg/dL)LDL-C (mg/dL) 93.3 93.3 ++ 4.8 4.8 98.8 98.8 ++ 4.7 4.7 93.2 93.2 ++ 4.5 4.5 95.1 95.1 ++ 4.8 4.8 95.1 95.1 ++ 2.3 2.3 96.2 96.2 ++ 5.1 5.1
HDL-C ( mg/dL)HDL-C ( mg/dL) 47.4 47.4 ++ 1.6 1.6 46.0 46.0 ++ 1.2 1.2 48.0 48.0 ++ 1.7 1.7 48.9 48.9 ++ 1.7 1.7 47.6 47.6 ++ 0.8 0.8 50.1 50.1 ++ 1.5 1.5
TG (mg/dL)TG (mg/dL) 169 169 ++ 12.4 12.4 161 161 ++ 10.1 10.1 161 161 ++ 10.6 10.6 171 171 ++ 18.0 18.0 165 165 ++ 6.5 6.5 152 152 ++ 11.5 11.5
LDL-P (nmol/L)*LDL-P (nmol/L)* 1076.51076.5
(344-2531)(344-2531)
1105.01105.0
(502-2443)(502-2443)
1043.51043.5
(451-2422)(451-2422)
1076.01076.0
(445-2410)(445-2410)
1085.01085.0
(344-2531)(344-2531)
1183 1183 ++ 47.447.4
Small LDL-P (nmol/L)*Small LDL-P (nmol/L)* 755.0 755.0
(16-2251)(16-2251)
779.0779.0
(57-2143)(57-2143)
741.5741.5
(29-2185)(29-2185)
838.0838.0
(48-1980)(48-1980)
777.0777.0
(16-2251)(16-2251)
1065.01065.0
(509-2641)(509-2641)
Apo B, (mg/dL)Apo B, (mg/dL) 93.1 93.1 ++ 4.6 4.6 96.4 96.4 ++ 4.1 4.1 96.3 96.3 ++ 3.9 3.9 98.0 98.0 ++ 4.5 4.5 96.0 96.0 ++ 2.1 2.1 98.4 98.4 ++ 4.3 4.3
Ox-LDL (mU/L)Ox-LDL (mU/L) 60.8 60.8 ++ 2.5 2.5 60.1 60.1 ++ 2.1 2.1 59.5 59.5 ++ 2.3 2.3 60.2 60.2 ++ 2.2 2.2 60.2 60.2 ++ 1.1 1.1 61.8 61.8 ++ 2.4 2.4
Baseline Plasma Levels of Lipid, Lipoprotein and Baseline Plasma Levels of Lipid, Lipoprotein and Inflammatory MarkersInflammatory Markers
*sPLA2 Mass, LDL-P and Small LDL-P in medians and interquartile ranges
0 weeks
2 weeks
4 weeks
8 weeks*
0
0.5
1
1.5
2
2.5
sPL
A2
mas
s (n
g/m
L)
50 mg 100 mg 250 mg 500 mg Placebo
Varespladib dosage
* **
* * * * ** * *
Secretory PLASecretory PLA2 2 Mass in Placebo and Mass in Placebo and Varespladib Treatment GroupsVarespladib Treatment Groups
* p<0.0001Data are expressed as medians
Baseline
Week 2
Week 4
Week 8
50
60
70
80
100
110
50 mg 100 mg
250 mg 500 mg Placebo
Varespladib dosage
LD
L c
ho
les
tero
l (m
g/d
L)
** *
* † †‡‡
§
LDL-C in Placebo and Varespladib LDL-C in Placebo and Varespladib Treatment GroupsTreatment Groups
* p<0.05; † p<0.005; ‡ p<0.001; § p=0.0005Data are expressed as means
90
40
LDL-C Levels in Patients Taking Varespladib Monotherapy
80
90
110
120
140
150
50 mg 100 mg
250 mg 500 mg Placebo
Varespladib dosage
LD
L c
ho
les
tero
l (m
g/d
L)
130
70
Baseline
Week 8
Data are expressed as means
**
* p<0.05
BaselineWeek 2Week 4Week 8
50
60
70
80
100
110
120
50 mg 100 mg 250 mg 500 mg Placebo
Varespladib dosage
LD
L c
ho
lest
ero
l (m
g/d
L)
LDL-C in Statin-Treated Subjects with Baseline LDL-C > 70 LDL-C in Statin-Treated Subjects with Baseline LDL-C > 70 mg/dL in Placebo and Varespladib Treatment Groupsmg/dL in Placebo and Varespladib Treatment Groups
* p<0.05; † p<0.01; ‡ p<0.005
*‡
‡
‡*
Data are expressed as means
90
40
† †
‡
Effects of Varespladib on LDL SubclassesEffects of Varespladib on LDL Subclasses
• In varespladib-treated subjects, median LDL In varespladib-treated subjects, median LDL particle concentration was reduced by 80 particle concentration was reduced by 80 nmol/L (p <0.05) primarily due to lowering of nmol/L (p <0.05) primarily due to lowering of small LDL particles (58 nmol/L, p<0.01).small LDL particles (58 nmol/L, p<0.01).
• Overall LDL particle size increased in the Overall LDL particle size increased in the varespladib-treated subjects by 0.02 nm varespladib-treated subjects by 0.02 nm compared to a decrease in placebo=treated compared to a decrease in placebo=treated subjects (-0.17 nm), p = 0.015).subjects (-0.17 nm), p = 0.015).
• Oxidized LDL was reduced in varespladib Oxidized LDL was reduced in varespladib treated patients (p = 0.011). treated patients (p = 0.011).
hs-CRP Levels in Placebo and Varespladib hs-CRP Levels in Placebo and Varespladib Treatment GroupsTreatment Groupsh
s-C
RP
(m
g/L
)
0.1
0.3
0.4
0.5
0.6
0
0.2
50 mg 100 mg 250 mg 500 mg Placebo
Baseline
8 Weeks
Varespladib dosageData are expressed as means
Safety and Adverse Events Safety and Adverse Events
• The proportion of subjects reporting TEAEs and The proportion of subjects reporting TEAEs and receiving varespladib (47%) was no different from receiving varespladib (47%) was no different from placebo (44%).placebo (44%).
• Most frequent amongst the varespladib treatment Most frequent amongst the varespladib treatment groups were headache 6.4%; nausea 5.4%; groups were headache 6.4%; nausea 5.4%; diarrhea 3.8%; ALT increase 3.2%; dizziness diarrhea 3.8%; ALT increase 3.2%; dizziness 2.9%; AST increased 2.2%; back pain 2.2%.2.9%; AST increased 2.2%; back pain 2.2%.
• There was one serious adverse event (SAE) in the There was one serious adverse event (SAE) in the varespladib 50 mg BID treatment group resulting varespladib 50 mg BID treatment group resulting
in discontinuation.in discontinuation. An exacerbation of COPD An exacerbation of COPD was reported in a subject who had a viral was reported in a subject who had a viral
prodrome (fever, headache) 2 days earlierprodrome (fever, headache) 2 days earlier..
ConclusionsConclusions
1.1. Varespladib treatment markedly reduced Varespladib treatment markedly reduced median sPLAmedian sPLA22 mass by 69% to 96% in a mass by 69% to 96% in a dose-dependent manner.dose-dependent manner.
2.2. Compared to placebo, varespladib Compared to placebo, varespladib reduced LDL-C by 8.0 to 11.9% primarily reduced LDL-C by 8.0 to 11.9% primarily mediated by a reduction in small LDL mediated by a reduction in small LDL particles.particles.
3.3. The maximal reduction in LDL-C was The maximal reduction in LDL-C was larger among statin-treated patients with larger among statin-treated patients with baseline LDL-C >70 mg/dL ranging from baseline LDL-C >70 mg/dL ranging from 6.1 to 17.1%.6.1 to 17.1%.
Plasma Investigators
• The investigators that participated in the PLASMA study are as follows – United States: M. Matsumura, M. Imburgia, S. Chrysant, J. Rozanski, S. Smith, R. Weiss, P. Underwood, D. Ende, D. Brown, C. Brown, V. Nadar, R. Carlson, D. Wombolt, F. Matar, P. Rossi, F. Eder, B. Bowling, R. Pellegrino, N. Ferrier, D. Hotchkiss, S. Broadwater. Ukraine: K. Amosova, O. Korkushko, V. Kovalenko, O. Kupchynska, M. Lutay, V. Lizogub, B. Mankovsky, O. Mitchenko, Y. Sirenko, L. Yena, V. Volkov, I. Kraiz, M. Perepelytsya, V. Vizir, G. Dzyak.