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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 A 2 on Low Density Lipoproteins and Inflammatory Pathways. Robert S. Rosenson, MD, FACC 1 Colin Hislop, MD 2 Daniel McConnell, Ph.D 3 Michael Elliott, MA 2 Yuri Stasiv, Ph.D 2 David Waters, MD 4 For the PLASMA Investigators.

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Robert S. Rosenson, MD, FACC 1 Colin Hislop, MD 2 Daniel McConnell, Ph.D 3 Michael Elliott, MA 2

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  1. 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, MI 2 Anthera Pharmaceuticals, San Mateo, CA 3 Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 4 Division of Cardiology, San Francisco General Hospital, San Francisco, CA

  2. DisclosureInformation 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 Disclosures Michael 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. – Consultant/Advisor: Merck Schering Plough, Atherogenic, modest level; Pfizer, significant level; Equity Interests/Stock Options:Anthera, modest level; Lecture Fees: Pfizer, significant level;

  3. Atherosclerosis, sPLA2 and Inflammation Plaque Monocyte Adhesion LDL CirculatingsPLA2 sPLA2 Circulating HDL sPLA2 Foam Cells LDL Aggregates sPLA2 Small LDL Modified LDL Macrophage/Foam Cell OX-LDL NEFA Lyso-PC Arachidonic Acid Ox-NEFA Smooth muscle cells Cytokines

  4. PLASMA: PhospholipaseLevels And Serological Markers of Atherosclerosis (PLASMA: NCT00455546) (n=79) Varespladib 50 mg BID (n=80) Varespladib 100 mg BID • 396 Patients • Stable CHD • 12wk post MI • 6wk post UA • Therapeutic standard care (n=78) Varespladib 250 mg BID (n=77) Varespladib 500 mg BID (n=79) Placebo BID 8-week double-blind treatment period • Secondary End Points • Lipids • Lipoprotein subclasses • Apo B • Ox-LDL • hs-CRP • Safety in CHD patients • Primary End Point • sPLA2 -IIA mass Varespladib (A-002), Anthera Pharmaceutical, San Mateo, CA, USA

  5. 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

  6. Methods • sPLA2 mass was analyzed by a quantitative two-site using a monoclonal antibody specific for sPLA2-Group IIA EIA (Cayman Chemical, Ann Arbor, MI). • Lipoproteinsubclasses were measured by NMR spectroscopic assay (LipoScience, Inc., Raleigh, NC, USA). • Oxidized LDL was measured by ELISA using the specific antibody 4E6 (Mercodia, Uppsula Sweden). • CRP with a high-sensitivity assay (Dade Behring Nephelometer II, Quest Diagnostics, Van Nuys, CA, USA).

  7. Demographic and Baseline Characteristics Data are expressed as means + standard deviations * Race was determined by the investigator

  8. Baseline Plasma Levels of Lipid, Lipoprotein and Inflammatory Markers *sPLA2 Mass, LDL-P and Small LDL-P in medians and interquartile ranges

  9. Secretory PLA2 Mass in Placebo and Varespladib Treatment Groups 0 weeks 2 weeks 4 weeks 8 weeks 2.5 2 1.5 sPLA2 mass (ng/mL) * 1 * * * 0.5 * * * * * * * * 0 50 mg 100 mg 250 mg 500 mg Placebo Varespladib dosage Data are expressed as medians * p<0.0001

  10. LDL-C in Placebo and Varespladib Treatment Groups 110 Baseline 100 Week 2 * * Week 4 90 Week 8 * * † † § ‡ ‡ 80 LDL cholesterol (mg/dL) 70 60 50 40 50 mg 100 mg 250 mg 500 mg Placebo Varespladib dosage Data are expressed as means * p<0.05; † p<0.005; ‡ p<0.001; § p=0.0005

  11. LDL-C Levels in Patients Taking Varespladib Monotherapy Baseline Week 8 150 140 130 * * 120 LDL cholesterol (mg/dL) 110 90 80 70 50 mg 100 mg 250 mg 500 mg Placebo Varespladib dosage Data are expressed as means * p<0.05

  12. LDL-C in Statin-Treated Subjects with Baseline LDL-C > 70 mg/dL in Placebo and Varespladib Treatment Groups 120 Baseline 110 Week 2 Week 4 Week 8 100 ‡ † 90 † LDL cholesterol (mg/dL) ‡ * 80 ‡ * ‡ 70 60 50 40 50 mg 100 mg 250 mg 500 mg Placebo Varespladib dosage Data are expressed as means * p<0.05; † p<0.01; ‡ p<0.005

  13. Effects of Varespladib on LDL Subclasses • In varespladib-treated subjects, median LDL particle concentration was reduced by 80 nmol/L (p <0.05) primarily due to lowering of small LDL particles (58 nmol/L, p<0.01). • Overall LDL particle size increased in the varespladib-treated subjects by 0.02 nm compared to a decrease in placebo=treated subjects (-0.17 nm), p = 0.015). • Oxidized LDL was reduced in varespladib treated patients (p = 0.011).

  14. hs-CRP Levels in Placebo and Varespladib Treatment Groups Baseline 8 Weeks 0.6 0.5 0.4 hs-CRP (mg/L) 0.3 0.2 0.1 0 50 mg 100 mg 250 mg 500 mg Placebo Varespladib dosage Data are expressed as means

  15. Safety and Adverse Events • The proportion of subjects reporting TEAEs and receiving varespladib (47%) was no different from placebo (44%). • Most frequent amongst the varespladib treatment groups were headache 6.4%; nausea 5.4%; diarrhea 3.8%; ALT increase 3.2%; dizziness 2.9%; AST increased 2.2%; back pain 2.2%. • There was one serious adverse event (SAE) in the varespladib 50 mg BID treatment group resulting in discontinuation.An exacerbation of COPD was reported in a subject who had a viral prodrome (fever, headache) 2 days earlier.

  16. Conclusions • Varespladib treatment markedly reduced median sPLA2 mass by 69% to 96% in a dose-dependent manner. • Compared to placebo, varespladib reduced LDL-C by 8.0 to 11.9% primarily mediated by a reduction in small LDL particles. • The maximal reduction in LDL-C was larger among statin-treated patients with baseline LDL-C >70 mg/dL ranging from 6.1 to 17.1%.

  17. 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.

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