Effects of 1-H-indole-3-glyoxamide (A-002) on concentration of secretory phospholipase A2 (PLASMA study): a phase II double-blind, randomised,placebo-controlled trial Robert S Rosenson, Colin Hislop, Daniel McConnell, Michael Elliott, Yuri Stasiv, Nan Wang, David D Waters, for the PLASMA Investigators R2 Jungwook Kim / Prof. Kwonsam Kim Lancet 2009; 373: 649–58

Introduction sPLA2 - produced & secreted in human blood vessels & hepatocytes - development of atherosclerosis through mechanism (both dependent and independent of lipoprotein)

Introduction  sPLA-modified lipoproteins → highly oxidised LDL particle → activate inflammatory path Various sPLA2 isoenzyme : lipoprotein modification, retention, macrophage uptake  sPLA 2 -IIA ↑ - predict CHD events in Pts c stable CAD & UA - a/w ↑ risk of incident CHD in healthy men/women  A-002 (selective sPLA 2 inhibitor) effect - sPLA 2 conc. & activity, - plasma lipoproteins & inflammatory biomarkers in Pt c CHD

Methods (patients)  a phase II, randomised, double-blind, placebo- controlled, dose-response study  Eligible Pts : aged 18yrs or older c stable CHD ☞ previous MI (more than 12 weeks) ☞ unstable angina (more than 6 weeks) ☞ objective evidence of atherosclerotic CAD ☞ previous revascularisation procedure (12 weeks)  Major exclusion criteria ☞ active inflammatory dis ☞ drugs likely to modulate the inflammatory response

Methods (procedure)  Placebo Vs one of four doses of A-002 (50mg, 100mg, 250mg, 500mg twice daily for 8weeks)  Safety and efficacy data ( baseline, weeks 2, 4, 8 )  Primary end point → change from baseline to week 8 in sPLA2 conc. or activity  Secondary end point → change from baseline to week 8 inflammatory markers, lipid and biochemical indices, lipoprotein subclasses, oxidised LDL  LDL-chol, lipoprotein subclass profiles, sPLA2-IIA activity, oxidised LDL, plasma arachidonic acid, LTB4

Methods (statistical analysis)  Primary efficacy analysis : comparison of change in sPLA2-IIA conc. from baseline to week 8 between the pooled A-002 & placebo group  Secondary efficacy analysis ☞ pair-wise comparisons of each dose of A-002 with all higher doses of the drug, ☞ comparison of changes from baseline to week 2, 4, and 8 between each treatment group and the placebo group

Materials & Methods 275 US 121 Ukraine 348 (89%)

Results

Results (statin-treated Pts)  295 pts were taking a statin (US : 242/274, Ukraine : 17/120)  Baseline LDL cholesterol in this subgroup was lower (1.9~2.0 Vs 0.7~4.7)  the mean reduction in LDL cholesterol in patients taking a statin was greater than or similar to that seen in the total study population

Statin-treated patients

Conclusion  The reductions in sPLA2-IIA concentration in the A- 002 groups were dose dependent and differed significantly from placebo  The reduction in LDL cholesterol, CRP, arachidonic acid, and oxidised LDL cholesterol resulting from A- 002 treatment over a background of statin therapy is potentially clinically relevant.  Combined use of A-002 with a statin may have complementary benefits.