SJ Nicholls, CM Ballantyne , JJP Kastelein , A Taylor, A Gordon, J Johansson, K Wolski , M Borgman and SE Nissen

1. Results of the First Major Clinical Trial of An Oral Agent Inducing ApoA-I Synthesis:A New Approach to Raising HDL and CV Risk Modification SJ Nicholls, CM Ballantyne, JJP Kastelein, A Taylor, A Gordon, J Johansson, K Wolski, M Borgman and SE Nissen The ASSERT Study Cleveland Clinic Heart & Vascular Institute

2. Disclosures • Honoraria and consultant: AstraZeneca, Abbott, Merck, Anthera, Omthera, Takeda, Roche • Research support from Resverlogix, Anthera, AstraZeneca, Novartis, Karo Bio, Eli Lilly and Roche • The ASSERT study was sponsored by Resverlogix

3. The Challenge of Promoting HDL • Residual cardiovascular risk persists in many patients despite substantial LDL-C reduction. • While raising HDL is a theoretically attractive target, the optimal approach remains uncertain. • An alternative to elevations in HDL-C involves strategies to enhance HDL functionality. • Although preclinical data suggest that enhancing apoA-I synthesis may be beneficial, finding an effective agent has proven challenging.

4. RVX-208 • RVX-208 is an oral inducer of apoA-I synthesis. • Enhanced apoA-I synthesis should generate functional HDL particles that facilitate reverse cholesterol transport. • In animals and healthy volunteers, RVX-208 treatment is associated with an increase in pre-β HDL and α1 particles, resulting in increased cholesterol efflux potential. • Improved HDL quantity and quality may produce other non-lipid-related beneficial effects on inflammation and endothelial function.

5. Objective of ASSERT Study The ASSERT study aimed to characterize the short-term (12 weeks) efficacy, safety and tolerability of RVX-208 in statin-treated patients with stable coronary artery disease.

6. ASSERT Study Design 299 Statin-Treated Patients with Stable Coronary Artery Disease at 35 sites in the US 12 Week Treatment Period RVX-208 50 mg bid 2 Week Screening Period 4 Week Follow-up Period RVX-208 100 mg bid RVX-208 150 mg bid Placebo

7. Baseline Patient Characteristics

8. Baseline Biochemical Values

9. Median Change in ApoA-I from Baseline +5.6%¥ P=0.035 for trend +3.8%# Median Percent Change +0.9% +0.1%* RVX-208 *P=0.09, #P=0.10 and ¥P=0.06 compared with placebo

10. Median Percent Change in Biochemical Markers * P<0.05 and ** P<0.01 compared with placebo

11. Median Percent Change in NMR Lipid Markers * P<0.05, ** P<0.01 and *** P<0.001 compared with placebo

12. Increase in Larger α1 HDL Particles: 2-D Gel Analysis Least Square Mean Percent Change from Baseline * P<0.05 compared with placebo

13. Timing of Increase in HDL Measures Median Percentage Change from Baseline HDL Cholesterol Large HDL 4 8 12 0 6 12 0 Weeks Weeks Placebo RVX 100 mg RVX 200 mg RVX 300 mg * P<0.05, ** P<0.01 and *** P<0.001 compared with placebo

14. Biochemical Safety Measures Median Percentage Change in ALT Percent 0 2 4 6 8 10 12 16 Weeks Placebo RVX 100 mg RVX 200 mg RVX 300 mg

15. Biochemical Safety Measures Number of Patients

16. Proposed Mechanism Underlying Findings ApoA-I Synthesis Lipid-deplete Preb1 HDL Hepatic Lipid Uptake Medium HDL Large α1 HDL Biliary Excretion

17. Summary • While not achieving the primary endpoint, RVX-208 was associated with dose-dependent increases in levels of apoA-I, HDL-C and large HDL particles. • These changes are consistent with enhanced mobilization of lipid into functional HDL particles. • The time course of changes suggest that a greater benefit may be observed with longer treatment. • Reversible transaminase elevations without evidence of impaired liver function were observed.

18. Conclusion • Induction of apoA-I synthesis represents a novel approach to HDL therapy targeting functionality rather than quantitative measures of HDL. • The impact of RVX-208 on plaque burdenand cardiovascular outcomes remains to be determined in future studies.