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Effect of on Oral Agent Inducing ApoA-I Synthesis on Progression of Coronary Atherosclerosis: Results of the ASSURE Study. SJ Nicholls, CM Ballantyne , PJ Barter, HB Brewer, JJP Kastelein , A Gordon, J Johansson, N Wong, R Puri , M Borgman , K Wolski and SE Nissen. Disclosures.

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  1. Effect of on Oral Agent Inducing ApoA-I Synthesis on Progression of Coronary Atherosclerosis: Results of the ASSURE Study SJ Nicholls, CM Ballantyne, PJ Barter, HB Brewer, JJP Kastelein, A Gordon, J Johansson, N Wong, R Puri, M Borgman, K Wolski and SE Nissen

  2. Disclosures • Research support: AstraZeneca, Amgen, Anthera, Eli Lilly, Novartis, Resverlogix, InfraReDx, Roche and LipoScience • Consulting and honoraria: AstraZeneca, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Aventis, CSL Behring, Esperion, Boehringer Ingelheim • ASSURE was sponsored by Resverlogix

  3. Steering Committee • Steven Nissen (Chair) • Stephen Nicholls (Principal Investigator) • Christie Ballantyne • Philip Barter • Bryan Brewer • John Kastelein • Jan Johansson (non-voting)

  4. Background • There remains considerable interest in the development of novel agents that promote the biological activity of HDL. • Induction of synthesis of apoA-I is a novel therapeutic approach to the generation of functional HDL particles • The bromodomain and extra-terminal (BET) protein inhibitor, RVX-208, induces apoA-I synthesis, with favorable effects on HDL related measures and cholesterol efflux. • The impact of RVX-208 on atherosclerotic plaque in humans has not been investigated.

  5. Objective To evaluate the early effects of RVX-208 100 mg bid on progression of coronary atherosclerosis compared to baseline assessed by intravascular ultrasound when administered for 26 weeks to patients with coronary disease and low HDL-C levels.

  6. ASSURE Study Design 323 patients with symptomatic CAD (angiographic stenosis >20%) and low HDL-C levels Placebo (n=80) RVX-208 100 mg bid (n=243) Visit: Week: 1 –4 2 0 3 2 4 4 5 6 6 8 7 11 8 14 9 17 10 20 11 26 11 23 IVUS IVUS Randomization Period Screening Period

  7. ASSURE Trial: Flow of Patients 676 patients screened and 323 patients treated at centers in Europe and South America 3:1 Randomization 26 weekstreatment Placebo (n=80) RVX-208 100 mg bid (n=243) 42 (13%) patients withdrew or did not have an evaluable final IVUS Follow-up IVUS of originally imaged “target” vessel (n=281)

  8. Clinical Characteristics

  9. Baseline Laboratory and Plaque Measures

  10. Change in Biochemical Parameters

  11. Primary IVUS Efficacy Parameter Median Change Percent Atheroma Volume P=0.81† Change Percent Atheroma Volume -0.30 P=0.23* -0.40 P=0.08* * Primary endpoint: comparison from baseline † comparison between groups.

  12. Secondary IVUS Efficacy Parameters -1.3 P=0.01* P=0.86† Change Atheroma Volume (mm3) -2.2 P<0.001* P=0.79† -3.8 -4.2 P=0.01* P<0.001* Whole Segment Most Diseased 10-mm Placebo RVX-208 † comparison between groups. * comparison from baseline

  13. Fraction of Patients Exhibiting Regression 56.2% 56.3% 55.3% 54.8% Percent of Patients P=0.99 P=0.94 Percent Atheroma Volume Total AtheromaVolume Placebo RVX-208

  14. Exploratory Analysis: Plaque Composition P=0.04 P=0.007 P=0.002 P=0.37 P=0.34 P=0.84 P=0.27 P<0.001 P=0.09* P=0.46* P=0.37* P=0.04* Expressed as LS mean change P values for comparison with baseline *P value for comparison with placebo Fibrous Placebo Fibro-fatty Necrotic RVX-208 Calcific

  15. Adverse Clinical and Biochemical Events

  16. Conclusions • Increases in HDL-C and apoA-I and a decrease in LDL-C compared with baseline with RVX-208 did not differ from the placebo group. • For the primary endpoint, a trend to regression with RVX-208 was observed. • For the secondary endpoints, regression of all IVUS measures with RVX-208 did not differ from placebo. • RVX-208 administration was associated with liver enzyme elevations as previously observed.

  17. A Final Thought • Potentially protective properties of HDL has stimulated an immense search for a new therapeutic agent for patients with CAD. • Administration of RVX-208 for 26 weeks did not produce an incremental benefit on atherosclerotic plaque compared with placebo. • The search for benefit of RVX-208 and an effective HDL targeted therapy continues.

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