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CSL112 ENHANCES THE ABILITY OF SERUM TO EFFLUX CHOLESTEROL IN PATIENTS WITH MODERATE RENAL IMPAIRMENT
54 JACC March 21, 2017 Volume 69, Issue 11
Acute and Stable Ischemic Heart Disease CSL112 ENHANCES THE ABILITY OF SERUM TO EFFLUX CHOLESTEROL IN PATIENTS WITH MODERATE RENAL IMPAIRMENT Poster Contributions Poster Hall, Hall C Friday, March 17, 2017, 10:00 a.m.-10:45 a.m. Session Title: Updates in Stable Ischemic Heart Disease Abstract Category: 3. Acute and Stable Ischemic Heart Disease: Therapy Presentation Number: 1125-315 Authors: Andreas Gille, Danielle Duffy, Michael Tortorici, Samuel Wright, Larry Deckelbaum, Denise D’Andrea, CSL Limited, Parkville, Australia, CSL Behring, King of Prussia, PA, USA
Background: CSL112 is a novel formulation of plasma-derived apolipoprotein A-I (apoA-I) that is in development for cardiovascular (CV) event reduction following acute coronary syndrome (ACS) by enhancement of cholesterol efflux capacity (CEC). Completed clinical trials have demonstrated favourable safety, pharmacokinetic (PK) and biomarker response to infusions of CSL112 in healthy subjects, patients with stable atherothrombotic disease, and patients with myocardial infarction with normal renal function (NRF) or mild renal impairment.
Methods: This Phase 1 double-blind single ascending dose study assessed PK, safety and biomarkers of CSL112 in adults with moderate renal impairment (MRI) compared with gender, age, and weight matched adults with NRF. Subjects (N=32) were randomized within a renal function and dose cohort to receive CSL112 (2 g or 6 g, N=6 per cohort) or placebo (N=2 per cohort). CEC and lipoprotein biomarkers were compared at baseline and in response to CSL112. Results: Subjects with MRI vs. NRF had higher baseline global CEC (11.5 ± 2.5 vs. 9.0 ± 1.8 %/4h, p=0.003), ABCA1-dependent CEC (3.6 ± 1.7 vs. 2.0 ± 1.2 %/4h, p=0.004) and preβ1-HDL levels (22.8 ± 9.8 vs 16.1 ± 3.2 µg/mL, p=0.01). ApoA-I, HDL-C, total cholesterol, apolipoprotein B (apoB), triglycerides (TG), and high sensitivity CRP were not different between renal function groups. Infusion of CSL112 in subjects with MRI and NRF resulted in similar immediate, robust, dose-dependent elevations in apoA-I and CEC. MRI subjects had greater elevations in preβ1-HDL (p=0.003) and a trend to greater elevation of ABCA1-dependent CEC (N.S.). LCAT activity, depicted by a time-dependent change of the ratio of free cholesterol to esterified cholesterol, appeared similar in MRI and NRF patients. No changes from baseline were observed in association with CSL112 in apoB, non-HDL cholesterol, or TG concentrations in either group.
Conclusions: CSL112 enhances biomarkers of reverse cholesterol transport similarly in subjects with MRI and NRF. CSL112 may provide a novel therapy to rapidly lower the burden of atherosclerosis and to reduce the risk of recurrent CV events in patients with and without MRI following ACS.
Acute and Stable Ischemic Heart Disease CSL112 ENHANCES THE ABILITY OF SERUM TO EFFLUX CHOLESTEROL IN PATIENTS WITH MODERATE RENAL IMPAIRMENT Poster Contributions Poster Hall, Hall C Friday, March 17, 2017, 10:00 a.m.-10:45 a.m. Session Title: Updates in Stable Ischemic Heart Disease Abstract Category: 3. Acute and Stable Ischemic Heart Disease: Therapy Presentation Number: 1125-315 Authors: Andreas Gille, Danielle Duffy, Michael Tortorici, Samuel Wright, Larry Deckelbaum, Denise D’Andrea, CSL Limited, Parkville, Australia, CSL Behring, King of Prussia, PA, USA
Background: CSL112 is a novel formulation of plasma-derived apolipoprotein A-I (apoA-I) that is in development for cardiovascular (CV) event reduction following acute coronary syndrome (ACS) by enhancement of cholesterol efflux capacity (CEC). Completed clinical trials have demonstrated favourable safety, pharmacokinetic (PK) and biomarker response to infusions of CSL112 in healthy subjects, patients with stable atherothrombotic disease, and patients with myocardial infarction with normal renal function (NRF) or mild renal impairment.
Methods: This Phase 1 double-blind single ascending dose study assessed PK, safety and biomarkers of CSL112 in adults with moderate renal impairment (MRI) compared with gender, age, and weight matched adults with NRF. Subjects (N=32) were randomized within a renal function and dose cohort to receive CSL112 (2 g or 6 g, N=6 per cohort) or placebo (N=2 per cohort). CEC and lipoprotein biomarkers were compared at baseline and in response to CSL112. Results: Subjects with MRI vs. NRF had higher baseline global CEC (11.5 ± 2.5 vs. 9.0 ± 1.8 %/4h, p=0.003), ABCA1-dependent CEC (3.6 ± 1.7 vs. 2.0 ± 1.2 %/4h, p=0.004) and preβ1-HDL levels (22.8 ± 9.8 vs 16.1 ± 3.2 µg/mL, p=0.01). ApoA-I, HDL-C, total cholesterol, apolipoprotein B (apoB), triglycerides (TG), and high sensitivity CRP were not different between renal function groups. Infusion of CSL112 in subjects with MRI and NRF resulted in similar immediate, robust, dose-dependent elevations in apoA-I and CEC. MRI subjects had greater elevations in preβ1-HDL (p=0.003) and a trend to greater elevation of ABCA1-dependent CEC (N.S.). LCAT activity, depicted by a time-dependent change of the ratio of free cholesterol to esterified cholesterol, appeared similar in MRI and NRF patients. No changes from baseline were observed in association with CSL112 in apoB, non-HDL cholesterol, or TG concentrations in either group.
Conclusions: CSL112 enhances biomarkers of reverse cholesterol transport similarly in subjects with MRI and NRF. CSL112 may provide a novel therapy to rapidly lower the burden of atherosclerosis and to reduce the risk of recurrent CV events in patients with and without MRI following ACS.