TY - JOUR
T1 - Efficacy and safety of a novel oral inducer of apolipoprotein A-I synthesis in statin-treated patients with stable coronary artery disease
T2 - A randomized controlled trial
AU - Nicholls, Stephen J.
AU - Gordon, Allan
AU - Johansson, Jan
AU - Wolski, Kathy
AU - Ballantyne, Christie M.
AU - Kastelein, John J.P.
AU - Taylor, Allen
AU - Borgman, Marilyn
AU - Nissen, Steven E.
N1 - Funding Information:
Dr. Nicholls has received honoraria from Pfizer, AstraZeneca, Merck, Roche, Takeda, and NovoNordisk; is a consultant for Abbott, Anthera Pharmaceuticals, AstraZeneca, Esperion Pharmaceuticals, Merck, Pfizer, Takeda, Omthera, Karo Bio, Roche, and LipoScience; and has received research support from AstraZeneca , Novartis , Resverlogix , Eli Lilly , Anthera Pharmaceuticals , and LipoScience . Drs. Gordon and Johansson are employees of Resverlogix Corporation. Dr. Ballantyne has received grant/research support from Abbott , AstraZeneca , GlaxoSmithKline , Merck , Sanofi-Synthelabo , Schering-Plough , and Takeda ; has consulted for Abbott, Amylin, Bristol-Myers Squibb, Kowa, Merck/Schering-Plough, Metabasis, NicOx, Novartis, Pfizer, Resverlogix, Roche, Sanofi-Synthelabo, Schering-Plough, and Takeda; has served on the Speakers' Bureau for Merck/Schering-Plough, Pfizer; and Schering-Plough; and has received honoraria from Abbott, AstraZeneca, GlaxoSmithKline, Kowa, Merck, Merck/Schering-Plough, Novartis, Pfizer, Sanofi-Synthelabo, Schering-Plough, and Takeda. Dr. Kastelein has received consulting fees from Roche, AstraZeneca, Merck, Schering-Plough, Karo Bio, Novartis, Genzyme, ISIS, Amarin, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Sanofi-Aventis, Cerenis, Anthera, Aegerion, and Resverlogix; and has received grant support from Roche , AstraZeneca , Merck , Schering-Plough , ISIS , Amarin , Boehringer Ingelheim , Eli Lilly , Anthera , and Cerenis . Dr. Taylor has received honoraria from Abbott, which have been donated to charity. Dr. Nissen has received research support from Resverlogix , AstraZeneca , Eli Lilly , Pfizer , Takeda, Sankyo, and Sanofi-Aventis ; and he has consulted for a number of pharmaceutical companies without financial compensation; all honoraria, consulting fees, or any other payments from any for-profit entity are paid directly to charity, so that neither income nor any tax deduction is received. All other authors have reported that they have no relationships to disclose.
PY - 2011/3/1
Y1 - 2011/3/1
N2 - Objectives The purpose of this study was to investigate the safety, tolerability, and efficacy of RVX-208, the first oral agent designed to enhance apolipoprotein (apo) A-I synthesis. Background No agent that selectively induces synthesis of apoA-I has reached an advanced stage of clinical development. Methods A total of 299 statin-treated patients with coronary artery disease were treated with placebo or with RVX-208 at a dose of 50, 100, or 150 mg twice daily for 12 weeks. Changes in lipid-related biomarkers, in addition to safety and tolerability, of RVX-208 were investigated. Results For each dose of RVX-208, individual pairwise comparisons of apoA-I changes with placebo, the primary end point, did not achieve statistical significance. However, treatment with RVX-208 was associated with a dose-dependent increase in apoA-I levels by up to 5.6% (p = 0.035 for trend). Administration of RVX-208 resulted in significant increases in levels of high-density lipoprotein cholesterol (HDL-C) ranging from 3.2% to 8.3% (p = 0.02), and large HDL particles increased by 11.1% to 21.1% (p = 0.003). ApoA-I levels increased rapidly from 8 to 12 weeks, suggesting that peak pharmacological effect has not been achieved by the end of the 12-week study. Transient and reversible elevations in liver transaminases >3 times the upper limit of normal were observed in 18 patients treated with RVX-208, with no associated increase in bilirubin levels. Conclusions Administration of RVX-208 for 12 weeks was associated with increases in apoA-I, HDL-C, and concentration of large HDL particles, consistent with facilitation of cholesterol mobilization. Maximal increases in apoA-I may require longer exposure. An increase in liver enzymes was observed with active treatment. (Clinical Trial for Dose Finding and Safety of RVX000222 in Subjects With Stable Coronary Artery Disease; NCT01058018)
AB - Objectives The purpose of this study was to investigate the safety, tolerability, and efficacy of RVX-208, the first oral agent designed to enhance apolipoprotein (apo) A-I synthesis. Background No agent that selectively induces synthesis of apoA-I has reached an advanced stage of clinical development. Methods A total of 299 statin-treated patients with coronary artery disease were treated with placebo or with RVX-208 at a dose of 50, 100, or 150 mg twice daily for 12 weeks. Changes in lipid-related biomarkers, in addition to safety and tolerability, of RVX-208 were investigated. Results For each dose of RVX-208, individual pairwise comparisons of apoA-I changes with placebo, the primary end point, did not achieve statistical significance. However, treatment with RVX-208 was associated with a dose-dependent increase in apoA-I levels by up to 5.6% (p = 0.035 for trend). Administration of RVX-208 resulted in significant increases in levels of high-density lipoprotein cholesterol (HDL-C) ranging from 3.2% to 8.3% (p = 0.02), and large HDL particles increased by 11.1% to 21.1% (p = 0.003). ApoA-I levels increased rapidly from 8 to 12 weeks, suggesting that peak pharmacological effect has not been achieved by the end of the 12-week study. Transient and reversible elevations in liver transaminases >3 times the upper limit of normal were observed in 18 patients treated with RVX-208, with no associated increase in bilirubin levels. Conclusions Administration of RVX-208 for 12 weeks was associated with increases in apoA-I, HDL-C, and concentration of large HDL particles, consistent with facilitation of cholesterol mobilization. Maximal increases in apoA-I may require longer exposure. An increase in liver enzymes was observed with active treatment. (Clinical Trial for Dose Finding and Safety of RVX000222 in Subjects With Stable Coronary Artery Disease; NCT01058018)
KW - apoA-I
KW - coronary artery disease
KW - high-density lipoprotein
KW - prevention
KW - risk factors
UR - http://www.scopus.com/inward/record.url?scp=79952005101&partnerID=8YFLogxK
U2 - 10.1016/j.jacc.2010.11.015
DO - 10.1016/j.jacc.2010.11.015
M3 - Article
C2 - 21255957
AN - SCOPUS:79952005101
SN - 0735-1097
VL - 57
SP - 1111
EP - 1119
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 9
ER -