Efficacy and safety of a novel oral inducer of apolipoprotein a-I synthesis in statin-treated patients with stable coronary artery disease a randomized controlled trial.
OBJECTIVE
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).
Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio 44195, USA. nichols1@ccf.org
Stephen J
SJ
Nicholls
Allan
A
Gordon
Jan
J
Johansson
Kathy
K
Wolski
Christie M
CM
Ballantyne
John J P
JJ
Kastelein
Allen
A
Taylor
Marilyn
M
Borgman
Steven E
SE
Nissen
D000368:Aged; D016632:Apolipoprotein A-I / Q000096:biosynthesis / Q000097:blood* / Q000187:drug effects; D008076:Cholesterol, HDL / Q000097:blood* / Q000187:drug effects; D003324:Coronary Artery Disease / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D008297:Male; D011446:Prospective Studies; D011799:Quinazolines / Q000008:administration & dosage*; D052999:Quinazolinones; D016896:Treatment Outcome
D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011799:Quinazolines; D052999:Quinazolinones; C000628794:apabetalone