BACKGROUND:Lipoprotein-associated phospholipase A2 (Lp-PLA2) is being evaluated as a therapeutic target for treatment of atherosclerosis. This is the first study to examine the effects of darapladib, a novel selective Lp-PLA2 inhibitor, on Lp-PLA2 activity in Japanese dyslipidemic patients with/without the Val279Phe (V279F) single-nucleotide polymorphism (SNP) of the PLA2G7 gene. Exploratory analysis to examine the effects of V279F on Lp-PLA2 inhibition of darapladib was also performed. METHODS AND RESULTS: This was a 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging trial of darapladib in 107 Japanese patients with dyslipidemia receiving statins. Patients were randomized to placebo (n=25), darapladib 40 mg (n=28), 80 mg (n=28), or 16 0mg (n=26). All darapladib doses produced sustained dose-dependent inhibition of Lp-PLA2 activity of approximately 49%, 58%, and 67%, respectively (P<0.001 for all comparisons). The inhibitory effect achieved a plateau by 1 week. Patients with the V279F homogenous mutation who have no circulating levels of Lp-PLA2, were excluded from the study. The Lp-PLA2 activity was inhibited in both homozygous wild-type and heterozygote genotypes of the V279F polymorphism subjects to a similar extent, although the heterogeneous mutation has almost half the level of Lp-PLA2 activity compared with that of wild-type in Japanese people. The most common adverse events were odor related. No major safety concerns were noted. CONCLUSIONS:Darapladib produced sustained inhibition of Lp-PLA2 activity in Japanese dyslipidemic patients with/without the V279F SNP of Lp-PLA2.
RCT Entities:
BACKGROUND:Lipoprotein-associated phospholipase A2 (Lp-PLA2) is being evaluated as a therapeutic target for treatment of atherosclerosis. This is the first study to examine the effects of darapladib, a novel selective Lp-PLA2 inhibitor, on Lp-PLA2 activity in Japanese dyslipidemic patients with/without the Val279Phe (V279F) single-nucleotide polymorphism (SNP) of the PLA2G7 gene. Exploratory analysis to examine the effects of V279F on Lp-PLA2 inhibition of darapladib was also performed. METHODS AND RESULTS: This was a 4-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging trial of darapladib in 107 Japanese patients with dyslipidemia receiving statins. Patients were randomized to placebo (n=25), darapladib 40 mg (n=28), 80 mg (n=28), or 16 0mg (n=26). All darapladib doses produced sustained dose-dependent inhibition of Lp-PLA2 activity of approximately 49%, 58%, and 67%, respectively (P<0.001 for all comparisons). The inhibitory effect achieved a plateau by 1 week. Patients with the V279F homogenous mutation who have no circulating levels of Lp-PLA2, were excluded from the study. The Lp-PLA2 activity was inhibited in both homozygous wild-type and heterozygote genotypes of the V279F polymorphism subjects to a similar extent, although the heterogeneous mutation has almost half the level of Lp-PLA2 activity compared with that of wild-type in Japanese people. The most common adverse events were odor related. No major safety concerns were noted. CONCLUSIONS:Darapladib produced sustained inhibition of Lp-PLA2 activity in Japanese dyslipidemic patients with/without the V279F SNP of Lp-PLA2.
Authors: John M Gregson; Daniel F Freitag; Praveen Surendran; Nathan O Stitziel; Rajiv Chowdhury; Stephen Burgess; Stephen Kaptoge; Pei Gao; James R Staley; Peter Willeit; Sune F Nielsen; Muriel Caslake; Stella Trompet; Linda M Polfus; Kari Kuulasmaa; Jukka Kontto; Markus Perola; Stefan Blankenberg; Giovanni Veronesi; Francesco Gianfagna; Satu Männistö; Akinori Kimura; Honghuang Lin; Dermot F Reilly; Mathias Gorski; Vladan Mijatovic; Patricia B Munroe; Georg B Ehret; Alex Thompson; Maria Uria-Nickelsen; Anders Malarstig; Abbas Dehghan; Thomas F Vogt; Taishi Sasaoka; Fumihiko Takeuchi; Norihiro Kato; Yoshiji Yamada; Frank Kee; Martina Müller-Nurasyid; Jean Ferrières; Dominique Arveiler; Philippe Amouyel; Veikko Salomaa; Eric Boerwinkle; Simon G Thompson; Ian Ford; J Wouter Jukema; Naveed Sattar; Chris J Packard; Abdulla Al Shafi Majumder; Dewan S Alam; Panos Deloukas; Heribert Schunkert; Nilesh J Samani; Sekar Kathiresan; Børge G Nordestgaard; Danish Saleheen; Joanna Mm Howson; Emanuele Di Angelantonio; Adam S Butterworth; John Danesh Journal: Eur J Prev Cardiol Date: 2016-12-08 Impact factor: 7.804