1. Volume 24, Issue 2, Pages 223-233 (August 2016)
Beneficial and Adverse Effects of an LXR Agonist on Human Lipid and Lipoprotein Metabolism and Circulating Neutrophils 
Todd G. Kirchgessner, Paul Sleph, Jacek Ostrowski, John Lupisella, Carol S. Ryan, Xiaoqin Liu, Gayani Fernando, Denise Grimm, Petia Shipkova, Rongan Zhang, Ricardo Garcia, Jun Zhu, Aiqing He, Harold Malone, Richard Martin, Kamelia Behnia, Zhaoqing Wang, Yu Chen Barrett, Robert J. Garmise, Long Yuan, Jane Zhang, Mohit D. Gandhi, Philip Wastall, Tong Li, Shuyan Du, Lisa Salvador, Raju Mohan, Glenn H. Cantor, Ellen Kick, John Lee, Robert J.A. Frost 
Cell Metabolism 
Volume 24, Issue 2, Pages (August 2016)
DOI: /j.cmet
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2. Cell Metabolism 2016 24, 223-233DOI: (10.1016/j.cmet.2016.07.016)
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3. Figure 1
BMS Has Broader Therapeutic Window Compared to Compounds with Greater LXRα Activity in the Cynomolgus Monkey Model
Therapeutic window is defined as the drug exposure response for blood ABCG1 mRNA induction versus plasma lipids, CETP mass, and hepatic lipids and lipogenic gene expression.
(A) Plasma BMS and TO exposure response for plasma TG, LDL-C, HDL-C, and CETP mass, and blood ABCG1 mRNA in a 14 day PD study. Values shown are percent change from baseline on day 14.
(B) Liver BMS and BMS exposure response for liver SREBP1c, FAS, and SCD1 mRNA. Data were obtained as part of 28 day (BMS ) and 14 day (BMS ) toxicology studies.
(C) Liver TG determined by MRS following 7 days of vehicle, BMS , and BMS dosing. Values are expressed as percent change from baseline.
Plasma exposures in (A) and (B) are adjusted for differences in in vitro potency and expressed as fold over the WBA EC50 for BMS (10 nM) and TO (310 nM). Values are mean ± SEM. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < versus vehicle; #p < 0.05, ##p < 0.01, ###p < versus baseline by ANOVA, using Dunnett’s post hoc test.
Cell Metabolism  , DOI: ( /j.cmet )
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4. Figure 2
BMS Stimulates RES Macrophage Cholesterol Efflux in Mice and RCT in Cynomolgus Monkeys and Inhibits Atherosclerosis in Mice
(A and B) C57Bl/6J (A) and C57Bl/6J LDLR−/− (B) mice were orally dosed for 7 days with vehicle or indicated doses (mg/kg/day, or mpk) of BMS followed by i.v. injection of [3H]-cholesterol:BSA particulate complexes, and total radioactivity in plasma was determined at the indicated times post-injection. Note the rapid radioactivity clearance phase followed by the reappearance phase, indicative of macrophage cholesterol efflux. Both the full time course (left panels) and initial rates (right panels) of efflux are plotted as percent of total label injected versus time post-injection. Initial rates were determined by linear regression, and two-tailed p values for differences in slopes among the treatment groups were calculated.
(C) C57Bl/6J LDLR−/− mice on a western diet were orally dosed daily for 12 weeks with vehicle, the indicated doses of BMS , or 10 mg/kg/day TO Lesion area as a percent of total aortic area was determined by en face analysis.
(D) SREBP2 target gene transcript levels (cholesterol biosynthetic pathway, LDLR, and PCSK9) as a percent of vehicle control in liver and spleen from cynomolgus monkeys (n = 3/group) after dosing 7 days with vehicle or 15 mg/kg/day BMS
All values are mean ± SEM. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < versus vehicle using ANCOVA of the slopes (A and B) and using ANOVA with Dunnett’s post hoc test (C and D).
Cell Metabolism  , DOI: ( /j.cmet )
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5. Figure 3
BMS Induction of LXR Target Genes in Blood and Adipose Tissue in Healthy Subjects in MAD Trial
(A–C) Time course of blood ABCA1 (A), ABCG1 (B), and SCD1 (C) mRNA induction on day 1 in placebo and BMS treated subjects at the indicated doses.
(D) Dose response of mRNAs at their Tmax (4 hr post-dose for ABCA1 and ABCG1, and 16 hr post-dose for SCD1).
(E) CETP mRNA dose response in subcutaneous adipose tissue biopsies taken on day 12 of treatment. Values are fold induction over baseline, determined from biopsies on day −2.
(A and B) p < 0.05 versus placebo for all doses ≥1 mg and times ≥2 hr except 1 mg at 12 (ABCA1 only), 16, and 24 hr, and 2.5 mg at 24 hr. (C) p < 0.05 versus placebo for all doses ≥1 mg and times ≥1 hr except 1 mg at 1, 8, 12, 16, and 24 hr; 2.5 mg at 24 hr; and 5 and 15 mg at 1 hr. Values are mean ± SEM. ∗∗p < 0.01 versus placebo (pbo); ANOVA, with Dunnett’s post hoc test.
Cell Metabolism  , DOI: ( /j.cmet )
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6. Figure 4
BMS Treatment Increased Plasma LDL-C, Plasma and Hepatic TG, and apoB and Decreased HDL-C and Circulating Neutrophils, with No Effect on apoAI in Healthy Subjects in MAD Trial
Time course and dose response of (A) LDL-C, (B) plasma TG, (C) HDL-C, (D) neutrophils, (E) plasma apoB, (F) plasma apoAI, and (G) liver TG. (A–F) Values shown are percent change from baseline (day −2). (D) Absolute neutrophil counts are shown from day −2 (baseline) through day 18. (G) Liver triglyceride, percent by weight, was determined by MRS at baseline (day −2) and on day 15 of the study following 14 days of treatment with placebo or the indicated doses of BMS (left panel); change of percent liver TG from baseline (right panel). Values are mean ± SEM. ∗p < 0.05, ∗∗p < 0.01 versus placebo; #p < 0.05, ##p < 0.01, ###p < versus baseline; ANOVA with Dunnett’s post hoc test.
Cell Metabolism  , DOI: ( /j.cmet )
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7. Figure 5
Cynomolgus Monkey Model Overestimated the Clinical BMS Lipid Therapeutic Window
The dose response on day 14 of treatment of RCT-related blood transcripts, ABCA1, and ABCG1, and percent change from baseline (%CFB) of plasma TG and LDL-C are plotted together to illustrate the therapeutic windows in humans in the MAD trial (left panel) and cynomolgus monkeys in the monkey PD study (right panel).
Cell Metabolism  , DOI: ( /j.cmet )
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8. Figure 6
BMS Induces Blood ABCA1 and ABCG1 mRNAs but Also Increases Plasma LDL-C and TG, and Decreases HDL-C and Circulating Neutrophils in Statin-Treated Hypercholesterolemic Patients
(A and B) Time course and dose response of ABCA1 (A) and ABCG1 (B) blood mRNAs on day 1 of treatment.
(C–F) Time course and dose response of LDL-C (C), TG (D), HDL-C (E), and circulating neutrophils (F) through 28 days of treatment and 7 days of follow-up.
Values are mean ± SEM of percent change from baseline (A–E) and absolute neutrophil counts (F) on the indicated days of the study. ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.01 versus placebo; #p < 0.05, ##p < 0.01 versus baseline; ANOVA with Dunnett’s post hoc test.
Cell Metabolism  , DOI: ( /j.cmet )
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9. Figure 7
BMS Treatment of Mice Causes Decreased Circulating Neutrophils In Vivo and Modulation of Neutrophil Homeostatic Pathways in Macrophages In Vitro
(A) Male C57Bl/6J mice (n = 8/group) were treated orally with the indicated doses of vehicle, BMS , and GW3965 for 3 days and neutrophil counts were determined at 5 hr post-final dose and expressed as a percent of vehicle treated.
(B) Duplicate monolayers of thioglycolate-elicited peritoneal macrophages from male C57Bl/6J mice were treated with indicated concentrations of compounds or PBS for 20 hr in serum-free conditions, followed by the addition of LPS (20 ng/mL) or PBS for 5 hr. The effect of compounds on IL-23α and Mertk mRNAs was quantitated by qRT-PCR.
Values are mean ± SEM. ∗p < 0.05 versus vehicle treated, ∗∗p < 0.01 versus vehicle for trend (A); by ANOVA.
Cell Metabolism  , DOI: ( /j.cmet )
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