Extended Data Fig. 8: PK analysis of TLC-2716 and the effect of TLC-2716 on lipid metabolism in humans.
(a-b) Line plot showing the plasma exposure in humans treated with 2 mg (n = 6), 6 mg (n = 8/condition), or 12 mg (n = 8) TLC-2716 for 14 days (a) and the PK parameters for each dose group were indicated. (b). TLC-2716 was administered in fed state unless indicated. PK parameters presented as mean (%CV) except t1/2 and Tmax, which are presented as median (min, max). (c-e) Box plots indicating the relative (%) change from Day 1 to Day 14 of TG (c), remnant cholesterol (d), and LDL-C (e) in individuals with normal or elevated baseline values: TG ( ≥ 100 mg/dL), remnant cholesterol ( ≥ 20 mg/dL), and LDL-C ( ≥ 100 mg/dL), respectively. Significance was calculated by two-tailed Mann-Whitney U test and BH adjustment. Elevated TG: n = 4 (placebo), 3 (0.5 mg), 3 (2 mg), 8 (6 mg), 3 (12 mg). Normal TG: n = 5 (placebo), 4 (0.5 mg), 4 (2 mg), 6 (6 mg), 3 (12 mg). Elevated RC: n = 4 (placebo), 2 (0.5 mg), 3 (2 mg), 7 (6 mg), 2 (12 mg), Normal RC: n = 5 (placebo), 5 (0.5 mg), 4 (2 mg), 7 (6 mg), 4 (12 mg). Elevated LDL-C: n = 6 (placebo), 4 (0.5 mg), 6 (2 mg), 8 (6 mg), 3 (12 mg). Normal LDL-C: n = 3 (placebo), 3 (0.5 mg), 1 (2 mg), 6 (6 mg), 3 (12 mg). (f-g) Dot plots showing the effect of 14-days feeding of TLC-2716 at 0.5 mg, 2 mg, 6 mg, or 12 mg on plasma levels of ApoC3 (f, n = 8/group) and ANGPTL3 (g, n = 8/group). The significance of comparisons between Day 14 and Day 1 within the same dose group calculated by two-tailed Wilcoxon signed-rank test and BH adjustment, while the significance of changes of each parameter upon 14 days of treatment compared to placebo [(Day 14 – Day 1) / Day 1] calculated by two-tailed Mann-Whitney U test and BH adjustment. ANGPTL3 and ApoC3 were measured 12 h post dose in the postprandial state. (h) Boxplot showing the effect of TLC-2716 on plasma expression of genes involved in peripheral reverse cholesterol transport (ABCA1 and ABCG1). Pbo: placebo. n = 4 (placebo-Predose), 3 (placebo-4h), 8/treatment group. Significance was calculated by two-tailed Mann-Whitney U test. Box plots indicate the median (center line), interquartile range (IQR) (box bounds, 25th and 75th percentiles) and smallest and largest values within 1.5× IQR (whiskers) (c-e& h).
