Abstract 13118: The Novel Highly Potent and Specific Peroxisome Proliferator-Activated Receptor Alpha Agonist K-877 Improved Liver Enzymes and Lipid Profile Without Adversely Affecting Renal Functions; Integrated Analysis of Phase 2 and Phase 2/3 Double Blind Clinical Trials
Background: K-877 is a specific PPAR alpha-agonist. K-877 may offer greater efficacy and fewer adverse effects than other PPAR-alpha agonists. In dyslipidemia, hepatic and renal abnormalities are commonly observed therefore lipid improvement with safer profile is highly desired. We hypothesized that K-877 has strong triglyceride (TG)-reduction with a safer hepatic and renal profile, and shows a favorable risk and benefit profile in dyslipidemic patients.
Method: This is an integrated analysis of a Phase 2 (N=224) and Phase 2/3 study (N=526) that were both 12-week randomized, multicenter, double-blind, placebo and active controlled studies for patients with high fasting TG levels (200mg/dL or over) in Japan. We examined the safety and efficacy of K-877 0.05, 0.1, 0.2 and 0.4mg/day bid, and fenofibrate 100, 200mg/day qd.
Result: In the two trials, a total of 750 subjects were enrolled and the baseline characteristics of all groups were similar. The percent TG reduction at 12 weeks from baseline was significantly better (p<0.01) in K-877 0.1, 0.2 and 0.4mg (-45.0, -46.7 and -52.1%, respectively) than fenofibrate 100mg (-38.1%), but not 0.05mg (-39.6%). However, fenofibrate 200mg (-51.2%) showed a similar efficacy to K-877.
K-877 did not affect eGFR (-1.55[[Unable to Display Character: —]]+1.3 mL/min/1.73m2), while fenofibrate showed a significant detrimental effect (-7.82[[Unable to Display Character: —]]-10.19, p<0.001). K-877 reduced both ALT and γ-GTP (-5.9[[Unable to Display Character: —]]-4,3 and -18.3[[Unable to Display Character: —]]-27.2 IU/L, respectively), in contrast to both fenofibrate groups increased enzyme levels (-0.4[[Unable to Display Character: —]]4.6 and 7.4[[Unable to Display Character: —]]7.9. IU/L, respectively). The change in AST was comparable among all groups including placebo. Uric acid was unchanged by K-877 (-0.06[[Unable to Display Character: —]]-0.18 mg/dL), but significantly decreased by fenofibrate (-1.13[[Unable to Display Character: —]]-1.72 mg/dL). Additionally, the effect of K-877 on homocysteine elevation was less than that of fenofibrate.
The most frequently reported adverse reaction was liver function test abnormality in K-877 treatment (1.2[[Unable to Display Character: —]]2.4%), yet the incidence was significantly lower than fenofibrate (5.7[[Unable to Display Character: —]]12.9%).
Conclusions: K-877 demonstrated strong TG-reducing effects and improved liver enzymes without adversely affecting renal functions. The integrated data showed that K-877 had a better benefit to risk balance than fenofibrate.
- © 2013 by American Heart Association, Inc.