Abstract 13374: Efficacy and Safety of K-877, a Potent and Selective PPAR-α Modulator (SPPARMα), in Combination With Statins in Japanese Patients With Dyslipidemia

Background: Residual cardiovascular risk remains despite intensive statin treatment. K-877, a Selective PPAR-α Modulator (SPPARMα), has shown significant reductions in atherogenic lipids with fewer adverse effects than existing PPARα agonists. We hypothesized that K-877 in combination with statins may provide further benefit and risk reduction than statins alone in patients with dyslipidemia. Methods: This is a multi-center double-blind parallel-group study. A total of 423 patients with fasting high TG (≥200 mg/dL), treated with any statins (stable dosage at least 4 weeks prior to the first screening visit) were randomized to the following 24-weeks treatment groups; placebo (n=108), twice-daily K-877 0.2 mg/day (n=150) and 0.2/0.4 mg/day [patients took 0.2 mg/day, those with TG >150 mg/dL at week 8 were uptitrated to 0.4 mg/day from week 12] (n=165 [n=58]). The primary endpoint was the percentage change of TG from baseline, and rates of adverse drug reactions (ADRs) and adverse events (AEs) were assessed. Results: Fasting TG reduction was as follows; placebo: -0.8%, K-877 0.2 mg: -46.8% and K-877 0.2/0.4 mg: -50.8%. K-877 groups had significant reductions compared with placebo (P<0.01). By dose titration at week 12, more patients achieved the target (fasting TG≤150 mg/dL) at week 24 (36.2% in 0.4 mg group and 29.7% in 0.2 mg group). The incidence of AEs/ADRs in K-877 groups was similar to placebo [placebo, K-877 0.2 and 0.2/0.4 mg: 57.4%/15.7%, 56.0%/19.3% and 63.6%/19.4%, respectively]. The study discontinuation rate was also similar across all dosing groups. K-877 reduced liver enzymes compared to placebo [ALT; placebo, K-877 0.2 and 0.2/0.4 mg: -0.9, -12.8 and -8.0 IU/L, respectively] and [γ-GT; -1.8, -42.6 and -40.4 IU/L, respectively]. Severe liver failure, severe renal failure or the rhabdomyolysis were not observed. Frequencies of AEs, such as CK increase and musculoskeletal and connective tissue disorders were comparable to those of placebo. Conclusions: K-877 significantly reduced TG concentrations in dyslipidemic patients on stable statin treatment, was well tolerated, and associated with reductions in liver enzymes. Thus K-877 has a favorable profile of efficacy and safety and may be useful to reduce residual risk in dyslipidemic patients.