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19 July 2016
K-877, a novel SPPARM? agent, for reducing atherogenic lipoproteins: Phase II results

K-877 significantly improved atherogenic dyslipidaemia (high triglycerides [TG] and low high-density lipoprotein cholesterol [HDL-C] concentration) compared with placebo. Treatment was also associated with a favourable tolerability profile, including decreases in liver enzymes and a lack of adverse effects on serum creatinine or homocysteine.

Ishibashi S, Yamashita S, Arai H et al. Effects of K-877, a novel selective PPARa modulator (SPPARMa), in dyslipidaemic patients: A randomized, double blind, active- and placebo-controlled, phase 2 trial. Atherosclerosis 2016;249:36-43.
Comments & References
Objective: To assess the efficacy and safety of K-877 (pemafibrate), a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα), compared with placebo and fenofibrate in dyslipidaemic patients with high plasma triglycerides (TG) and low plasma high-density lipoprotein cholesterol (HDL-C) levels
Study design: Double blind, placebo-controlled, parallel-group study. Patients were screened for the study for up to 8 weeks before randomization. Eligible patients were randomly allocated in a 1:1:1:1:1:1 ratio, to treatment with either K-877 (0.025, 0.05, 0.1, or 0.2 mg twice daily; i.e. 0.05, 0.1, 0.2, and 0.4 mg/day, respectively), fenofibrate (100 mg once daily), or matching placebo for 12 weeks. Randomization was performed centrally with stratification according to the HDL-C value at the first screening visit so as to avoid imbalance. During the treatment period, fasting blood and urine samples were collected at weeks 0 (randomization), 2, 4, 8 and 12 for assessment of clinical laboratory findings, including lipids. Patients were then followed up for 4 weeks after the end of the treatment period.
Study population: In total, 224 Japanese patients with TG≥200 mg/dl and <500 mg/dl and low HDL-C were randomly assigned to treatment (see Table). The per protocol population comprised 214 patients, as 10 patients were excluded due to concomitant use of prohibited treatment, missing TG baselines or last evaluation points. The study was completed by 213 patients (one patient discontinued fenofibrate treatment due to liver function test abnormalities).
Key outcomes:

·       Least squares mean percent change from the baseline in fasting triglycerides

·       Least squares mean per cent change from baseline in other atherogenic lipoproteins (i.e. very-low-density lipoprotein cholesterol VLDL-C], chylomicron cholesterol, remnant lipoprotein cholesterol, apolipoprotein (apo) B100 (apoB), apoB48 and apoC-III)

·       Change in fibroblast growth factor 21 (FGF-21)

Incidence of adverse events and routine laboratory safety variables

Methods: The percent change from baseline to week 12 in TG (primary endpoint) was compared using an analysis of covariance model with the baseline value as covariate. The primary analysis was an evaluation of the dose-dependent relationship of all K-877 groups, including the placebo group, using the maximum contrast method. Secondary analysis was investigation of the superiority of the K-877 group compared to placebo by Dunnett's test (if statistical significance was confirmed during primary analysis). Exploratory analysis of the primary endpoint was the difference of K-877 in each group and fenofibrate using the ANCOVA model. The primary safety endpoint was the event ratio of adverse events.
Main results:

The effect of K-877 on atherogenic lipoproteins is summarised in Table 1. There was a dose-dependent reduction in TG with K-877, which appeared to plateau at the 0.1 mg twice daily dose. The reduction in TG with K-877 at the highest doses was greater than with fenofibrate 100 mg once daily (p<0.001). Treatment with K?877 was also associated with significant improvement from baseline in HDL-C, as well as reduction in other atherogenic lipoproteins, including VLDL- cholesterol (VLDL-C), remnant cholesterol, apoB100 and non-HDL-C.

 Treatment with K-877 was also associated with significant improvement from baseline in FGF-21.

 Table. Percent change from baseline to week 12 in key lipoproteins

Lipid parameter


K-877 (mg twice daily)





































Remnant C










-8.9±13.6 δ

-7.8±15.0 δ

-8.1±11.6 δ
















Data are given as least squares mean percent change ± standard error of the mean for TG and HDL-C; and mean ± standard deviation for other variables

 For all K-877 groups, *p<0.001 versus baseline and placebo; §p<0.001 versus baseline and p<0.01 versus placebo; ¥p<0.05 versus baseline; δ significantly different from baseline (p<0.01 and p<0.001)

 K-877 was well tolerated, with a similar incidence of adverse events (32-57%) as observed with placebo (47%) or fenofibrate (57%). Few patients treated with K?877 had elevation in AST or ALT > upper limit of normal [ULN). The rate of elevated AST levels in the K-877 groups was similar to that of placebo, and lower than with fenofibrate. Additionally, the rate of elevated ALT levels in the K-877 groups was lower than observed in either placebo or fenofibrate groups. None of the patients treated with K-877 had elevation in serum creatinine.

Authors’ conclusion: In dyslipidaemic patients with high TG and low HDL-C, K-877 improved TG, HDL-C, and other lipid parameters without increasing adverse events, compared to placebo and fenofibrate. K-877 can be expected to improve atherogenicity and to be a new beneficial treatment for dyslipidaemic patients.


This phase II study shows promising results with the first SPPARMα agent in patients with atherogenic dyslipidaemia (elevated TG and low HDL-C). The study showed a dose-dependent effect for TG lowering, with an apparent plateau at 0.1 mg twice daily, with superior reduction at the higher doses compared with fenofibrate 100 mg daily. Importantly, K-877 also significantly reduced other atherogenic apoB100-containing lipoproteins, in particular reducing VLDL and remnant cholesterol by about 50% at the two higher doses. This is of relevance given accumulating evidence that remnant cholesterol is causal for ischaemic heart disease.1 The study also indicated a favourable tolerability profile for K-877, especially with respect to the frequency of increased liver enzymes and lack of serum creatinine elevation, albeit in the limited number of patients in this study. Incidentally, treatment with K-877 also increased FGF-21 activity, of interest given accumulating evidence that this endocrine regulator is critical for metabolic homeostasis,2 and also may be involved in mediating central effects that have favourable effects in obesity and related metabolic disorders.3,4

 The SPPARMα concept proposes that an agent designed to have a higher PPARα agonistic activity and tissue selectivity than the existing PPARα agents (fibrates) may show an improved efficacy and safety profile.5 The results from this phase II support this concept and provide a basis for further investigation of this novel, first-in-class pharmacotherapeutic for management of atherogenic dyslipidaemia and lipid-related residual cardiovascular risk.


1. Varbo A, Benn M, Tybjaerg-Hansen A et al. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol. 2013;61:427–36.

2. Kharitonenkov A, DiMarchi R. FGF21 revolutions: recent advances illuminating FGF21 biology and medicinal properties. Trends Endocrinol Metab 2015;26:608-617

3. Chu AY, Workalemahu T, Paynter NP et al. Novel locus including FGF21 is associated with dietary macronutrient intake. Hum Mol Genet 2013;22:1895-902.

4. Talukdar S, Owen BM, Song P et al. FGF21 regulates sweet and alcohol preference. Cell Metab 2016;23:344-95.

5. Fruchart JC. Selective peroxisome proliferator-activated receptor α modulators (SPPARMα): the next generation of peroxisome proliferator-activated receptor α-agonists. Cardiovasc Diabetol 2013;12:82.

Key words peroxisome proliferator-activated receptor α modulator (SPPARMα); K-877; pemafibrate, triglycerides, remnant cholesterol; residual cardiovascular risk