Efficacy and Safety of Pemafibrate Extended-Release Tablet: a Phase 3, Multicenter, Randomized, Double-Blind, Active-Controlled, Parallel-Group Comparison Trial

Abstract

Aims: Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator that lowers serum triglyceride levels and increases high-density lipoprotein cholesterol levels, is approved for treating dyslipidemia as twice-daily immediate-release (IR) tablets. A once-daily extended-release (XR) tablet has also been developed. We aimed to confirm the non-inferiority of XR (0.2 or 0.4 mg/day; once daily) to IR (0.2 mg/day; twice daily) in lowering triglyceride levels in patients with hypertriglyceridemia.

Methods: This phase 3, multicenter, randomized, double-blind study included patients with fasting triglycerides ≥ 200 mg/dL who received IR (0.2 mg/day) or XR (0.2 or 0.4 mg/day). The primary efficacy endpoint was the percentage change in fasting triglyceride levels from baseline to 4, 8, and 12 weeks. Common treatment effects at weeks 4 through 12 were compared between groups using repeated analysis of covariance.

Results: In 356 randomized patients, fasting triglyceride levels decreased by 48.0%, 43.8%, and 48.0% with IR 0.2, XR 0.2, and XR 0.4 mg/day, respectively, confirming the non-inferiority of both XR regimens to IR. The proportion of patients who achieved fasting triglycerides ＜150 mg/dL was 45.7%, 37.4%, and 51.7%, while the percentage change of triglycerides in the subgroup with baseline triglycerides ≥ 500 mg/dL was -59.3%, -52.2%, and -66.3% with IR 0.2, XR 0.2, and XR 0.4 mg/day, respectively.

Conclusions: XR (0.2 and 0.4 mg/day) was non-inferior to IR (0.2 mg/day). XR 0.4 mg/day demonstrated a more potent triglyceride-lowering effect than XR 0.2 mg/day and should be considered for patients with high triglyceride levels.

See editorial vol. 31: 1512-1514

Introduction

Pemafibrate is a selective peroxisome proliferator-activated receptor alpha (PPARα) modulator (SPPARMα)^1-3), which regulates PPARα-targeted genes involved in lipid metabolism within the liver to improve dyslipidemia by lowering serum triglyceride (TG) levels. Pemafibrate is approved for hyperlipidemia treatment in Japan, Thailand, Singapore, and Malaysia as twice-daily immediate-release (IR) tablets containing 0.1 mg pemafibrate.

Less frequent dosing is associated with better drug adherence⁴⁾, and many drugs for lifestyle-related diseases such as dyslipidemia, hypertension, and type 2 diabetes, which are common comorbidities, have once-daily formulations. Therefore, once-daily extended-release (XR) pemafibrate tablets have been developed for better adherence.

Aim

This trial was conducted to confirm whether XR at 0.2 or 0.4 mg/day (once daily) is non-inferior to IR at 0.2 mg/day (twice daily) based on the percentage reduction in fasting serum TG levels in patients with hypertriglyceridemia for 12 weeks.

Methods

Trial Design

This phase 3, multicenter, randomized, double-blind, active-controlled, parallel-group comparison trial (ClinicalTrials.gov identifier: NCT04714151) was conducted across 11 medical institutions, in compliance with the Declaration of Helsinki and Good Clinical Practice. Ethical approval was obtained from the Institutional Review Board of each trial center.

Patients

After obtaining written informed consent, we included patients with dyslipidemia who were at least 20 years of age, received constant instruction on diet and exercise for at least 12 weeks before the first screening testing, and had fasting serum TG ≥ 200 mg/dL in two consecutive tests within 7 weeks.

Key exclusion criteria included fasting serum TG ＞1000 mg/dL, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels exceeding the upper limit of the normal range (ULN) three times or more, creatine kinase (CK) exceeding the ULN five times or more, hepatic cirrhosis or biliary obstruction, a history of acute myocardial infarction within 3 months before consent, and Class III or IV heart failure as per the New York Heart Association functional classification.

Eligible patients were randomly assigned to IR 0.2, XR 0.2, or XR 0.4 mg/day in a ratio of 1:1:1. IR 0.2 was selected as the positive control as it is the typical approved dose and elicits a marginal difference in lowering TG levels compared to IR 0.4. Trial drug administration was initiated from week 0, at least 7 days after the second screening visit, with a double-dummy design using three kinds of placebo tablets, indistinguishable from the treatment tablets. Patients received a specific combination of one active tablet and two placebo tablets of 0.1 mg IR, 0.2 mg XR, and 0.4 mg XR in the morning, in addition to active or placebo 0.1 mg IR tablets in the evening for 12 weeks. Trial drugs were administered before or after meals at the investigator’s discretion throughout the treatment period.

Randomization was performed by an independent third party. Patient eligibility was determined by the Patient Registration Center. Double-blinding was implemented using key codes prepared by a person responsible for drug allocation and stored until the key was opened after the database lock.

Endpoints

Fasting blood and urine samples were collected at the two screening visits as well as at weeks 0, 4, 8, and 12 during the treatment period. However, no urine samples were collected, and only fasting TG levels were measured at the first screening visit. Cholesterol and TG contents by lipoprotein class and subclass as well as apolipoprotein (Apo) (AI, AII, B, B48, CII, CIII, and E) levels were measured at weeks 0 and 12. A high-fat meal test was conducted at weeks 0 and 12 in 90 patients at study sites where feasible, using the test meal (1,000 kcal energy, 66.7 g fat, 62.5 g carbohydrate, and 37.5 g protein for men; 800 kcal energy, 53.3 g fat, 50.0 g carbohydrate, and 30.0 g protein for women) as described in Supplementary Materials. The baseline for efficacy assessments was defined as the mean of measurements at screening and week 0 if the measurements used for screening were available, or as the measurement at week 0 if no other pre-treatment value was available. Clinical laboratory tests were performed mainly by LSI Medience Corporation (Tokyo, Japan). Remnant-like lipoprotein cholesterol (RemL-C) was measured using MetaboLead RemL-C by Minaris Medical Co., Ltd. (Tokyo, Japan). ApoB48 was measured by SRL, Inc. (Tokyo, Japan). Cholesterol and TG contents by lipoprotein class and subclass were measured using gel-permeation high-performance liquid chromatography (GP-HPLC) by Immuno-Biological Laboratories Co, Ltd. (Gunma, Japan).

The primary efficacy endpoint was the percentage change in fasting serum TG levels from baseline to weeks 4, 8, and 12. Secondary efficacy endpoints included the proportion of patients who achieved TG of ＜150 mg/dL at week 12; the percentage change from baseline to weeks 4, 8, and 12 in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), RemL-C, LDL-C/HDL-C, and non-HDL-C/HDL-C; the percentage change from baseline to week 12 in apolipoprotein, ApoB/ApoAI, ApoCIII/ApoCII, cholesterol and TG contents by lipoprotein class and subclass; the change from baseline to week 12 in total ketone bodies, acetoacetic acid, and β-hydroxybutyrate as well as in hepatobiliary markers AST, ALT, γ-glutamyl transpeptidase (γ-GT), alkaline phosphatase (ALP), bilirubin, and fibrinogen.

The primary safety endpoints were the incidence of adverse events (AEs) and adverse drug reactions (ADRs). ADRs were defined as AEs for which a causal relationship with the trial drug could not be ruled out. Secondary safety endpoints included clinical laboratory test assessment results for glucose, glycated albumin, insulin, hemoglobin A1c, and homeostasis model assessment-insulin resistance (HOMA-IR).

Statistical Analysis

Randomized patients who took the trial drugs at least once were included in the safety analysis set. Those with available data for the primary efficacy endpoint at weeks 4, 8, and 12 (at least one of these) were included in the full analysis set. Efficacy and safety analyses were performed using the full analysis set and safety analysis set, respectively. The primary efficacy analysis involved analyzing the primary efficacy endpoint using a repeated measures analysis of covariance (ANCOVA) model with the baseline, sex, timing of trial drug administration (before or after meal), presence or absence of concomitant statin use, and study site as covariates. The analysis model included treatment, time point (weeks 4, 8, and 12), and the covariates as fixed effects, having a compound symmetry covariance structure. The primary efficacy endpoint evaluation followed a fixed-sequence procedure comprised of three steps, which could proceed only when each previous step was achieved: (1) testing the non-inferiority of XR 0.4 mg/day to IR 0.2 mg/day; (2) testing the non-inferiority of XR 0.2 mg/day to IR 0.2 mg/day; and (3) testing whether the point estimate in the XR 0.4 mg/day group was lower than that in the XR 0.2 mg/day group. The non-inferiority margin was set at 10%. The primary endpoint was also examined through subgroup analyses in patients with baseline TG levels ≥ 500 and ＜500 mg/dL.

Among the secondary efficacy endpoints, the same repeated measures ANCOVA model was used for the percentage changes from baseline for TC, LDL-C, HDL-C, non-HDL-C, and RemL-C levels. Cholesterol and TG contents by lipoprotein class and subclass as well as apolipoproteins were analyzed using a similar but non-repeated ANCOVA model for the percentage change from baseline to week 12. The percentage change and change from baseline to week 12 in non-lipid related parameters were analyzed using mixed models for repeated measures which included treatment, time point, the interaction between treatment and time point, baseline levels, sex, trial drug administration timing, concomitant statin use, and study sites as fixed effects. An unstructured covariance matrix was used to model the within-subject errors.

Unless otherwise stated, Fisher’s exact test was used to compare binary variables with the 95% confidence intervals (CIs) calculated for the difference. Analysis of variance was used to compare continuous variables among the three groups. Changes from baseline at each visit in clinical safety laboratory tests were compared between groups using the Wilcoxon rank-sum test. The proportion of patients with abnormal test results above or below the cutoff values was calculated (for example, three times the ULN).

All statistical analyses were performed using SAS version 9.4 (SAS Institute, NC, USA) with a significance level of 5%.

Sample Size

Based on the data from a previous clinical trial on pemafibrate IR tablets compared with fenofibrate⁵⁾, the interindividual and intraindividual variances of the percentage change in TG levels in response to pemafibrate were conservatively assumed to be 250. In the same clinical trial⁵⁾ and a previous trial of XR (K-877-CR-01, data on file), the percentage changes in TG with IR at 0.2 mg/day and XR at 0.4 mg/day were assumed to be the same, i.e., -45%. For XR at 0.2 mg/day, a conservative assumption of -44% was made based on the analysis of integrated data from clinical trials of IR tablets conducted until the New Drug Application submission. The proportion of patients to discontinue the trial was assumed to be 6%. The number of patients required to obtain a power of 80% was estimated to be 115 in each group, achieving the first and second steps with the stated conditions and the third step without the conservative assumptions.

Results

Baseline Characteristics

This study was conducted from March to September 2021. Written informed consent was obtained from 643 patients, 356 of whom were eligible and randomly assigned to the three treatment groups (Fig.1). One patient in the XR 0.2 mg/day group withdrew consent and was excluded before taking the trial drug. Eventually, 355 patients were administered the trial drugs and were included in the safety analysis set (118, 118, and 119 in the IR 0.2 mg/day, XR 0.2 mg/day, and XR 0.4 mg/day groups, respectively). One patient each in the IR 0.2 mg/day and XR 0.2 mg/day groups was excluded and lacked on-treatment data. Therefore, 353 patients were included in the full analysis set (117, 117, and 119 in the IR 0.2 mg/day, XR 0.2 mg/day, and XR 0.4 mg/day groups, respectively).

Fig.1. Disposition of patients

a, some patients had both conditions. FAS, full analysis set; SAS, safety analysis set.

Table 1 presents the baseline characteristics of patients in the full analysis set. The mean age was 54.9 years; the mean body mass index was 26.7 kg/m². Overall, 86.7% of patients were men, 13.0% were taking concomitant statins, and 83.0% were administered the trial drug after a meal. Baseline lipid levels by treatment group are presented in Table 2. The median fasting TG and mean fasting HDL-C, LDL-C, and non-HDL-C levels in the total population were 313.7, 44.5, 136.2, and 191.6 mg/dL, respectively, with no significant differences among the three groups (p=0.601, 0.630, 0.416, and 0.315, respectively).

Table 1.Characteristics of patients at baseline (full analysis set)

Characteristics	Immediate-release 0.2 mg/day (twice daily)	Extended-release 0.2 mg/day (once daily)	Extended-release 0.4 mg/day (once daily)	Total
N	117	117	119	353
Age, years, mean±SD	54.5±10.4	54.8±10.0	55.4±10.4	54.9±10.2
Height, cm, mean±SD	168.4±7.5	168.9±7.1	168.5±6.9	168.6±7.2
Waist circumference, cm, mean±SD	93.7±9.2	92.7±8.8	94.7±9.7	93.7±9.2
Weight, kg, mean±SD	76.0±12.9	75.5±12.1	77.0±13.1	76.2±12.7
Body mass index, kg/m2, mean±SD	26.7±3.7	26.4±3.6	27.1±3.7	26.7±3.7
eGFR, mL/min/1.73 m2, mean±SD	72.6±12.4	73.2±12.3	72.6±14.0	72.8±12.9
Hemoglobin A1C, %, mean±SD	5.8±0.5	5.9±0.6	5.9±0.6	5.9±0.6
Men, N (%)	102 (87.2)	101 (86.3)	103 (86.6)	306 (86.7)
Never smoker, N (%)	52 (44.4)	49 (41.9)	48 (40.3)	149 (42.2)
Former smoker, N (%)	37 (31.6)	38 (32.5)	51 (42.9)	126 (35.7)
Current smoker, N (%)	28 (23.9)	30 (25.6)	20 (16.8)	78 (22.1)
Alcohol intake, N (%)	69 (59.0)	72 (61.5)	72 (60.5)	213 (60.3)
Hypertension, N (%)	42 (35.9)	44 (37.6)	47 (39.5)	133 (37.7)
Type 2 diabetes, N (%)	12 (10.3)	11 (9.4)	19 (16.0)	42 (11.9)
Metabolic syndrome, N (%)	54 (46.2)	56 (47.9)	49 (41.2)	159 (45.0)
Concomitant statin use, N (%)	15 (12.8)	15 (12.8)	16 (13.4)	46 (13.0)

eGFR, estimated glomerular filtration rate.

Table 2.Lipid-related biomarkers of secondary efficacy endpoints (full analysis set)

Parameter		Immediate-release 0.2 mg/day (twice daily)	Extended-release 0.2 mg/day (once daily)	Extended-release 0.4 mg/day (once daily)
Triglycerides	N	116	115	118
	Baseline, mg/dL
	Median	311.7 (265.2 to 404.0)	305.3 (245.7 to 398.3)	319.8 (270.3 to 388.7)
	Mean	355.1±142.5	336.6±115.6	355.2±158.1
	Week 12, mg/dL
	Median	161.0 (113.0 to 211.5)	169.0 (126.0 to 233.0)	148.5 (117.0 to 202.0)
	Mean	173.5±80.7	192.1±90.6	166.5±81.6
	TG ＜150 mg/dL at week 12, N (%)	53 (45.7)	43 (37.4)	61 (51.7)
	p-value vs IR 0.2 mg/daya		0.230	0.364
	p-value vs XR 0.2 mg/daya			0.035
Total cholesterol	N	117	117	119
	Baseline, mg/dL	238.4±42.2	238.4±44.3	231.7±35.5
	Week 12 (LOCF), mg/dL	222.9±41.5	226.4±38.1	224.3±36.8
	Percentage change, % b	-5.0 [-7.0, -2.9]	-4.1 [-6.2, -2.1]	-2.6 [-4.7, -0.6]
	p-value vs IR 0.2 mg/day b		0.570	0.110
LDL-C	N	117	117	119
	Baseline, mg/dL	137.3±42.2	139.0±43.6	132.3±35.5
	Week 12 (LOCF), mg/dL	140.4±38.7	141.9±33.3	141.9±34.4
	Percentage change, % b	7.1 [2.7, 11.5]	6.7 [2.3, 11.1]	10.5 [6.1, 14.8]
	p-value vs IR 0.2 mg/day b		0.899	0.289
HDL-C	N	117	117	119
	Baseline, mg/dL	44.0±9.2	45.2±10.2	44.5±9.9
	Week 12 (LOCF), mg/dL	50.1±11.9	50.2±10.5	50.0±11.4
	Percentage change, % b	16.6 [14.3, 18.9]	14.8 [12.5, 17.0]	16.2 [13.9, 18.4]
	p-value vs IR 0.2 mg/day b		0.260	0.785
Non-HDL-C	N	117	117	119
	Baseline, mg/dL	194.4±41.7	193.2±40.7	187.2±33.9
	Week 12 (LOCF), mg/dL	172.9±43.3	176.2±36.3	174.3±38.6
	Percentage change, % b	-10.1 [-12.7, -7.5]	-8.5 [-11.1, -5.9]	-6.8 [-9.4, -4.2]
	p-value vs IR 0.2 mg/day b		0.391	0.079
RemL-C	N	114	117	118
	Baseline, mg/dL
	Median	16.5 (12.2 to 21.9)	15.3 (11.2 to 23.2)	15.0 (10.9 to 22.5)
	Mean	19.2±10.9	18.3±10.6	18.1±10.0
	Week 12 (LOCF), mg/dL
	Median	6.7 (4.5 to 9.8)	7.6 (5.1 to 10.7)	6.1 (4.6 to 9.2)
	Mean	7.8±5.1	8.8±5.5	7.3±4.7
	Percentage change, % b	-52.9 [-57.4, -48.3]	-47.5 [-52.0, -43.1]	-51.9 [-56.3, -47.4]
	p-value vs IR 0.2 mg/day b		0.101	0.759
Apolipoprotein AI	N	113	115	117
	Baseline, mg/dL	133.4±20.7	136.4±22.6	135.6±21.5
	Week 12, mg/dL	136.2±20.0	138.6±19.1	137.3±19.6
	Percentage change, % c	2.5 [1.0, 4.1]	2.6 [1.0 , 4.1]	2.0 [0.4, 3.5]
	p-value vs IR 0.2 mg/day c		0.976	0.595
Apolipoprotein AII	N	113	115	117
	Baseline, mg/dL	33.1±4.1	34.0±5.1	33.3±5.1
	Week 12, mg/dL	40.8±7.9	41.2±7.5	42.9±8.5
	Percentage change, % c	23.4 [20.1, 26.6]	22.0 [18.8, 25.2]	28.8 [25.6, 31.9]
	p-value vs IR 0.2 mg/day c		0.553	0.020
Apolipoprotein B	N	113	115	117
	Baseline, mg/dL	110.9±20.8	111.4±19.7	109.4±18.1
	Week 12, mg/dL	104.2±22.0	105.4±18.6	105.7±20.0
	Percentage change, % c	-5.5 [-8.1, -2.9]	-4.2 [-6.7, -1.6]	-2.7 [-5.2, -0.1]
	p-value vs IR 0.2 mg/day c		0.474	0.130
Apolipoprotein B48	N	115	115	118
	Baseline, mg/L
	Median	8.8 (6.0 to 11.3)	7.8 (5.3 to 11.3)	8.2 (5.6 to 11.3)
	Mean	10.2±6.6	9.4±6.4	9.6±6.2
	Week 12, mg/L
	Median	4.1 (3.0 to 5.8)	4.6 (2.8 to 6.4)	3.7 (2.4 to 5.5)
	Mean	5.2±4.3	5.7±4.1	4.7±3.4
	Percentage change, % c	-41.1 [-48.1, -34.1]	-31.8 [-38.8, -24.8]	-44.0 [-50.8, -37.1]
	p-value vs IR 0.2 mg/day c		0.064	0.567
Apolipoprotein CII	N	113	115	117
	Baseline, mg/dL
	Median	9.7 (8.6 to 11.2)	9.8 (8.4 to 11.2)	9.8 (8.4 to 10.6)
	Mean	10.1±3.0	9.8±2.3	9.9±2.7
	Week 12, mg/dL
	Median	7.8 (6.0 to 9.4)	7.7 (6.1 to 9.4)	7.0 (5.6 to 9.2)
	Mean	7.7±2.5	7.6±2.2	7.4±2.7
	Percentage change, % c	-22.4 [-26.1, -18.7]	-21.9 [-25.5, -18.2]	-25.1 [-28.7, -21.4]
	p-value vs IR 0.2 mg/day c		0.847	0.308
Apolipoprotein CIII	N	113	115	117
	Baseline, mg/dL
	Median	17.7 (14.6 to 22.8)	17.7 (15.3 to 22.9)	17.9 (15.8 to 22.3)
	Mean	19.4±6.2	19.3±5.9	19.5±6.1
	Week 12, mg/dL
	Median	12.1 (9.5 to 14.6)	12.4 (9.7 to 14.7)	11.0 (9.0 to 13.5)
	Mean	12.3±3.7	13.1±4.5	11.8±4.3
	Percentage change, % c	-34.1 [-37.4, -30.9]	-30.9 [-34.2, -27.7]	-37.3 [-40.6, -34.1]
	p-value vs IR 0.2 mg/day c		0.171	0.171
Apolipoprotein E	N	113	115	117
	Baseline, mg/dL	4.7±1.7	4.4±1.4	4.5±1.3
	Week 12, mg/dL	3.2±1.1	3.3±1.1	3.1±1.0
	Percentage change, % c	-27.2 [-31.1, -23.4]	-23.9 [-27.8, -20.1]	-28.5 [-32.3, -24.7]
	p-value vs IR 0.2 mg/day c		0.234	0.649
LDL-C / HDL-C ratio	N	117	117	119
	Baseline	3.2±1.1	3.1±0.9	3.1±0.9
	Week 12 (LOCF)	3.0±1.1	2.9±0.9	3.0±1.1
	Percentage change, % b	-7.7 [-11.7, -3.6]	-6.9 [-11.0, -2.9]	-3.5 [-7.6, 0.5]
	p-value vs IR 0.2 mg/dayb		0.812	0.160
Non-HDL-C / HDL-C ratio	N	117	117	119
	Baseline	4.6±1.4	4.4±1.1	4.4±1.2
	Week 12 (LOCF)	3.7±1.4	3.7±1.1	3.7±1.3
	Percentage change, % b	-22.1 [-25.1, -19.1]	-19.3 [-22.2, -16.3]	-18.1 [-21.0, -15.1]
	p-value vs IR 0.2 mg/dayb		0.185	0.058
Apolipoprotein B / apolipoprotein AI ratio	N	113	115	117
	Baseline	0.9±0.2	0.8±0.2	0.8±0.2
	Week 12	0.8±0.2	0.8±0.2	0.8±0.2
	Percentage change, % c	-7.0 [-10.1, -3.9]	-6.0 [-9.0, -2.9]	-3.1 [-6.1, -0.1]
	p-value vs IR 0.2 mg/day c		0.652	0.080
Apolipoprotein CIII / apolipoprotein CII ratio	N	113	115	117
	Baseline	2.0±0.5	2.0±0.4	2.0±0.4
	Week 12	1.7±0.4	1.8±0.4	1.7±0.4
	Percentage change, % c	-14.0 [-16.9, -11.2]	-10.5 [-13.2, -7.7]	-14.4 [-17.2, -11.6]
	p-value vs IR 0.2 mg/day c		0.075	0.862

Baseline levels and measured values are presented as median (interquartile range) and mean±standard deviation for triglycerides, RemL-C, apolipoprotein AI, apolipoprotein AII, apolipoprotein B48, apolipoprotein CII, apolipoprotein CIII, and apolipoprotein E and as mean±standard deviation for other biomarkers. a. p-values were estimated using Fisher’s exact test. b. The percentage changes are presented as least-squares means [95% CI], estimated using repeated measures ANCOVA at weeks 4, 8 and 12 with p-values. c. The percentage changes are presented as least- squares means [95% CI], estimated using ANCOVA at week 12 with p-values.

ANCOVA, analysis of covariance; CI, confidence interval; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein- cholesterol; LOCF, last observation carried forward; RemL-C, remnant-like lipoprotein cholesterol.

Efficacy

Primary Endpoint and Subgroup Analysis

Least-squares means [95% CI] of the percentage change in fasting serum TG from baseline at weeks 4, 8, and 12 were -48.0% [-51.4%, -44.6%] in the IR 0.2 mg/day group, -43.8% [-47.2%, -40.4%] in the XR 0.2 mg/day group, and -48.0% [-51.4%, -44.6%] in the XR 0.4 mg/day group (Fig.2A). Compared with the IR 0.2 mg/day group, the differences were 4.2% [-0.6%, 9.0%] in the XR 0.2 mg/day group and 0.0% [-4.8%, 4.8%] in the XR 0.4 mg/day group. These results confirm that XR at 0.2 mg/day and 0.4 mg/day are non-inferior to IR at 0.2 mg/day, with the upper limit of the 95% CI less than 10%, the non-inferiority margin. Furthermore, the XR 0.4 mg/day group demonstrated a greater decrease in the point estimate of the percentage change in fasting serum TG than did the XR 0.2 mg/day group, with a difference of -4.2%.

Fig.2. The percentage changes in fasting serum triglycerides from baseline to week 4, 8, and 12

The percentage changes in fasting serum triglycerides from baseline to week 4, 8, and 12 in the (A) total population, (B) subgroup with baseline triglycerides ＜500 mg/dL, and (C) subgroup with baseline triglycerides ≥ 500 mg/dL.

Data are presented as the least-squares mean and 95% confidence interval estimated using repeated analysis of covariance. Brackets indicate median baseline levels (mg/dL).

The subgroup with baseline TG ＜500 mg/dL revealed percentage changes in TG levels of -46.3%, -42.8%, and -45.9% in the IR 0.2 mg/day, XR 0.2 mg/day, and 0.4 mg/day groups, respectively, while those with baseline TG ≥ 500 mg/dL revealed percentage changes of -59.3%, -52.2%, and -66.3%, respectively (Figs.2B and 2C).

Secondary Endpoints

As presented in Table 2, the proportion of patients who achieved fasting serum TG of ＜150 mg/dL at week 12 was 37.4% in the XR 0.2 mg/day group and 51.7% in the XR 0.4 mg/day group, with no significant difference compared with 45.7% in the IR 0.2 mg/day group. However, a significant difference was observed between the two XR groups (p=0.035).

For the other fasting lipid-related parameters (TC, LDL-C, HDL-C, non-HDL-C, RemL-C, and apolipoproteins), the percentage changes from baseline exhibited no significant differences between the IR 0.2 mg/day group and the XR groups, except that the increase in ApoAII was significantly greater in the XR 0.4 mg/day than in the IR 0.2 mg/day group. However, a consistent trend was observed, revealing that the effect of XR at 0.4 mg/day on LDL-C, HDL-C, RemL-C, and ApoAII, ApoB48, ApoCII, ApoCIII, and ApoE levels was greater than that of XR at 0.2 mg/day. Analyses of cholesterol and TG contents by lipoprotein class and subclass revealed no considerable differences among the groups (Supplementary Tables 1, 2, 3, 4).

Supplementary Table 1.Lipoprotein cholesterol by lipoprotein class measured using gel-permeation high-performance liquid chromatography

Class		IR 0.2 mg/day	XR 0.2 mg/day	XR 0.4 mg/day
Total cholesterol	N	115	115	118
	Baseline, mg/dL	222.2±43.6	221.8±43.5	215.6±36.6
	Percentage change, %	-3.0 [-5.5, -0.6]	-1.4 [-3.8, 1.1]	-0.3 [-2.7, 2.1]
	p value vs IR 0.2 mg/day		0.351	0.127
Chylomicron	N	115	115	118
	Baseline, mg/dL	10.0±9.9	9.1±8.7	8.8±7.4
	Percentage change, %	-65.0 [-78.5, -51.4]	-48.7 [-62.3, -35.2]	-51.9 [-65.3, -38.6]
	p value vs IR 0.2 mg/day		0.097	0.178
VLDL	N	115	115	118
	Baseline, mg/dL	64.4±21.2	59.9±17.9	60.6±17.8
	Percentage change, %	-28.7 [-32.5, -24.9]	-23.3 [-27.1, -19.6]	-26.3 [-30.1, -22.6]
	p value vs IR 0.2 mg/day		0.050	0.384
LDL	N	115	115	118
	Baseline, mg/dL	107.6±32.4	110.9±33.1	105.0±28.2
	Percentage change, %	15.1 [10.5, 19.7]	14.2 [9.7, 18.8]	18.6 [14.1, 23.1]
	p value vs IR 0.2 mg/day		0.789	0.289
HDL	N	115	115	118
	Baseline, mg/dL	40.3±8.8	41.8±10.0	41.2±9.9
	Percentage change, %	19.3 [16.4, 22.2]	16.8 [13.9, 19.7]	17.0 [14.2, 19.9]
	p value vs IR 0.2 mg/day		0.219	0.268

N indicates the number of patients in the full analysis set. Baseline levels are presented as mean±standard deviation. Percentage changes are presented as least-squares mean [95% confidence interval], estimated using ANCOVA at week 12, providing p-values vs. IR 0.2 mg/day.

HDL, high-density lipoproteins; IR 0.2 mg/day, pemafibrate immediate-release tablets 0.2 mg/day (twice daily); LDL, low-density lipoproteins; VLDL, very low-density lipoproteins; XR 0.2 mg/day, pemafibrate extended-release tablets 0.2 mg/day (once daily); XR 0.4 mg/day, pemafibrate extended-release tablets 0.4 mg/day (once daily).

Supplementary Table 2.Lipoprotein cholesterol by lipoprotein subclasses measured using gel-permeation high-performance liquid chromatography

Subclass		IR 0.2 mg/day	XR 0.2 mg/day	XR 0.4 mg/day
Chylomicron	N	115	115	118
	Baseline, mg/dL	10.0±9.9	9.1±8.7	8.8±7.4
	Percentage change, %	-65.0 [-78.5, -51.5]	-48.7 [-62.2, -35.2]	-51.9 [-65.2, -38.6]
	p value vs IR 0.2 mg/day		0.096	0.177
Large VLDL	N	115	115	118
	Baseline, mg/dL	43.2±15.6	39.8±12.4	40.5±12.6
	Percentage change, %	-35.4 [-39.8, -31.0]	-28.2 [-32.6, -23.8]	-33.7 [-38.1, -29.4]
	p value vs IR 0.2 mg/day		0.023	0.599
Medium VLDL	N	115	115	118
	Baseline, mg/dL	13.3±4.5	12.7±4.5	12.7±4.5
	Percentage change, %	-22.0 [-26.3, -17.7]	-20.0 [-24.3, -15.7]	-19.2 [-23.5, -15.0]
	p value vs IR 0.2 mg/day		0.520	0.362
Small VLDL	N	115	115	118
	Baseline, mg/dL	7.8±2.9	7.5±2.9	7.3±2.6
	Percentage change, %	2.9 [-2.6, 8.3]	5.4 [-0.1,10.8]	10.9 [5.6, 16.3]
	p value vs IR 0.2 mg/day		0.520	0.039
Large LDL	N	115	115	118
	Baseline, mg/dL	21.4±7.2	21.6±8.1	20.5±6.9
	Percentage change, %	52.4 [44.9, 59.9]	52.7 [45.2, 60.2]	66.8 [59.4, 74.2]
	p value vs IR 0.2 mg/day		0.950	0.008
Medium LDL	N	115	115	118
	Baseline, mg/dL	48.0±15.9	49.9±16.2	46.8±13.7
	Percentage change, %	20.8 [15.2, 26.3]	18.9 [13.4, 24.5]	24.0 [18.5, 29.5]
	p value vs IR 0.2 mg/day		0.644	0.414
Small LDL	N	115	115	118
	Baseline, mg/dL	28.4±9.1	29.4±8.7	27.9±8.6
	Percentage change, %	-8.4 [-13.4, -3.4]	-9.0 [-14.0, -4.0]	-9.5 [-14.5, -4.6]
	p value vs IR 0.2 mg/day		0.864	0.754
Very small LDL	N	115	115	118
	Baseline, mg/dL	9.8±2.7	10.0±2.7	9.7±2.8
	Percentage change, %	-10.0 [-14.0, -6.0]	-8.5 [-12.6, -4.5]	-9.8 [-13.7, -5.8]
	p value vs IR 0.2 mg/day		0.616	0.933
Very large HDL	N	115	115	118
	Baseline, mg/dL	2.1±0.6	2.1±0.6	2.0±0.6
	Percentage change, %	0.9 [-1.8, 3.6]	0.8 [-1.9, 3.5]	-1.8 [-4.4, 0.9]
	p value vs IR 0.2 mg/day		0.939	0.160
Large HDL	N	115	115	118
	Baseline, mg/dL	4.7±3.5	4.5±3.3	4.6±3.1
	Percentage change, %	-0.6 [-11.2, 10.0]	2.4 [-8.2, 13.0]	-14.5 [-25.0, -4.1]
	p value vs IR 0.2 mg/day		0.699	0.067
Medium HDL	N	115	115	118
	Baseline, mg/dL	14.6±3.9	15.4±4.4	15.2±4.6
	Percentage change, %	23.5 [19.2, 27.9]	19.2 [14.9, 23.6]	18.7 [14.5, 23.0]
	p value vs IR 0.2 mg/day		0.17	0.12
Small HDL	N	115	115	118
	Baseline, mg/dL	14.1±2.4	15.0±2.9	14.5±2.8
	Percentage change, %	25.6 [22.3, 28.8]	24.3 [21.1, 27.5]	28.1 [24.9, 31.2]
	p value vs IR 0.2 mg/day		0.577	0.276
Very small HDL	N	115	115	118
	Baseline, mg/dL	4.9±0.8	5.0±1.0	4.9±0.9
	Percentage change, %	22.2 [19.0, 25.3]	25.3 [22.1, 28.4]	25.1 [22.0, 28.2]
	p value vs IR 0.2 mg/day		0.173	0.192

N indicates the number of patients in the full analysis set. Baseline levels are presented as mean±standard deviation. Percentage changes are presented as least-squares mean [95% confidence interval], estimated using ANCOVA at week 12, providing p-values vs. IR 0.2 mg/day.

HDL, high-density lipoproteins; IR 0.2 mg/day, pemafibrate immediate-release tablets 0.2 mg/day (twice daily); LDL, low-density lipoproteins; VLDL, very low-density lipoproteins; XR 0.2 mg/day, pemafibrate extended-release tablets 0.2 mg/day (once daily); XR 0.4 mg/day, pemafibrate extended-release tablets 0.4 mg/day (once daily).

Supplementary Table 3.Lipoprotein triglycerides by lipoprotein class measured using gel-permeation high-performance liquid chromatography

Class		IR 0.2 mg/day	XR 0.2 mg/day	XR 0.4 mg/day
Total triglycerides	N	115	115	118
	Baseline, mg/dL	341.7±161.4	314.5±117.5	327.2±123.3
	Percentage change, %	-40.8 [-45.3, -36.3]	-34.5 [-39.0, -29.9]	-41.4 [-45.9, -37.0]
	p value vs IR 0.2 mg/day		0.052	0.847
Chylomicron	N	115	115	118
	Baseline, mg/dL	54.9±59.8	51.3±46.0	49.6±42.0
	Percentage change, %	-58.4 [-71.4, -45.5]	-42.8 [-55.7, -29.9]	-50.6 [-63.3, -37.9]
	p value vs IR 0.2 mg/day		0.094	0.397
VLDL	N	115	115	118
	Baseline, mg/dL	226.8±93.7	206.2±67.8	219.4±79.1
	Percentage change, %	-41.1 [-46.0, -36.2]	-34.6 [-39.5, -29.7]	-43.3 [-48.1, -38.5]
	p value vs IR 0.2 mg/day		0.065	0.528
LDL	N	115	115	118
	Baseline, mg/dL	37.7±10.9	36.2±10.5	36.8±10.2
	Percentage change, %	-17.3 [-20.3, -14.3]	-15.6 [-18.6, -12.6]	-12.0 [-14.9, -9.0]
	p value vs IR 0.2 mg/day		0.439	0.014
HDL	N	115	115	118
	Baseline, mg/dL	22.3±11.4	20.8±8.2	21.4±7.9
	Percentage change, %	-28.8 [-32.8, -24.9]	-22.9 [-26.8, -18.9]	-28.8 [-32.7, -24.9]
	p value vs IR 0.2 mg/day		0.035	0.983

N indicates the number of patients in the full analysis set. Baseline levels are presented as mean±standard deviation. Percentage changes are presented as least-squares mean [95% confidence interval], estimated using ANCOVA at week 12, providing p-values vs. IR 0.2 mg/day.

HDL, high-density lipoproteins; IR 0.2 mg/day, pemafibrate immediate-release tablets 0.2 mg/day (twice daily); LDL, low-density lipoproteins; VLDL, very low-density lipoproteins; XR 0.2 mg/day, pemafibrate extended-release tablets 0.2 mg/day (once daily); XR 0.4 mg/day, pemafibrate extended-release tablets 0.4 mg/day (once daily).

Supplementary Table 4.Lipoprotein triglycerides by lipoprotein subclass measured using gel-permeation high-performance liquid chromatography

Subclass		IR 0.2 mg/day	XR 0.2 mg/day	XR 0.4 mg/day
Chylomicron	N	115	115	118
	Baseline, mg/dL	54.9±59.8	51.3±46.0	49.6±42.0
	Percentage change, %	-58.4 [-71.4, -45.5]	-42.8 [-55.7, -29.9]	-50.6 [-63.4, -37.9]
	p value vs IR 0.2 mg/day		0.094	0.397
Large VLDL	N	115	115	118
	Baseline, mg/dL	186.3±82.5	169.3±60.5	179.8±68.5
	Percentage change, %	-42.5 [-48.0, -37.0]	-34.8 [-40.3, -29.3]	-45.0 [-50.4, -39.7]
	p value vs IR 0.2 mg/day		0.051	0.520
Medium VLDL	N	115	115	118
	Baseline, mg/dL	30.0±10.8	27.2±7.9	29.4±10.4
	Percentage change, %	-37.3 [-41.0, -33.6]	-35.3 [-38.9, -31.6]	-39.1 [-42.7, -35.5]
	p value vs IR 0.2 mg/day		0.439	0.496
Small VLDL	N	115	115	118
	Baseline, mg/dL	10.5±3.3	9.7±2.7	10.2±3.2
	Percentage change, %	-21.2 [-24.4, -18.1]	-21.4 [-24.5, -18.2]	-19.8 [-22.9, -16.7]
	p value vs IR 0.2 mg/day		0.953	0.522
Large LDL	N	115	115	118
	Baseline, mg/dL	13.0±3.5	12.3±3.4	12.7±3.6
	Percentage change, %	-6.2 [-9.6, -2.8]	-5.4 [-8.8, -2.0]	0.5 [-2.9, 3.9]
	p value vs IR 0.2 mg/day		0.729	0.006
Medium LDL	N	115	115	118
	Baseline, mg/dL	13.3±3.5	12.9±3.8	13.0±3.4
	Percentage change, %	-10.8 [-14.0, -7.7]	-9.3 [-12.5, -6.2]	-4.2 [-7.3, -1.1]
	p value vs IR 0.2 mg/day		0.497	0.003
Small LDL	N	115	115	118
	Baseline, mg/dL	7.1±2.5	6.9±2.3	6.9±2.3
	Percentage change, %	-32.4 [-35.8, -29.1]	-30.2 [-33.5, -26.8]	-29.4 [-32.7, -26.1]
	p value vs IR 0.2 mg/day		0.349	0.202
Very small LDL	N	115	115	118
	Baseline, mg/dL	4.3±2.4	4.0±1.8	4.1±1.9
	Percentage change, %	-43.8 [-48.0, -39.6]	-38.5 [-42.7, -34.3]	-41.7 [-45.9, -37.6]
	p value vs IR 0.2 mg/day		0.078	0.490
Very large HDL	N	115	115	118
	Baseline, mg/dL	1.8±1.4	1.6±1.0	1.6±0.9
	Percentage change, %	-44.9 [-50.5, -39.3]	-37.3 [-42.9, -31.7]	-45.2 [-50.7, -39.8]
	p value vs IR 0.2 mg/day		0.060	0.926
Large HDL	N	115	115	118
	Baseline, mg/dL	4.0±3.9	3.4±2.3	3.6±2.1
	Percentage change, %	-47.3 [-52.6, -42.1]	-41.0 [-46.3, -35.7]	-52.3 [-57.5, -47.1]
	p value vs IR 0.2 mg/day		0.097	0.19
Medium HDL	N	115	115	118
	Baseline, mg/dL	7.9±3.9	7.5±2.9	7.7±3.0
	Percentage change, %	-23.4 [-27.7, -19.0]	-16.4 [-20.7, -12.1]	-22.7 [-26.9, -18.4]
	p value vs IR 0.2 mg/day		0.026	0.828
Small HDL	N	115	115	118
	Baseline, mg/dL	5.7±2.0	5.6±1.9	5.6±1.8
	Percentage change, %	-20.7 [-25.0, -16.3]	-14.2 [-18.6, -9.8]	-17.2 [-21.5, -12.8]
	p value vs IR 0.2 mg/day		0.041	0.265
Very small HDL	N	115	115	118
	Baseline, mg/dL	2.9±1.2	2.8±1.0	2.8±1.0
	Percentage change, %	-27.4 [-31.3, -23.5]	-20.9 [-24.8, -17.1]	-25.9 [-29.7, -22.1]
	p value vs IR 0.2 mg/day		0.022	0.591

N indicates the number of patients in the full analysis set. Baseline levels are presented as mean±standard deviation. Percentage changes are presented as least-squares mean [95% confidence interval], estimated using ANCOVA at week 12, providing p-values vs. IR 0.2 mg/day.

HDL, high-density lipoproteins; IR 0.2 mg/day, pemafibrate immediate-release tablets 0.2 mg/day (twice daily); LDL, low-density lipoproteins; VLDL, very low-density lipoproteins; XR 0.2 mg/day, pemafibrate extended-release tablets 0.2 mg/day (once daily); XR 0.4 mg/day, pemafibrate extended-release tablets 0.4 mg/day (once daily).

Similarly, in the high-fat meal test, TG levels at each time point revealed significant reductions from the time-matched baseline to the corresponding sampling time at week 12 in all groups. However, the reduction in area under the curve from 0 to 6 h (AUC_0-6h) and incremental AUC_0-6h of TG revealed no significant differences between the IR 0.2 mg/day and the XR groups, but a dose-dependent trend was observed in the latter (Supplementary Fig.1 and Supplementary Tables 5 and 6). Fasting ketone body levels increased with no significant difference between the IR 0.2 mg/day and the XR groups (Supplementary Table 7). Furthermore, hepatobiliary biomarker and fibrinogen levels revealed no significant differences in change from baseline at week 12 between the IR 0.2 mg/day group and the XR groups, except that the reductions in γ-GT and ALP were significantly greater in the XR 0.4 mg/day than in the IR 0.2 mg/day group (Supplementary Table 7). A consistent trend was observed, revealing that the effect of XR at 0.4 mg/day was larger than that of XR at 0.2 mg/day for ALT, γ-GT, ALP, bilirubin, and fibrinogen levels.

Supplementary Fig.1. Serum TG levels after taking high-fat meal

Measured values at each measurement time point are presented as mean±SD. (A) IR 0.2 mg/day, (B) ER 0.2 mg/day, and (C) XR 0.4 mg/day. IR 0.2 mg/day, pemafibrate immediate-release tablets 0.2 mg/day (twice daily); XR 0.2 mg/day, pemafibrate extended-release tablets 0.2 mg/day (once daily); XR 0.4 mg/day, pemafibrate extended-release tablets 0.4 mg/day (once daily); TG, triglycerides; SD, standard deviation.

Supplementary Table 5.Measured values at weeks 0 and 12 and percentage changes from time-matched baseline at week 12 in fasting (0 h) and postprandial serum triglycerides at each measurement time point in the high-fat meal test

Week 0
Time after meal		0hr	0.5hr	1hr	1.5hr	2hr	3hr	4hr	6hr
IR 0.2 mg/day	N	28	28	28	28	28	28	28	28
	Value	301.8±113.0	305.2±111.3	334.5±111.0	384.0±119.2	437.4±126.5	542.1±144.1	596.6±164.0	610.8±263.9
XR 0.2 mg/day	N	29	29	29	29	29	29	29	29
	Value	337.9±209.2	326.6±181.4	345.4±162.2	384.2±155.6	436.1±157.2	528.2±153.4	586.5±160.1	568.9±191.3
XR 0.4 mg/day	N	31	31	31	31	31	31	31	31
	Value	342.6±134.4	340.3±126.6	362.8±119.1	414.7±140.4	472.0±148.9	584.7±186.7	649.9±211.0	668.5±232.4
Week 12
Time after meal		0hr	0.5hr	1hr	1.5hr	2hr	3hr	4hr	6hr
IR 0.2 mg/day	N	27	27	27	27	27	27	27	27
	Value	160.4±69.8	165.9±73.4	188.1±79.4	223.1±90.3	253.6±101.0	314.2±125.7	323.7±146.9	290.9±195.1
	% Change	-44.68	-43.56	-41.87	-40.29	-40.63	-40.85	-44.78	-49.84
		[-51.93, -37.42]	[-51.23, -35.89]	[-49.47, -34.28]	[-47.75, -32.84]	[-48.34, -32.92]	[-48.88, -32.83]	[-53.01, -36.55]	[-59.03, -40.64]
	p value	0.000＊＊	0.000＊＊	0.000＊＊	0.000＊＊	0.000＊＊	0.000＊＊	0.000＊＊	0.000＊＊
XR 0.2 mg/day	N	28	28	28	28	28	28	28	28
	Value	172.7±101.1	181.3±94.9	207.6±92.1	245.1±100.1	280.5±114.9	351.8±153.1	370.3±172.6	333.4±162.7
	% Change	-40.53	-36.69	-33.90	-30.84	-31.37	-31.25	-35.38	-38.27
		[-51.80, -29.27]	[-48.63, -24.74]	[-44.85, -22.96]	[-41.67, -20.00]	[-42.15, -20.60]	[-41.59, -20.90]	[-45.38, -25.38]	[-49.40, -27.14]
	p value	0.000＊＊	0.000＊＊	0.000＊＊	0.000＊＊	0.000＊＊	0.000＊＊	0.000＊＊	0.000＊＊
XR 0.4 mg/day	N	31	31	31	31	31	31	31	31
	Value	145.9±56.9	160.5±55.4	186.0±57.0	218.5±71.4	253.1±87.6	309.1±117.9	313.5±132.5	288.9±111.6
	% Change	-53.15	-48.40	-45.74	-44.57	-43.87	-44.15	-48.14	-51.75
		[-61.36, -44.95]	[-56.48, -40.32]	[-52.27, -39.21]	[-50.91, -38.23]	[-50.57, -37.17]	[-51.61, -36.70]	[-56.23, -40.05]	[-60.71, -42.79]
	p value	0.000＊＊	0.000＊＊	0.000＊＊	0.000＊＊	0.000＊＊	0.000＊＊	0.000＊＊	0.000＊＊

Measured values at weeks 0 and 12 are presented as mean±standard deviation. Percentage changes from time-matched baseline at week 12 are presented as mean [95% confidence interval]. ^＊: p ≤ 0.05. ^＊＊: p ≤ 0.01. IR 0.2 mg/day, pemafibrate immediate-release tablets 0.2 mg/day (twice daily); N, the number of patients in the full analysis set; XR 0.2 mg/day, pemafibrate extended-release tablets 0.2 mg/day (once daily); XR 0.4 mg/ day, pemafibrate extended-release tablets 0.4 mg/day (once daily).

Supplementary Table 6.Area under the curve of postprandial serum triglycerides

Parameter		IR 0.2 mg/day	XR 0.2 mg/day	XR 0.4 mg/day
AUC	N	27	28	31
	Baseline, mg∙hr/dL	2972.8±908.9	2917.6±911.3	3226.6±1000.3
	Percentage change, %	-43.8 [-51.5, -36.2]	-38.2 [-45.8, -30.6]	-46.1 [-53.3, -38.9]
	p value vs IR 0.2 mg/day		0.304	0.663
Incremental AUC	N	27	28	31
	Baseline, mg∙hr/dL	1154.6±377.9	877.2±763.3	1171.1±682.9
	Change, mg∙hr/dL	-422.0 [-547.6, -296.4]	-282.5 [-408.0, -157.0]	-381.4 [-498.5, -264.2]
	p value vs IR 0.2 mg/day		0.127	0.637

Baseline levels are presented as mean±standard deviation. Percentage changes and changes from baseline at week 12 are presented as least-squares mean [95% confidence interval], which were estimated using an ANCOVA model with baseline levels, sex, the timing of trial drug administration (before or after meal), concomitant use of statins or not, and study sites. AUC was calculated for the levels from the start time of breakfast to 6 h later. AUC, area under the curve; IR 0.2 mg/day, pemafibrate immediate-release tablets 0.2 mg/day (twice daily); N, the number of patients in the full analysis set; XR 0.2 mg/day, pemafibrate extended-release tablets 0.2 mg/day (once daily); XR 0.4 mg/day, pemafibrate extended-release tablets 0.4 mg/day (once daily).

Supplementary Table 7.Change in the ketone bodies and the secondary efficacy endpoints other than lipid-related biomarkers

Parameter		IR 0.2 mg/day	XR 0.2 mg/day	XR 0.4 mg/day
Total ketone bodies	N	116	117	119
	Baseline, μmol/L	80.26±61.02	83.71±63.45	89.86±76.02
	Change, μmol/L	49.17 [25.76, 72.58]	39.55 [16.18, 62.93]	54.05 [30.94, 77.15]
	p value vs IR 0.2 mg/day		0.568	0.771
Acetoacetic acid	N	116	117	119
	Baseline, μmol/L	28.33±18.89	30.41±21.11	30.55±23.81
	Change, μmol/L	21.86 [14.47, 29.26]	16.76 [9.37, 24.14]	21.40 [14.11, 28.70]
	p value vs IR 0.2 mg/day		0.338	0.931
β-hydroxybutyrate	N	116	117	119
	Baseline, μmol/L	51.93±43.36	53.28±44.40	59.29±52.84
	Change, μmol/L	27.31 [11.05, 43.58]	22.71 [6.47, 38.96]	32.72 [16.66, 48.78]
	p value vs IR 0.2 mg/day		0.694	0.643
AST	N	117	117	119
	Baseline, U/L	26.9±9.7	25.4±7.7	27.5±11.2
	Change, U/L	0.7 [-1.1, 2.5]	-0.8 [-2.6, 1.0]	0.3 [-1.4, 2.1]
	p value vs IR 0.2 mg/day		0.226	0.749
ALT	N	117	117	119
	Baseline, U/L	36.7±23.0	33.0±16.2	35.0±20.3
	Change, U/L	-4.7 [-7.5, -2.0]	-7.4 [-10.2, -4.7]	-7.9 [-10.6, -5.2]
	p value vs IR 0.2 mg/day		0.170	0.106
γ-GT	N	117	117	119
	Baseline, U/L	68.5±51.1	63.9±53.4	62.8±61.5
	Change, U/L	-25.1 [-28.9, -21.2]	-26.3 [-30.2, -22.5]	-30.8 [-34.6, -27.0]
	p value vs IR 0.2 mg/day		0.651	0.038＊
ALP	N	117	117	119
	Baseline, U/L	75.7±18.8	77.1±20.5	73.1±18.5
	Change, U/L	-23.0 [-24.6, -21.4]	-22.0 [-23.5, -20.4]	-26.1 [-27.7, -24.6]
	p value vs IR 0.2 mg/day		0.358	0.006＊＊
Bilirubin	N	117	117	119
	Baseline, mg/dL	0.81±0.30	0.81±0.26	0.80±0.23
	Change, mg/dL	-0.10 [-0.13, -0.06]	-0.09 [-0.13, -0.06]	-0.11 [-0.14, -0.08]
	p value vs IR 0.2 mg/day		0.881	0.538
Fibrinogen	N	117	117	119
	Baseline, mg/dL	309.9±46.7	308.7±47.2	312.3±49.8
	Change, mg/dL	-50.3 [-59.6, -41.0]	-42.3 [-51.6, -33.0]	-61.7 [-70.9, -52.5]
	p value vs IR 0.2 mg/day		0.234	0.085

N indicates the number of patients in the full analysis set. Baseline levels are presented as mean±standard deviation. Changes in ketone bodies and the secondary efficacy endpoints other than lipid-related biomarkers are presented as least-squares mean [95% confidence interval]. Least-squares mean, 95% confidence interval, and p-value were estimated using mixed models for repeated measures.

^＊: p ≤ 0.05, ^＊＊: p ≤ 0.01. ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; γ-GT, gamma-glutamyl transpeptidase; IR 0.2 mg/day, pemafibrate immediate-release tablets 0.2 mg/day (twice daily); N, the number of patients in the full analysis set; XR 0.2 mg/day, pemafibrate extended-release tablets 0.2 mg/day (once daily); XR 0.4 mg/day, pemafibrate extended-release tablets 0.4 mg/day (once daily).

Safety Endpoints

AEs were observed in 30 patients (25.4%) in the IR 0.2 mg/day group, 21 patients (17.8%) in the XR 0.2 mg/day group, and 32 patients (26.9%) in the XR 0.4 mg/day group (Table 3). No significant difference was observed in the incidence of total AEs, total ADRs, and laboratory test abnormalities among the treatment groups.

Table 3.Summary of safety endpoints (safety analysis set)

	Immediate-release 0.2 mg/day (twice daily)	Extended-release 0.2 mg/day (once daily)	Extended-release 0.4 mg/day (once daily)
N	118	118	119
Total adverse events	30 (25.4)	21 (17.8)	32 (26.9)
Total adverse drug reactions	7 (5.9)	3 (2.5)	7 (5.9)
Death	0	0	0
Serious adverse events other than death	1 (0.8)	2 (1.7)	0
Adverse events leading to discontinuation	2 (1.7)	0	0
Alanine aminotransferase increase	1 (0.8)	2 (1.7)	0
Renal impairment	0	0	1 (0.8)
Blood creatinine increase	0	1 (0.8)	0
Protein urine present	0	1 (0.8)	0
Serum creatine kinase increased	0	1 (0.8)	1 (0.8)
Myalgia	1 (0.8)	0	0
Laboratory test abnormalities
Aspartate aminotransferase ≥ 3xULN	0	0	1 (0.8)
Alanine aminotransferase ≥ 3xULN	0	0	0
Creatine kinase ＞2.5xULN	0	2 (1.7)	1 (0.8)
Creatine kinase ＞5xULN	0	0	1 (0.8)
Serum creatinine ＞1.5 mg/dL	0	1 (0.8)	0

Data are presented as N (%). ULN, upper limit of normal.

No deaths occurred. Serious AEs included coronavirus disease (COVID-19), occurring in one patient each in the IR 0.2 mg/day and XR 0.2 mg/day groups, as well as COVID-19-caused pneumonia in the XR 0.2 mg/day group. These patients recovered with appropriate treatment, and the investigators dismissed a causal relationship with trial drugs. Two patients in the IR 0.2 mg/day group discontinued the trial drug because of dizziness or myalgia, which recovered or improved, respectively, after discontinuation. The investigator believed that the trial drug could have been resumed in the case of myalgia; however, both cases led to consent withdrawal.

AEs observed in more than 2% of patients in the IR 0.2 mg/day, XR 0.2 mg/day, and XR 0.4 mg/day groups included injection site pain in three (2.5%), two (1.7%), and four (3.4%) patients, respectively; malaise in three (2.5%), one (0.8%), and five (4.2%) patients, respectively; pyrexia in six (5.1%), two (1.7%), and eight (6.7%) patients, respectively; as well as headache in one (0.8%), zero, and three (2.5%) patients, respectively. These events were concluded to be due to an mRNA-based COVID-19 vaccine, and no ADRs were observed in more than 2% of patients for any group.

An increased AST level of more than three times the ULN was observed in one patient in the XR 0.4 mg/day group, which was considered to be due to a complication rather than a safety problem by the investigator. An increase in CK levels of more than 2.5 times the ULN was observed in two patients in the XR 0.2 mg/day group and one patient in the XR 0.4 mg/day group, determined to be due to exercise or unrelated to the trial drug. An increased serum creatinine level of more than 1.5 mg/dL was observed in the XR 0.2 mg/day group, with 1.00, 0.97, and 3.40 mg/dL at weeks 0, 4, and 8. It decreased to 1.06 mg/dL at an unscheduled visit 1 week later and was 1.04 mg/dL at week 12 without discontinuation or specific treatment.

Blood glucose-related biomarkers revealed no considerable changes within the group or large differences between groups. Changes in serum creatinine and estimated glomerular filtration rate (eGFR) were similar across groups (Supplementary Table 8).

Supplementary Table 8.Change in blood glucose-related and renal biomarkers

Parameter		IR 0.2 mg/day	XR 0.2 mg/day	XR 0.4 mg/day
Glucose	N	116	115	118
	Baseline, mmol/L	6.0±0.7	6.0±0.9	6.2±1.0
	Change, mmol/L	0.0±0.9	0.0±0.1	-0.2±0.7
	p value vs IR 0.2 mg/day		0.219	0.050＊
	p value vs XR 0.2 mg/day			0.004＊＊
Glycated Albumin	N	116	115	117
	Baseline, %	13.07±1.44	12.96±1.72	13.38±1.79
	Change, %	0.30±1.28	0.23±0.85	0.25±1.41
	p value vs IR 0.2 mg/day		0.848	0.248
	p value vs XR 0.2 mg/day			0.324
Insulin	N	112	112	116
	Baseline, pmol/L	66.7±36.4	58.9±26.6	71.0±51.0
	Change, pmol/L	-5.3±36.7	10.8±111.9	-17.4±49.5
	p value vs IR 0.2 mg/day		0.174	0.026＊
	p value vs XR 0.2 mg/day			0.000＊＊
Hemoglobin A1c (NGSP)	N	116	115	118
	Baseline, %	5.81±0.47	5.90±0.61	5.93±0.63
	Change, %	0.08±0.30	0.04±0.19	0.10±0.43
	p value vs IR 0.2 mg/day		0.380	0.934
	p value vs XR 0.2 mg/day			0.477
HOMA-IR	N	112	112	116
	Baseline	2.57± 1.46	2.28±1.18	2.88±2.52
	Change	-0.14±1.71	0.78±7.70	-0.74±2.47
	p value vs IR 0.2 mg/day		0.208	0.029＊
	p value vs XR 0.2 mg/day			0.000＊＊
Creatinine	N	116	114	118
	Baseline, mg/dL	0.861±0.150	0.849±0.133	0.858±0.162
	Change, mg/dL	0.047±0.066	0.046±0.068	0.065±0.063
	p value vs IR 0.2 mg/day		0.493	0.034＊
	p value vs XR 0.2 mg/day			0.155
eGFR	N	116	114	118
	Baseline, mL/min/1.73m2	72.67±12.39	73.05±12.38	72.64±14.03
	Change, mL/min/1.73m2	-3.98±5.30	-4.10±6.16	-5.47±5.10
	p value vs IR 0.2 mg/day		0.649	0.047＊
	p value vs XR 0.2 mg/day			0.224

Baseline levels and changes at week 12 are presented as mean±standard deviation. p-values were estimated using Wilcoxon rank-sum test. ^＊: p ≤ 0.05, ^＊＊: p ≤ 0.01.

eGFR, estimated glomerular filtration rate; IR 0.2 mg/day, pemafibrate immediate-release tablets 0.2 mg/day (twice daily); N, the number of patients in the safety analysis set; NGSP, national glycohemoglobin standardization program; XR 0.2 mg/day, pemafibrate extended-release tablets 0.2 mg/day (once daily); XR 0.4 mg/day, pemafibrate extended-release tablets 0.4 mg/day (once daily).

Discussion

This 12-week randomized phase 3 trial in patients with hypertriglyceridemia confirmed that the percentage changes in fasting serum TG in the XR 0.2 mg/day and XR 0.4 mg/day groups were non-inferior to those in the IR 0.2 mg/day group. The TG-lowering effect of XR at 0.4 mg/day was more potent than that of XR at 0.2 mg/day, as indicated by the point estimate of the percentage change in fasting serum TG levels, the percentage reduction in TG levels in the subpopulation with baseline TG ≥ 500 mg/dL, and the proportion of patients who achieved TG of ＜150 mg/dL. Previous trials on IR have yielded mixed results indicating that the TG-lowering effect was more potent with IR at 0.4 mg/day than with IR at 0.2 mg/day or that the effect may have already reached the maximum at 0.2 mg/day. These inconsistencies could be attributed to the large variance in TG data and variations in patient populations. However, the TG-lowering effect of a higher dose may become more evident in patients with higher TG levels. Regarding the comparability of XR 0.4 to IR 0.4, not examined in the present study, the TG-lowering effect can be considered similar due to previously reported marginal differences between IR 0.2 and IR 0.4 ^{5, 7-8, 12-15)} and IR 0.2 and XR 0.4 in the present study. IR 0.2 mg/day (once daily) was not included in this study because the approved dosing frequency for IR is twice daily. The approval was based on that IR 0.2 mg/day (twice daily) has demonstrated higher efficacy compared with IR 0.2 mg/day (once daily) with changes in TG levels of -22.7% and -30.8% in the once daily and twice daily groups, respectively¹⁶⁾.

Another point of interest in the present study is that it is the first to demonstrate the TG-lowering effect of pemafibrate with an XR formulation after a high-fat meal. In previous clinical trials of IR formulations^6-8), meal tolerance tests were conducted using cookie-type test meals (592 kcal energy, 28.5 g fat, 75 g carbohydrate, and 8.0 g protein), where postprandial TG levels returned to baseline 6 to 8 h after the meal even before treatment with pemafibrate. After administering IR 0.2 mg/day or 0.4 mg/day, the postprandial TG levels peaked earlier with decreased AUC^6-8). Herein, the high-fat meal test resulted in sustained high TG levels even 6 h after the meal before pemafibrate treatment. Postprandial lipid metabolism abnormalities can be observed more readily with high-fat meals compared to cookie-type test meals. The increase in non-fasting TG levels is associated with the risk of developing atherosclerotic cardiovascular disease, independently of total cholesterol, non-HDL-C, or LDL-C levels, which minimally change before and after meals^{9, 10)}. Therefore, the increase in non-fasting TG levels is recognized as a risk predictor in routine clinical practice^{10, 11)}. In this context, within the current study, after a high-fat meal, the postprandial levels, AUC_0-6h, and incremental AUC_0–6h decreased with pemafibrate. This may be suggestive of the effects of pemafibrate on postprandial TG metabolism, including intestinal absorption, chylomicron production, and its clearance. Hence, this might have clinical relevance, providing valuable insights into personalized management based on the patient profile. Notably, the sustained increase in postprandial TG levels were similar between pemafibrate XR and IR formulations.

In previous clinical trials on the IR formulation, 0.4 mg/day consistently had greater effects on ApoAII, ApoCIII, γ-GT, ALP, and fibrinogen than 0.2 mg/day^{5, 7-8, 12-16)}. We observed a similar trend in our study, where XR at 0.4 mg/day had greater effects on these biomarkers than XR at 0.2 mg/day. As these markers are mainly produced by the liver, our findings suggest direct actions of pemafibrate in the liver, which may directly and indirectly lead to more potent effects with a higher dose. IR or XR at 0.4 mg/day is used in studies of patients with non-alcoholic fatty liver disease or non-alcoholic steatohepatitis, respectively^{17, 18)}. In the former, a 27.1% reduction in ALT levels and an improvement in liver stiffness were observed in patients with elevated ALT at week 24 ¹⁷⁾.

The safety profiles were similar across the groups in this study, with no marked differences in AE and ADR incidence or in the number of patients whose laboratory tests exceeded threshold values, in line with past trials on the IR formulation^{5, 7-8, 12-14)}. The decreases in fasting glucose, insulin, and HOMA-IR score were significantly greater in the XR 0.4 mg/day group than in the IR 0.2 mg/day group. The increase in serum creatinine level and decrease in eGFR were significantly greater in the XR 0.4 mg/day group than in the IR 0.2 mg/day group. However, the changes were within the range of those observed with IR at 0.2 to 0.4 mg/day in previous studies^{5, 8, 12-15)}.

Based on these findings, the recommended dosage of XR would be similar to that of IR, usually a daily dose of 0.2 mg. However, for patients with an inadequate TG-lowering response or high TG levels, a maximum daily dose of 0.4 mg is worth considering. XR may allow for better drug adherence and combination regimens, such as once-daily fixed-dose combinations with statins and anti-diabetic drugs. For example, a combination with a sodium-glucose cotransporter 2 inhibitor is under development for non-alcoholic steatohepatitis/non-alcoholic fatty liver disease¹⁸⁾.

LDL-C and TG control is central to managing atherosclerotic cardiovascular risk, particularly under elevated TG levels¹⁹⁾. Statin and PPARα agonist use is avoided due to the risk of rhabdomyolysis. However, pemafibrate has no pharmacokinetic interaction with statins²⁰⁾. Its safety and efficacy in lipid management were similar regardless of concomitant statin therapy in 12-week and 24-week phase 3 studies¹⁴⁾. The safety of pemafibrate in combination with statins was also confirmed in an outcome trial involving 10,497 patients with a median follow-up period of 3.4 years. No significant increased risk of musculoskeletal AEs, including myopathy and rhabdomyolysis, was observed compared with that in the placebo group²¹⁾. Therefore, a fixed-dose combination of pemafibrate and statin may be feasible to control both LDL-C and TG levels with a single drug.

The present study had some limitations. First, this was a 12-week trial, which warrants a long-term study for validating the current results. Second, the patients included in this trial were all Japanese. Thus, further studies are needed to confirm the efficacy and safety of this formulation in other populations.

Conclusion

This phase 3 trial confirmed that 0.2 mg or 0.4 mg pemafibrate in the form of XR once daily is non-inferior to 0.1 mg IR tablets administered twice daily in reducing TG levels during 12 weeks of treatment in patients with hypertriglyceridemia. All treatment regimens were similarly well tolerated. Furthermore, XR at 0.4 mg/day is suggested to have higher efficacy in TG management than XR at 0.2 mg/day, as a number of evaluated parameters possibly respond better to the former regimen. Therefore, XR at 0.4 mg may be considered rather than XR at 0.2 mg in patients requiring stricter TG control.

Acknowledgements and Notice of Grant Support

We acknowledge the investigators and patients who participated in these studies. This study was conducted at Medical Corporation Yuhokai Miho Clinic (Otoya Miho), Motomachi Takatsuka Naika Clinic (Yoji Takatsuka), Medical Corp. SEIKOUKAI New Medical Research System Clinic (Atsuko Abe), Fukuwa Clinic (Yasushi Fukushima), Medical Corporation Heishinkai OCROM Clinic (Satoshi Inoue), Medical Corporation Asbo Tokyo Asbo Clinic (Hiroshige Itakura), Tokyo-Eki Center-building Clinic (Arihiro Kiyosue), Medical Corporation Heishinkai ToCROM Clinic (Osamu Matsuoka). Dojinkinenkai Meiwa Hospital (Kazuyuki Mizuyama), Medical Corporation Chiseikai Tokyo Center Clinic (Hirotaka Nagashima), and Ikebukuro Metropolitan Clinic (Akira Numata). This study was funded by Kowa Company, Ltd. The study sponsor had a role in the study design; data collection, analysis, and interpretation; and writing of the report. We would like to thank Editage (www.editage.com) for English language editing.

Conflicts of Interest

Arai H has received personal fees from Daiichi Sankyo Company, Limited, MSD K.K., Kowa Company, Ltd., Takeda Pharmaceutical Company Limited, and Otsuka Pharmaceutical Co., Ltd. Yamashita S has received personal fees from Kowa Company, Ltd., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Skylight Biotech, Inc., and Hayashibara Co., Ltd. Araki E has received personal fees and grants from Ono Pharmaceutical Co., Ltd., Sumitomo Pharma Co., Ltd., and Novo Nordisk Pharma Ltd.; personal fees from AstraZeneca K.K., Eli Lilly Japan K.K., MSD K.K., Kowa Company, Ltd., and Daiichi Sankyo Company, Limited; and grants from Takeda Pharmaceutical Company Limited, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., and Roche Diagnostics K.K. Yokote K has received personal fees and grants from MSD K.K., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Company Limited, Astellas Pharma Inc., Sumitomo Pharma Co., Ltd., Ono Pharmaceutical Co., Ltd., Kowa Company, Ltd., Daiichi Sankyo Company, Limited, and Taisho Pharmaceutical Co., Ltd.; personal fees from AstraZeneca K.K., Novartis Pharma K.K., Boehringer Ingelheim International GmbH., and Pfizer Japan Inc.; and grants from Shionogi & Co., Ltd., Bayer Yakuhin, Ltd., Nippon Boehringer Ingelheim Co., Ltd., and Abbott Japan LLC. Ishibashi S has received personal fees from Kowa Company, Ltd. Tanigawa R, Saito A, Yamasaki S, and Suganami H are employees of Kowa Company, Ltd.

Supplementary Materials

Investigators

Otoya Miho	Medical Corporation Yuhokai Miho Clinic
Yoji Takatsuka	Motomachi Takatsuka Naika Clinic
Atsuko Abe	Medical Corp. SEIKOUKAI New Medical Research System Clinic
Yasushi Fukushima	Fukuwa Clinic
Satoshi Inoue	Medical Corporation Heishinkai OCROM Clinic
Hiroshige Itakura	Medical Corporation Asbo Tokyo Asbo Clinic
Arihiro Kiyosue	Tokyo-Eki Center-building Clinic
Osamu Matsuoka	Medical Corporation Heishinkai ToCROM Clinic
Kazuyuki Mizuyama	Dojinkinenkai Meiwa Hospital
Hirotaka Nagashima	Medical Corporation Chiseikai Tokyo Center Clinic
Akira Numata	Ikebukuro Metropolitan Clinic

Additional Information on Methods

Patients Eligibility Criteria

Inclusion Criteria

1) Patients with dyslipidemia who were aged at least 20 years at the time of providing informed consent

2) Patients who had been receiving constant instruction on diet and exercise for at least 12 weeks before the first screening testing

3) Patients who had fasting serum TG levels of ≥ 200 mg/dL in two consecutive tests conducted during the screening period within 8 weeks.

Exclusion Criteria

1) Patients who had a fasting serum TG level of ＞1000 mg/dL at the screening test.

2) Patients who would need contraindicated drugs during the trial period.

3) Patients with poorly controlled thyroid disease.

4) Patients with type 1 diabetes or poorly controlled diabetes (hemoglobin A1c ≥8.0% at the screening test).

5) Patients with poorly controlled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg).

6) Patients who had an aspartate aminotransferase (AST) or alanine aminotransferase (ALT) level exceeding three times the upper limit of the normal range (ULN) at the screening test.

7) Patients who had a creatine kinase (CK) level exceeding five times ULN at the screening test.

8) Patients with hepatic cirrhosis or biliary obstruction.

9) Patients with a history of acute myocardial infarction within 3 months before consent.

10) Patients with heart failure in the New York Heart Association functional classification Class III or IV.

11) Patients with malignant tumors or those considered at high risk of recurrence.

12) Patients with a history of serious drug allergies (such as anaphylaxis).

13) Pregnant women, breastfeeding women, women who planned to become pregnant or breastfeed during the trial period, or women who had reproductive potential and did not use any contraception method.

14) Patients who were engaged in blood donation of 400 mL or more within 16 weeks before the screening test, blood donation of 200 mL or more within 4 weeks before the screening test, or plasma and platelet donation within 2 weeks before the screening test.

15) Patients who had received pemafibrate.

16) Patients who participated in another clinical trial and received a drug at the time of providing informed consent or any study drug other than placebo less than 16 weeks prior to the time of providing informed consent.

17) Patients who were considered not eligible for any other reason by the trial investigators.

Methods of High-Fat Meal Test

A high-fat meal test was conducted at weeks 0 and 12 in 90 patients involved in initiating week 0 at study sites where the test was feasible. In the high-fat meal test, postprandial TG was measured 0.5, 1, 1.5, 2, 3, 4, and 6 h after the test meal (1,000 kcal energy, 66.7 g fat, 62.5 g carbohydrate, and 37.6 g protein for men; 800 kcal energy, 53.3 g fat, 50.0 g carbohydrate, and 30.0 g protein for women).

A fasting level before the test meal was defined as a pre-meal baseline against the postprandial levels, and each of the fasting and postprandial levels at week 0 was defined as a time-matched baseline against the levels corresponding to sampling time at week 12.

As the secondary efficacy endpoints, the percentage change from time-matched baseline to week 12 in TG levels at each time point before and after meals in the high-fat meal test; the percentage change from baseline to week 12 in the area under the curve from 0 to 6 h (AUC_0-6h); and the change from baseline to week 12 in incremental AUC_0-6h of postprandial TG in the high-fat meal test were analyzed.

The changes from time-matched baseline to the corresponding sampling time at week 12 in TG were assessed with the one-sample t-test. The percentage change in AUC_0-6h of TG and the change in incremental AUC_0-6h of TG from baseline to week12 were analyzed using an analysis of covariance (ANCOVA) model with the baseline, sex, timing of trial drug administration (before or after meal), presence or absence of concomitant statin use, and study site as covariates. The analysis model included treatment and the covariates as fixed effects and had a compound symmetry covariance structure.

All statistical analyses were performed using SAS version 9.4 (SAS Institute, NC, USA) with a significance level of 5%.

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