Long-Term Effects of Extended-Release Pemafibrate Tablets on Dyslipidemia and Safety in Triglyceridemic Patients: A Phase 3, Multicenter, Randomized, Open-Label, Parallel-Group Study

Abstract

Aims: Long-term safety and efficacy of pemafibrate once-daily extended-release (XR) tablets, taken in morning or evening, were evaluated in dyslipidemic patients with high triglycerides (TG).

Methods: In this multicenter, randomized, open-label, parallel-group, phase 3 long-term study, dyslipidemic patients with high TG were randomly assigned to morning or evening administration of XR for 52 weeks. The dose was started at 0.2 mg/day and increased to 0.4 mg/day for patients having fasting serum TG ≥ 150mg/dL during treatment. The primary efficacy endpoint was percent change in fasting serum TG.

Results: The study enrolled 121 patients, assigning 61 to morning and 60 to evening administration. The study population included 71.1% males. Mean age was 58.5±11.1 (mean±SD) years, body mass index 27.7±4.3 kg/m², and fasting TG 264.0±109.2 mg/dL. Fasting serum TG decreased significantly from baseline to 52 weeks among patients overall and in the morning and evening groups (−45.7%, −44.8%, and −46.6%, respectively, p＜0.001 vs. baseline). The difference in least-squares mean between the morning and evening groups was 3.0%, not statistically significant. The dose was increased in 82 patients (44 morning and 38 evening), with 57.3% (95%CI 45.9, 68.2) achieving fasting serum TG ＜150 mg/dL. Adverse events occurred in 83.5% and adverse drug reactions in 19.0% but with no notable safety problems.

Conclusions: Long-term, once-daily administration of XR was effective and safe in dyslipidemic patients with high TG. XR provided favorable TG-lowering effects regardless of morning or evening administration, and the XR dose increase proved effective in patients having initially inadequate response.

Introduction

Previous large-scale clinical studies of dyslipidemia have shown that cardiovascular event suppression remains insufficient even under adequate LDL-C management with strong statin therapy. These findings raise the issue of residual risk. Better treatment options are needed, not only for non-lipid-related residual risks such as poor control of blood glucose or blood pressure and of renal dysfunction, but also for lipid-related residual risks associated with TRLs (TG-rich lipoproteins), Lp(a), and HDL-C^{1, 2)}. TRLs, which appear to strongly induce atherosclerosis, have been a particular area of focus in recent years, and findings suggest that intervention for hypertriglyceridemia may soon become an important part of residual risk management³⁾. These findings are substantiated by results from multiple clinical studies that have shown elevated fasting serum triglycerides (TG) to be an independent risk factor for cardiovascular disease^4-7). Pemafibrate is a selective PPARα modulator (SPPARMα)^8-10) that improves lipid metabolism, including lowering serum TG, primarily by regulating the expression of a group of PPARα-targeted genes associated with lipid metabolism in the liver. Pemafibrate was developed in Japan and approved there in July 2017 for the treatment of hyperlipidemia, and has been marketed in Japan since June 2018. It is currently also approved and used in clinical practice in other Asian countries (Thailand, Singapore and Malaysia).

The initial pemafibrate formulation was an immediate-release (IR) tablet for administration twice daily. However, medication adherence is known to decrease with increased number of daily doses¹¹⁾, and statins and ezetimibe, which are often used in combination with pemafibrate, are taken once daily. In this context, to improve convenience and adherence, an extended-release (XR) tablet has been developed for once-daily use. This multiple-unit formulation of pemafibrate consists of a tablet containing sustained-release granules. The tablet disintegrates rapidly after administration, and the granules then release the drug over time. An earlier 12-week phase 3 study of dyslipidemic Japanese patients with high TG showed that XR at either 0.2 mg/day or 0.4 mg/day was non-inferior to IR 0.2 mg/day in percent reduction of fasting serum TG. In addition, XR 0.4 mg/day provided higher efficacy in TG management than XR 0.2 mg/day. The safety profile for both XR doses was similar to IR¹²⁾.

Aim

A phase 3, randomized, open-label trial was designed to evaluate the long-term efficacy and safety profiles of pemafibrate XR once daily in the morning or evening in dyslipidemic patients with high TG. We also examined the safety and efficacy of increasing the XR dose to 0.4 mg/day for patients who did not reach their fasting serum TG goal of ＜150mg/dL during this study at the initial XR dose of 0.2 mg/day.

Methods

Study Design

This multicenter, randomized, open-label, parallel-group comparison, phase 3 long-term dosing study was conducted in hospitals and clinics across Japan. The study consisted of a screening period and a treatment period. After obtaining written consent to participate in the clinical trial, patients were screened twice for eligibility, with a maximum of 56 days from first screening to Week 0 of treatment, a minimum of 72 hours between screenings, and a minimum of seven days from last screening to Week 0. Eligible patients were randomly assigned to morning or evening administration at 1:1 and received XR for 52 weeks.

This clinical trial was conducted in compliance with ethical principles declared in the spirit of the Declaration of Helsinki and the Ministerial Ordinance No. 28 “Ministerial Ordinance on Good Clinical Practice for Drugs” (the GCP Ministerial Ordinance) dated March 27, 1997 of the Ministry of Health and Welfare. Ethical approval was obtained from the Institutional Review Board at each trial center.

Participants

Eligible participants were dyslipidemic patients aged 20 years or older at the time of consent, who were under consistent dietary or exercise guidance for at least 12 weeks prior to the screening test and had fasting serum TG ≥ 150 mg/dL on two consecutive screening tests.

The major exclusion criteria were fasting serum TG ＞1000 mg/dL at screening, necessity for use of prohibited concomitant medications after giving consent and during the study period, poorly controlled thyroid disease, type 1 diabetes mellitus or poorly controlled type 2 diabetes with hemoglobin A1c (HbA1c) ≥ 10.0% at screening, poorly controlled hypertension with systolic blood pressure (SBP) ≥ 160 mmHg or diastolic blood pressure (DBP) ≥ 100 mmHg, or previous treatment with pemafibrate. Inclusion and exclusion criteria related to renal function (eGFR and/or creatinine) were not established. Details of exclusion criteria are provided in Supplementary Table 1, and prohibited concomitant medications are listed in Supplementary Table 2.

Supplementary Table 1.Exclusion criteria

1) Fasting serum TG ＞1000 mg/dL at screening

2) Necessity for use of prohibited concomitant medications after giving consent and during study period

3) Poorly controlled thyroid disease

4) Type 1 diabetes mellitus or poorly controlled type 2 diabetes, with HbA1c (NGSP) ≥ 10.0% at screening

5) Poorly controlled hypertension, with SBP ≥ 160 mmHg or DBP ≥ 100 mmHg

6) AST or ALT exceeding 3 times the upper reference limit at screening

7) Creatine kinase exceeding 5 times the upper reference limit at screening

8) Liver cirrhosis or biliary obstruction

9) Acute myocardial infarction within 3 months prior to providing consent

10) Complication of heart failure NYHA Class 3 or higher

11) Complication of malignant tumor or high likelihood of malignant tumor recurrence

12) History of serious drug allergy (e.g., anaphylactic shock)

13) Women who are pregnant or lactating, are considering pregnancy or lactation during the course of the study, and/or are of childbearing potentialand unwilling or unable to use designated contraceptive measures

14) Provision of 400 mL or more of whole blood within 16 weeks or 200 mL or more within 4 weeks prior to the screening test, or of component blood samples (plasma and platelet components) within 2 weeks prior to the screening test

15) Previous treatment with pemafibrate

16) Participation in another clinical trial with administration of medication at the time of giving consent for this study, or administration of any study drug other than a placebo within 16 weeks prior to giving consent

17) Otherwise judged by the investigator or other responsible staff as inappropriate for participation in this study

ALT, alanine aminotransferase; AST, aspartate aminotransferase; DBP, diastolic blood pressure; HbA1c, hemoglobin A1c; NGSP, national glycohemoglobin standardization program; NYHA, New York Heart Association; SBP, systolic blood pressure; TG, triglycerides.

Supplementary Table 2.Prohibited concomitant medications

From 4 weeks before the screening test to the end of tahe clinical trial

1) Fibrates

From 4 weeks before the start of study drug administration until the end of the study (patients taking amiodarone should not be included in this study)

2) Drugs that moderately or strongly inhibit or induce CYP2C8, 2C9, or 3A4§

3) Drugs that inhibit P-gp§

4) Drugs that inhibit BCRP§

5) Drugs that inhibit OCT2§

6) Drugs that inhibit OATP1B1 or OATP1B3§

^§ Based on the following guidelines:

- PSEHB/ELD. Drug-Drug Interaction Guideline for Pharmaceutical Development and Appropriate Information Provision. Notification No. 0723-6 July 23, 2018.

- Food and Drug Administration. Guidance for Industry: Clinical Drug Interaction Studies − Cytochrome P450 Enzyme- and Transporter- Mediated Drug Interactions. January 2020.

- European Medicines Agency. Guideline on the Investigation of Drug Interactions. June 2012.

BCRP, breast cancer resistance protein; CYP, cytochrome; OATP, organic anion-transporting polypeptide; OCT, organic cation-transporter; P-gp, P-glycoprotein.

Randomization and Study Drug Administration

Patients were randomly assigned 1:1 to the morning or evening group by the dynamic allocation method, with adjustment factors including study site, sex, timing of study drug administration (before or after meals), and concomitant statin use, using a computer-generated list of random numbers. The investigator inputted the necessary information for this registration into the web registration system. The patient registration center used that information to determine the eligibility of each patient, assigned eligible patients to the morning or evening group, and notified the site and the study sponsor of those results and of the group to which each eligible patient was assigned. The investigator, subinvestigator, or clinical trial collaborator received and recorded information from the patient registration center on each patient’s group assignment and administered the dispensing of the study drug.

XR 0.2 mg was taken orally once daily in the morning or evening. Patients in the morning group started taking the study drug as soon as possible after completing examination for Week 0 of the treatment period. The investigators instructed the patients to take XR consistently, either before or after the relevant meal, throughout the study period. If fasting serum TG was ≥ 150 mg/dL at any time from Week 8 to Week 40, the dose was increased to 0.4 mg/day, in the form of two tablets of 0.2 mg, after examination at the next visit (Week 12 to Week 44).

Sample Collection and Assessment

Blood and urine samples were taken after patients had fasted for at least 10 hours. Samples were collected at screening and at four-week intervals from 0 to 52 weeks after the start of treatment. All laboratory tests were performed at a central laboratory, primarily by LSI Medience Corporation (Tokyo, Japan), except for ApoB48 assays conducted by SRL Corporation (Tokyo, Japan), in accordance with the prescribed procedures at each laboratory.

Endpoints

The primary efficacy endpoint was the mean percent change in fasting serum TG, using the percent change from baseline to the last evaluation (Week 52 or at discontinuation) and from baseline to the immediately preceding time point. The four secondary efficacy endpoints were 1) the mean percent change of each lipid-related marker, excluding TG, using the percent change from baseline to the last evaluation and from baseline to the immediately preceding time point, 2) the change and percent change from baseline to each time point for fasting serum TG and secondary assessment markers (lipid-related markers other than TG, aspartate aminotransferase [AST], alanine aminotransferase [ALT], gamma-glutamyl transferase [γ-GT], alkaline phosphatase [ALP], and total bilirubin), 3) the percentage of patients who achieved fasting serum TG ＜150 mg/dL for the mean of the TG values at the last evaluation and at the immediately preceding time point, and 4) the difference in mean percent change in fasting serum TG before and after dose increase, with each mean percent change using the percent change from baseline to the last evaluation and from baseline to the immediately preceding time point. We performed subgroup analysis of TG-lowering effects in specific subsets of patient characteristics. TG changes were also evaluated in those patients who were up-titrated to the higher dose.

The primary safety endpoint was occurrence of adverse events (AEs) and adverse drug reactions (ADRs). Secondary safety endpoints were physiological and laboratory values and change from baseline. AE severity and causal relationship to XR administration are defined in Supplementary Table 3.

Supplementary Table 3.Definition of AE severity, extent, and causal relationship to XR administration

Criteria for seriousness

1) Serious: A serious AE is defined as any untoward medical occurrence, irrespective of its dose-relatedness, that occurs after theadministration of a pharmaceutical agent and meets one or more of the following criteria:

a) Results in death

b) Is life-threatening or places the patient at immediate risk of death from the event

c) Requires or prolongs hospitalization

d) Causes persistent or significant disability or incapacity

e) Results in congenital anomalies or birth defects

f ) Results in serious morbidity because of any of the conditions in categories a) through e)

2) Non-serious: Any AE that does not meet the above criteria

Criteria for evaluating extent of severity

1) Mild: Does not interfere with activities of daily life§

2) Moderate: Interferes with activities of daily life§

3) Severe: Not possible to perform activities of daily life§

Criteria for evaluating causal relationship to the study drug

1) Unrelated: The event can be conclusively attributed to an etiology other than the investigational drug, such as the participant’s medicalcondition or specific study procedures

2) Probably unrelated: The event lacks a reasonable temporal association sufficient to implicate the investigational drug as a causative factor

3) Possibly related†: The AE exhibits a reasonable temporal relationship with the administration of the investigational drug. However, alternative causative factors, including the participant’s medical condition or specific study procedures, remain possible

4) Probably related†: The AE manifests a reasonable temporal association with the administration of the investigational drug or is consistent with known or predictable pharmacological effects of the drug or drugs in its class. Other potential causes, such as the participant’s condition or study procedures, are less likely

5) Definitively related†: The AE not only displays a reasonable temporal linkage with the administration of the investigational drug but is also consistent with known or predictable pharmacological effects of the drug or analogous drugs. Alternative explanations, such as the participant’scondition or study methodology, are implausible

^§Activities such as eating, sleeping, bathing, going out of the house, working, and exercising. ^†For the purposes of this clinical trial, AEs in the categories of 3) to 5) will be treated as adverse drug reactions.

AE, adverse event; XR, extended-release.

For fasting serum TG, the baseline value was the mean of test results from the first and second screenings (to determine eligibility for participation) and Week 0 of the treatment period. Other assessments used the mean of values at eligibility screening and Week 0 if available. If the only available value was from Week 0, that was used as the baseline value.

Statistical Analysis

Based on the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E1 guideline “The Extent of Population Exposure to Assess Clinical Safety: For Drugs Intended for Long-Term Treatment of Non-Life-Threatening Conditions,” we assumed a drop-out rate of 10% and selected a total sample size of 110 patients (55 patients in each group) to ensure that at least 100 patients would receive XR for one year. The primary analysis set for efficacy was the full analysis set (FAS), which was the set of patients who were randomly assigned, took XR at least once, and had assessable baseline and post-baseline data for assessing efficacy. The safety analysis set consisted of all randomly assigned patients who had taken XR at least once.

For the primary efficacy endpoint, the mean percent change in fasting serum TG was calculated for the overall population and for the morning and evening groups, using the percent change from baseline to the last evaluation and the percent change from baseline to the immediately preceding time point. Summary statistics were calculated, and a one-sample t-test was performed. The morning and evening groups were compared by analysis of covariance, with baseline values, sex, timing of XR administration (before or after meals), presence or absence of concomitant statin use, and study site as covariates.

For the secondary endpoints, similar parameters were analyzed in the same manner as for the primary endpoints. In addition, a mixed model for repeated measures (MMRM) was used to analyze the percent change from pre-treatment baseline to Week 12, 24, or 52. The morning and evening groups were compared at each time point, and at 12, 24, and 52 weeks with the last observation carried forward (LOCF), by analysis of covariance using baseline values, sex, timing of XR administration (before or after meals), concomitant statin use, and study site as covariates. The percentage of patients who reached mean fasting serum TG ＜150 mg/dL was calculated, along with the 95% confidence interval (CI). For patients who were administered the consecutive increase in the dose, descriptive statistics were calculated for the difference in mean percent change in fasting serum TG before and after dose increase, with each mean percent change using the percent change from baseline to the last evaluation and from baseline to the time point immediately preceding the last evaluation. A one-sample t-test was then performed on these descriptive statistics results, and the percentage of patients who reached mean fasting serum TG ＜150 mg/dL (95% CI) was calculated.

Subgroup analysis was applied to the TG-lowering effect for each of the following subpopulations, in the same way as for the primary endpoint, and for TG changes in patients who were up-titrated, in the same way as for the overall population. Patients were subgrouped by age (＜65 years, ≥ 65 years), sex (male, female), BMI (＜25 kg/m², ≥ 25 kg/m²), type 2 diabetes (yes, no), metabolic syndrome (yes, no), concurrent use of statin (yes, no), fasting serum baseline TG (＜500 mg/dL, ≥ 500 mg/dL), baseline HDL-C (direct method) (＜40 mg/dL, ≥ 40 mg/dL), baseline AST and ALT (both values within the reference range, at least one value exceeds the upper reference limit), baseline estimated glomerular filtration rate (eGFR) (＜60 mL/min/1.73m², ≥ 60 mL/min/1.73m² and ＜90 mL/min/1.73m², ≥ 90 mL/min/1.73m²), and timing of administration (before, after a meal).

For the safety evaluation, information was collected on AEs, and the recorded names of those AEs were converted as appropriate to specific terms from the Japanese version of the ICH Medical Dictionary for Regulatory Activities (MedDRA/J). For primary endpoint analysis, the number of treatment-emergent AEs and ADRs in the overall population were calculated as number of patients, number of occurrences, and incident proportion. Secondary analysis involved summarizing safety data by System Organ Class (SOC) and Preferred Term (PT), and also by the severity of AEs, the association of AEs with XR, deaths or other serious AEs, and other important AEs that required discontinuation of study treatment. Summaries were also prepared as needed for AEs that occurred relatively frequently (in 2% or more of patients in either group) and for timing of AE onset. AEs were grouped for analysis in a variety of ways, including by Standardized MedDRA Query (SMQ). The Wilcoxon signed-rank test was used to evaluate values in physiological and laboratory parameters and change from baseline to each time point in the overall population and in the morning and evening groups. Results were compared for the morning and evening groups at each time point.

The significance level was set at 5% (two-sided) with 95% CI (two-sided). SAS ver. 9.4 or higher was used for analysis.

Results

Patient Characteristics

The study was conducted from February 2021 to June 2022 at 16 sites across Japan. A total of 163 patients gave written consent, and 121 patients who were eligible after screening were randomly assigned to administration in the morning group (61 patients) or evening group (60 patients). All 121 patients received XR and were included in the FAS and safety analysis set. Seven patients (two in the morning group and five in the evening group) discontinued the study due to AEs, and 114 patients completed the study (59 in the morning group and 55 in the evening group) (Fig.1).

Fig.1. Disposition of patients

^§Colon cancer (n = 1); arrhythmia (n = 1).

^†Myocardial infarction (n = 1); myalgia (n = 1); aortic valve stenosis, asthenia, myalgia, feeling abnormal (n = 1); eczema (n = 1); blood creatine phosphokinase increased (n = 1).

TG, triglycerides.

The age of patients was 58.5±11.1 years (mean±standard deviation [SD]), body weight was 76.8±15.6 kg, and body mass index (BMI) was 27.7±4.3 kg/m². Patients were 71.1% male (86/121), 90.1% (109/121) took XR after meals, and 47.1% (57/121) were also taking statins (Table 1). Mean baseline fasting serum TG was 264.0±109.2 mg/dL (median [interquartile range]: 235.3 [191.3 to 292.7]), low-density lipoprotein cholesterol (LDL-C) was 125.2±36.3 mg/dL, high-density lipoprotein cholesterol (HDL-C) was 48.5±10.0 mg/dL, and non-HDL-C was 171.4±37.3 mg/dL (Table 2). Dose was increased in 82 patients (44 in the morning group and 38 in the evening group).

Table 1.Patient characteristics

	Total (N = 121)	Morning group (N = 61)	Evening group (N = 60)
Age, years	58.5±11.1	57.9±11.5	59.1±10.8
≥ 65	39 (32.2)	18 (29.5)	21 (35.0)
Male	86 (71.1)	43 (70.5)	43 (71.7)
Weight, kg	76.8±15.6	79.1±18.1	74.5±12.4
BMI, kg/m2	27.7±4.3	28.4±5.2	26.9±3.1
≥ 25	87 (71.9)	42 (68.9)	45 (75.0)
Smoking status
Never	44 (36.4)	22 (36.1)	22 (36.7)
Former	40 (33.1)	22 (36.1)	18 (30.0)
Current	37 (30.6)	17 (27.9)	20 (33.3)
Alcohol intake	64 (52.9)	31 (50.8)	33 (55.0)
Concomitant disease
Hypertension	77 (63.6)	40 (65.6)	37 (61.7)
Type 2 diabetes mellitus	59 (48.8)	29 (47.5)	30 (50.0)
Metabolic syndrome	79 (65.3)	40 (65.6)	39 (65.0)
Primary dyslipidemia	1 (0.8)	0 (0.0)	1 (1.7)
Concomitant statin use	57 (47.1)	29 (47.5)	28 (46.7)
Timing of administration of XR
Preprandial	12 (9.9)	7 (11.5)	5 (8.3)
Postprandial	109 (90.1)	54 (88.5)	55 (91.7)

Data are presented as mean±standard deviation for continuous parameters and n (%) for categorical parameters. BMI, body mass index; XR, extended-release.

Table 2.Mean percent change^§ in lipid-related markers (TG, TC, LDL-C, HDL-C, non-HDL-C, LDL-C/HDL-C, and non- HDL-C/HDL-C)

		Total (N = 121)		Morning group (N = 61)		Evening group (N = 60)
		Mean±SD	Median (IQR)	Mean±SD	Median (IQR)	Mean±SD	Median (IQR)
TG	Baseline, mg/dL	264.0±109.2	235.3 (191.3 to 292.7)	273.5±107.0	245.0 (197.3 to 298.3)	254.5±111.5	221.5 (188.0 to 269.7)
	Week 52, mg/dL	136.3±58.9	119.0 (100.0 to 160.5)	145.7±68.5	120.5 (100.0 to 166.0)	126.7±45.8	114.0 (100.0 to 145.3)
	% Change	−45.7±18.6＊＊＊		−44.8±19.1＊＊＊		−46.6±18.3＊＊＊
TC	Baseline, mg/dL	219.8±37.9	217.0 (194.0 to 242.0)	214.3±28.5	215.0 (191.5 to 236.0)	225.4±45.1	219.5 (195.5 to 256.0)
	Week 52, mg/dL	207.9±33.9	207.0 (184.0 to 225.5)	208.5±28.7	207.0 (193.5 to 222.0)	207.3±38.7	207.0 (179.8 to 226.5)
	% Change	−4.3±13.5＊＊		−1.9±12.9		−6.7±13.7＊＊＊
LDL-C	Baseline, mg/dL	125.2±36.3	125.0 (98.5 to 142.5)	120.4±30.7	123.5 (98.5 to 141.0)	130.1±40.9	125.5 (105.5 to 149.8)
	Week 52, mg/dL	122.1±30.8	122.0 (101.0 to 135.5)	122.3±26.1	123.5 (111.0 to 136.0)	121.8±35.2	120.5 (98.0 to 135.5)
	% Change	2.4±29.9		6.5±30.2		−1.7±29.3
HDL-C	Baseline, mg/dL	48.5±10.0	47.5 (41.0 to 55.0)	47.3±8.9	46.5 (40.0 to 54.5)	49.7±10.9	48.8 (42.0 to 57.3)
	Week 52, mg/dL	53.4±11.9	52.0 (45.5 to 61.0)	52.7±12.7	52.0 (43.0 to 59.5)	54.1±11.0	52.3 (46.8 to 61.8)
	% Change	10.8±15.8＊＊＊		11.5±16.9＊＊＊		10.2±14.6＊＊＊
non-HDL-C	Baseline, mg/dL	171.4±37.3	168.0 (152.0 to189.0)	167.0±27.6	165.0 (154.5 to 185.0)	175.8±44.8	172.0 (147.3 to 204.8)
	Week 52, mg/dL	154.6±34.2	154.0 (131.5 to 171.0)	155.9±29.9	154.0 (138.5 to 171.0)	153.2±38.4	154.5 (123.8 to 166.3)
	% Change	−8.2±17.2＊＊＊		−5.5±16.7＊		−10.9±17.3＊＊＊
LDL-C/HDL-C	Baseline	2.7±0.9	2.6 (2.2 to 3.3)	2.6±0.8	2.5 (2.2 to 3.2)	2.7±0.9	2.7 (2.1 to 3.3)
	Week 52	2.4±0.9	2.3 (1.8 to 2.8)	2.5±0.9	2.3 (1.9 to 2.8)	2.4±0.9	2.3 (1.7 to 2.7)
	% Change	−6.3±27.9＊		−2.7±28.7		−9.9±26.9＊＊
non-HDL-C/HDL-C	Baseline	3.7±1.1	3.6 (3.0 to 4.4)	3.7±1.0	3.6 (3.0 to 4.3)	3.7±1.3	3.6 (2.8 to 4.6)
	Week 52	3.1±1.1	2.9 (2.3 to 3.4)	3.2±1.2	2.9 (2.5 to 3.4)	3.0±1.0	2.9 (2.2 to 3.4)
	% Change	−15.3±20.7＊＊＊		−12.9±21.3＊＊＊		−17.7±20.0＊＊＊

Measured value of Week 52 are mean using the last evaluation and immediately preceding time point. ^§Mean percent change using the percent change from baseline to the last evaluation and from baseline to the immediately preceding time point. ^＊ p＜0.05, ^＊＊ p＜0.01, ^＊＊＊ p＜0.001 vs. baseline by one-sample t-test.

HDL-C, high-density lipoprotein cholesterol; IQR, interquartile range; LDL-C, low-density lipoprotein cholesterol; SD, standard deviation; TC, total cholesterol; TG, triglycerides.

The proportion of cumulative adherence up to 52 weeks of treatment was more than 80% among the 117 patients. The duration of study drug administration was 354.7±51.7 days in the overall population, 362.9±13.5 days for the morning group, and 346.4±71.5 days for the evening group.

Efficacy

The primary endpoint, the mean change in fasting serum TG from baseline to the last evaluation and from baseline to the immediately preceding time point, showed statistically significant decreases in all three groups: −45.7% (95% CI −49.1, −42.4) in the overall population, −44.8% (−49.7, −39.9) in the morning group, and −46.6% (−51.3, −41.9) in the evening group (p＜0.001 for each) (Fig.2A). Analysis of covariance showed a difference of 3.0% (−4.5, 10.5) in the least-squares mean between the morning and evening groups, which was not statistically significant (p = 0.426) (Supplementary Table 4). Trends from baseline are shown in Fig.2B.

Fig.2. Change in fasting serum TG levels

(A) Mean percent change in fasting serum TG at 52 weeks (overall population, morning group, evening group)

Basic statistics. Data are presented as mean ±95%CI for basic statistics. ^＊＊＊p＜0.001 vs. baseline.

(B) Changes in actual measured values for fasting serum TG (overall population, morning group, evening group)

Data are presented as mean±standard deviation. ^＊＊＊p＜0.001 vs. baseline by one-sample t-test for each group.

CI, confidence interval; LS, least squares; TG, triglycerides.

Supplementary Table 4.Comparison of percent change from baseline to final evaluation in lipid-related parameters between morning and evening groups

Group		n	Baseline Mean±SD	LS means Estimate (95%CI)	Differences (vs. evening group)
					Estimate (95%CI)	P value
TG, mg/dL	Morning	61	273.5±107.0	−44.6 (−49.7, −39.4)	3.0 (−4.5, 10.5)	0.426
	Evening	60	254.5±111.5	−47.6 (−52.8, −42.4)
TC, mg/dL	Morning	61	214.3±28.5	−3.7 (−6.9, −0.4)	1.8 (−3.0, 6.5)	0.460
	Evening	60	225.4±45.1	−5.4 (−8.7, −2.2)
LDL-C, mg/dL	Morning	61	120.4±30.7	2.3 (−3.9, 8.6)	1.9 (−7.2, 11.0)	0.678
	Evening	60	130.1±40.9	0.4 (−5.9, 6.7)
HDL-C, mg/dL	Morning	61	47.3±8.9	9.8 (5.9, 13.7)	−2.3 (−8.0, 3.4)	0.425
	Evening	60	49.7±10.9	12.1 (8.2, 16.1)
non-HDL-C, mg/dL	Morning	61	167.0±27.6	−7.1 (−11.4, −2.7)	3.1 (−3.3, 9.4)	0.340
	Evening	60	175.8±44.8	−10.1 (−14.5, −5.7)
LDL-C/HDL-C	Morning	61	2.6±0.8	−3.8 (−10.9, 3.3)	6.8 (−3.6, 17.1)	0.197
	Evening	60	2.7±0.9	−10.5 (−17.7, −3.4)
non-HDL-C/HDL-C	Morning	61	3.7±1.0	−12.9 (−18.3, −7.4)	5.8 (−2.1, 13.7)	0.148
	Evening	60	3.7±1.3	−18.7 (−24.1, −13.2)
RemL-C, mg/dL	Morning	61	14.6±10.9	−50.8 (−57.0, −44.7)	2.2 (−6.9, 11.2)	0.634
	Evening	58	15.0±15.5	−53.0 (−59.4, −46.7)
FFA, mEq/L	Morning	61	0.6±0.2	11.4 (1.8, 21.0)	23.5 (9.3, 37.8)	0.001
	Evening	58	0.5±0.2	−12.2 (−22.0, −2.3)
Apo AI, mg/dL	Morning	61	141.1±19.7	1.7 (−0.8, 4.1)	0.6 (−3.0, 4.1)	0.755
	Evening	58	142.9±17.2	1.1 (−1.4, 3.6)
Apo AII, mg/dL	Morning	61	33.4±4.0	29.0 (23.9, 34.1)	1.4 (−6.1, 8.8)	0.719
	Evening	58	34.3±5.9	27.6 (22.4, 32.9)
Apo B, mg/dL	Morning	61	102.4±15.2	−6.1 (−9.8, −2.3)	3.3 (−2.2, 8.8)	0.242
	Evening	58	103.3±20.7	−9.3 (−13.2, −5.5)
Apo B48, mg/L	Morning	61	8.6±5.7	−47.6 (−57.6, −37.6)	−3.4 (−18.1, 11.3)	0.644
	Evening	58	9.4±9.4	−44.2 (−54.4, −33.9)
Apo CII, mg/dL	Morning	61	9.1±2.9	−18.3 (−23.8, −12.8)	1.8 (−6.3, 9.9)	0.657
	Evening	58	8.7±3.6	−20.1 (−25.7, −14.5)
Apo CIII, mg/dL	Morning	61	18.7±7.5	−34.1 (−37.7, −30.4)	0.1 (−5.3, 5.5)	0.959
	Evening	58	18.3±7.4	−34.2 (−38.0, −30.4)
Apo B/Apo AI	Morning	61	0.7±0.2	−7.1 (−10.9, −3.3)	2.4 (−3.2, 8.0)	0.395
	Evening	58	0.7±0.2	−9.5 (−13.4, −5.6)
Apo CIII/Apo CII	Morning	61	2.1±0.6	−17.8 (−21.1, −14.5)	−0.8 (−5.6, 4.0)	0.752
	Evening	58	2.2±0.6	−17.0 (−20.4, −13.7)

Data for final evaluation (Week 52) were imputed using LOCF.

Apo, apolipoproteins; CI, confidence interval; FFA, free fatty acids; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LOCF, last observation carried forward; LS, least square; RemL-C, remnant-like particle cholesterol; SD, standard deviation; TC, total cholesterol; TG, triglycerides.

The percentage of patients reaching fasting serum TG ＜150 mg/dL (n/N) was 70.2% (85/121) in the overall population, 62.3% (38/61) in the morning group, and 78.3% (47/60) in the evening group. Among the 82 patients whose XR dose was increased from 0.2 mg to 0.4 mg during the study period, that percentage was 57.3% (47/82): 47.7% (21/44) among the 44 patients in the morning group and 68.4% (26/38) among the 38 patients in the evening group (Table 3A). The difference in mean percent change for fasting serum TG before and after the dose increase was −11.4% (−15.7, −7.1) in the overall population, −10.4% (−15.5, −5.4) for the morning group, and −12.5% (−20.0, −5.1) for the evening group, a statistically significant decrease in all three groups (p＜0.001 for the overall and morning groups, p = 0.002 for the evening group) (Table 3B).

Table 3.Percentage of patients reaching TG target and difference in mean percent TG change before and after dose increase

(A) Percentage of patients reaching fasting serum TG ＜150 mg/dL: overall population and patients who were up-titrated
	Total			Morning group			Evening group
	N	n	% (95%CI)	N	n	% (95%CI)	N	n	% (95%CI)
Overall population	121	85	70.2 (61.3, 78.2)	61	38	62.3 (49.0, 74.4)	60	47	78.3 (65.8, 87.9)
Patients who were up-titrated	82	47	57.3 (45.9, 68.2)	44	21	47.7 (32.5, 63.3)	38	26	68.4 (51.3, 82.5)
(B) Difference in mean percent change for fasting serum TG before and after up-titration: patients who were up-titrated
	Total (n = 82)			Morning group (n = 44)			Evening group (n = 38)
% Change before up-titration§	−31.6±21.2			−31.3±16.3			−31.9±25.9
% Change after up-titration§	−42.9±20.1			−41.7±18.9			−44.4±21.7
Difference	−11.4±19.6＊＊＊			−10.4±16.6＊＊＊			−12.5±22.7＊＊

Data are presented as mean±standard deviation. ^§Mean percent change using the percent change from baseline to the last evaluation and from baseline to the immediately preceding time point. ^＊＊ p＜0.01, ^＊＊＊ p＜0.001 vs. baseline by one-sample t-test.

CI, confidence interval; TG, triglycerides.

Table 2 shows the mean percent change in the lipid-related markers of TG, total cholesterol (TC), LDL-C, HDL-C, non-HDL-C, LDL-C/HDL-C, and non-HDL-C/HDL-C from baseline to the last evaluation and the immediately preceding time point. In the overall population, TC, LDL-C, HDL-C, and non-HDL-C values were –4.3±13.5%, 2.4±29.9%, 10.8±15.8%, and −8.2±17.2%, respectively, with statistically significant changes in TC (p＜0.01) and in HDL-C and non-HDL-C (p＜0.001 for both). The percent changes from baseline to final evaluation of the other lipid-related markers are shown in Supplementary Table 5, and the percent changes in the lipid-related markers are compared by group in Supplementary Table 4.

Supplementary Table 5.Percent change from baseline to final evaluation of lipid-related markers (RemL-C, FFA, and apolipoproteins)

		Total			Morning group			Evening group
		n	Mean±SD	Median (IQR)	n	Mean±SD	Median (IQR)	n	Mean±SD	Median (IQR)
RemL-C	Baseline, mg/dL	121	14.8±13.2	10.7 (8.0 to 16.1)	61	14.6±10.9	11.0 (8.4 to 17.2)	60	15.0±15.3	9.9 (7.9 to 16.0)
	Week 52, mg/dL	119	5.6±3.2	4.7 (3.4 to 6.4)	61	6.0±3.5	5.1 (3.7 to 6.3)	58	5.2±2.7	4.6 (3.4 to 6.4)
	% Change		−51.9±25.8＊＊＊			−50.4±28.0＊＊＊			−53.5±23.4＊＊＊
FFA	Baseline, mEq/L	121	0.6±0.2	0.6 (0.4 to 0.7)	61	0.6±0.2	0.6 (0.5 to 0.8)	60	0.5±0.2	0.5 (0.4 to 0.7)
	Week 52, mEq/L	119	0.5±0.2	0.5 (0.4 to 0.7)	61	0.6±0.2	0.6 (0.4 to 0.7)	58	0.4±0.2	0.4 (0.3 to 0.5)
	% Change		−0.1±43.3			6.2±45.2			−6.8±40.5
Apo AI	Baseline, mg/dL	121	141.6±18.6	141.0 (127.0 to 151.0)	61	141.1±19.7	141.0 (127.0 to 151.0)	60	142.1±17.6	140.5 (130.0 to 151.5)
	Week 52, mg/dL	119	143.3±19.3	140.0 (129.0 to 156.0)	61	143.3±20.1	142.0 (129.0 to 156.0)	58	143.3±18.5	140.0 (133.0 to 153.0)
	% Change		1.4±10.1			2.0±9.6			0.7±10.5
Apo AII	Baseline, mg/dL	121	33.8±5.0	33.5 (30.2 to 36.0)	61	33.4±4.0	33.5 (31.3 to 35.5)	60	34.1±5.9	33.6 (29.9 to 36.7)
	Week 52, mg/dL	119	43.3±8.9	41.9 (36.0 to 50.3)	61	43.1±9.1	42.6 (35.3 to 49.4)	58	43.5±8.8	41.3 (36.8 to 50.3)
	% Change		28.3±21.3＊＊＊			29.2±23.4＊＊＊			27.4±19.0＊＊＊
Apo B	Baseline, mg/dL	121	103.0±17.9	102.0 (89.0 to 115.0)	61	102.4±15.2	101.0 (89.0 to 113.0)	60	103.7±20.5	103.0 (91.0 to 115.0)
	Week 52, mg/dL	119	94.0±18.2	94.0 (82.0 to 104.0)	61	95.3±16.6	96.0 (83.0 to 103.0)	58	92.7±19.8	91.0 (80.0 to 104.0)
	% Change		−7.7±15.1＊＊＊			−6.0±16.1＊＊			−9.4±13.9＊＊＊
Apo B48	Baseline, mg/L	121	8.9±7.7	7.0 (4.9 to 10.0)	61	8.6±5.7	7.2 (5.6 to 10.3)	60	9.3±9.3	6.9 (4.3 to 10.0)
	Week 52, mg/L	119	3.9±3.0	3.0 (2.0 to 4.9)	61	4.0±3.3	2.9 (2.0 to 5.1)	58	3.7±2.7	3.1 (2.2 to 4.7)
	% Change		−45.9±39.7＊＊＊			−46.5±43.1＊＊＊			−45.3±36.2＊＊＊
Apo CII	Baseline, mg/dL	121	8.8±3.2	8.5 (6.9 to 10.0)	61	9.1±2.9	8.8 (7.3 to 10.3)	60	8.6±3.6	8.2 (6.4 to 9.6)
	Week 52, mg/dL	119	6.9±2.3	6.6 (5.1 to 8.5)	61	7.1±2.1	7.2 (5.3 to 8.5)	58	6.7±2.5	6.5 (4.9 to 7.9)
	% Change		−19.2±22.3＊＊＊			−19.0±21.4＊＊＊			−19.3±23.4＊＊＊
Apo CIII	Baseline, mg/dL	121	18.4±7.4	16.4 (13.5 to 20.9)	61	18.7±7.5	16.5 (14.2 to 20.6)	60	18.1±7.3	16.2 (13.0 to 21.1)
	Week 52, mg/dL	119	11.5±3.6	10.8 (9.3 to 13.3)	61	11.6±3.9	10.8 (9.5 to 13.0)	58	11.3±3.3	10.8 (9.2 to 13.4)
	% Change		−34.1±17.4＊＊＊			−34.1±16.3＊＊＊			−34.2±18.5＊＊＊
Apo B/Apo AI	Baseline	121	0.7±0.2	0.7 (0.6 to 0.9)	61	0.7±0.2	0.7 (0.6 to 0.8)	60	0.7±0.2	0.8 (0.6 to 0.9)
	Week 52	119	0.7±0.2	0.7 (0.6 to 0.7)	61	0.7±0.2	0.7 (0.6 to 0.8)	58	0.7±0.2	0.7 (0.5 to 0.7)
	% Change		−8.3±15.9＊＊＊			−7.3±16.5＊＊			−9.3±15.4＊＊＊
Apo CIII/Apo CII	Baseline	121	2.1±0.6	2.0 (1.8 to 2.4)	61	2.1±0.6	2.0 (1.8 to 2.4)	60	2.2±0.6	2.0 (1.8 to 2.4)
	Week 52	119	1.8±0.5	1.6 (1.4 to 2.0)	61	1.7±0.5	1.6 (1.4 to 1.9)	58	1.8±0.5	1.7 (1.4 to 2.0)
	% Change		−17.4±13.4＊＊＊			−17.1±13.8＊＊＊			−17.7±13.1＊＊＊

Data for Week 52 were imputed using LOCF. ^＊＊p＜0.01, ^＊＊＊p＜0.001 by one-sample t-test.

Apo, apolipoproteins; FFA, free fatty acids; IQR, interquartile range; LOCF, last observation carried forward; RemL-C, remnant-like particle cholesterol; SD, standard deviation.

Table 4 shows results of subgroup analysis for the percent change in TG, and Supplementary Table 6 shows the difference in TG percent change before and after dose increase in each subpopulation.

Table 4.Percent changes in TG (subgroup）

	n	Baseline Median (IQR)	Week 52 Median (IQR)	% Change Mean±SD
Age
＜65 years, mg/dL	82	235.2 (196.7 to 272.7)	116.8 (99.5 to 162.5)	−44.4±20.1＊＊＊
≥ 65 years, mg/dL	39	237.0 (185.7 to 347.0)	120.0 (100.5 to 157.0)	−48.5±14.9＊＊＊
Sex
Male, mg/dL	86	236.2 (197.3 to 292.7)	123.8 (102.5 to 166.0)	−43.8±19.4＊＊＊
Female, mg/dL	35	223.7 (180.7 to 298.3)	111.0 (95.0 to 130.5)	−50.5±15.9＊＊＊
BMI
＜25 kg/m2, mg/dL	34	229.5 (196.7 to 327.3)	112.8 (97.0 to 130.5)	−51.6±17.7＊＊＊
≥ 25 kg/m2, mg/dL	87	235.3 (186.3 to 273.3)	124.0 (100.0 to 165.5)	−43.4±18.6＊＊＊
Type 2 diabetes mellitus
Without, mg/dL	62	221.7 (186.3 to 270.7)	115.3 (99.5 to 157.5)	−44.4±19.1＊＊＊
With, mg/dL	59	243.3 (213.3 to 339.0)	120.0 (100.0 to 165.5)	−47.1±18.2＊＊＊
Metabolic syndrome
Without, mg/dL	42	228.0 (188.3 to 298.3)	111.8 (96.0 to 124.5)	−52.8±17.0＊＊＊
With, mg/dL	79	236.0 (197.0 to 276.7)	132.5 (102.0 to 172.5)	−41.9±18.5＊＊＊
Concomitant statin
Without, mg/dL	64	237.5 (211.2 to 302.3)	116.8 (100.0 to 158.5)	−49.0±19.9＊＊＊
With, mg/dL	57	222.3 (181.7 to 273.3)	120.0 (100.0 to 165.5)	−42.0±16.5＊＊＊
TG
＜500 mg/dL, mg/dL	115	232.0 (189.7 to 273.3)	115.5 (100.0 to 160.5)	−44.5±18.0＊＊＊
≥ 500 mg/dL, mg/dL	6	585.7 (543.3 to 693.7)	146.3 (120.0 to 289.0)	−69.3±15.9＊＊＊
HDL-C
＜40 mg/dL, mg/dL	25	270.7 (222.3 to 366.7)	145.0 (119.0 to 201.5)	−42.2±23.5＊＊＊
≥ 40 mg/dL, mg/dL	96	226.8 (186.0 to 268.5)	112.5 (96.8 to 152.5)	−46.6±17.2＊＊＊
AST, ALT
AST and ALT ≤ ULN, mg/dL	94	235.7 (197.0 to 276.7)	113.0 (96.0 to 157.0)	−47.6±18.8＊＊＊
AST or ALT ＞ULN, mg/dL	27	235.0 (177.3 to 308.7)	131.5 (112.5 to 186.5)	−39.1±16.8＊＊＊
eGFR
＜60 mL/min/1.73m2, mg/dL	22	232.8 (213.3 to 272.7)	137.5 (106.5 to 173.5)	−41.3±12.6＊＊＊
≥ 60, ＜90 mL/min/1.73m2, mg/dL	85	232.0 (185.7 to 276.7)	115.0 (100.0 to 156.0)	−46.6±19.3＊＊＊
≥ 90 mL/min/1.73m2, mg/dL	14	256.7 (206.7 to 372.7)	121.3 (95.5 to 206.0)	−47.1±22.4＊＊＊
Timing of administration of XR
Preprandial, mg/dL	12	240.3 (185.8 to 288.3)	116.8 (100.0 to 158.3)	−48.7±11.0＊＊＊
Postprandial, mg/dL	109	235.0 (191.3 to 292.7)	119.0 (100.0 to 162.5)	−45.4±19.3＊＊＊

^＊＊＊ p＜0.001 vs. baseline by one-sample t-test.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; eGFR, estimated glomerular filtration rate; HDL-C, high- density lipoprotein cholesterol; IQR, interquartile range; SD, standard deviation; TG, triglycerides; ULN, upper limit of normal; XR, extended- release.

Supplementary Table 6.Difference in mean percent change for fasting serum TG before and after up-titration: patients who were up-titrated (subgroup)

	n	% Change before up-titration§	% Change after up-titration§	Difference
Age
＜65 years	58	−30.8±22.5	−41.4±21.4	−10.5±21.5＊＊＊
≥ 65 years	24	−33.4±18.0	−46.8±16.5	−13.4±13.9＊＊＊
Sex
Male	60	−28.6±21.1	−40.0±20.1	−11.4±21.8＊＊＊
Female	22	−39.7±19.5	−51.0±18.4	−11.3±12.0＊＊＊
BMI
＜25 kg/m2	23	−30.8±30.7	−51.0±19.8	−20.2±22.3＊＊＊
≥ 25 kg/m2	59	−31.9±16.4	−39.8±19.6	−7.9±17.4＊＊
Type 2 diabetes mellitus
Without	39	−30.3±24.6	−41.9±21.6	−11.7±22.5＊＊
With	43	−32.7±17.7	−43.9±18.9	−11.1±16.7＊＊＊
Metabolic syndrome
Without	25	−34.8±29.2	−51.1±18.9	−16.3±21.6＊＊
With	57	−30.1±16.6	−39.4±19.8	−9.2±18.3＊＊＊
Concomitant statin
Without	42	−36.6±22.9	−45.7±21.3	−9.1±20.6＊＊
With	40	−26.3±18.0	−40.1±18.7	−13.8±18.3＊＊＊
TG
＜500 mg/dL	77	−30.1±19.9	−41.4±19.4	−11.3±19.9＊＊＊
≥ 500 mg/dL	5	−54.0±29.1	−67.0±16.7	−13.0±15.5
HDL-C
＜40 mg/dL	19	−33.2±30.8	−41.7±25.8	−8.5±29.2
≥ 40 mg/dL	63	−31.1±17.6	−43.3±18.4	−12.3±15.7＊＊＊
AST, ALT
AST and ALT ≤ ULN	59	−33.8±21.8	−44.6±21.1	−10.8±20.7＊＊＊
AST or ALT ＞ULN	23	−25.8±18.8	−38.8±17.1	−13.0±16.7＊＊
eGFR
＜60 mL/min/1.73m2	12	−26.5±15.3	−36.9±14.4	−10.4±12.9＊
≥ 60, ＜90 mL/min/1.73m2	61	−31.1±22.5	−44.4±20.8	−13.3±20.6＊＊＊
≥ 90 mL/min/1.73m2	9	−41.4±16.5	−40.9±22.2	0.5±16.4
Timing of administration of XR
Preprandial	10	−20.4±33.1	−47.2±11.6	−26.8±30.6＊
Postprandial	72	−33.1±18.8	−42.4±21.1	−9.2±16.7＊＊＊

Data are presented as mean±SD. ^§Mean percent change using the percent change from baseline to the last evaluation and from baseline to the immediately preceding time point. ＊p＜0.05, ＊＊p＜0.01, ＊＊＊p＜0.001 vs. baseline by one-sample t-test.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; eGFR, estimated glomerular filtration rate; HDL-C, high- density lipoprotein cholesterol; SD, standard deviation; TG, triglycerides; ULN, upper limit of normal; XR, extended-release.

Table 5 shows the mean change in liver-related and gall bladder-related markers and in fibrinogen from baseline to the last evaluation. In the overall population, values for change in AST, ALT, and γ-GT were −1.2±15.6 U/L, −10.9±15.6 U/L, and −33.7±57.9 U/L, respectively, with statistically significant decreases in ALT and γ-GT (p＜0.001). The changes in liver-related and gall bladder-related markers and in fibrinogen are compared by group in Supplementary Table 7.

Table 5.Changes in liver-related and gall bladder-related markers, and in fibrinogen

		Total (N = 121)	Morning group (N = 61)	Evening group (N = 60)
AST, U/L	Baseline	26.8±12.1	26.9±11.3	26.6±13.0
	Week 52	25.6±15.9	23.0±7.3	28.3±21.1
	Change	−1.2±15.6	−4.0±8.2＊＊＊	1.7±20.3
ALT, U/L	Baseline	33.5±19.0	34.1±18.0	33.0±20.0
	Week 52	22.7±12.8	21.1±10.3	24.3±14.9
	Change	−10.9±15.6＊＊＊	−13.0±14.9＊＊＊	−8.7±16.1＊＊＊
γ-GT, U/L	Baseline	65.0±75.2	61.9±74.2	68.3±76.7
	Week 52	31.3±24.0	26.9±15.8	35.8±29.7
	Change	−33.7±57.9＊＊＊	−35.0±62.3＊＊＊	−32.5±53.6＊＊＊
ALP, U/L	Baseline	79.8±25.2	78.9±19.4	80.7±30.1
	Week 52	50.8±13.5	49.8±11.6	51.9±15.2
	Change	−28.9±17.5＊＊＊	−29.1±12.8＊＊＊	−28.8±21.3＊＊＊
Total bilirubin, mg/dL	Baseline	0.79±0.26	0.79±0.24	0.78±0.28
	Week 52	0.63±0.18	0.65±0.19	0.61±0.18
	Change	−0.16±0.17＊＊＊	−0.15±0.17＊＊＊	−0.17±0.18＊＊＊
Fibrinogen, mg/dL	Baseline	319.7±48.8	320.6±52.5	318.8±45.1
	Week 52	270.4±54.9	273.3±60.0	267.5±49.5
	Change	−49.3±48.6＊＊＊	−47.3±49.2＊＊＊	−51.3±48.3＊＊＊

Data are presented as mean±standard deviation. Data for Week 52 were imputed using LOCF. ^＊＊＊ p＜0.001 vs. baseline by one-sample t-test. ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; γ-GT, gamma-glutamyl transferase; LOCF, last observation carried forward.

Supplementary Table 7.Comparison of change from baseline to final evaluation in liver-related and gall bladder-related markers, and in fibrinogen, between the morning and evening groups

	Group	n	Baseline Mean±SD	LS means Estimate (95%CI)	Differences (vs. evening group)
					Estimate (95%CI)	P value
AST, U/L	Morning	61	26.9±11.3	−4.0 (−7.7, −0.2)	−5.6 (−11.1, −0.1)	0.046
	Evening	60	26.6±13.0	1.7 (−2.2, 5.5)
ALT, U/L	Morning	61	34.1±18.0	−12.7 (−15.4, −10.0)	−3.7 (−7.6, 0.2)	0.061
	Evening	60	33.0±20.0	−9.0 (−11.7, −6.3)
γ-GT, U/L	Morning	61	61.9±74.2	−37.2 (−41.0, −33.5)	−7.1 (−12.5, −1.6)	0.011
	Evening	60	68.3±76.7	−30.2 (−34.0, −26.4)
ALP, U/L	Morning	61	78.9±19.4	−29.5 (−31.9, −27.1)	−1.1 (−4.5, 2.4)	0.536
	Evening	60	80.7±30.1	−28.4 (−30.8, −26.0)
Total bilirubin, mg/dL	Morning	61	0.79±0.24	−0.14 (−0.17, −0.11)	0.04 (−0.01, 0.08)	0.120
	Evening	60	0.78±0.28	−0.18 (−0.21, −0.15)
Fibrinogen, mg/dL	Morning	61	320.6±52.5	−46.5 (−58.6, −34.3)	5.8 (−11.9, 23.4)	0.518
	Evening	60	318.8±45.1	−52.2 (−64.5, −40.0)

Data for final evaluation (Week 52) were imputed using LOCF.

ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; γ-GT, gamma-glutamyl transferase; LOCF, last observation carried forward; LS, least square; SD, standard deviation.

Safety

AEs occurred in 83.5% (101/121 patients) overall, in 86.9% (53/61) for the morning group, and in 80.0% (48/60) for the evening group. ADRs developed in 19.0% (23/121) overall, 18.0% (11/61) for the morning group, and 20.0% (12/60) for the evening group (Table 6). There was one death due to myocardial infarction in the evening group, but the physician did not attribute the cause of death to XR. A total of seven other serious AEs, excluding death, occurred in seven patients overall: five events (arrhythmia, retinal hemorrhage, bladder cancer, colon cancer, and carotid artery stenosis) in five patients in the morning group and two events (COVID-19 and contusion) in two patients in the evening group. Although the arrhythmia could have been caused by comorbidities (first-degree atrioventricular block and right bundle branch block), the investigators could not rule out a causal relationship to XR because the arrhythmia occurred after study drug administration. A causal relationship was ruled out for the other six serious AEs. The AEs that led to discontinuation of XR, excluding death and serious AEs, consisted of seven events in four patients in the evening group. A list of ADRs is shown in Supplementary Table 8. The only ADR occurring in more than 2% of patients in the overall population was myalgia (2.5%, 3/121 patients). No notable clinically problematic changes were observed in laboratory measurements or changes from baseline values (Table 7), although some markers showed statistically significant differences between the morning and evening groups (Supplementary Table 7).

Table 6.Summary of adverse events and adverse drug reactions

	AEs			ADRs
	Total (N = 121)	Morning group (N = 61)	Evening group (N = 60)	Total (N = 121)	Morning group (N = 61)	Evening group (N = 60)
Total	101 (83.5) [312]	53 (86.9) [153]	48 (80.0) [159]	23 (19.0) [35]	11 (18.0) [15]	12 (20.0) [20]
Deaths	1 (0.8) [1]	0	1 (1.7) [1]	0	0	0
Serious (other than death)	7 (5.8) [7]	5 (8.2) [5]	2 (3.3) [2]	1 (0.8) [1]	1 (1.6) [1]	0
Arrhythmia	1 (0.8) [1]	1 (1.6) [1]	0	1 (0.8) [1]	1 (1.6) [1]	0
Retinal hemorrhage	1 (0.8) [1]	1 (1.6) [1]	0	0	0	0
COVID-19	1 (0.8) [1]	0	1 (1.7) [1]	0	0	0
Contusion	1 (0.8) [1]	0	1 (1.7) [1]	0	0	0
Bladder cancer	1 (0.8) [1]	1 (1.6) [1]	0	0	0	0
Colon cancer	1 (0.8) [1]	1 (1.6) [1]	0	0	0	0
Carotid artery stenosis	1 (0.8) [1]	1 (1.6) [1]	0	0	0	0
Leading to discontinuation of study drug (other than death and serious)	4 (3.3) [7]	0	4 (6.7) [7]	4 (3.3) [6]	0	4 (6.7) [6]
Aortic valve stenosis	1 (0.8) [1]	0	1 (1.7) [1]	0	0	0
Asthenia	1 (0.8) [1]	0	1 (1.7) [1]	1 (0.8) [1]	0	1(1.7) [1]
Feeling abnormal	1 (0.8) [1]	0	1 (1.7) [1]	1 (0.8) [1]	0	1(1.7) [1]
Blood creatine phosphokinase increased	1 (0.8) [1]	0	1 (1.7) [1]	1 (0.8) [1]	0	1(1.7) [1]
Myalgia	2 (1.7) [2]	0	2 (3.3) [2]	2 (1.7) [2]	0	2(3.3) [2]
Eczema	1 (0.8) [1]	0	1 (1.7) [1]	1 (0.8) [1]	0	1(1.7) [1]

Data are presented as number of patients (%) [number of occurrences]. Indented items (diseases and other medical conditions) are MedDRA terms. ADR, adverse drug reaction; AE, adverse event; MedDRA, Medical Dictionary for Regulatory Activities.

Supplementary Table 8.Incidence of adverse drug reactions by MedDRA^§ term (SOC, PT)

	Total (N = 121)	Morning group (N = 61)	Evening group (N = 60)
Total	23 (19.0) [35]	11 (18.0) [15]	12 (20.0) [20]
Cardiac disorders	1 (0.8) [1]	1 (1.6) [1]	0
Arrhythmia	1 (0.8) [1]	1 (1.6) [1]	0
Eye disorders	1 (0.8) [1]	1 (1.6) [1]	0
Vitreous floaters	1 (0.8) [1]	1 (1.6) [1]	0
Gastrointestinal disorders	4 (3.3) [4]	2 (3.3) [2]	2 (3.3) [2]
Abdominal pain	1 (0.8) [1]	1 (1.6) [1]	0
Diarrhoea	1 (0.8) [1]	0	1 (1.7) [1]
Oesophagitis	1 (0.8) [1]	1 (1.6) [1]	0
Stomatitis	1 (0.8) [1]	0	1 (1.7) [1]
General disorders and administration site conditions	1 (0.8) [2]	0	1 (1.7) [2]
Asthenia	1 (0.8) [1]	0	1 (1.7) [1]
Feeling abnormal	1 (0.8) [1]	0	1 (1.7) [1]
Infections and infestations	3 (2.5) [3]	2 (3.3) [2]	1 (1.7) [1]
Dermatophytosis of nail	1 (0.8) [1]	1 (1.6) [1]	0
Herpes zoster	1 (0.8) [1]	1 (1.6) [1]	0
Urinary tract infection	1 (0.8) [1]	0	1 (1.7) [1]
Investigations	3 (2.5) [3]	1 (1.6) [1]	2 (3.3) [2]
Activated partial thromboplastin time prolonged	1 (0.8) [1]	0	1 (1.7) [1]
Blood creatine phosphokinase increased	2 (1.7) [2]	1 (1.6) [1]	1 (1.7) [1]
Metabolism and nutrition disorders	1 (0.8) [1]	0	1 (1.7) [1]
Diabetes mellitus	1 (0.8) [1]	0	1 (1.7) [1]
Musculoskeletal and connective tissue disorders	7 (5.8) [7]	2 (3.3) [2]	5 (8.3) [5]
Muscle spasms	2 (1.7) [2]	1 (1.6) [1]	1 (1.7) [1]
Myalgia	3 (2.5) [3]	0	3 (5.0) [3]
Periarthritis	2 (1.7) [2]	1 (1.6) [1]	1 (1.7) [1]
Nervous system disorders	2 (1.7) [2]	2 (3.3) [2]	0
Dizziness	1 (0.8) [1]	1 (1.6) [1]	0
Headache	1 (0.8) [1]	1 (1.6) [1]	0
Renal and urinary disorders	3 (2.5) [3]	2 (3.3) [2]	1 (1.7) [1]
Nocturia	1 (0.8) [1]	0	1 (1.7) [1]
Renal impairment	1 (0.8) [1]	1 (1.6) [1]	0
Ureterolithiasis	1 (0.8) [1]	1 (1.6) [1]	0
Respiratory, thoracic and mediastinal disorders	1 (0.8) [1]	0	1 (1.7) [1]
Cough variant asthma	1 (0.8) [1]	0	1 (1.7) [1]
Skin and subcutaneous tissue disorders	3 (2.5) [5]	1 (1.6) [1]	2 (3.3) [4]
Eczema	1 (0.8) [1]	0	1 (1.7) [1]
Rash	2 (1.7) [4]	1 (1.6) [1]	1 (1.7) [3]
Vascular disorders	2 (1.7) [2]	1 (1.6) [1]	1 (1.7) [1]
Hypertension	2 (1.7) [2]	1 (1.6) [1]	1 (1.7) [1]

Data are presented as number of patients (%) [number of occurrences]. The unindented lines are SOC terms, and the indented lines are PT.

^§MedDRA/J Ver. 24.1.

MedDRA, Medical Dictionary for Regulatory Activities; PT, preferred term; SOC, system organ class.

Table 7.Changes in safety markers

		Total (N = 121)	Morning group (N = 61)	Evening group (N = 60)
Creatinine, mg/dL	Baseline	0.85±0.27	0.83±0.21	0.87±0.33
	Week 52	0.89±0.33	0.86±0.25	0.91±0.40
	Change	0.04±0.09＊＊＊	0.03±0.08＊	0.05±0.11＊＊＊
eGFR, mL/min/1.73m2	Baseline	71.9±16.5	72.3±16.4	71.4±16.8
	Week 52	69.2±17.2	70.4±17.8	68.1±16.6
	Change	−2.6±6.4＊＊＊	−2.0±6.4＊	−3.3±6.4＊＊＊
Creatine kinase, U/L	Baseline	131.4±108.3	131.4±132.5	131.4±77.4
	Week 52	125.9±70.5	116.1±55.6	136.0±82.3
	Change	−5.4±89.7	−15.3±102.4	4.6±74.3
Glucose, mg/dL	Baseline	123.4±27.5	124.1±27.4	122.6±27.9
	Week 52	121.5±27.5	123.0±28.0	119.9±27.2
	Change	−1.9±15.9	−1.1±14.9	−2.7±16.8
Insulin, mU/L	Baseline	16.8±44.1	15.1±35.7	18.5±51.5
	Week 52	15.7±39.1	12.3±20.6	19.3±51.5
	Change	−1.1±16.4	−2.9±18.6	0.7±13.7
HbA1c, %	Baseline	6.6±1.0	6.6±1.0	6.6±1.0
	Week 52	6.7±1.0	6.7±1.0	6.7±1.1
	Change	0.1±0.4＊＊	0.1±0.4＊	0.1±0.5
HOMA-IR	Baseline	5.5±16.1	4.9±13.6	6.2±18.4
	Week 52	4.9±12.4	3.8±6.6	6.0±16.3
	Change	−0.7±8.9	−1.1±9.3	−0.2±8.5

Data are presented as mean±standard deviation. Data for Week 52 were imputed using LOCF. ^＊p＜0.05, ^＊＊p＜0.01, ^＊＊＊p＜0.001 vs. baseline by Wilcoxon signed rank test.

eGFR, estimated glomerular filtration rate; HbA1c, hemoglobin A1c; HOMA-IR, homeostatic model assessment-insulin resistance; LOCF, last observation carried forward.

Discussion

This study examined the safety and efficacy of a once-daily extended-release tablet of pemafibrate in the morning or evening for 52 weeks in 121 dyslipidemic patients with high TG. The results showed fasting serum TG decreased in approximately 45% after four weeks, and that TG-lowering effect was sustained for up to 52 weeks. No differences were found between the morning and evening groups. In patients who had an inadequate response to the 0.2 mg/day dose, further TG lowering (−11.4%) was achieved by increasing the dose to 0.4 mg/day. AEs occurred in 83.5% of patients and ADRs in 19.0%. There were no clinically notable safety problems.

This was the first study of XR in long-term use. Findings over a 52-week period confirmed the TG-lowering effect of XR that was seen in the previously reported 12-week results¹²⁾. There was a statistically significant decrease in fasting serum TG, with a percent change from baseline of −45.7% in the overall population. This decrease is comparable to the percent change in TG seen in previous clinical studies of an IR formulation for twice-daily administration in patient populations comparable to the participants in this study^{13, 14)}, confirming that XR can be used in the same way as IR in clinical practice and will provide similar efficacy. In addition, XR offers the convenience of once-daily dosing in the treatment of dyslipidemic patients with high TG. No statistically significant difference was noted between the morning and evening groups regarding the percent change from baseline in fasting serum TG. This means that physicians can choose the timing that is easiest for each patient based on concomitant medication schedule and lifestyle considerations. In addition to the once-daily regimen, this scheduling flexibility is expected to further improve medication adherence.

In this study, the dose was increased to 0.4 mg/day for patients who showed inadequate response after 12 weeks of treatment at the starting dose of 0.2 mg/day. This dose increase was followed by an additional 11.4% reduction in fasting serum TG. Our findings were consistent with the results from a Japanese phase 3 trial in dyslipidemic patients with high TG, which suggested a trend toward greater TG reduction with XR 0.4 mg/day than with XR 0.2 mg/day (−48.0% vs. −43.8%)¹²⁾. That difference was particularly pronounced in patients with higher baseline TG (TG＞500 mg/dL: −66.3% vs. −52.2%)⁹⁾. In the U.S., the Framingham study defined fasting serum TG ≥ 150 mg/dL as hypertriglyceridemia¹⁵⁾, and epidemiological studies in Japan have reported an increased incidence of coronary artery disease in patients with fasting serum TG ≥ 150 mg/dL^{16, 17)}. The Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2022 recommends a target of fasting serum TG ＜150 mg/dL¹⁸⁾, supporting the importance of using higher XR doses to further reduce TG and reach treatment goals in dyslipidemic patients. In the previously mentioned Japanese phase 3 trial in dyslipidemic patients with high TG, a significantly higher percentage of patients achieved fasting serum TG ＜150 mg/dL with XR 0.4 mg/day (51.7%, baseline TG 355.0±157.5 mg/dL) than with XR 0.2 mg/day (37.4%, 338.6±117.0 mg/dL)¹²⁾. Results of the present study suggest that increasing the dose in patients who initially fail to reach the target will enable more patients to achieve fasting serum TG ＜150 mg/dL at 52 weeks of treatment. The 0.4 mg XR dose is now being marketed as a single tablet, which is expected to be more convenient than the 4 tablets needed to achieve a 0.4 mg/day IR dose.

In subgroup analysis, no groups differed markedly from the general trend, suggesting that sufficient TG reduction can be expected regardless of the patient background, although differences were not significant in some subpopulations with small numbers of patients. Similar findings were obtained for the effects of dose increase in patients who did not respond sufficiently to the initial dose, suggesting that up-titration was associated with additional TG reduction regardless of patient characteristics. The PROMINENT (Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes) trial, a previous global study to investigate the effects of pemafibrate in dyslipidemic patients with high TG and low HDL-C, complicated by type 2 diabetes, did not show significant suppression of cardiovascular events, for which an insufficient TG reduction may be one of the possible reasons^{19, 20)}. In the present study, median TG was below 150 mg/dL after pemafibrate administration, and subgroup analysis showed TG reduction of over 40% in almost all subgroups. These findings suggest that pemafibrate may be more effective in specific populations than in the PROMINENT trial population. This remains a topic for future investigation.

Among the liver-related markers that were evaluated as efficacy endpoints, statistically significant reductions were observed from baseline to final assessment of ALT and γ-GT. The PEMA-FL study (PEMAfibrate randomised placebo-controlled study in patients with non-alcoholic Fatty Liver disease), a phase 2 study of IR in patients with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis (NAFLD/NASH), showed that treatment with IR 0.4 mg/day for 72 weeks was associated with improvement in liver stiffness and liver-related markers (ALT and γ-GT)²¹⁾. Similarly, pooled analysis of IR clinical trials showed that IR improved liver function, and that improvement was particularly favorable in patients whose liver-related markers exceeded the reference values at baseline^{22, 23)}. Although the present study did not specifically target patients with hepatic dysfunction, XR is expected to improve liver function in the same way as IR.

AEs developed in 83.5% of patients (101/121), which did not differ notably from the IR clinical trials (77.8-82.0%)^{13, 14)}. The evening group showed more AEs that led to discontinuation of XR, but three of those events occurred in the same patient, suggesting that there was no meaningful difference between the morning and the evening groups in the proportion of patients who developed AEs.

Although some changes from baseline in laboratory values reached statistical significance, none of the changes in laboratory values or physical examination findings were considered clinically problematic. A decrease in eGFR and an increase in creatinine were noted, both comparable to changes seen in previous IR trials^{13, 14)}. For further reference, in another IR trial using fenofibrate as a control, the study results showed smaller increases in creatinine and smaller decreases in eGFR in the pemafibrate group than the fenofibrate group²⁴⁾. The effects of XR on renal parameters such as eGFR and creatinine are inferred to be similar to the effects of IR.

A slight increase in HbA1c was observed, but we consider it to be of limited clinical importance. PPARα agonists have been found to improve the deformability of red blood cells by modifying erythrocyte membrane lipids²⁵⁾, potentially affecting erythrocyte dynamics and lifespans, as well as HbA1c levels. We assume that XR will provide a similar effect.

Limitations

This phase 3 long-term study enrolled only slightly over 100 patients. The strict eligibility and exclusion criteria meant that only a small patient population was available for enrollment, which may limit the generalizability of the study results. In actual clinical practice, a wider range of patients would be considered eligible for treatment with this drug. The study was not conducted as a double-blind study with a placebo group because a comparison with placebo was deemed unnecessary based on previous clinical trial results using IR. Since this study was a phase 3 clinical trial, 52 weeks was set as the long-term administration period. However, XR is actually expected to be administered for many years in some patients, so information on the efficacy and safety of XR in actual clinical practice is warranted for even longer time periods.

Conclusion

This study demonstrated the efficacy of long-term XR administration once daily in dyslipidemic patients with elevated TG. The TG-lowering effect was independent of time of XR administration (morning or evening). In patients showing insufficient response to the initial dose of 0.2 mg/day, a dose increase to 0.4 mg/day proved to be more effective. The long-term safety profile of XR was favorable, both for the starting dose of 0.2 mg/day and for the subsequent dose of 0.4 mg/day. The XR tablet is expected to improve patient adherence.

Acknowledgements

Authors acknowledge the investigators and patients who participated in this study. Medical writing support was provided by EDIT, Inc. (Tokyo, Japan) and was funded by Kowa Company, Ltd.

Grant Support

This study has not been the recipient of grants from any funding agency in the public, commercial, or not-for-profit sectors.

Funding

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.

Conflicts of Interest

Arai H has received personal fees from Kowa Company, Ltd., Daiichi Sankyo Company, Limited, and Astellas Pharma Inc. Yamashita S has received personal fees from Kowa Company, Ltd., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., and Skylight Biotech, Inc. Araki E has received personal fees and grants from Sumitomo Pharma Co., Ltd., and Novo Nordisk Pharma Ltd.; personal fees from AstraZeneca K.K., Eli Lilly Japan K.K., MSD K.K., Ono Pharmaceutical Co., Ltd., Kowa Company, Ltd., and Daiichi Sankyo Company, Limited; grants from Takeda Pharmaceutical Company Limited, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., and Roche Diagnostics K.K.; and endowed courses by Ono Pharmaceutical Co., Ltd., and Terumo Corporation. Yokote K has received personal fees and grants from Mitsubishi Tanabe Pharma Corporation, Sumitomo Pharma Co., Ltd., Kowa Company, Ltd., Boehringer Ingelheim International GmbH., and Taisho Pharmaceutical Co., Ltd.; personal fees from MSD K.K., Sanofi K.K., Daiichi Sankyo Company, Limited, Novartis Pharma K.K., Novo Nordisk Pharma Ltd., Bayer Yakuhin, Ltd., and Pfizer Japan Inc.; grants from Abbott Japan LLC, Eisai Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited, TEIJIN PHARMA LIMITED, Eli Lilly Japan K.K., and MOCHIDA PHARMACEUTICAL CO., LTD. Tanigawa R, Saito A, Furukawa D, and Suganami H are employees of Kowa Company, Ltd. Ishibashi S has received personal fees from Kowa Company, Ltd.

Author Contributions

Arai H was responsible for conceptualization, methodology, and writing review and editing; Yamashita S for conceptualization, methodology, and writing review and editing; Araki E for conceptualization, methodology, and writing review and editing; Yokote K for conceptualization, methodology, supervision, visualization, writing the original draft, and writing review and editing; Tanigawa R for methodology and writing review and editing; Saito A for methodology and writing review and editing; Furukawa D for methodology and writing review and editing; Suganami H for data curation, formal analysis, methodology, visualization, and writing review and editing; and Ishibashi S for conceptualization, methodology, and writing review and editing. All authors read and approved the final manuscript.

Data Sharing

Data sharing including the protocol are not applicable in this study.

Registration Identifier: NCT04716595

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