Abstract
Aims: Efficacy, safety, and pharmacokinetics of the selective PPARα modulator pemafibrate as once-daily extended-release (XR) tablets were compared with those of twice-daily immediate-release (IR) tablets in patients with hypertriglyceridemia.
Methods: A multicenter, randomized, single-blind, active-controlled crossover, phase 2 clinical pharmacology study was performed in patients with hypertriglyceridemia. Patients were randomly assigned to IR 0.2 mg/day, XR 0.4 mg/day, or XR 0.8 mg/day before/after meals (fasted/fed) and treated for a total of eight weeks. The primary endpoint was percentage change in fasting serum triglycerides (TG).
Results: Of 63 randomized patients, 60 received the study drug. Patients were 78.3% male, mean age (±SD) 57.5±9.8 years, BMI 25.5±3.7 kg/m2, and fasting TG 221.3±68.1 mg/dL. Fasting serum TG decreased significantly from baseline in all groups (LS mean [95% CI];−43.6 [−47.7, −39.5] % for IR 0.2 mg/day, −41.1 [−45.1, −37.0] % for XR 0.4mg/day, −39.7 [−43.8, −35.6] % for XR 0.8 mg/day), indicating that XR 0.4 and XR 0.8 mg/day were not inferior to IR 0.2 mg/day. TG-lowering effects tended to be stronger for fed than fasted administration. MRTss, tmax, and t1/2 were longer for XR than for IR. Adverse events showed no major inter-group differences: 12.5% (5/40 patients) for IR 0.2, 17.5% (7/40) for XR 0.4, and 20.0% (8/40) for XR 0.8 mg/day.
Conclusions: In patients with hypertriglyceridemia, XR substantially lowered TG at all doses, with maximum effectiveness at 0.4 mg/day, the dose approved in Japan, to a level comparable to IR 0.2 mg/day. There were no safety concerns up to 0.8 mg/day.
Registration Identifier: NCT04079530
Introduction
Dyslipidemia, including elevated low-density lipoprotein-cholesterol (LDL-C), comprise a major risk factor for atherosclerotic cardiovascular disease (ASCVD) and has been clearly associated with the development of atherosclerosis1). Statin therapy is strongly recommended to decrease the risk of ASCVD1). However, LDL-C reduction alone is not sufficient to completely eliminate that risk. Several potential residual risks have been identified2). In particular, numerous epidemiological studies have shown high fasting serum triglycerides (TG) to be an independent risk factor for ASCVD3, 4). Mendelian randomized studies confirmed that TG is a true risk factor for coronary artery disease5).
Pemafibrate is a selective peroxisome proliferator-activated receptor α modulator (SPPARMα) that improves many aspects of lipid metabolism. Mainly, it lowers serum TG by regulating the expression of target genes associated with the metabolism of lipids and glucose in the liver6-8). This drug was approved in Japan in July 2017 for the treatment of hyperlipidemia (Parmodia® Tablets, Kowa Co., Ltd.) and has been marketed in Japan since June 2018. It is also approved and in clinical use in Thailand and Singapore.
Conventional pemafibrate (Parmodia® Tablets) was formulated as an immediate-release (IR) product used twice daily. However, drug adherence tends to decline with increasing number of daily doses9), suggesting that adherence might improve with a once-daily option. In particular, dyslipidemia patients who are targeted for pemafibrate prescription also often receive multiple additional drugs for lifestyle-related diseases such as hypertension and type 2 diabetes. Since many of those drugs are used once daily, the once-daily pemafibrate should be more convenient for patients and might improve adherence. To this end, a once-daily pemafibrate extended-release formulation (eXtended Release: XR) was developed and approved in Japan in June 2023.
In a Japanese phase 3 study in patients with hypertriglyceridemia, XR (0.2 mg/day or 0.4 mg/day) for 12 weeks showed non-inferiority to IR 0.2 mg/day in lowering fasting serum TG at either dose10). The safety profiles for XR 0.2 mg/day and XR 0.4 mg/day were similar to that for IR 0.2 mg/day, and XR 0.4 mg/day appeared to provide a stronger TG-lowering effect than XR 0.2 mg/day. Another Japanese phase 3 study of XR for 52 weeks showed long-term efficacy and safety in morning or evening administration, and a dose increase to 0.4 mg/day showed favorable outcome when the starting dose of 0.2 mg/day was inadequate11).
Aim
This phase 2 study was aimed to verify a once-daily XR formulation at two dose levels (0.4 mg or 0.8 mg, fasted or fed) for four weeks is not inferior to the conventional twice-daily IR formulation (0.1 mg, morning and evening, fasted or fed) for reducing serum TG levels. Pharmacokinetics and safety of the two formulations were also compared.
Methods
Trial Design
This multicenter, randomized, single-blind, active-controlled, 12-group, two-period, crossover, comparative, phase 2 clinical pharmacology study was conducted at three institutions in Japan. This study consisted of a screening period, treatment period 1, and treatment period 2. After obtaining written consent, patients were screened for eligibility from four days to eight weeks before drug administration. Each eligible patient was randomly assigned to a group, received either XR (0.4 mg/day, 0.8 mg/day) or IR (0.2 mg/day) for four weeks (treatment period 1), and was then switched to a different formulation or dose for an additional four weeks (treatment period 2) (Fig.1). IR 0.2 mg/day was selected as the active control because it was the approved usual dose in Japan, with a marginal difference in lowering TG levels compared to IR 0.4 mg/day. XR 0.4 mg/day and XR 0.8 mg/day were selected as a basis for estimating the maximum dose.
The study was conducted in compliance with ethical principles in the spirit of the Declaration of Helsinki and the Ordinance of the Ministry of Health and Welfare No. 28 of March 27, 1997, “Ministerial Ordinance on Good Clinical Practice for Drugs (the GCP Ministerial Ordinance)”. Prior approval was obtained from an Institutional Review Board operated in common by the three participating medical institutions.
Participants
The study population consisted of patients with hypertriglyceridemia, men at least 20 years of age and women who were postmenopausal at the time of consent. The patients had received regular guidance on diet and/or exercise for at least 12 weeks prior to screening and had fasting serum TG ≥ 150 mg/dL at screening. The main exclusion criteria included fasting serum TG ＞500 mg/dL at screening, need for prohibited concomitant medications during the study period, poorly controlled thyroid disease, poorly controlled diabetes with HbA1c (National Glycohemoglobin Standardization Program [NGSP]) ≥ 8.0% at screening, poorly controlled hypertension with systolic blood pressure (SBP) ≥ 160 mmHg or diastolic blood pressure (DBP) ≥ 100 mmHg, and presence of liver cirrhosis or biliary obstruction. Details of exclusion criteria are provided in Supplementary Table 1.
Supplementary Table 1.Exclusion criteria
| 1) Fasting serum TG ＞500 mg/dL at screening |
| 2) Necessity for use of prohibited concomitant medications§ after giving consent and during study period
|
| 3) Malabsorption, history of malabsorption, or history of surgical procedures (excluding appendectomy or hernia treatment) that may affect absorption |
| 4) Poorly controlled thyroid disease |
| 5) Poorly controlled diabetes, with HbA1c (NGSP) ≥ 8.0 % at screening |
| 6) Uncontrolled hypertension (SBP ≥ 160 mmHg or DBP ≥ 100 mmHg) |
| 7) AST or ALT exceeding 3 times the upper reference limit at screening |
| 8) Liver cirrhosis or biliary obstruction |
| 9) Complication of malignant tumor or high likelihood of malignant tumor recurrence |
| 10) Provision of 400 mL or more of whole blood within 16 weeks or 200 mL or more of whole blood 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 |
| 11) History of serious drug allergy (e.g. anaphylactic shock) |
| 12) History of hypersensitivity to pemafibrate or those who have stopped taking pemafibrate for reasons of insufficient efficacy or safety |
| 13) Participation in another clinical trial with administration of medication at the time of giving consent, or administration of any study drug other than placebo within 16 weeks prior to the screening test |
| 14) Otherwise judged by the investigator or other responsible staff as inappropriate for participation in this study |
§From 4 weeks before the screening test to the end of the study: 1) fibrates, 2) corticosteroids (other than topical administration), 3) protease inhibitors, 4) anabolic hormone agents, 5) progestogen. From 12 weeks before the screening test to the end of the study: 6) diabetes drugs (insulin preparation, TZD preparation). From 4 weeks before the start of study drug administration until the end of the study (amiodarone washout prohibited): 7) drugs that moderately or strongly inhibit or induce CYP2C8, 2C9, 3A4, 8) drugs that inhibit P-gp, 9) drugs that inhibit BCRP, 10) drugs that inhibit OCT2, 11) drugs that inhibit OATP1B1, OATP1B3. From the day before administration of the investigational drug to the end of the study: 12) anion-exchange resin (cholestyramine, colestimide).
TG, triglycerides; HbA1c, hemoglobin A1c; NGSP, national glycohemoglobin standardization program; SBP, systolic blood pressure; DBP, diastolic blood pressure; AST, aspartate aminotransferase; ALT, alanine aminotransferase; TZD, thiazolidinediones; CYP, cytochrome P450; P-gp, P-glycoprotein; BCRP, breast cancer resistance protein; OCT, organic cation-transporter; OATP, organic anion-transporting polypeptide.
The patients were randomly allocated to one of 12 groups using a dynamic allocation method, with adjustment factors including institution conducting the study, sex, and the use or non-use of concomitant statins (Fig.1). The investigators confirmed patient eligibility based on screening test results. Study collaborators entered the necessary information into the web-based registration system and assigned each patient to a treatment group. Although the investigational drug is identifiable in this study, blinding was maintained by not disclosing information on group assignment to the investigator or to other personnel responsible for assessing data.
The study drug was taken orally. After group assignment, patients in the IR 0.2 mg/day group took two tablets containing IR 0.1 mg, one in the morning and one in the evening, fasted or fed. Patients took one or two tablets of 0.4 mg in the XR 0.4 mg/day and 0.8 mg/day groups respectively, once daily in the morning, fasted or fed. This was a 12-arm, two-period crossover study, with treatment period 1 followed by treatment period 2 without a washout period. Each treatment period continued for four weeks (Fig.1).
Sample Collection and Assessment
Blood and urine samples for clinical laboratory tests were collected after patients had fasted for at least 10 hours. Tests at screening and during treatment periods 1 and 2 were performed every two weeks from Week 0 to Week 8. Laboratory test samples were measured at a centralized facility, with laboratory tests performed primarily by LSI Medience Corporation (Tokyo, Japan) and some tests (ApoB48, lathosterol, campesterol, β-sitosterol) conducted by SRL Inc. (Tokyo, Japan).
The pharmacokinetics (PK) of unchanged pemafibrate were measured quantitatively. At four weeks in each treatment period, blood samples were collected at 15 time points, including the morning before drug administration and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16, and 24 hours after administration. At four and eight weeks, patients were hospitalized overnight, and blood samples were collected at each participating medical institution to assess plasma drug concentration. Centralized measurements were performed at Shin Nippon Biomedical Laboratories, Ltd. (Tokyo, Japan). Breakfast on the day of blood collection was a high-fat meal based on the relevant Food and Drug Administration (FDA) Guidance12) and provided 1000 kcal (men) / 800 kcal (women), 66.7/53.3 g fat, 62.5/50.0 g carbohydrate, and 37.5/30.0 g protein.
Endpoints
The primary efficacy endpoint was the percentage change in fasting serum TG from baseline to four weeks of treatment in each period. The secondary efficacy endpoints were the percentage change or change from baseline to four weeks of treatment in each period in the lipid-related indexes other than TG, the liver- and gall bladder-related indexes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], gamma-glutamyl transferase [γ-GT], alkaline phosphatase [ALP], total bilirubin, and bile acids), the glucose metabolism-related indexes (glucose, glycoalbumin, insulin, HbA1c) and the other indexes (lathosterol, campesterol and β-sitosterol). The lipid-related indexes other than TG included total cholesterol (TC), LDL-C (direct method), high-density lipoprotein cholesterol (HDL-C, direct method), remnant like particles-cholesterol (RemL-C, direct method), non-HDL-C (calculated as TC − HDL-C); apolipoproteins (Apo) AI, AII, B, B48, CII, CIII, and E; free fatty acids (FFA); ApoB/AI, ApoCIII/CII, LDL-C/HDL-C, and non-HDLC/HDL-C.
The pharmacokinetic index was the plasma concentration of unchanged pemafibrate at four weeks in each treatment period, and the plasma pharmacokinetic parameters were tmax, Cmax, area under the concentration-time curve (AUC0-τ), mean residence time (MRTss), and t1/2 for unchanged pemafibrate.
Safety was evaluated from the incidence of adverse events (AEs) and adverse drug reactions (ADRs), and from laboratory test findings for serum creatinine, estimated glomerular filtration rate (eGFR), and creatine kinase (CK). Baseline values were determined as the mean of measurements taken on the day before drug administration in period 1 and at Week 0, if available. If only one measurement was available before the first administration, the baseline value was defined as the value from the day before administration in period 1. If fasting blood samples were obtained at two time points for each period, the mean value of the two time points was used for evaluation.
Statistical Analysis
We conservatively estimated the variance and the correlation coefficient between repeated time points for the percentage change in TG to be 400 and 0.55, respectively. For these estimates, we referenced the variance in the percentage change of TG based on Japanese study data for IR13) and the correlation coefficients between repeated measurements when multiple assessments were conducted. Assuming that the percentage reductions in TG were comparable between IR 0.2 mg/day and XR 0.4 mg/day, and setting the non-inferiority margin at 10%, we estimated that a minimum total sample size of 60 patients (five patients per group) would be required to achieve ≥ 80% probability that the upper limit of the two-sided 95% confidence interval (CI) would fall below the non-inferiority margin.
The efficacy analysis population was the full analysis set (FAS), consisting of randomly assigned patients who took at least one dose of the study drug and had baseline and post-baseline measurements for the primary endpoint. The safety analysis population was defined as the safety analysis set (SAS), consisting of all randomly assigned patients who took at least one dose of the study drug. The pharmacokinetics analysis population was defined as patients who took the study drug and had subsequent plasma drug concentration data. PK/pharmacodynamics (PD) analysis was performed on the per protocol set (PPS), consisting of patients who were randomly assigned, took at least one dose of the study drug, had no major protocol deviations, and had baseline and post-baseline TG measurements.
The primary efficacy endpoint was the percentage change in fasting serum TG from baseline to four weeks of treatment in each period. The two-sided significance level was 5%, and the two-sided confidence coefficient was 95%. For the primary analysis, differences in the least-squares (LS) means and the two-sided 95% CIs for each XR group with respect to the IR group were calculated using a marginal model, assuming compound symmetry (CS) in the error variance-covariance matrix for each patient. In this calculation, fixed effects were allocation groups pooled for the timing of administration (fasted or fed), time period (period 1 or period 2), formulation and dose (IR 0.2 mg/day, XR 0.4 mg/day, or XR 0.8 mg/day), baseline values, institution, sex, and whether concomitant statins were used. The non-inferiority margin was set at 10%, and non-inferiority was claimed when the upper confidence limit of the two-sided 95% CI did not exceed the non-inferiority margin. Multiplicity was addressed by employing a fixed-sequence method, in which the comparison between XR 0.8 mg/day and IR 0.2 mg/day was conducted only after non-inferiority to IR 0.2 mg/day was achieved for XR 0.4 mg/day. For secondary analysis, in a model in which administration timing and the interaction between formulation/dose and timing were added as fixed effects to the main analysis model, the effects of timing (fasted or fed) were evaluated for each treatment. The secondary efficacy endpoints were analyzed in the same way as the primary efficacy endpoint.
For the pharmacokinetic evaluation, the mean plasma concentrations of unchanged pemafibrate at four weeks of treatment with IR 0.2 mg/day, XR 0.4 mg/day, or XR 0.8 mg/day were plotted graphically over time for fasted or fed administration. The basic statistics of tmax, Cmax, AUC0-τ, MRTss, and t1/2 were calculated as pharmacokinetic parameters of unchanged pemafibrate at four weeks of treatment in each period. For Cmax and AUC0-τ, the ratio of geometric means of the three groups and their 90% CIs were calculated. After the start of the study, additional analysis was performed for AUC0-τ by correcting AUC0-τ in the IR group to be equivalent to the respective pemafibrate daily doses in the XR groups. The ratio of the geometric mean and the 90% CI for fasted and fed administration in each XR group were also calculated for Cmax and AUC0-τ. For additional PK/PD analysis, scatter plots were generated to evaluate the percentage change in fasting serum TG at four weeks of treatment and of pharmacokinetic parameters for unchanged pemafibrate.
For safety analysis, appropriate terms were selected from the Japanese version of the International Council for Harmonization (ICH) Medical Dictionary for Regulatory Activities (MedDRA/J) and were used to replace non-standard terms used by the investigators to describe AEs. The incidence of AEs and of ADRs that occurred after drug administration were calculated separately for the IR 0.2 mg/day group, the XR 0.4 mg/day group, and the XR 0.8 mg/day group. Basic statistics for changes in laboratory values from baseline to four weeks were calculated for each group.
SAS ver. 9.4 or higher was used for analysis.
Results
Patient Characteristics
The study was conducted between September and December in 2019. Written consent was obtained from 87 patients, and 63 eligible patients were randomly assigned to each group. After enrollment, three patients were withdrawn from the study by the investigator or at the patient’s request, resulting in 60 patients receiving the study drug. All 60 (12 groups, five patients per group) were included in the FAS and SAS. Those 60 patients completed treatment period 1, and 59 of them also completed treatment period 2 (Supplementary Fig. 1).
Patient age was 57.5±9.8 years (mean±standard deviation [SD]), body weight was 71.5±13.6 kg, and BMI was 25.5±3.7 kg/m2. A total of 78.3% (47/60) of patients were male, and 10.0% (6/60) were concurrent statin users. Baseline fasting TG was 221.3±68.1 mg/dL, HDL-C was 42.6±9.3 mg/dL, LDL-C was 134.5±31.2 mg/dL, and non-HDL-C was 174.1±33.7 mg/dL (Table 1).
Table 1.Patient characteristics
|
Total
(n= 60)
|
IR 0.2 mg/day
(n= 40)
|
XR 0.4 mg/day
(n= 40)
|
XR 0.8 mg/day
(n= 40)
|
| Age, years |
57.5±9.8 |
57.4±9.6 |
56.8±10.1 |
58.4±9.7 |
| Male |
47 (78.3) |
33 (82.5) |
30 (75.0) |
31 (77.5) |
| Weight, kg |
71.5±13.6 |
73.0±13.7 |
69.9±13.0 |
71.5±14.0 |
| BMI, kg/m2
|
25.5±3.7 |
25.9±3.8 |
25.2±3.4 |
25.5±4.0 |
| TG, mg/dL |
221.3±68.1 |
220.9±76.3 |
229.0±68.3 |
214.0±58.6 |
| LDL-C (direct), mg/dL |
134.5±31.2 |
132.3±29.8 |
131.2±30.6 |
140.0±32.8 |
| HDL-C, mg/dL |
42.6±9.3 |
42.4±10.5 |
43.0±9.1 |
42.5±8.4 |
| non-HDL-C, mg/dL |
174.1±33.7 |
171.7±30.3 |
172.2±35.4 |
178.4±35.2 |
| Creatinine, mg/dL |
0.85±0.18 |
0.86±0.19 |
0.82±0.15 |
0.85±0.19 |
| eGFR, mL/min/1.73m2
|
71.3±13.1 |
70.9±13.7 |
72.8±12.9 |
70.2±12.9 |
| HbA1c, % |
5.9±0.5 |
5.9±0.5 |
5.8±0.4 |
5.9±0.5 |
| Concomitant disease |
| Hypertension |
17 (28.3) |
11 (27.5) |
11 (27.5) |
12 (30.0) |
| Type 2 diabetes mellitus |
10 (16.7) |
8 (20.0) |
3 (7.5) |
9 (22.5) |
| Metabolic syndrome |
32 (53.3) |
22 (55.0) |
20 (50.0) |
22 (55.0) |
| Concomitant statin use |
6 (10.0) |
4 (10.0) |
5 (12.5) |
3 (7.5) |
Data are presented as mean±standard deviation for continuous parameters and n (%) for categorical parameters.
IR, immediate-release; XR, extended-release; BMI, body mass index; TG, triglycerides; LDL-C, low-density lipoprotein cholesterol; HDL-C, high- density lipoprotein cholesterol; eGFR, estimated glomerular filtration rate; HbA1c, hemoglobin A1c.
Cumulative adherence (percentage of drug taken) was ≥ 80% in all except two patients: one forgot to bring the drug on an extended trip and the other withdrew from the study for personal reasons. There were no differences in medication adherence between treatment groups.
Efficacy
For the primary analysis of the primary endpoint, defined as the LS mean (95% CI), the percentage change in fasting serum TG from baseline to four weeks of treatment was −43.6% (−47.7, −39.5) for IR 0.2 mg/day, −41.1% (−45.1, −37.0) for XR 0.4 mg/day, and −39.7% (−43.8, −35.6) for XR 0.8 mg/day, showing statistically significant reduction in all groups (Fig.2A). The difference in the LS means (95% CI) vs. IR 0.2 mg/day were 2.5% (−1.5, 6.5) for XR 0.4 mg/day and 3.9% (−0.1, 7.8) for XR 0.8 mg/day (Table 2). For both XR doses, the upper limit of the 95% CI was below the non-inferiority margin of 10%, indicating that they were not inferior to IR 0.2 mg/day.
Table 2.Percentage changes in lipid-related markers
|
|
IR 0.2 mg/day
(n = 40)
|
XR 0.4 mg/day
(n = 40)
|
XR 0.8 mg/day
(n = 39)§
|
| TG, mg/dL |
Baseline |
220.9±76.3 |
229.0±68.3 |
214.0±58.6 |
| Week 4 |
123.3±39.3 |
127.7±40.2 |
124.8±39.6 |
| % Change |
−43.6 (−47.7, −39.5) |
−41.1 (−45.1, −37.0) |
−39.7 (−43.8, −35.6) |
| Differences |
|
2.5 (−1.5, 6.5) |
3.9 (−0.1, 7.8) |
| Total cholesterol, mg/dL |
Baseline |
214.1±31.0 |
215.2±34.0 |
221.6±35.9 |
| Week 4 |
198.7±33.0 |
200.4±32.8 |
193.4±27.2 |
| % Change |
−5.5 (−8.7, −2.4) |
−7.5 (−10.6, −4.4) |
−11.2 (−14.4, −8.0) |
| Differences |
|
−2.0 (−5.5, 1.6) |
−5.7 (−9.3, −2.1) ＊＊
|
| LDL-C (direct), mg/dL |
Baseline |
132.3±29.8 |
131.2±30.6 |
140.3±33.2 |
| Week 4 |
124.3±30.5 |
121.8±29.4 |
117.1±23.6 |
| % Change |
−3.5 (−8.4, 1.4) |
−7.0 (−11.9, −2.1) |
−11.3 (−16.2, −6.4) |
| Differences |
|
−3.5 (−8.0, 0.9) |
−7.8 (−12.3, −3.3) ＊＊
|
| HDL-C, mg/dL |
Baseline |
42.4±10.5 |
43.0±9.1 |
42.8±8.1 |
| Week 4 |
46.8±9.8 |
49.8±10.0 |
47.4±9.9 |
| % Change |
16.2 (12.1, 20.3) |
15.0 (11.0, 19.1) |
8.6 (4.5, 12.8) |
| Differences |
|
−1.2 (−5.5, 3.2) |
−7.6 (−12.0, −3.2) ＊＊
|
| non-HDL-C, mg/dL |
Baseline |
171.7±30.3 |
172.2±35.4 |
178.7±35.6 |
| Week 4 |
151.9±34.2 |
150.6±34.5 |
146.0±27.3 |
| % Change |
−10.7 (−14.6, −6.9) |
−12.8 (−16.6, −9.0) |
−15.8 (−19.6, −12.0) |
| Differences |
|
−2.1 (−5.9, 1.7) |
−5.1 (−8.9, −1.2) ＊
|
| FFA, mEq/L |
Baseline |
0.56±0.23 |
0.55±0.18 |
0.57±0.22 |
| Week 4 |
0.49±0.18 |
0.54±0.12 |
0.50±0.15 |
| % Change |
−9.3 (−18.1, −0.6) |
5.7 (−3.0, 14.5) |
−2.1 (−11.0, 6.7) |
| Differences |
|
15.1 (3.4, 26.8) ＊
|
7.2 (−4.6, 19.0) |
| LDL-C[mg/dL] / HDL-C[mg/dL] |
Baseline |
3.3±0.9 |
3.2±1.1 |
3.4±1.0 |
| Week 4 |
2.8±1.0 |
2.6±1.0 |
2.6±0.8 |
| % Change |
−16.2 (−21.5, −10.9) |
−18.4 (−23.8, −13.1) |
−17.4 (−22.8, −12.1) |
| Differences |
|
−2.3 (−6.1, 1.6) |
−1.2 (−5.2, 2.7) |
| non-HDL-C[mg/dL] / HDL-C[mg/dL] |
Baseline |
4.3±1.2 |
4.2±1.4 |
4.3±1.2 |
| Week 4 |
3.4±1.2 |
3.2±1.2 |
3.2±1.0 |
| % Change |
−22.1 (−26.2, −18.1) |
−23.4 (−27.4, −19.3) |
−21.1 (−25.3, −17.0) |
| Differences |
|
−1.2 (−4.7, 2.3) |
1.0 (−2.5, 4.5) |
| RLP-C, mg/dL |
Baseline |
13.5±7.6 |
14.1±7.6 |
13.2±5.2 |
| Week 4 |
6.3±3.6 |
6.3±3.5 |
5.8±2.5 |
| % Change |
−52.5 (−57.6, −47.4) |
−51.0 (−56.0, −45.9) |
−51.0 (−56.2, −45.9) |
| Differences |
|
1.5 (−3.7, 6.7) |
1.5 (−3.8, 6.7) |
| ApoAI, mg/dL |
Baseline |
125.0±17.3 |
126.8±16.7 |
125.7±14.5 |
| Week 4 |
129.8±15.4 |
138.4±15.8 |
136.7±17.0 |
| % Change |
6.8 (4.2, 9.3) |
8.2 (5.7, 10.7) |
8.2 (5.7, 10.8) |
| Differences |
|
1.4 (−1.4, 4.2) |
1.5 (−1.4, 4.3) |
| ApoAII, mg/dL |
Baseline |
30.3±4.3 |
31.5±4.9 |
31.4±5.3 |
| Week 4 |
41.9±8.7 |
48.5±7.4 |
49.5±9.3 |
| % Change |
42.6 (36.2, 48.9) |
50.9 (44.6, 57.2) |
59.9 (53.5, 66.2) |
| Differences |
|
8.4 (2.5, 14.3) ＊＊
|
17.3 (11.4, 23.3) ＊＊＊
|
| ApoB, mg/dL |
Baseline |
103.2±15.7 |
103.0±17.0 |
107.4±17.7 |
| Week 4 |
92.9±17.6 |
91.5±18.2 |
90.4±14.6 |
| % Change |
−9.8 (−13.0, −6.6) |
−11.9 (−15.1, −8.7) |
−13.4 (−16.7, −10.2) |
| Differences |
|
−2.1 (−5.3, 1.1) |
−3.7 (−6.9, −0.4) ＊
|
| ApoB48, mg/L |
Baseline |
9.0±5.7 |
9.2±6.0 |
9.0±4.2 |
| Week 4 |
4.4±3.3 |
4.4±3.3 |
4.0±1.6 |
| % Change |
−51.4 (−56.7, −46.1) |
−49.1 (−54.4, −43.8) |
−49.3 (−54.6, −43.9) |
| Differences |
|
2.3 (−3.6, 8.2) |
2.1 (−3.8, 8.1) |
| ApoCII, mg/dL |
Baseline |
7.8±2.6 |
8.3±2.6 |
7.9±2.2 |
| Week 4 |
6.6±2.6 |
7.0±2.5 |
6.5±2.3 |
| % Change |
−15.1 (−20.0, −10.2) |
−16.0 (−20.9, −11.1) |
−17.7 (−22.6, −12.7) |
| Differences |
|
−0.9 (−6.1, 4.3) |
−2.6 (−7.8, 2.7) |
| ApoCIII, mg/dL |
Baseline |
14.9±3.7 |
15.3±2.9 |
15.1±3.2 |
| Week 4 |
10.4±2.6 |
10.9±2.7 |
10.2±2.9 |
| % Change |
−28.4 (−32.7, −24.1) |
−29.1 (−33.4, −24.8) |
−31.9 (−36.2, −27.6) |
| Differences |
|
−0.7 (−5.9, 4.5) |
−3.5 (−8.7, 1.7) |
| ApoE, mg/dL |
Baseline |
4.0±1.5 |
4.1±1.4 |
3.9±1.2 |
| Week 4 |
2.9±0.8 |
2.8±0.7 |
2.7±0.6 |
| % Change |
−23.3 (−27.4, −19.3) |
−26.6 (−30.7, −22.6) |
−27.8 (−31.9, −23.7) |
| Differences |
|
−3.3 (−7.8, 1.2) |
−4.5 (−9.0, 0.1) |
| ApoB[mg/dL] / ApoAI[mg/dL] |
Baseline |
0.8±0.2 |
0.8±0.2 |
0.9±0.2 |
| Week 4 |
0.7±0.2 |
0.7±0.2 |
0.7±0.1 |
| % Change |
−15.0 (−18.3, −11.6) |
−18.3 (−21.6, −14.9) |
−19.1 (−22.5, −15.8) |
| Differences |
|
−3.3 (−6.1, −0.5) ＊
|
−4.2 (−7.0, −1.3) ＊＊
|
| ApoCIII[mg/dL] / ApoCII[mg/dL] |
Baseline |
2.0±0.5 |
1.9±0.5 |
2.0±0.4 |
| Week 4 |
1.7±0.4 |
1.7±0.4 |
1.6±0.3 |
| % Change |
−14.4 (−18.6, −10.2) |
−14.9 (−19.1, −10.7) |
−16.0 (−20.3, −11.8) |
| Differences |
|
−0.5 (−5.1, 4.1) |
−1.7 (−6.3, 3.0) |
Data are presented as mean±standard deviation for baseline and Week 4, and LS means (95% CI) for percentage change and differences. Differences are vs. IR 0.2 mg/day. ＊p＜0.05, ＊＊p＜0.01, ＊＊＊p＜0.001 (vs. IR 0.2 mg/day). §n = 40 for the marker of TG.
IR, immediate-release; XR, extended-release; TG, triglycerides; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; FFA, free fatty acids; RLP-C, remnant lipoprotein cholesterol; Apo, apolipoproteins; LS means, least-squares means; CI, confidence interval.
The LS means of the percentage change in fasting serum TG were −38.7%, −37.4%, and −36.7% for IR 0.2 mg/day, XR 0.4 mg/day, and XR 0.8 mg/day, respectively, for fasted administration, and −48.5%, −44.8%, and −42.7%, respectively, for fed administration (Fig.2B). The differences in the LS means (95% CI) between fed and fasted administration were −9.8% (−18.0, −1.6) for IR 0.2 mg/day, −7.4% (−15.5, 0.8) for XR 0.4 mg/day and −6.0% (−14.2, 2.2) and XR 0.8 mg/day, respectively. There was a trend toward stronger TG-lowering effects for fed than for fasted administration, but that timing of administration did not influence the effectiveness of treatment (interaction between treatment and timing of administration, p=0.621). TG-lowering effects for each of the XR doses in comparison to IR 0.2 mg/day were similar for fed and fasted administration.
Table 2 shows the LS means of the percentage change in lipid-related indexes from baseline to four weeks of treatment. Liver- and gall bladder-related indexes, glucose metabolism-related indexes and other indexes are provided in Supplementary Table 2. The LS means of the percentage change or change in FFA, ApoAII, ApoB/ApoAI, γ-GT, and ALP were statistically significant in XR 0.4 mg/day compared to IR 0.2mg/day. In XR 0.8 mg/day compared to IR 0.2 mg/day, the LS means of the percentage change or change in TC, LDL-C, HDL-C, non-HDL-C, ApoAII, ApoB, ApoB/ApoAI, γ-GT, ALP, and lathosterol showed statistically significant differences.
Supplementary Table 2.Changes in markers related to glucose metabolism, liver, and gall bladder, and cholesterol synthesis/ absorption markers
| (A) Glucose metabolism-related markers |
|
IR 0.2 mg/day
(n= 40)
|
XR 0.4 mg/day
(n= 40)
|
XR 0.8 mg/day
(n= 40) §
|
| Glucose, mg/dL |
Baseline |
110.5±13.9 |
107.2±11.2 |
112.0±13.6 |
| Change |
−2.0 (−3.6, −0.4) |
−3.2 (−4.8, −1.6) |
−2.5 (−4.1, −0.9) |
| Differences |
|
−1.2 (−3.5, 1.2) |
−0.5 (−2.9, 1.8) |
| Insulin, mU/L |
Baseline |
8.7±3.6 |
7.9±2.7 |
8.5±3.7 |
| Change |
−0.7 (−1.2, −0.2) |
−0.7 (−1.2, −0.2) |
−0.8 (−1.3, −0.3) |
| Differences |
|
0.0 (−0.5, 0.5) |
−0.1 (−0.6, 0.5) |
| HOMA-R |
Baseline |
2.4±1.2 |
2.1±0.9 |
2.4±1.2 |
| Change |
−0.2 (−0.4, −0.1) |
−0.28 (−0.4, −0.1) |
−0.3 (−0.4, −0.1) |
| Differences |
|
0.0 (−0.2, 0.1) |
0.0 (−0.2, 0.1) |
| HbA1c, % |
Baseline |
5.9±0.5 |
5.8±0.4 |
6.0±0.5 |
| Change |
0.0 (0.0, 0.1) |
0.0 (0.0, 0.1) |
0.0 (0.0, 0.1) |
| Differences |
|
0.0 (0.0, 0.1) |
0.0 (0.0, 0.1) |
| (B) Liver-related and gall bladder-related markers |
|
IR 0.2 mg/day
(n= 40)
|
XR 0.4 mg/day
(n= 40)
|
XR 0.8 mg/day
(n= 39) †
|
| AST, U/L |
Baseline |
24.6±9.0 |
23.2±7.3 |
24.1±9.1 |
| Change |
0.7 (−1.3, 2.7) |
−0.1 (−2.0, 1.9) |
1.4 (−0.6, 3.4) |
| Differences |
|
−0.8 (−2.8, 1.3) |
0.7 (−1.3, 2.7) |
| ALT, U/L |
Baseline |
31.4±17.1 |
28.6±17.6 |
29.6±18.9 |
| Change |
−4.1 (−6.7, −1.6) |
−6.9 (−9.4, −4.3) |
−6.7 (−9.3, −4.1) |
| Differences |
|
−2.7 (−5.7, 0.2) |
−2.6 (−5.6, 0.4) |
| γ-GT, U/L |
Baseline |
52.0±56.0 |
60.0±60.5 |
54.7±35.5 |
| Change |
−22.5 (−26.4, −18.6) |
−28.8 (−32.7, −24.9) |
−29.0 (−32.9, −25.0) |
| Differences |
|
−6.3 (−11.9, −0.7) ＊
|
−6.4 (−12.1, −0.8) ＊
|
| ALP, U/L |
Baseline |
202.6±49.9 |
208.2±46.6 |
201.9±41.9 |
| Change |
−54.2 (−59.3, −49.2) |
−63.8 (−68.9, −58.8) |
−71.1 (−76.2, −66.1) |
| Differences |
|
−9.6 (−15.1, −4.1) ＊＊
|
−16.9 (−22.4, −11.4) ＊＊＊
|
| Bilirubin, mg/dL |
Baseline |
0.81±0.25 |
0.80±0.28 |
0.80±0.27 |
| Change |
−0.16 (−0.19, −0.12) |
−0.14 (−0.17, −0.10) |
−0.17 (−0.20, −0.13) |
| Differences |
|
0.02 (−0.01, 0.06) |
−0.01 (−0.05, 0.03) |
| Bile acid, umol/L |
Baseline |
4.6±2.4 |
5.4±6.8 |
5.8±6.9 |
| Change |
−0.8 (−1.5, −0.2) |
−0.4 (−1.0, 0.3) |
−0.6 (−1.3, 0.0) |
| Differences |
|
0.4 (−0.4, 1.3) |
0.2 (−0.7, 1.1) |
| (C) Cholesterol synthesis/absorption markers |
|
IR 0.2 mg/day
(n= 40)
|
XR 0.4 mg/day
(n= 40)
|
XR 0.8 mg/day
(n= 40)
|
| Lathosterol, mg/L |
Baseline |
3.7±1.7 |
3.6±1.8 |
3.7±1.6 |
| Change |
−0.7 (−0.9, −0.5) |
−0.9 (−1.1, −0.7) |
−1.0 (−1.3, −0.8) |
| Differences |
|
−0.2 (−0.4, 0.0) |
−0.4 (−0.6, −0.2) ＊＊
|
| β-sitosterol, mg/L |
Baseline |
2.2±0.8 |
2.1±0.6 |
2.2±0.8 |
| Change |
−0.6 (−0.7, −0.5) |
−0.6 (−0.7, −0.5) |
−0.6 (−0.7, −0.5) |
| Differences |
|
0.0 (−0.2, 0.1) |
−0.1 (−0.2, 0.1) |
| Campesterol, mg/L |
Baseline |
3.9±1.4 |
3.8±1.1 |
4.0±1.5 |
| Change |
−0.9 (−1.1, −0.7) |
−1.0 (−1.1, −0.8) |
−1.0 (−1.2, −0.8) |
| Differences |
|
−0.1 (−0.4, 0.2) |
−0.2 (−0.4, 0.1) |
Data are presented as mean±standard deviation for baseline and LS means (95% CI) for change and differences. Differences are vs. IR 0.2 mg/day. ＊p＜0.05, ＊＊p＜0.01, ＊＊＊p＜0.001 (vs. IR 0.2 mg/day). §n = 39 for the marker of HbA1c. †n = 40 for the marker of bile acid.
IR, immediate-release; XR, extended-release; HOMA-R, homeostatic model assessment ratio; HbA1c, hemoglobin A1c; AST, aspartate aminotransferase; ALT, alanine aminotransferase; γ-GT, gamma-glutamyl transferase; ALP, alkaline phosphatase; LS means, least-squares means; CI, confidence interval.
Changes in the mean plasma drug concentration of unchanged pemafibrate at four weeks of treatment in the IR 0.2 mg/day, XR 0.4 mg/day, and XR 0.8 mg/day groups are shown in Fig.3A and C for fasted administration and in Fig.3B and D for fed administration. Findings for fasted and fed administration are compared in Supplementary Fig.2. Supplementary Table 3 shows basic statistics for the pharmacokinetic parameters of unchanged pemafibrate at four weeks of treatment in each group. Greater prolongation of MRTss, tmax, and t1/2 was observed with the XR formulation compared to the IR formulation for both fasted and fed administration.
Supplementary Table 3.Changes in mean plasma drug concentration of unchanged pemafibrate by formulation and dose: comparison between fasted and fed
|
IR 0.2 mg/day |
XR 0.4 mg/day |
XR 0.8 mg/day |
| Fasted (n = 20), ng/mL
|
Fed (n = 18), ng/mL
|
Fasted (n = 20), ng/mL
|
Fed (n = 19), ng/mL
|
Fasted (n = 20), ng/mL
|
Fed (n = 19), ng/mL
|
| Before dose |
0.10±0.14 |
0.31±0.20 |
0.20±0.17 |
0.18±0.13 |
0.28±0.18 |
0.58±0.74 |
| 0.25h |
0.32±0.37 |
0.27±0.16 |
0.19±0.16 |
0.20±0.13 |
0.26±0.15 |
0.56±0.58 |
| 0.5h |
0.83±0.66 |
0.38±0.22 |
0.22±0.17 |
0.20±0.14 |
0.30±0.16 |
0.56±0.54 |
| 1h |
2.04±0.86 |
0.71±0.57 |
0.75±0.56 |
0.20±0.14 |
1.35±1.07 |
0.56±0.51 |
| 1.5h |
1.97±0.80 |
1.01±0.64 |
1.94±1.64 |
0.23±0.18 |
3.79±2.45 |
0.59±0.54 |
| 2h |
1.58±0.70 |
1.20±0.59 |
2.73±2.45 |
0.32±0.41 |
5.23±3.05 |
0.61±0.54 |
| 3h |
1.08±0.67 |
1.22±0.51 |
2.87±2.97 |
0.43±0.71 |
5.05±2.84 |
0.64±0.46 |
| 4h |
0.75±0.60 |
1.16±0.44 |
2.33±2.27 |
0.43±0.60 |
4.06±2.04 |
0.72±0.56 |
| 6h |
0.38±0.35 |
0.85±0.42 |
1.53±1.37 |
0.91±0.77 |
2.84±1.21 |
1.88±1.51 |
| 8h |
0.22±0.26 |
0.51±0.38 |
1.18±1.01 |
3.29±2.82 |
2.49±1.34 |
6.52±3.70 |
| 10h |
0.11±0.16 |
0.23±0.16 |
1.57±1.14 |
2.84±1.47 |
3.16±2.56 |
7.56±4.06 |
| 12h |
0.07±0.12 |
0.15±0.11 |
1.20±0.90 |
2.00±0.75 |
2.52±1.96 |
5.95±3.40 |
| 14h |
1.35±0.72 |
0.65±0.45 |
0.82±0.57 |
1.07±0.40 |
1.73±1.30 |
3.57±2.44 |
| 16h |
0.70±0.50 |
1.09±0.61 |
0.50±0.34 |
0.66±0.31 |
1.09±0.76 |
2.06±1.49 |
| 24h |
0.10±0.13 |
0.22±0.13 |
0.19±0.10 |
0.29±0.35 |
0.40±0.20 |
0.57±0.37 |
Data are presented as mean±standard deviation.
IR, immediate-release; XR, extended-release.
To evaluate the relative bioavailability of XR against IR, the ratios of the geometric means of Cmax and AUC0‑τ were calculated for IR 0.2 mg/day vs. XR 0.4 and 0.8 mg/day. Results are shown in Supplementary Table 4. Because linearity had been confirmed up to 1 mg/day for the IR formulation, the IR results in this study were corrected to provide pemafibrate dose equivalence to the daily dose of pemafibrate administered with the XR formulation. After correction, the ratios (90% CI) for the AUC0-τ geometric mean between XR and IR were 0.86 (0.80, 0.93) for XR 0.4 mg/day and 0.88 (0.81, 0.95) for XR 0.8 mg/day for fasted administration and 0.87 (0.79, 0.96) for XR 0.4 mg/day and 1.04 (0.94, 1.14) for XR 0.8 mg/day for fed administration, with no major differences in pemafibrate exposure between each XR dose and IR (Supplementary Table 5). No major differences were found between XR 0.4 and 0.8 mg/day for the geometric mean ratios of Cmax and AUC0-τ between fasted and fed: Cmax 1.12 (0.84, 1.50) for XR 0.4 mg/day and 1.25 (1.03, 1.52) for XR 0.8 mg/day; AUC0-τ 1.10 (0.88, 1.37) for XR 0.4 mg/day and 1.27 (1.04, 1.55) for XR 0.8 mg/day (Supplementary Table 6). PK/PD analysis showed no apparent relationship between percentage change in fasting serum TG and plasma drug concentrations or pharmacokinetic parameters (Cmax, AUC0-τ, MRTss) at four weeks of treatment (data not shown).
Supplementary Table 4.Basic statistics for pharmacokinetic parameters of unchanged pemafibrate
|
IR 0.2 mg/day |
XR 0.4 mg/day |
XR 0.8 mg/day |
| Fasted |
Fed |
Fasted |
Fed |
Fasted |
Fed |
| Cmax, ng/mL
|
n
|
20 |
18 |
20 |
19 |
20 |
19 |
|
2.1 (37.9) |
1.5 (32.1) |
3.1 (70.6) |
3.5 (59.3) |
6.7 (31.7) |
8.3 (39.1) |
| tmax, h
|
n
|
20 |
18 |
20 |
19 |
20 |
19 |
|
1.2±0.2 |
3.3±1.5 |
5.2±3.9 |
8.5±2.1 |
4.7±3.7 |
9.7±1.7 |
| 1.0 (1.0, 1.5) |
3.0 (1.5, 6.0) |
3.0 (1.5, 14.0) |
8.0 (3.0, 11.9) |
3.0 (1.5, 11.9) |
10.0 (8.0, 14.0) |
| AUC0-τ, ng・h/mL
|
n
|
20 |
18 |
20 |
19 |
20 |
19 |
|
6.5 (63.5) |
7.7 (38.2) |
22.7 (61.8) |
24.9 (37.7) |
48.0 (32.4) |
61.0 (45.1) |
| t1/2, h
|
n
|
20 |
18 |
17 |
17 |
19 |
16 |
|
2.0 (30.1) |
2.1 (25.7) |
5.5 (43.6) |
4.2 (23.6) |
5.2 (50.0) |
3.8 (21.3) |
| MRTss, h
|
n
|
20 |
18 |
17 |
17 |
19 |
16 |
|
3.3 (26.8) |
5.2(18.2) |
9.2 (20.6) |
12.0 (14.1) |
9.4 (23.0) |
12.0 (9.7) |
Cmax, AUC0-τ, t1/2, and MRTss are presented as geometric means (coefficient of variation, %). tmax is presented as mean±standard deviation and median (min, max).
IR, immediate-release; XR, extended-release; AUC, area under the concentration-time curve; MRT, mean residence time.
Supplementary Table 5.Ratio of geometric means for C
max and AUC
0-τ, XR vs. IR
|
XR 0.4 mg/day / IR 0.2 mg/day |
XR 0.8 mg/day / IR 0.2 mg/day |
| Fasted |
Fed |
Fasted |
Fed |
| Cmax
|
0.38 (0.32, 0.45) |
0.63 (0.53, 0.75) |
0.39 (0.33, 0.46) |
0.71 (0.60, 0.85) |
| AUC0-τ
|
0.86 (0.80, 0.93) |
0.87 (0.79, 0.96) |
0.88 (0.81, 0.95) |
1.04 (0.94, 1.14) |
Data are presented as ratio (90% CI). Cmax and AUC0-τ values of IR 0.2 mg/day were corrected to be equivalent to the respective daily doses of XR. The calculation was made by multiplying by 4 times for comparison to XR 0.4 mg/day, and multiplying by 8 times for comparison to XR 0.8 mg/ day.
XR, extended-release; IR, immediate-release; AUC, area under the concentration-time curve; CI, confidence interval.
Supplementary Table 6.Ratio of geometric means of C
max and AUC
0-τ, fed to fasted, for each formulation and dose
|
IR 0.2 mg/day (Fed/Fasted) |
XR 0.4 mg/day (Fed/Fasted) |
XR 0.8 mg/day (Fed/Fasted) |
| Cmax
|
0.71 (0.60, 0.85) |
1.12 (0.84, 1.50) |
1.25 (1.03, 1.52) |
| AUC0-τ
|
1.20 (0.93, 1.54) |
1.10 (0.88, 1.37) |
1.27 (1.04, 1.55) |
Data are presented as ratio (90% CI).
IR, immediate-release; XR, extended-release; AUC, area under the concentration-time curve; CI, confidence interval.
AEs developed in 12.5% (5/40) of patients in the IR 0.2 mg/day groups, 17.5% (7/40) in the XR 0.4 mg/day groups, and 20.0% (8/40) in the XR 0.8 mg/day groups (Table 3). No ADRs were noted in the IR 0.2 mg/day groups, while 7.5% (3/40) occurred in the XR 0.4 mg/day and 7.5% (3/40) in the XR 0.8 mg/day groups. All ADRs were mild and resolved without serious sequelae.
Table 3.Summary of adverse events and adverse drug reactions
|
IR 0.2 mg/day
(n= 40)
|
XR 0.4 mg/day
(n= 40)
|
XR 0.8 mg/day
(n= 40)
|
| AEs |
ADRs |
AEs |
ADRs |
AEs |
ADRs |
| Total |
5 (12.5) |
0 |
7 (17.5) |
3 (7.5) |
8 (20.0) |
3 (7.5) |
| Deaths |
0 |
0 |
0 |
0 |
0 |
0 |
| Serious |
0 |
0 |
0 |
0 |
0 |
0 |
| Leading to discontinuation |
0 |
0 |
0 |
0 |
0 |
0 |
Data are presented as number of patients (%).
IR, immediate-release; XR, extended-release; AE, adverse event; ADR, adverse drug reaction.
The most common AE was nasopharyngitis, occurring in 5.0% of patients (2/40) at IR 0.2 mg/day and at XR 0.8 mg/day (Supplementary Table 7A). All other AEs were seen in only one patient each (2.5%, 1/40). No trends were detected toward a higher incidence of specific events with the XR than with the IR. No serious AEs or AEs leading to discontinuation were observed. Except for one moderate AE (nasopharyngitis, resolved without treatment) in the XR 0.8 mg/day group, all AEs were mild, and all resolved without issue. ADRs of constipation, stomatitis, and muscle spasms occurred in one patient each at XR 0.4 mg/day, and increased blood creatine phosphokinase, arthralgia, and rash occurred in one patient each at XR 0.8 mg/day (2.5%) (Supplementary Table 7B). All ADRs were mild and resolved without any issues.
Supplementary Table 7.Incidence of adverse events and adverse drug reactions, classified by MedDRA
§ SOC and PT and stratified by dosing conditions for each treatment
| (A) AEs |
|
IR 0.2 mg/day |
XR 0.4 mg/day |
XR 0.8 mg/day |
| All (n = 40)
|
Fasted (n = 20)
|
Fed (n = 20)
|
All (n = 40)
|
Fasted (n = 20)
|
Fed (n = 20)
|
All (n = 40)
|
Fasted (n = 20)
|
Fed (n = 20)
|
| Total |
5 (12.5) |
2 (10.0) |
3 (15.0) |
7 (17.5) |
6 (30.0) |
1 (5.0) |
8 (20.0) |
7 (35.0) |
1 (5.0) |
| Gastrointestinal disorders |
0 |
0 |
0 |
2 (5.0) |
1 (5.0) |
1 (5.0) |
0 |
0 |
0 |
| Constipation |
0 |
0 |
0 |
1 (2.5) |
0 |
1 (5.0) |
0 |
0 |
0 |
| Stomatitis |
0 |
0 |
0 |
1 (2.5) |
1 (5.0) |
0 |
0 |
0 |
0 |
| General disorders and administration site conditions |
0 |
0 |
0 |
1 (2.5) |
1 (5.0) |
0 |
0 |
0 |
0 |
| Oedema peripheral |
0 |
0 |
0 |
1 (2.5) |
1 (5.0) |
0 |
0 |
0 |
0 |
| Infections and infestations |
2 (5.0) |
0 |
2 (10.0) |
2 (5.0) |
2 (10.0) |
0 |
3 (7.5) |
3 (15.0) |
0 |
| Cystitis |
0 |
0 |
0 |
0 |
0 |
0 |
1 (2.5) |
1 (5.0) |
0 |
| Nasopharyngitis |
2 (5.0) |
0 |
2 (10.0) |
1 (2.5) |
1 (5.0) |
0 |
2 (5.0) |
2 (10.0) |
0 |
| Otitis externa |
0 |
0 |
0 |
1 (2.5) |
1 (5.0) |
0 |
0 |
0 |
0 |
| Investigations |
1 (2.5) |
1 (5.0) |
0 |
1 (2.5) |
1 (5.0) |
0 |
1 (2.5) |
1 (5.0) |
0 |
| Blood creatine phosphokinase increased |
0 |
0 |
0 |
0 |
0 |
0 |
1 (2.5) |
1 (5.0) |
0 |
| Blood urine present |
0 |
0 |
0 |
1 (2.5) |
1 (5.0) |
0 |
0 |
0 |
0 |
| White blood cell count increased |
1 (2.5) |
1 (5.0) |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
| Metabolism and nutrition disorders |
0 |
0 |
0 |
0 |
0 |
0 |
1 (2.5) |
0 |
1 (5.0) |
| Hyperuricemia |
0 |
0 |
0 |
0 |
0 |
0 |
1 (2.5) |
0 |
1 (5.0) |
| Musculoskeletal and connective tissue disorders |
0 |
0 |
0 |
1 (2.5) |
1 (5.0) |
0 |
1 (2.5) |
1 (5.0) |
0 |
| Arthralgia |
0 |
0 |
0 |
0 |
0 |
0 |
1 (2.5) |
1 (5.0) |
0 |
| Muscle spasms |
0 |
0 |
0 |
1 (2.5) |
1 (5.0) |
0 |
0 |
0 |
0 |
| Nervous system disorders |
1 (2.5) |
0 |
1 (5.0) |
0 |
0 |
0 |
0 |
0 |
0 |
| Presyncope |
1 (2.5) |
0 |
1 (5.0) |
0 |
0 |
0 |
0 |
0 |
0 |
| Respiratory, thoracic and mediastinal disorders |
1 (2.5) |
1 (5.0) |
0 |
0 |
0 |
0 |
1 (2.5) |
1 (5.0) |
0 |
| Upper respiratory tract inflammation |
1 (2.5) |
1 (5.0) |
0 |
0 |
0 |
0 |
1 (2.5) |
1 (5.0) |
0 |
| Skin and subcutaneous tissue disorders |
0 |
0 |
0 |
0 |
0 |
0 |
1 (2.5) |
1 (5.0) |
0 |
| Rash |
0 |
0 |
0 |
0 |
0 |
0 |
1 (2.5) |
1 (5.0) |
0 |
| (B) ADRs |
|
IR 0.2 mg/day |
XR 0.4 mg/day |
XR 0.8 mg/day |
| All (n = 40)
|
Fasted (n = 20)
|
Fed (n = 20)
|
All (n = 40)
|
Fasted (n = 20)
|
Fed (n = 20)
|
All (n = 40)
|
Fasted (n = 20)
|
Fed (n = 20)
|
| Total |
0 |
0 |
0 |
3 (7.5) |
2 (10.0) |
1 (5.0) |
3 (7.5) |
3 (15.0) |
0 |
| Gastrointestinal disorders |
0 |
0 |
0 |
2 (5.0) |
1 (5.0) |
1 (5.0) |
0 |
0 |
0 |
| Constipation |
0 |
0 |
0 |
1 (2.5) |
0 |
1 (5.0) |
0 |
0 |
0 |
| Stomatitis |
0 |
0 |
0 |
1 (2.5) |
1 (5.0) |
0 |
0 |
0 |
0 |
| Investigations |
0 |
0 |
0 |
0 |
0 |
0 |
1 (2.5) |
1 (5.0) |
0 |
| Blood creatine phosphokinase increased |
0 |
0 |
0 |
0 |
0 |
0 |
1 (2.5) |
1 (5.0) |
0 |
| Musculoskeletal and connective tissue disorders |
0 |
0 |
0 |
1 (2.5) |
1 (5.0) |
0 |
1 (2.5) |
1 (5.0) |
0 |
| Arthralgia |
0 |
0 |
0 |
0 |
0 |
0 |
1 (2.5) |
1 (5.0) |
0 |
| Muscle spasms |
0 |
0 |
0 |
1 (2.5) |
1 (5.0) |
0 |
0 |
0 |
0 |
| Skin and subcutaneous tissue disorders |
0 |
0 |
0 |
0 |
0 |
0 |
1 (2.5) |
1 (5.0) |
0 |
| Rash |
0 |
0 |
0 |
0 |
0 |
0 |
1 (2.5) |
1 (5.0) |
0 |
Data are presented as number of patients (%). The major categories are SOC, and the minor categories are PT. §MedDRA/J Ver. 22.0.
AE, adverse event; IR, immediate-release; XR, extended-release; ADR, adverse drug reaction; SOC, system organ class; PT, preferred term; MedDRA, Medical Dictionary for Regulatory Activities.
The incidence of AEs for fasted and fed was 10.0% (2/20) and 15.0% (3/20), respectively, for IR 0.2 mg/day, 30.0% (6/20) and 5.0% (1/20) for XR 0.4 mg/day, and 35.0% (7/20) and 5.0% (1/20) for XR 0.8 mg/day (Supplementary Table 7A). The XR groups showed a slightly lower incidence of AEs for fed than fasted administration, but there was no trend toward a higher incidence of any specific events.
Table 4 shows the change in various laboratory values from baseline to four weeks. There were no clinically important changes.
Table 4.Changes in safety markers
|
|
IR 0.2 mg/day
(n= 40)
|
XR 0.4 mg/day
(n= 40)
|
XR 0.8 mg/day
(n= 39)
|
| Creatinine, mg/dL |
Baseline |
0.86±0.19 |
0.82±0.15 |
0.85±0.19 |
| Week 4 |
0.87±0.20 |
0.84±0.16 |
0.90±0.20 |
| Change |
0.01±0.05 |
0.02±0.05 |
0.05±0.07＃
|
| eGFR, mL/min/1.73m2
|
Baseline |
70.9±13.7 |
72.8±12.9 |
70.1±13.0 |
| Week 4 |
70.6±13.8 |
71.5±12.8 |
66.4±12.2 |
| Change |
−0.3±4.8 |
−1.3±5.0 |
−3.8±5.6＃
|
| Creatine kinase, U/L |
Baseline |
120.2±70.8 |
101.8±45.9 |
113.3±77.5 |
| Week 4 |
120.2±64.2 |
107.0±53.8 |
126.2±130.3 |
| Change |
0.1±45.6 |
5.3±58.6 |
12.9±113.7 |
Data are presented as mean±standard deviation. ＃p＜0.001 (vs. baseline).
IR, immediate-release; XR, extended-release; eGFR, estimated glomerular filtration rate.
Discussion
This crossover study investigated the efficacy, safety, and pharmacokinetics of a once-daily extended-release formulation (XR 0.4 or 0.8 mg/day) of pemafibrate by fasted or fed administration for four weeks compared to the immediate-release formulation (IR 0.2 mg/day) in 60 patients with hypertriglyceridemia. The percentage change in fasting serum TG for XR 0.4 mg/day and XR 0.8 mg/day showed non-inferiority to IR 0.2 mg/day. The TG-lowering effect tended to be more pronounced for fed than for fasted administration, but effects in the XR 0.4 and XR 0.8 mg/day groups, both fasted and fed, were non-inferior to those in the IR 0.2 mg/day group. The XR groups showed 17.5% to 20.0% AEs and 7.5% ADRs during the study, but no specific events were associated more frequently with XR at both doses than IR, suggesting that the XR formulation has a favorable safety profile up to a dose of 0.8 mg/day. The pharmacokinetic profiles of XR showed prolongation of MRTss, tmax, and t1/2, indicating more sustained absorption than with IR.
This clinical pharmacology study confirmed the TG-lowering effects of XR, as previously demonstrated in a 12-week phase 3 study10) and a 52-week phase 3 study11). In this clinical pharmacology study, a statistically significant decrease in fasting serum TG was noted in the XR 0.4 and 0.8 mg/day groups, but the decrease was not dose-dependent, suggesting that the TG-lowering effect of XR reached a plateau at 0.4 mg/day, which is the approved dose of in Japan. The TG percentage change in the XR 0.4 mg/day group was −41.1%, comparable to the TG percentage change in the IR 0.4 mg/day group in a previous clinical trial of a similar patient population14), which suggests that with regard to efficacy, the XR formulation can be used in the same manner as the IR formulation.
In this study, fed administration tended to be associated with slightly greater percentage changes in fasting TG, but analysis of the interaction between treatment and administration timing showed that those differences were not significant. Additionally, the TG-lowering effects observed with fasted administration were clinically satisfactory, and the TG-lowering effects of XR were similar to IR for both fasted and fed administration. These findings suggest that the observed differences in TG-lowering effect for timing of administration were not caused by differences in the formulation profiles, and may involve topics to be considered in the future, including other currently unknown factors. Also of importance, a previous phase 3 study of XR showed no difference in efficacy between morning and evening administration11). We thus conclude that individual clinicians can be allowed to select the timing of administration of the XR formulation based on each patient’s concomitant medications and lifestyle patterns. In this regard, the XR formulation is expected to contribute to improved adherence in addition to providing the convenience of once-daily administration.
In this study, the XR 0.8 mg/day dose was associated with relatively low levels of HDL-C elevation. Although similar to findings from previous reports suggesting that the increase in HDL-C is not dose-dependent15), gel-permeation high-performance liquid chromatography (GP-HPLC) studies have shown that the cholesterol content in small HDL particles, which are characterized by their strong cholesterol efflux capacity, increased in a dose-dependent manner15), and that higher doses of pemafibrate (0.4 mg/day) improved this capacity for cholesterol efflux13). This study did not evaluate HDL functionality or particle size through GP-HPLC analysis, but we anticipate effects similar to those previously documented, suggesting a potential improvement in HDL function.
In humans, pemafibrate is metabolized primarily in the liver. The main pemafibrate metabolites in plasma include a form oxidized at the benzyl position and a glucuronide conjugate mixture of dicarboxylated and N-dealkylated forms16). The transactivation assay revealed that the activation of human PPARα by the pemafibrate metabolites was lower than by unchanged pemafibrate17). Therefore, in this study, the concentrations of unchanged pemafibrate were evaluated. The present study showed more sustained absorption in the XR pharmacokinetic profile, with confirmed prolongation of MRTss, tmax, and t1/2 in comparison to the IR formulation in Japanese patients with dyslipidemia. However, after correction for equivalent daily doses of XR and IR, the geometric mean ratio of AUC0-τ for XR at 0.4 mg/day and 0.8 mg/day ranged from 0.86 to 1.04 in relation to IR at 0.2 mg/day, indicating no significant differences in exposure. In this study, we found no apparent relationship between the percentage change from baseline in serum TG and plasma drug concentration or pharmacokinetic parameters (Cmax, AUC0-τ, MRTss). Previous reports have shown that the higher doses provided a more pronounced effect in patients with high TG levels or inadequate response to regular doses10, 11). In the present study, the patients had only mildly elevated TG (mean 221.3 mg/dL), suggesting that the TG-lowering effect reached a plateau at a blood concentration equivalent to IR 0.2 mg/day. This would explain why no clear relationship was noted between drug exposure and TG-lowering effect. Further investigation is needed on how TG lowering is related to differences in plasma drug concentration at different doses for both fasted and fed administration.
In this short study of two distinct four-week periods, the incidence of AEs for the XR doses ranged from 17.5% to 20.0% (7-8/40 patients), in comparison to 12.5% (5/40 patients) for IR. Notably, these were lower than in the previously reported 12-week study of IR, which showed a 41.0% incidence of AEs14). The AE findings from the present study confirmed a favorable safety profile for XR at doses up to 0.8 mg/day. There were no serious AEs or AEs leading to study discontinuation, no dose-dependent increases in AEs with XR, and no tendency for specific events to occur more frequently with XR.
Although there tended to be a slightly higher incidence of AEs with fasted administration, no specific events occurred at a higher incidence when XR was administered either fasted or fed, so that tendency was not considered to be clinically important. Although it is unclear whether differences in plasma drug concentrations affected the occurrence of AEs, there were no significant differences in AUC0-τ or Cmax between fasted and fed administration of the XR.
The change in the laboratory test indexes showed no clinically important fluctuations, although there were statistically significant fluctuations in some parameters. Previous reports have shown that eGFR and creatinine fluctuated early in the course of treatment and less frequently thereafter18), and that laboratory values became comparable to those in the placebo group after drug discontinuation19). These findings suggest that the eGFR and creatinine fluctuations do not necessarily indicate worsening of renal function20), but can be attributed to the effects of PPARα on creatinine production20, 21) and of vasodilatory prostaglandin suppression on renal dynamics and intraglomerular pressure22). We thus believe that our results may have reflected fluctuations in laboratory values immediately after drug administration.
Limitations
First, this study was a phase 2 clinical trial, enrolling a small number of patients (n=60) and applying strict eligibility and exclusion criteria. These factors may limit the generalizability of the study, since actual clinical practice is likely to include a wider range of patients. Second, because the purpose of this study was to compare the usual IR dose to XR doses including the maximum tolerated dose, the daily dose of pemafibrate differed between IR and XR. No comparison was made between IR 0.4 mg/day and XR 0.4 mg/day, although IR and XR are considered to be equally effective at the same dose10). Third, this study was not conducted as a double-blind, placebo-controlled trial. However, pemafibrate is widely used in clinical practice, it was considered ethically appropriate to evaluate efficacy and safety of XR with an existing IR formulation as a control. Fourth, 10% of patients used concomitant statins, and such use is anticipated in actual clinical practice, but the efficacy and safety of concomitant statin use was not addressed in the present study. However, since the efficacy and safety of concomitant statin use have been confirmed for IR23), we expect that the same will be true for XR. Fifth, this phase 2 clinical pharmacology study implemented a crossover design without a washout period between the two four-week periods of drug use. Previous results of pemafibrate clinical trials have confirmed that the TG-lowering effect of pemafibrate reaches a steady state two to four weeks after administration and reverts to the pre-treatment level four weeks after administration is discontinued14, 18), and we assumed a similar pattern by the end of the study. However, little information is available on whether pemafibrate would similarly affect indexes other than TG during a four-week period. In addition, although the efficacy and safety of XR were confirmed over a 52-week period in a phase 3 trial11), dyslipidemia treatment can be continued for many years in clinical practice. To ensure the health of patients, extensive data collection is essential, and evaluation in real-world clinical settings must be continued.
Conclusions
In patients with hypertriglyceridemia, the XR 0.4 mg/day and XR 0.8 mg/day doses demonstrated significant TG-lowering effects. These effects were not inferior to those observed with the IR 0.2 mg/day, irrespective of fasted or fed administration. The TG-lowering effect of XR was greatest at 0.4 mg/day, which is the approved dose in Japan. Safety profiles of XR were considered to be similar to IR up to 0.8 mg/day. The pharmacokinetic profile of XR showed a more prolonged excursion of serum drug concentration than was seen with IR.
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.
Conflict of Interests
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 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. Arai H has received personal fees from Kowa Company, Ltd., Daiichi Sankyo Company, Limited, and Astellas Pharma Inc. 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. Ishibashi S has received personal fees from Kowa Company, Ltd. Tanigawa R, Saito A, Suganami H, and Minamikawa S are employees of Kowa Company, Ltd.
Author Contributions
Yamashita S collected data and wrote the original draft of the manuscript. Araki E, Arai H, Yokote K and Ishibashi S collected data, edited the manuscript, and contributed to the interpretation of data and writing. Tanigawa R and Saito A conducted the clinical trial. Suganami H analyzed data. Minamikawa S edited the manuscript. All authors reviewed the final manuscript.
Data Sharing
Data sharing including the protocol are not applicable in this study.
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