Abstract
Fenofibrate is contraindicated in patients with advanced hepatic fibrosis due to limited clinical data. We evaluated the pharmacokinetics and safety of fenofibrate in participants with mild hepatic impairment (phase 1 study) or advanced fibrosis due to metabolic‐associated fatty liver disease (MAFLD; phase 2a study). In the phase 1 study, participants with mild hepatic impairment and healthy matched controls (each n = 10) received a single, oral dose of fenofibrate 48 mg. In the phase 2a study, participants with hypertriglyceridemia and advanced fibrosis due to MAFLD were randomly assigned (1:1) fenofibrate 48 mg (n = 15) or fenofibrate 145 mg (n = 16) combined with firsocostat 20 mg, taken orally once daily for 24 weeks. Pharmacokinetics and safety were assessed in both studies. In the phase 1 study, the AUCinf of fenofibric acid was 25% higher in participants with mild hepatic impairment than in healthy matched participants. In the phase 2a study, the AUCss,0‐24 of fenofibric acid (fenofibrate 48 mg dose) in participants with F3 fibrosis and F4 cirrhosis was approximately 60% and 80%, respectively, higher than the AUCinf in healthy participants in the phase 1 study, and was 20% higher in participants with F4 cirrhosis than in participants with F3 fibrosis. In both studies, most adverse events and laboratory abnormalities were grade 1‐2. In the phase 2a study, three participants had grade 3 hypertriglyceridemia. Fenofibrate was well tolerated, and modest differences were observed in fenofibric acid exposure in participants with mild hepatic impairment or advanced fibrosis due to MAFLD.
Keywords: fenofibrate, fibrosis, hepatic impairment, MAFLD/MASH, NASH/NAFLD, pharmacokinetics
Introduction
Fenofibrate is a prodrug of the active chemical moiety fenofibric acid, which is a peroxisome proliferator‐activated receptor‐α (PPAR‐α) agonist. 1 By activating PPAR‐α, fenofibrate upregulates lipoprotein lipase synthesis, induces high‐density lipoprotein (HDL) synthesis, and decreases production of apolipoprotein C in the liver. 1 Fenofibrate also enhances fatty acid oxidation via acyl‐coenzyme A synthetase and other enzymes, further reducing the synthesis of triglycerides. 1
Fenofibrate is indicated as an adjunct to diet to reduce elevated levels of low‐density lipoprotein (LDL), total cholesterol, triglycerides, and apolipoprotein B, to increase levels of HDL in adult patients with primary hypercholesterolemia or mixed dyslipidemia, and for the treatment of adult patients with severe hypertriglyceridemia. 1 , 2 , 3 Although the use of fenofibrate is contraindicated in patients with active liver disease, 3 the efficacy of fibrate therapy, including fenofibrate, has been evaluated in liver diseases such as primary or secondary sclerosing cholangitis, primary biliary cholangitis, cirrhosis due to primary biliary cholangitis, and intrahepatic cholestasis of pregnancy. 4 , 5 , 6 , 7
The recommended initial dosage of fenofibrate in adults is 43 to 130 mg taken orally once daily, which can be increased to 200 mg daily depending on the formulation. 8 Fenofibrate is not detected in plasma following oral administration because the drug is rapidly converted throughout the body by tissue and plasma esterases into the active metabolite fenofibric acid. Peak plasma concentration of fenofibric acid is achieved approximately 4‐8 h after fenofibrate administration and the exposure of fenofibric acid is dose proportional between the low (48 mg) and high (145 mg) fenofibrate doses evaluated in the current study. 9 , 10 , 11 Fenofibric acid is a highly protein‐bound drug (99%) that conjugates with glucuronic acid, so that approximately 60% of the initial fenofibrate dose is excreted in urine as fenofibric acid and fenofibric acid glucuronide, and 25% is excreted in feces. 1 , 9 , 12
There are limited data supporting the efficacy and safety of fenofibrate in patients with advanced liver fibrosis or compensated cirrhosis due to metabolic‐associated fatty liver disease (MAFLD) or metabolic dysfunction‐associated steatohepatitis (MASH). The available literature reports small studies that evaluate fenofibrate in patients with primary biliary cholangitis whose disease has an inadequate response to ursodeoxycholic acid. 4 , 13 , 14 Furthermore, the pharmacokinetics of fenofibrate have not been previously reported in patients with hepatic impairment or advanced liver fibrosis.
We aimed to evaluate the pharmacokinetics and safety of fenofibrate in participants with mild hepatic impairment and in participants with advanced fibrosis due to MAFLD to support potential combination therapy of fenofibrate with firsocostat, an investigational drug being evaluated for the treatment of MASH. 15 Firsocostat is an acetyl‐coenzyme A carboxylase (ACC) inhibitor that reduces hepatic de novo lipogenesis. 15 , 16 Previous studies have shown that a combination of cilofexor and firsocostat for the treatment of MASH with advanced fibrosis (stage F3 or F4) was well tolerated and considerably improved necroinflammatory and fibrosis‐related outcomes compared with the individual agents, which supports the potential benefit of a combination therapy. 17 , 18 However, increases in serum triglycerides have been observed in some patients treated with ACC inhibitors, including firsocostat. 19 , 20 , 21
Here we describe the pharmacokinetics and safety of fenofibrate from phase 1 and phase 2a studies. The phase 1 study evaluated the pharmacokinetics, safety, and tolerability of a single dose of fenofibrate in participants with mild hepatic impairment and healthy matched participants. The phase 2a study evaluated the pharmacokinetics, safety, and tolerability of fenofibrate in combination with firsocostat in participants with noncirrhotic and cirrhotic MAFLD.
Methods
Ethics Statement
Both the phase 1 and phase 2a studies were conducted in accordance with recognized international scientific and ethical standards, including, but not limited to, the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guideline for Good Clinical Practice and the original principles embodied in the Declaration of Helsinki. The phase 1 study was conducted at five sites (American Research Corporation at the Texas Liver Institute, San Antonio, TX; Clinical Pharmacology of Miami, Miami, FL; DaVita Clinical Research, Minneapolis, MN; Orange County Research Center, Tustin, CA; and Orlando Clinical Research Center, Orlando, FL). The phase 2a study was conducted at five sites (Altman Clinical and Translational Research Clinic, La Jolla, CA; American Research Corporation at the Texas Liver Institute, San Antonio, TX; Florida Research Institute, Lakewood Ranch, FL; Gastro One, Germantown, TN; and Ruane Clinical Research Group Inc., Los Angeles, CA). The protocols of both studies were approved by the independent ethics committees or Institutional Review Boards of the participating study sites. Informed consent was obtained from all participants.
Study Design and Participants, Phase 1 Study
The phase 1 study was an open‐label, multicenter, single‐dose, parallel‐group study that evaluated firsocostat and fenofibrate in participants with hepatic impairment and participants with normal hepatic function (ClinicalTrials.gov NCT02891408). This study consisted of four cohorts; cohorts 1‐3 received firsocostat (n = 54) and cohort 4 received fenofibrate (n = 20). Only participants with mild hepatic impairment or normal hepatic function who received fenofibrate were included for analysis in this publication (cohort 4, Figure 1). Participants with normal hepatic function were matched one‐to‐one for age (±10 years), sex, race, and body mass index (BMI) (±15%) to participants with hepatic impairment. Participants received a single oral dose of fenofibrate 48 mg on day 1, following an overnight fast (no food or drink except water for at least 10 h), and were discharged from the clinic on day 5. The primary endpoint of the study was the pharmacokinetics of fenofibrate in participants with mild hepatic impairment and normal hepatic function. The secondary endpoint was the safety and tolerability of fenofibrate in both groups.
Figure 1.
Study design of the phase 1 and phase 2a studies. aAn optional pharmacokinetic substudy was performed between day 1 and week 24 in a subset of 16 participants across both cohorts. Pharmacokinetic samples were collected over 24 h after study drug administration to determine the steady‐state pharmacokinetics of fenofibric acid. PK, pharmacokinetics; QD once daily.
Eligible participants were 18‐70 years old with a BMI of 18‐36 kg/m2 and were in general good health at the time of screening. Participants with mild hepatic impairment also had to have a chronic diagnosis (>6 months) of hepatic impairment with a Child–Pugh A classification, no clinically significant changes in disease in the 3 months before fenofibrate administration, and no changes to concomitant medications in the 4 weeks before fenofibrate administration. Participants with chronic hepatitis B virus infection, who were pregnant, or had any contraindication to fenofibrate other than hepatic impairment (per the approved package insert) were excluded from the study.
Study Design and Participants, Phase 2a Study
The phase 2a study was a multicenter, proof‐of‐concept, open‐label study (ClinicalTrials.gov NCT02781584). Eligible participants were randomly assigned (1:1) to receive pretreatment with fenofibrate 48 mg or fenofibrate 145 mg once daily for 2 weeks (from day −14 to day −1). After the pretreatment phase, participants continued to receive the same fenofibrate dose administered in the pretreatment phase in addition to firsocostat 20 mg once daily for 24 weeks (Figure 1). The primary endpoint of the study was the safety of fenofibrate and firsocostat in participants with MAFLD. The pharmacokinetic profile of fenofibric acid (the primary metabolite of fenofibrate) was evaluated as an exploratory endpoint.
Eligible participants for the phase 2a study were at least 18 years old with a clinical diagnosis of MAFLD and advanced liver fibrosis, as determined by a noninvasive test or historical biopsy, and a serum triglyceride level of ≥150 mg/dL at screening. Eligible participants also had fibrosis stage F3 (defined by liver biopsy or screening magnetic resonance elastography [MRE] with liver stiffness <4.67 kPa) or stage F4 (defined by liver biopsy or screening MRE with liver stiffness ≥4.67kPa). The MRE threshold of 4.67 kPa was considered the most appropriate F4 threshold based on a pooled analysis of data from participants with MAFLD. 22 Participants who were pregnant or lactating were excluded from the study. In addition, participants were excluded from the study if they had other causes of liver disease (including autoimmune, viral, and alcoholic liver disease) or a history of decompensated liver disease (including ascites, hepatic encephalopathy, or variceal bleeding), liver transplantation, or hepatocellular carcinoma.
Pharmacokinetic Sampling
In the phase 1 study, pharmacokinetic sampling occurred on day 1 at predose (≤5 min before dosing) and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 48, 72, and 96 h after dosing.
In the phase 2a study, intensive pharmacokinetic sampling was performed in a subset of participants who provided additional consent. Samples were collected over 24 h after dosing at a single visit between day 1 and week 24. As participants had been pretreated continuously with fenofibrate for 14 days before the fenofibrate and firsocostat co‐administration phase (study day −14 to −1), all fenofibrate parameter values derived from the intensive pharmacokinetic sampling were considered steady state.
Bioanalytical Methods
A commercially available bioanalytical method for evaluating fenofibric acid in human plasma was developed and validated at Covance Laboratories (Madison, WI). The samples were analyzed by high‐performance liquid chromatography‐tandem mass spectroscopy (LC‐MS/MS). Method validation met the expectations presented in the US Food and Drug Administration (FDA) guidance for bioanalytical method validation. 23 All samples were analyzed in the time frame supported by frozen stability storage data. The lower and upper limits of quantitation for fenofibric acid were 50 and 25,000 ng/mL, respectively. Intraday precision, expressed as percentage coefficient of variation, and accuracy, expressed as percentage relative error, ranged from 1.2% to 6.5% and −3.0% to 7.4%, respectively. Interday precision, expressed as percentage coefficient of variation, and accuracy, expressed as percentage relative error, ranged from 2.7% to 4.5% and from −1.0% to 3.4%, respectively.
Pharmacokinetic Analyses
Pharmacokinetic parameters were estimated with Phoenix WinNonlin 7.0 software (Certara, LP, Princeton, NJ) using noncompartmental methods. Samples quantified below the lower limit of quantification (LLOQ) that occurred before achieving the first quantifiable concentration were assigned a concentration value of zero. Samples that were below the LLOQ at all other time points were treated as missing data. Pharmacokinetic parameters included the area under the plasma concentration versus time curve (AUC) extrapolated to infinite time (AUCinf) and the elimination half‐life (t1/2) for the phase 1 study, and the steady‐state AUC from time zero to 24 h (AUCss,0‐24) for the phase 2a study. Maximum observed plasma concentration (Cmax) and time to Cmax (Tmax) were assessed in both studies.
Sample Size and Statistical Analyses
In the phase 1 hepatic impairment study, a sample size of 16 evaluable participants (8 per group, as is typical for similar organ impairment studies) was calculated to achieve at least 90% probabilities for AUCinf and Cmax of estimated two‐sided 90% confidence intervals (CIs) being within 0.5‐2.0 for geometric least‐squares mean (GLSM) ratios of mild hepatic impairment relative to the normal hepatic function group if the estimated GLSM ratio was 1.0. These estimates assumed a standard deviation of no more than 0.387 on a natural logarithmic scale, as supported by FDA review data on the pharmacokinetics of fenofibrate tablets. 24 A total sample size of 20 participants was required to account for a 25% overage.
The sample size for the phase 2a study (30 participants per group) was based on determining whether fenofibrate mitigates triglyceride elevations observed in patients with MASH treated with cilofexor and firsocostat. 16 For the current pharmacokinetic analysis, a subset of 16 participants from the phase 2a study was expected to provide an adequate characterization of the pharmacokinetic profile, as per the sample sizes typically used for phase 1 studies.
Statistical analyses were conducted using SAS Software v9.4 (Statistical Analysis System [SAS], Cary, NC). A parametric analysis of variance model appropriate for a parallel design was fitted to the logarithmically transformed pharmacokinetic parameters AUC and Cmax. Two‐sided 90% CIs were calculated for the GLSM ratios of the pharmacokinetic parameters between the mild hepatic impairment group and matched healthy control group in the phase 1 study, and between the participants with F3 bridging fibrosis and F4 compensated cirrhosis in the phase 2a study.
Safety Assessments
Safety was monitored throughout both studies and was evaluated by assessing clinical laboratory tests, electrocardiograms, periodic physical examinations, including vital sign measurements, and documentation of treatment‐emergent adverse events (TEAEs). Clinical and laboratory TEAEs were coded using the Medical Dictionary for Regulatory Activities Version (MedDRA) 22.0 for the phase 1 study and Version 23.1 for the phase 2a study.
Results
Participants Disposition and Demographics
The phase 1 study was conducted across five centers in the United States. Between October 2016 and May 2019, 74 participants enrolled in the overall study, of whom 20 received fenofibrate and were included in the fenofibric acid pharmacokinetic analysis set and the safety analysis set (Figure 1). Most participants were male (n = 14, 70.0%), White (n = 16, 80.0%), and Hispanic or Latino (n = 12, 60.0%).
The phase 2a study was conducted across five centers in the United States. Between July 2016 and February 2019, 31 participants were enrolled and randomly assigned to receive fenofibrate 48 mg/firsocostat 20 mg (n = 15) or fenofibrate 145 mg/firsocostat 20 mg (n = 16). All participants completed study treatment and were included in the safety analysis set. Most participants were female (n = 19, 61.3%), White (n = 30, 96.8%), and Hispanic or Latino (n = 12, 38.7%). A subset of 16 participants (9 from the fenofibrate 48 mg/firsocostat 20 mg group and 7 from the fenofibrate 145 mg/firsocostat 20 mg group) was included in the pharmacokinetic analysis set. Demographics and baseline characteristics for both studies are presented in Table 1.
Table 1.
Demographics and Baseline Characteristics (Safety Analysis Set)
| Phase 1 Study | Phase 2a Study | |||
|---|---|---|---|---|
|
Mild Hepatic Impairment (n = 10) |
Normal Hepatic Function (n = 10) |
Fenofibrate 48 mg QD + Firsocostat 20 mg QD (n = 15) |
Fenofibrate 145 mg QD + Firsocostat 20 mg QD (n = 16) |
|
| Age, years, mean (SD) | 58 (6.4) | 58 (5.1) | 59 (9.7) | 52 (14.2) |
| Male, n (%) | 7 (70.0) | 7 (70.0) | 5 (33.3) | 7 (43.8) |
| Race, n (%) | ||||
| White | 8 (80.0) | 8 (80.0) | 14 (93.3) | 16 (100) |
| Black | 2 (20.0) | 2 (20.0) | 0 | 0 |
| Asian | 0 | 0 | 1 (6.7) | 0 |
| Hispanic or Latino, n (%) | 6 (60.0) | 6 (60.0) | 2 (13.3) | 10 (62.5) |
| BMI, kg/m2, mean (SD) | 32.2 (3.6) | 30.9 (2.5) | 35.4 (4.8) | 34.1 (4.9) |
| Child–Pugh score, n (%) a | ||||
| 5 | 7 (70.0) | N/A | 14 (93.3) | 16 (100) |
| 6 | 3 (30.0) | N/A | 1 (6.7) | 0 |
| Fibrosis score, n (%) | ||||
| F3 | ND | ND | 9 (60.0) | 11 (68.8) |
| F4 | ND | ND | 6 (40.0) | 5 (31.3) |
| MELD score, mean (SD) | ND | ND | 7 (2.4) | 7 (1.1) |
| Laboratory tests, mean (SD) | ||||
| Albumin, g/dL | 4.1 (0.4) | 4.1 (0.4) | 4.6 (0.3) | 4.7 (0.2) |
| Total bilirubin, mg/dL | 0.5 (0.2) | 0.6 (0.2) | 0.5 (0.2) | 0.6 (0.4) |
| INR | 1.0 (0.1) | 1.0 (0.1) | 1.1 (0.3) | 1.1 (0.1) |
| ALT, U/L | 37 (25.3) | 19 (7.6) | 52 (50.1) | 48 (19.3) |
| AST, U/L | 32 (17.1) | 20 (5.8) | 37 (24.8) | 44 (22.2) |
| GGT, U/L | 64 (82.6) | 25 (8.5) | 96 (186.7) | 46 (19.9) |
| ALP, U/L | 70 (34.2) | 72 (9.7) | 76 (32.4) | 64 (13.4) |
| Total cholesterol, mg/dL | 177 (33.4) | 203 (36.7) | 184 (33.8) | 176 (49.6) |
| HDL cholesterol, mg/dL | 45 (10.7) | 53 (21.3) | 39 (7.7) | 39 (7.9) |
| LDL cholesterol, mg/dL | 117 (30.6) | 137 (31.5) | 100 (26.0) | 104 (39.2) |
| Triglycerides, mg/dL | 137 (78.6) | 120 (33.6) | 229 (130.0) | 163 (50.9) |
ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate aminotransferase; BMI, body mass index; GGT, gamma‐glutamyl transferase; HDL, high‐density lipoprotein; INR, international normalized ratio; LDL, low‐density lipoprotein; MELD, model for end‐stage liver disease; N/A, not applicable; ND, not determined; QD, once daily; SD, standard deviation.
A total Child–Pugh score of 5 or 6 is considered Child–Pugh class A.
Pharmacokinetics
The mean plasma concentrations versus time profiles of fenofibric acid, the primary metabolite of fenofibrate, in the phase 1 study are depicted in Figure 2 and the corresponding pharmacokinetic parameters are presented in Table 2. Following the administration of a single dose of fenofibrate 48 mg, the AUCinf and Cmax of fenofibric acid was 25% and 9% higher, respectively, in participants with mild hepatic impairment compared with matched participants with normal hepatic function. The difference in AUC observed after a single dose of fenofibrate is expected to be representative of difference expected at steady state. Peak plasma concentrations of fenofibric acid were achieved shortly after fenofibrate administration with a median Tmax of 3.0 and 2.5 h in participants with mild hepatic impairment and participants with normal hepatic function, respectively. The terminal t1/2 of fenofibrate was 21.3 and 18.3 h in participants with mild hepatic impairment and participants with normal hepatic function, respectively.
Figure 2.
The mean (± SD) plasma concentrations versus time profiles of fenofibric acid in participants with mild hepatic impairment or normal hepatic function (phase 1 study). SD, standard deviation.
Table 2.
Fenofibric Acid Pharmacokinetic Parameters
| Phase 1 Study a | |||
|---|---|---|---|
|
Pharmacokinetic Parameter |
Mild Hepatic Impairment (Single‐Dose Fenofibrate 48 mg) (n = 10) |
Normal Hepatic Function (Single‐Dose Fenofibrate 48 mg) (n = 10) |
GLSM Ratio (90% CI) |
| AUCinf (ng•h/mL) | 65,500 (39.6) | 50,800 (36.0) | 1.25 (0.89, 1.74) |
| Cmax (ng/mL) | 2720 (39.6) | 2450 (33.0) | 1.09 (0.81, 1.46) |
| Tmax (h) | 3.0 (3.0, 4.0) | 2.5 (2.0, 3.0) | |
| t1/2 (h) | 21.3 (17.9, 26.4) | 18.3 (15.7, 21.3) | |
| Phase 2a Study b | |||
|---|---|---|---|
|
Fenofibrate 48 mg QD + Firsocostat 20 mg QD (n = 9) |
Fenofibrate 145 mg QD + Firsocostat 20 mg QD (n = 7) |
||
| AUCss,0‐24 (ng•h/mL) | 86,800 (29.8) | 244,300 (30.0) | |
| Cmax (ng/mL) | 5430 (28.1) | 14,420 (26.4) | |
| Tmax (h) | 2.1 (2.0, 2.1) | 2.0 (2.0, 6.0) | |
|
F4 Fibrosis n = 4 |
F3 Fibrosis n = 12 |
||
|---|---|---|---|
| AUCss,0‐24 (ng•h/mL); dose normalized to fenofibrate 48 mg c | 92,400 (14.5) | 81,400 (33.3) | 1.20 (0.95, 1.50) |
| Cmax (ng/mL); dose normalized to fenofibrate 48 mg c | 5210 (9.5) | 5120 (31.7) | 1.07 (0.87, 1.33) |
| Tmax (h) | 2.0 (2.0, 2.0) | 2.1 (2.0, 4.0) |
Pharmacokinetics were evaluated for fenofibric acid only.
% CV, percentage of coefficient variance; AUCss,0‐24, area under the plasma concentration versus time curve from time zero to the concentration at 24 h after dosing, at steady state; AUCinf, area under the plasma concentration versus time curve extrapolated to infinite time; CI, confidence interval; Cmax, maximum observed plasma concentration; GLSM, geometric least‐squares mean; IQR, interquartile range; MAFLD, metabolic‐associated fatty liver disease; QD, once daily; t1/2, elimination half‐life; Tmax, time of maximum observed plasma concentration.
Pharmacokinetic parameters calculated after a single dose of fenofibrate were expected to accurately reflect alterations in pharmacokinetics under steady‐state conditions.
Pharmacokinetic parameters were determined under steady‐state conditions.
Stratified by fibrosis stage (F3/F4) with exposures (AUCss,0‐24 and Cmax) dose normalized to fenofibrate 48 mg.
AUCinf, AUCss,0‐24, and Cmax are presented as unadjusted arithmetic mean (% CV). Tmax and t1/2 are presented as median (IQR).
Data are rounded to three significant figures.
The steady‐state mean plasma concentrations versus time profiles of fenofibric acid in the phase 2a study are depicted in Figure 3, stratified by fenofibrate dose, and in Figure 4, stratified by fibrosis stage and dose normalized to fenofibrate 48 mg. The corresponding steady‐state pharmacokinetic parameters are presented in Table 2. From a cross‐study comparison of fenofibrate 48 mg, the AUCss,0‐24 of fenofibric acid was approximately 60% and 80% higher in participants with F3 fibrosis and F4 cirrhosis, respectively, than the AUCinf of fenofibric acid in participants with normal hepatic function in the phase 1 study. The AUCss,0‐24 and the Cmax of fenofibric acid was 20% and 7% higher, respectively, in participants with F4 cirrhosis than in participants with F3 fibrosis following the administration of fenofibrate 48 mg/firsocostat 20 mg or fenofibrate 145 mg/firsocostat 20 mg.
Figure 3.
The steady‐state mean (± SD) plasma concentrations versus time profiles of fenofibric acid, stratified by fenofibrate dose, in participants with hypertriglyceridemia and advanced fibrosis due to MAFLD (phase 2a study). MAFLD, metabolic‐associated fatty liver disease; SD, standard deviation.
Figure 4.
The steady‐state mean (± SD) plasma concentrations versus time profiles of fenofibric acid, stratified by fibrosis stage and normalized to fenofibrate 48 mg (phase 2a study). SD, standard deviation.
Safety
There were no deaths, grade 3 or 4 TEAEs, serious adverse events (SAEs), or TEAEs leading to discontinuation from either study (Table 3). In the phase 1 study, no participants in the mild hepatic impairment group experienced any TEAE. One participant with normal hepatic function experienced grade 1 diarrhea, which was deemed related to the study drug. In total, 15 participants (75%) experienced a graded treatment‐emergent laboratory abnormality during the study (mild hepatic impairment group, n = 9; normal hepatic function group, n = 6). The most common abnormalities (≥2 events) reported for the mild hepatic impairment group were increased uric acid (n = 3), increased serum glucose (n = 2), increased alanine aminotransferase (n = 2), and increased third‐generation LDL (n = 2). The most common abnormalities (≥2 events) reported for the normal hepatic function group were increased serum glucose (n = 3) and increased third‐generation LDL (n = 3). One grade 2 increase in third‐generation LDL occurred in both groups. A grade 2 increase in serum glucose and a grade 2 increase in total cholesterol were observed in the normal hepatic function group. No grade 3 or 4 laboratory abnormalities were reported.
Table 3.
Overall Summary of Adverse Events (Safety Analysis Set)
| Phase 1 Study | Phase 2a Study | |||
|---|---|---|---|---|
| n (%) |
Mild Hepatic Impairment (n = 10) |
Normal Hepatic Function (n = 10) |
Fenofibrate 48 mg QD + Firsocostat 20 mg QD (n = 15) |
Fenofibrate 145 mg QD + Firsocostat 20 mg QD (n = 16) |
| TEAE | 0 | 1 (10.0) | 13 (86.7) | 14 (87.5) |
| TEAE related to study drug | 0 | 1 (10.0) | 3 (20.0) | 6 (37.5) |
| SAE | 0 | 0 | 0 | 0 |
| TEAE leading to study discontinuation | 0 | 0 | 0 | 0 |
| Death | 0 | 0 | 0 | 0 |
| Commonly reported TEAEs (≥3 participants) | ||||
| Arthralgia | 0 | 0 | 3 (20.0) | 0 |
| Constipation | 0 | 0 | 3 (20.0) | 0 |
| Fatigue | 0 | 0 | 0 | 3 (18.8) |
| Headache | 0 | 0 | 0 | 4 (25.0) |
| Myalgia | 0 | 0 | 0 | 3 (18.8) |
| Upper respiratory tract infection | 0 | 0 | 5 (33.3) | 0 |
| Grade 2 or higher laboratory abnormalities | ||||
| LDL third generation | 1 (10.0) | 1 (10.0) | ND | ND |
| Increased serum glucose | 0 | 1 (10.0) | 0 | 0 |
| Increased total cholesterol | 0 | 1 (10.0) | 0 | 1 (6.3) |
| Increased lymphocytes | 0 | 0 | 0 | 1 (6.3) |
| Decreased neutrophils | 0 | 0 | 0 | 1 (6.3) |
| Increased CPK | 0 | 0 | 1 (6.7) | 0 |
| Increased GGT | 0 | 0 | 0 | 1 (6.3) |
| Hyponatremia | 0 | 0 | 1 (6.7) | 0 |
| Increased total bilirubin | 0 | 0 | 0 | 1 (6.3) |
| Hypertriglyceridemia | 0 | 0 | 7 (46.7) | 6 (37.5) |
| Increased INR | 0 | 0 | 1 (6.7) | 0 |
CPK, creatine phosphokinase; GGT, gamma‐glutamyl transferase; INR, international normalized ratio; LDL, low‐density lipoprotein; ND, not available; QD, once daily; SAE, serious adverse event; TEAE, treatment‐emergent adverse event.
Most participants in the phase 2a study experienced at least one TEAE: 13 participants (86.7%) in the fenofibrate 48 mg/firsocostat 20 mg group and 14 participants (87.5%) in the fenofibrate 145 mg/firsocostat 20 mg group. All TEAEs were grade 1 or 2 in severity. The most common TEAEs (observed in at least three participants) in the fenofibrate 48 mg/firsocostat 20 mg group were upper respiratory tract infection (n = 5), arthralgia (n = 3), and constipation (n = 3). The most common TEAEs in the fenofibrate 145 mg/firsocostat 20 mg group were headache (n = 4), myalgia (n = 3), and fatigue (n = 3). Five participants (31.3%) in the fenofibrate 145 mg/firsocostat 20 mg group had TEAEs deemed related to the study drugs, which included headache (n = 2), myalgia (n = 2), dizziness (n = 1), fatigue (n = 1), gastroesophageal reflux disease (n = 1), and nausea (n = 1). One participant (6.7%) in the fenofibrate 48 mg/firsocostat 20 mg group had a headache deemed related to the study drugs.
In the phase 2a study, all participants (100%) in the fenofibrate 48 mg/firsocostat 20 mg group and 14 participants (87.5%) in the fenofibrate 145 mg/firsocostat 20 mg group experienced a graded treatment‐emergent laboratory abnormality. Most laboratory abnormalities were grade 1 or 2 in severity. No grade 4 laboratory abnormalities were reported during the study. The most common abnormalities (≥4 events) reported for the fenofibrate 48 mg/firsocostat 20 mg group were hypertriglyceridemia (n = 9), hyperglycemia (n = 4), hyponatremia (n = 4), and increased creatine phosphokinase (n = 4). The most common abnormalities (≥4 events) reported for the fenofibrate 145 mg/firsocostat 20 mg group were hypertriglyceridemia (n = 8), increased creatine phosphokinase (n = 5), anemia (n = 4), and increased aspartate aminotransferase (n = 4). One participant (6.7%) in the fenofibrate 48 mg/firsocostat 20 mg group and two participants (12.5%) in the fenofibrate 145 mg/firsocostat 20 mg group had grade 3 hypertriglyceridemia. The median percentage change (interquartile range) from baseline at week 24 in fasting triglycerides was 26.4% (−6.0, 50.3) in the fenofibrate 48 mg/firsocostat 20 mg group and 51.6% (15.6, 69.9) in the fenofibrate 145 mg/firsocostat 20 mg group.
Discussion
The two studies described here evaluated the effect of mild hepatic impairment, advanced fibrosis, and compensated cirrhosis on the pharmacokinetics, safety, and tolerability of fenofibrate. Pharmacokinetics data from the phase 1 study showed that the exposure of fenofibric acid, the primary metabolite of fenofibrate, was not impacted to a clinically meaningful extent by mild hepatic impairment, while a cross‐study comparison with the phase 2a study suggested a modest impact of advanced fibrosis or compensated cirrhosis on fenofibric acid exposure (approximately 60%‐80% increase). Fenofibrate was well tolerated in both studies and most TEAEs and laboratory abnormalities were mild or moderate in nature.
There were no hypertriglyceridemia events in the phase 1 study; however, three participants in the phase 2a study reported grade 3 hypertriglyceridemia. Hypertriglyceridemia is common in patients with MAFLD and it is associated with dyslipidemia, progression to MASH, and an increased risk of cardiovascular disease. 25 Fenofibrate, which mitigates increases in triglycerides associated with acetyl‐CoA carboxylase inhibition, 4 , 5 , 6 , 7 has been shown to reduce hypertriglyceridemia in patients with MASH when treated with firsocostat alone or with both cilofexor and firsocostat. The phase 1 and phase 2a studies described here were conducted to investigate the use of fenofibrate to overcome increased triglyceride levels induced by ACC inhibition 17 , 26 and to increase fatty acid oxidation and cholesterol metabolism. 27 As all participants had hypertriglyceridemia at baseline in the phase 2a study, fenofibrate doses 48 and 145 mg were selected based on the range of fenofibrate starting doses previously used for the treatment of hypertriglyceridemia. 16 , 28
To date, no pharmacokinetic data are reported in the literature for fenofibrate in patients with hepatic impairment or advanced fibrosis. As fenofibrate is primarily hydrolyzed by esterases and excreted in the urine as fenofibric acid and fenofibric acid glucuronide, 1 , 9 , 12 mild hepatic impairment, advanced fibrosis, or compensated cirrhosis were not expected to alter the exposure of fenofibric acid or its glucuronide conjugate by any large extent.
In the phase 2a study, the pharmacokinetic profile of fenofibric acid was evaluated in an optional pharmacokinetic substudy, which was conducted during the treatment phase in which participants received fenofibrate and firsocostat for 24 weeks. Based on nonclinical (data on file; Gilead Sciences, Inc.) and clinical 29 drug–drug interaction information and data indicating that neither fenofibrate nor fenofibric acid undergoes oxidative metabolism to a significant extent, 11 there were no expected pharmacokinetic interactions between fenofibrate and firsocostat. A small increase in fenofibric acid exposure in patients with mild hepatic impairment relative to normal hepatic function was observed in the phase 1 study which was comparable to the increase observed in patients with F4 cirrhosis relative to patients with F3 fibrosis in the phase 2a study.
It is noteworthy that for fenofibrate 48 mg in the phase 2a study, the AUCss,0‐24 of fenofibric acid in participants with F3 fibrosis and F4 cirrhosis was approximately 60% and 80%, respectively, higher than the AUCinf of fenofibric acid in participants with normal hepatic function in the phase 1 study. This higher exposure is consistent with an approximately 60% higher AUCss,0‐24 of fenofibric acid for fenofibrate 145 mg (dose normalized to fenofibrate 48 mg) in the phase 2a study in participants with F3 fibrosis or F4 cirrhosis relative to that calculated based on the reported AUCss,0‐24 for fenofibrate 160 mg (dose normalized to fenofibrate 48 mg). 24 To account for potential differences in protein binding to fenofibrate during hepatic impairment and thus differences in free fenofibric acid exposure, comparisons of the free fenofibric acid fraction between participants with varying stages of hepatic impairment should be considered in the future. Additionally, data obtained from sparse pharmacokinetic sampling throughout the two studies, along with additional data from other ongoing studies, can be used to develop population pharmacokinetic models to further characterize the pharmacokinetics of fenofibrate in patients with hepatic impairment and differing magnitudes of fibrosis. It is also worth noting that available data in the F4 cirrhosis group were limited since the phase 2a study had only four participants in the optional pharmacokinetic substudy.
Conclusions
In conclusion, fenofibrate was well tolerated by all study participants and the pharmacokinetics of fenofibric acid were not impacted in individuals with mild hepatic impairment. When comparing across the phase 1 and phase 2a studies, a modest increase in fenofibric acid exposure was observed in participants with advanced fibrosis or compensated cirrhosis relative to participants with normal hepatic function. Data from these studies provide information on the use of fenofibrate for managing hypertriglyceridemia in patients with advanced fibrosis or compensated cirrhosis. Furthermore, the data contribute to our understanding of the pharmacokinetic profile of fenofibric acid in a previously underrepresented population of patients with hepatic impairment.
Author Contributions
Cara Nelson and Ann R. Qin designed the study. Islam R. Younis, Elijah J. Weber, Cara Nelson, Ann R. Qin, Timothy R. Watkins, and Ahmed A. Othman analyzed and interpreted the data, and drafted the manuscript. All authors revised and approved the final version of the manuscript for publication.
Conflicts of Interest
Ann R. Qin and Timothy R. Watkins are employees of Gilead Sciences, Inc., and may own stocks in Gilead Sciences, Inc. Islam R. Younis, Elijah J. Weber, Cara Nelson, and Ahmed A. Othman are previous employees of Gilead Sciences, Inc., and may own stocks in Gilead Sciences, Inc.
Funding
This study was funded by Gilead Sciences, Inc.
Acknowledgments
The authors thank all the participants, their families, and the investigators involved in this study. The authors also thank Cara Kingston, PhD, and Henry Chung, PhD, of Oxford PharmaGenesis, Melbourne, Australia, for providing medical writing support, which was funded by Gilead Sciences, Inc. in accordance with Good Publication Practice (GPP) 2022 guidelines.
Islam R. Younis, Elijah J. Weber, Cara Nelson, and Ahmed A. Othman were at Gilead Sciences, Inc. at the time this research was conducted.
Islam Younis and Ahmed A. Othman are Fellows of the American College of Clinical Pharmacology (FCP).
Data Availability Statement
Gilead Sciences shares anonymized individual patient data upon request or as required by law or regulation with qualified external researchers based on submitted curriculum vitae and reflecting no conflicts of interest. The request proposal must also include a statistician. Approval of such requests is at Gilead Sciences’ discretion and is dependent on the nature of the request, the merit of the research proposed, the availability of the data, and the intended use of the data. Data requests should be sent to datarequest@gilead.com.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Gilead Sciences shares anonymized individual patient data upon request or as required by law or regulation with qualified external researchers based on submitted curriculum vitae and reflecting no conflicts of interest. The request proposal must also include a statistician. Approval of such requests is at Gilead Sciences’ discretion and is dependent on the nature of the request, the merit of the research proposed, the availability of the data, and the intended use of the data. Data requests should be sent to datarequest@gilead.com.