Evaluation of the Pharmacokinetics, Disposition, and Metabolism of Miricorilant, a Novel Glucocorticoid Receptor Modulator for the Treatment of Metabolic Dysfunction‐Associated Steatohepatitis in Nonclinical and Clinical Studies

Abstract

Miricorilant is a novel selective glucocorticoid receptor (GR) modulator with mixed agonist/antagonist effects at the GR and modest antagonism at the mineralocorticoid receptor that is being developed for the treatment of metabolic dysfunction‐associated steatohepatitis. Its overall pharmacokinetic characteristics were assessed, including its disposition (absorption, distribution, metabolism, and elimination [ADME]) and drug–drug interaction (DDI) potential. In vitro, miricorilant (1) demonstrated >99% plasma protein binding in mice, rats, monkeys, and humans, (2) was a modest inhibitor of CYP3A4, CYP2C8, CYP2C9, UGT1A1, and a strong inhibitor of BCRP, (3) was predominantly metabolized by CYP2C19 (≈94%), and (4) showed no induction potential for CYP1A2 and CYP2B6, but showed a concentration‐dependent induction of CYP3A4 (6.5‐fold) in 1 out of 3 donors tested. In a tissue distribution study in mice, miricorilant was distributed with high levels of radioactivity present in several tissues, including the liver. In animal and human ADME studies, the majority of total radioactivity was recovered in feces (>78%) versus urine (<5%), suggesting hepatic elimination with minor contribution of renal elimination. In phase 1 clinical studies in healthy subjects, miricorilant showed an approximately dose‐proportional increase in systemic exposure in the dose range 100–900 mg with an elimination half‐life of ≈20 h. In clinical DDI studies at the total plasma concentrations evaluated, miricorilant was a strong inhibitor of CYP2C8 and a moderate inhibitor of BCRP with no meaningful inhibition of CYP2C9, CYP3A4, or UGT1A1, and a moderately sensitive substrate of CYP2C19. Miricorilant was safe and well‐tolerated in the phase 1 studies.

Introduction

Metabolism dysfunction‐associated steatohepatitis (MASH) is a progressive liver disorder that can lead to cirrhosis and liver failure and predispose patients to hepatocellular cancer. ¹ , ² , ³ MASH is currently the third most common cause of cirrhosis and is expected to become the leading cause as the prevalence of metabolic disease increases and management of viral hepatitis improves. ⁴ , ⁵ MASH has become one of the leading causes of liver disease and hepatocellular cancer. ⁶ , ⁷ Resmetirom was recently approved in the United States for the treatment of MASH, but there remains a need for new drugs to treat this disease. Miricorilant (CORT118335) is a nonsteroidal selective glucocorticoid receptor modulator that acts as a mixed agonist/antagonist of the glucocorticoid receptor and a modest antagonist of the mineralocorticoid receptor. ⁸ Glucocorticoids such as cortisol (the natural ligand for glucocorticoid receptor) are involved in the regulation of energy homeostasis and increase the availability of energy substrates, such as free fatty acids. Increased glucocorticoid levels have been implicated in the pathogenesis of obesity, hyperglycemia, and fatty liver disease; the role of glucocorticoids in the pathogenesis of fatty liver disease has been reviewed previously. ³ Miricorilant has shown efficacy in mouse models of fatty liver disease. ⁹ In a phase 1b study in patients with presumed MASH, dosing with miricorilant was associated with rapid and substantial reduction of liver fat. ¹⁰ The phase 2 MONARCH study in patients with MASH is currently enrolling patients (NCT06108219).

In this manuscript, we report the assessment of absorption, distribution, metabolism, and elimination (ADME) of miricorilant using a range of preclinical and clinical studies.

Methods

All human studies were conducted in accordance with the latest versions of the International Conference for Harmonisation E6 Guideline for Good Clinical Practice, the Declaration of Helsinki, and appropriate regulatory guidelines. Approval was obtained from the UK Medicines and Healthcare products Regulatory Authority or the US Food and Drug Administration (FDA) as applicable, and from the relevant independent ethics committee or institutional review board. All studies were registered on an appropriate public registry. All study subjects provided written informed consent before any study‐specific procedure was performed.

Chemicals

Miricorilant used in the studies reported here was synthesized at Almac Sciences (Craigavon, UK). The [¹⁴C]‐labeled miricorilant was synthesized at Selcia Ltd (Essex, UK). The chemical structure of miricorilant and the position of the label are shown in Figure 1.

Figure 1.

Chemical structure of miricorilant.

In Vitro Studies

Plasma Protein Binding

The extent of protein binding of miricorilant in vitro was determined in mouse, rat, monkey, and human plasma by equilibrium dialysis. Liquid chromatography‐mass spectrometry (LC‐MS) was used to quantify miricorilant in each compartment and determine the percentage of protein binding.

Blood/Plasma Partitioning

The in vitro blood/plasma ratio for miricorilant was determined for rats, monkeys, and humans by adding miricorilant to whole blood, incubating the samples, and then centrifuging to generate plasma. The concentration of miricorilant in directly spiked plasma was determined by LC‐MS and compared with the concentration in the plasma obtained from the blood incubation.

Cytochrome P450 Inhibition

The inhibitory effects of miricorilant on cytochrome P450 (CYP) CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 activities were assessed simultaneously using CYPs heterologously expressed in Escherichia coli and purchased as a custom‐made mixture of all 5 isoforms. A selective and FDA‐accepted substrate for each isoform was present at a concentration close to its K_m (Michaelis‐Menten constant). Activity of each isoform was assessed by measuring the appearance of an isoform‐specific metabolite. The isoform‐specific substrates are listed in the Supplemental Methods.

Cytochrome P450 Induction

Miricorilant was evaluated for its induction potential of CYP1A2, CYP2B6, and CYP3A4 by the mRNA expression levels of these P450 isoforms in cryopreserved human hepatocytes from three individual donors incubated with concentrations of miricorilant up to 10 µM. CYP mRNA levels were determined by quantitative polymerase chain reaction. The isoform‐specific substrates are listed in the Supplemental Methods.

Transporter Inhibition

Miricorilant was assessed for inhibition of the adenosine triphosphate‐binding cassette transporters breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug resistance protein 1 (MDR1 or P‐glycoprotein [P‐gp]), and multidrug resistance‐associated protein‐2 (MRP2) using inside‐out vesicles prepared from cells overexpressing human adenosine triphosphate‐binding cassette transporters. The assay details are provided in the Supplemental Methods.

Inhibition of the solute carrier transporters multidrug and toxin extrusion protein (MATE) 1 and MATE2‐K (nominal miricorilant concentrations 0.8 and 8 µM), organic anion transporter (OAT) 1, OAT3, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, and organic cation transporter (OCT) 1 and OCT2 (nominal miricorilant concentrations 0.1 and 1 µM), was evaluated in human embryonic kidney mammalian cells expressing the transporters.

Metabolism by CYP Enzymes

The contribution of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 human CYP isoforms to the metabolism of miricorilant was assessed. The assay details are provided in the Supplemental Methods.

In Vivo Studies

Elimination, Metabolism, and Tissue Distribution in Mice

An ADME study was performed in male albino CD1 mice to assess the absorption, pharmacokinetics, and routes and rates of excretion of [¹⁴C]‐miricorilant after oral administration of a single dose of 50 mg/kg (5 MBq/kg) [¹⁴C]‐miricorilant. The relative proportions of miricorilant and identity of its metabolites in plasma, urine, and feces were determined. A quantitative whole‐body autoradiography study was also conducted in non‐pigmented and partially pigmented C57 mice to determine tissue distribution of radioactivity.

Blood and plasma were analyzed for radioactivity content, and the remaining plasma, urine, and feces were used for metabolite profiling and identification. Metabolite profiles were generated using radio‐high‐performance LC coupled to an Orbitrap MS. Online detection was used for feces, but offline radio detection was used for plasma and urine samples due to low levels of radioactivity. Selected samples were further analyzed by LC‐MS with tandem MS (LC‐MS/MS) to characterize the major metabolites. Whole‐body autoradiography was performed on frozen carcasses to determine the tissue distribution of radioactivity.

Metabolism and Excretion Study in Monkeys

In a similar study, cynomolgus monkeys were administered a single dose of 80 mg/kg (2 MBq/kg) [¹⁴C]‐miricorilant by oral gavage, and blood, urine, and feces samples were collected at predetermined timepoints postdose for total radioactivity analysis and metabolite profiling. The plasma, urine, and feces samples were analyzed using high‐resolution LC‐MS with online fraction collection and offline counting.

Human Phase 1 Studies

Subjects were admitted to the clinical pharmacology unit at least the day before the first administration of study medication and remained within the clinical pharmacology unit until at least 24 h after the last administration of study medication. A follow‐up visit or telephone call was held 4 to 7 days after the last administration of study medication (with the exception of the ADME study).

For the first‐in‐human study, the PI was Stuart Mair MBChB, DRCOG, DCPSA, FFPM and the protocol was submitted to and approved by the MHRA and the South Central ‐ Berkshire Research Ethics Committee (UK). For the human ADME and clinical DDI perpetrator studies, the PI was Sharan Sidhu, MBChB, BAO, MRCS, MFPM, and the protocol was submitted to and approved by the MHRA and London ‐ Hampstead Research Ethics Committee (UK). For the clinical DDI victim study, the PI was Jeffrey Levy, MD, PhD, and the protocol was submitted to and approved by the IRB, Advarra (Maryland, USA).

Clinical Study Population

All clinical studies enrolled healthy adults. Non‐lactating women of non‐childbearing potential were eligible for all except the ADME study. Major inclusion criteria included providing written informed consent; within specified ranges for body weight (≤102 kg) and body mass index (BMI) (18.0 to 30.0 kg/m²); and overall good health, based on the results of medical history, physical examination, vital signs, 12‐lead electrocardiogram, and clinical laboratory safety findings conducted at a screening examination within 28 days before the first dose of study medication. Subjects were excluded if they had a history of clinically significant cardiovascular, renal (eGFR of <60 mL/min/1.73m²), hepatic (alanine aminotransferase and/or aspartate aminotransferase >1.5× upper limit of normal), endocrine, metabolic, respiratory, gastrointestinal or neurological disease; clinically significant abnormal clinical chemistry; or were seropositive for hepatitis B, hepatitis C, or HIV. Additionally, subjects were excluded if they had taken any systemic glucocorticoid within 12 months or inhaled glucocorticoid within 3 months; any investigational or non‐investigational medicinal product in a clinical research study within 3 months; any enzyme inducer within 30 days; or any prescription, over‐the‐counter or herbal preparations within 14 days of the first dose of study medication (or longer for long half‐life products). Subjects were required to abstain from dietary products that could interfere with drug metabolism or safety assessments, including alcohol, caffeine, quinine, poppy seeds, grapefruit, or other exotic fruits during the clinical phase of the study.

First‐in‐Human Study (NCT03315338)

The first‐in‐human study of miricorilant was an adaptive‐dose, double‐blind, placebo‐controlled, six‐part, single‐ and multiple‐ascending dose (SAD and MAD, respectively) study of the safety, tolerability, pharmacokinetics, and pharmacological effects of orally administered miricorilant in healthy adult subjects that included evaluation of the effects of fed versus fasted dosing on miricorilant plasma exposures. The first‐in‐human study evaluated miricorilant administered as a spray‐dried dispersion (SDD) formulation. The SAD and MAD cohorts utilized an SDD suspension to allow for optimal flexibility and efficiency for selecting dose levels for each escalation. Subsequently, the SDD was administrated as a 100‐mg tablet to compare the plasma exposures after the tablet with those after the suspension on a dose‐normalized basis. A formal interim review of pharmacokinetic and safety data was conducted after each new dose level before selecting the next dose level. Dose escalation was permitted only if the safety and tolerability of all previous doses/dose regimens were acceptable. No dose was predicted to exceed an area under the concentration versus time curve AUC_0–24 for miricorilant in any individual subject of 36,540 ng h/mL.

This upper limit on the AUC value was set based on the findings in the 28‐day Good Laboratory Practice toxicology study in mice. No adverse effects were seen in 28‐day toxicology studies conducted in mice and monkeys, and the exposure cap was based on the combined gender mean no‐observed‐adverse‐effect‐level Day 28 miricorilant AUC_0–24 in mice, 36,540 ng h/mL.

Each daily dose level studied in the MAD part of the study was predicted to give an exposure (AUC_0–24 at steady state) for miricorilant that was no greater than that previously found to be tolerated well in the SAD part of the study.

Part 1 (SAD) was a double‐blind, randomized, placebo‐controlled assessment of single doses of miricorilant. Subjects were enrolled sequentially into one of four cohorts, each of eight subjects. Within each cohort, six subjects received miricorilant at the assigned dose (100, 300, 900, and 1500 mg) and two received matching placebo. Part 1 was initiated with a starting dose that represented the lowest pharmacologically active dose supported by safety and toxicology data, and based on the maximum recommended starting dose for single‐dose administration to human subjects, calculated based on the FDA Guidance and European Medicines Agency Guidelines. All dose levels were orally administered in the fasted state. One cohort (900 mg) additionally took part in an evaluation of the effect of coadministration with food and returned for a second period to receive the same dose with food.

Part 2 (MAD) was a double‐blind, randomized, placebo‐controlled assessment of 14 days of administration of miricorilant. Subjects were enrolled sequentially into one of three cohorts, each of 12 subjects. Within each cohort, nine subjects received miricorilant at the assigned dose (150, 450, or 900 mg) and three received matching placebo. All doses were administered once daily in the fasted state.

Part 3 evaluated the bioavailability and the effect of coadministration with food on exposure to single doses of miricorilant 100‐mg tablet in an open‐label, single‐sequence, crossover design. Subjects received miricorilant 200 mg in the fasted state. After a minimum washout of 7 days (greater than five half‐lives of miricorilant), subjects were readmitted to receive the same dose in the fed state, after a standard high‐fat breakfast.

Pharmacokinetic Sampling

Following administration of single doses of miricorilant, pharmacokinetic blood sampling was performed at predose (0 h), and 1, 2, 4, 8, 12, 16, 24, 36, 48, 72, and 96 h postdose. Following administration of multiple doses of miricorilant, pharmacokinetic blood sampling was performed at predose (0 h), and 1, 2, 4, 8, 12, 16, and 24 h (before next dose) after administration of miricorilant on days 1, 7 and 14; predose on days 2, 3, 5, 8, and 10; and at 24, 36, 48, 72, and 96 h after final administration of miricorilant on day 14. Blood samples were collected in tubes containing dipotassium ethylenediaminetetraacetic acid (K₂EDTA) as the anticoagulant. Tubes were kept on ice and centrifuged at 4°C to harvest plasma. Plasma samples were stored at −70°C until the bioanalysis was conducted.

Bioanalytical Procedure

The plasma concentrations of miricorilant in the first‐in‐human study (NCT03315338) and in the miricorilant victim study (NCT05712265), described later in the manuscript, were determined using a validated LC‐MS/MS method. The full details of the bioanalytical method used in this study are summarized in the Supplemental Methods.

Human ADME Study (NCT03878264)

This was a phase 1, single‐center, open‐label, single‐dose ADME study in healthy male subjects. Six subjects received a single oral dose of 150 mg [¹⁴C]‐miricorilant containing not more than 3.3 MBq (90 µCi) [¹⁴C] as an oral solution after a standard breakfast. The subjects remained in the clinical pharmacology unit until day 11. Blood samples were collected predose and at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 288, 312, and 336 h postdose for the measurement of total radioactivity and parent miricorilant. All urine and feces were collected throughout the 11 days. Feces samples were analyzed using high‐resolution LC‐MS with inline fraction collection and offline counting. Plasma samples were analyzed using accelerator mass spectrometry.

Drug–Drug Interaction Studies

Miricorilant as Perpetrator (ISRCTN10379288)

This was a phase 1, open‐label, fixed‐sequence, single‐center study conducted in 30 healthy subjects to evaluate the pharmacokinetics of a cocktail of probe substrates in the absence and presence of miricorilant as a perpetrator. The cocktail approach to conducting clinical drug–drug interaction (DDI) evaluations efficiently and effectively using concurrent administration of several CYP isoform‐selective probe drugs is common and includes examples such as the “Inje” or “Cooperstown 5+1” cocktails. ¹¹ , ¹² , ¹³ , ¹⁴ A sample size of 26 evaluable subjects was predicted to provide 80% power to show the confidence interval (CI) of the geometric mean ratio or the log‐transformed pharmacokinetic parameters are within the 80.00% to 125.00% equivalence criteria if the ratio is between 95% and 105% and the coefficient of variation is not more than 21%. Considering the possibility of up to a 13% withdrawal rate, in total, 30 subjects were intended to be enrolled in the study.

The probe cocktail consisted of 1 × 0.5 mg repaglinide tablet (CYP2C8), 1 × 10 mg rosuvastatin tablet (BCRP efflux transporter), 1 × 50 mg dolutegravir tablet (uridine diphosphate glucuronosyltransferase [UGT] 1A1), 1 × 500 mg tolbutamide tablet (CYP2C9) and 0.5 mL × 5 mg/mL (2.5 mg) midazolam solution (CYP3A), and was dosed in that order on the mornings of day 1 and day 10. Probe substrates were selected based on their specificity toward their respective enzymes and lack of any meaningful overlapping pathways with the other enzymes concurrently evaluated. Subjects received oral doses of 8 × 50‐mg miricorilant tablets once a day on days 4 to 12 (immediately before the second dose of the probe cocktail on day 10). All doses were administered after a standard breakfast.

Pharmacokinetic Sampling

The timing of blood samples was based on the pharmacokinetic profile of each probe drug to estimate the key pharmacokinetic parameters for evaluating potential DDIs, including AUC, the maximum observed plasma concentration (C_max), and the terminal elimination half‐life (t_1/2) adequately. Intensive pharmacokinetic sampling was performed following administration of probes cocktail on day 1 in the absence of miricorilant and again on day 10 in the presence of miricorilant as follows: repaglinide: predose (0 h), and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 h; rosuvastatin: predose (0 h), and 1, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, 48, and 72 h; dolutegravir: predose (0 h), and 1, 2, 3, 4, 8, 12, 18, 24, 36, 48, and 72 h; tolbutamide: predose (0 h), and 1, 2, 3, 4, 6, 8, 12, 18, 24, 36, and 48 h; and midazolam: predose (0 h), and 0.5, 1, 2, 3, 4, 6, 8, 12, 18, and 24 h. Miricorilant concentrations were measured: predose (0 h), and 1, 2, 4, 6, 8, 12, 18, and 24 h after dosing on day 10. Blood samples were collected in tubes containing K₂EDTA as the anticoagulant. Sample tubes were kept on ice and centrifuged within 30 min of collection at 4°C to harvest plasma. Plasma samples were stored at −70°C until the bioanalysis was conducted.

Bioanalytical Procedure

The validated miricorilant bioanalytical method for this study was further partially validated as a 2‐in‐1 assay method to include measurement of its major metabolite, miricorilant‐P9, with miricorilant (i.e., simultaneous measurement of miricorilant and miricorilant‐P9 in the study plasma samples). Additionally, the plasma concentrations of repaglinide, rosuvastatin, dolutegravir, tolbutamide, midazolam, and miricorilant were determined using validated LC‐MS/MS analytical methods. The full details of the bioanalytical methods used in this study are summarized in the Supplemental Methods.

Miricorilant as Victim (NCT05712265)

This was a phase 1, open‐label, fixed‐sequence, single‐center study in 26 healthy subjects to evaluate the pharmacokinetics of miricorilant in the presence and absence of a strong CYP2C19 inhibitor, fluvoxamine. Fluvoxamine was selected based on its specificity toward the CYP2C19 enzyme and lack of major overlapping pathways with the other enzymes. The proposed sample size was evaluated using a precision‐based approach to estimate the approximate CIs that the study could provide for the analysis of the DDI between miricorilant and fluvoxamine. Using the higher variability observed for C_max (i.e., 26.74% at the 200‐mg dose level in the first‐in‐human study [NCT03315338]) and targeting 22 evaluable subjects, it was estimated that the half‐width of the 90% CI for the comparison should be no more than 16.4% of the point estimate with 80% probability. This precision was judged sufficient to characterize any interaction.

Subjects received a single oral dose of 600 mg (6 × 100 mg tablets) miricorilant on day 1 and day 10, and fluvoxamine (1 × 50 mg tablet) once daily from day 4 to day 12. On each dosing occasion, subjects were dosed in the morning following a standard breakfast.

Pharmacokinetic Sampling

Blood sampling was performed at predose (0 h), and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 48, and 72 h after each dose of miricorilant (day 1 and day 10). Samples were collected in tubes containing K₂EDTA as the anticoagulant and kept on ice until centrifuged at 4°C to harvest plasma. Plasma samples were stored at −70°C until the bioanalysis was conducted.

Dose Administration

After an evening snack, subjects fasted overnight for at least 10 h. All doses were given with 240 mL of water. Subjects were allowed to drink water ad libitum up to 1 h before the scheduled dosing time and again beginning 1 h after dosing. For fed dosing, subjects were given breakfast 30 min before the scheduled dose time and asked to eat it evenly over 25 min.

Pharmacokinetic Analyses

The pharmacokinetic parameters in plasma were estimated where possible and appropriate for each analyte, study day, and study subject by non‐compartmental analysis methods using Phoenix WinNonlin software (v8.3, Certara USA, Inc., USA). The pharmacokinetic parameters were estimated with the linear up/log down trapezoidal rule. Select relevant pharmacokinetic parameters included AUC from time zero extrapolated to infinity (AUC_0‐inf), AUC from time zero to the last quantifiable concentration (AUC_0‐last), C_max, time to reach C_max (T_max), and t_1/2. The pharmacokinetic parameters were not calculated for subjects with fewer than three consecutive postdose time points with quantifiable concentrations. Subjects for whom there were insufficient data to calculate pharmacokinetic parameters were excluded from the statistical analysis. Actual elapsed postdose times were used for the non‐compartmental analysis. Plasma concentrations below the limit of quantification before the first quantifiable concentration were set to zero to prevent overestimation of the AUC. Plasma concentrations that were below the limit of quantification after the first quantifiable concentration were treated as missing so as not to bias the estimation of the terminal elimination rate constant (λ_z). The λ_z was determined using linear regressions composed of the least three data points (default setting in Phoenix WinNonlin). The λ_z was not assigned if (1) the terminal elimination phase was not apparent, (2) if C_max was one of the last three data points, or (3) if the R² value was <0.80.

Statistical Analyses for Both DDI Studies

A formal statistical analysis was performed on the probes’ (repaglinide, tolbutamide, midazolam, dolutegravir, and rosuvastatin) pharmacokinetic parameters (AUC_0‐inf, AUC_0‐last, and C_max) for miricorilant + probes (Test) versus probes alone (Reference) in the case of perpetrator study and miricorilant + perpetrator (Test) versus miricorilant (Reference) in the case of victim study. The pharmacokinetic parameters underwent a natural logarithmic transformation and were analyzed using mixed effects modeling techniques. The model included terms for treatment group (i.e., probes or miricorilant dosed alone [day 1] and probes or miricorilant dosed with perpetrator [day 10]) as a fixed effect and subject as a random effect. Only subjects who had sufficient individual probe pharmacokinetic profiles for both the Test and Reference periods were included in the statistical analysis. Furthermore, for AUC_0‐inf only, a subject required reliable estimates of AUC_0‐inf for both Test and Reference treatments to be included in the statistical analysis. If the number of subjects with reliable estimates for both treatments was fewer than 50% of the planned number of evaluable subjects, then no formal statistical analysis of AUC_0‐inf was performed (i.e., descriptive summaries only). For each parameter, the adjusted mean including difference from the pairwise comparison and associated 90% CI obtained from the model was back‐transformed on the log scale to obtain the adjusted geometric mean ratio (GMR) and 90% CI of the ratio. Although the study did not evaluate a specific hypothesis, if the 90% CI for the GMR was contained entirely within 80.00% to 125.00% then there was considered to be no interaction between miricorilant and the probe drug. The statistical analysis was performed using the actual treatment received. The model was fitted using the SAS Software procedure PROC MIXED (SAS Institute, Cary, North Carolina), the method was specified as restricted maximum likelihood, and the denominator degrees of freedom for the fixed effects were calculated using Kenward and Roger's method.

Safety

In each study, safety and tolerability were assessed by review of treatment‐emergent adverse events, clinical laboratory safety tests (hematology, clinical chemistry, urinalysis), 12‐lead electrocardiogram, vital signs measurements, and comprehensive physical examinations. Alcohol, cotinine, and drug screens were conducted at screening and on each admission to the clinical pharmacology unit.

Results

In Vitro Investigations

Binding to Plasma Proteins and Blood/Plasma Partitioning

At a concentration of 10 µM miricorilant, plasma protein binding was high (>99%) in mice, rats, monkeys, and humans. The blood/plasma ratio in humans was somewhat higher than in rats or monkeys (1.14, 0.84, and 0.83, respectively; mean of n = 2 measurements/species).

CYP Inhibition Studies

Modest inhibition of CYP3A4 (IC₅₀ 3.4 µM), CYP2C8 (IC₅₀ 7.5 µM), and CYP2C9 (IC₅₀ 7.7 µM) by miricorilant was observed (mean of n = 2 measurements/isoform). This inhibition was not time dependent. No inhibition of CYP1A2, CYP2B6, CYP2C19, or CYP3A5 was observed.

CYP Induction Studies

At concentrations of miricorilant up to 10 µM (limited by solubility), no induction of CYP1A2 or CYP2B6 was observed in any donor. There was no indication of CYP3A4 induction in two of three donors by miricorilant. In contrast, miricorilant caused a concentration‐dependent CYP3A4 induction in one donor with the highest observed induction of 6.5‐fold.

Transporter and Phase 2 Enzyme Studies

Miricorilant was not a substrate for MDR1/P‐gp, BCRP, OATP1B1, OATP1B3, UGT1A1, or UGT1A3. It was a strong inhibitor of BCRP (IC₅₀ 0.48 µM) and UGT1A1 (IC₅₀ 1.4 µM) but did not inhibit UGT1A3 or the other transporters tested. These results are summarized in Table S2.

Metabolism by CYP Enzymes

CYP2C19 was predominantly responsible for the metabolism of miricorilant (94%) with very minor contributions from CYP1A2, CYP2C8, CYP2C9, CYP2D6 (1% each), and CYP3A4 (2%). No metabolism by CYP2B6 or CYP3A5 was detected.

Animal and Human [¹⁴C] ADME Studies

Elimination, Metabolism, and Tissue Distribution in Mice

After oral administration of a single 50 mg/kg dose of [¹⁴C]‐miricorilant to male albino mice, plasma C_max of 0.86 µg equivalents/mL of total radioactivity was observed at 8 h postdose, and elimination of radioactivity thereafter was rapid as shown in Figure S1. The terminal elimination half‐life could not be determined due to lack of a robust elimination phase. Systemic exposure of total radioactivity (AUC_0‐last) was 8.52 µg equivalents × h/g.

The distribution of radioactivity in tissues was assessed in male albino and pigmented mice. At 1 h post dose in albino mice, the distribution of radioactivity in tissues was highest in gall bladder, liver, kidney (medulla and cortex), myocardium, adrenal gland (medulla and cortex), pancreas, Harderian gland, and salivary glands. Concentrations in the majority of the tissues increased thereafter, with peak concentration measured at 4 h postdose in pancreas, liver, gall bladder, Harderian gland, kidney medulla, myocardium, salivary glands, tongue, and brown fat. Lowest quantifiable levels were associated with the pineal body, blood, and nasal mucosa. Radioactivity was not present at quantifiable levels in the lens of the eye. Radioactivity was present, at low levels, in the brain and spinal cord at 4 and 8 h, suggesting that limited amounts of compound‐related material crossed the blood‐brain barrier and that penetration was reversible. A representative whole‐body autoradiogram taken 12 h postdose in a male albino mouse is provided in Figure 2. Similarly, at 1 h post dose in pigmented mice, quantifiable radioactivity was only present in the mucosa of the stomach, small and large intestine, gall bladder, liver and plasma and were not quantifiable in any tissue by 72 or 168 h post dose. As radioactivity was not present at quantifiable levels in melanin containing tissues (skin and uveal tract) there was no long‐term association of miricorilant‐related material with melanin.

Figure 2.

Whole‐body autoradiogram at 12 h postdose in a male albino mouse.

Parent miricorilant accounted for 69% of total radioactivity in plasma (P), making it the most abundant component. Four metabolites, M1, M2, M3, and M4, were detected in plasma, with each accounting for 8.2%, 6.2%, 2.6% and 9.7%, respectively of total radioactivity. These metabolites were generally formed by oxidation, and a metabolic pathway in mice is provided in Figure 3. M2 was not detectable by mass spectrometry, thus structural determination was not possible.

Figure 3.

Metabolic pathways in mice, monkeys, and humans.

Elimination of administered radioactivity was rapid, with quantitative recovery of radioactivity by 24 h postdose. Elimination in urine accounted for 0.13% ± 0.04%, while fecal (F) elimination represented the principal route of elimination, with 98.7% ± 2.48% recovered in this matrix. Given that the majority of radioactivity was eliminated in feces, together with the observations of radioactivity in the gall bladder in the animals subjected to whole‐body autoradiography assessment, some biliary elimination is implicated.

Elimination and Metabolism in Monkeys

After oral administration of a single 80 mg/kg dose of [¹⁴C]‐miricorilant to male and female cynomolgus monkeys, plasma mean ± standard deviation C_max of total radioactivity was at 12 h in male monkeys and 24 h in female monkeys (2.71 ± 1.22 and 1.66 ± 1.10 µg equivalents/g, respectively). Thereafter, plasma radioactivity concentrations generally declined in an apparent bi‐phasic manner and were below the limit of detection at 144 h postdose in male monkeys and 96 h postdose in female monkeys, as shown in Figure S2. The terminal elimination half‐life could not be determined due to a lack of a robust elimination phase, but appeared to be long (approximately 110 h in 1 male monkey, in which it could be determined). Mean systemic exposure of total radioactivity (AUC_0‐last) was 78.9 ± 37.1 and 51.9 ± 21.0 µg equivalents × h/g in male and female monkeys, respectively. The whole blood‐to‐plasma ratio of total radioactivity was 0.75 in male monkeys and 0.66 in female monkeys, based on AUC_0‐last values, indicating little distribution of radioactivity into red blood cells.

In the male and female plasma samples analyzed, up to 24 separate components were present, of which three accounted for at least 10% of total radioactivity. Parent miricorilant was the most abundant component in plasma at all timepoints, accounting for 18%–41% of total radioactivity. The two metabolites (designated as P15 and P16) were formed by oxidation and methylation. Up to 5 components were detected in feces, of which only 1 (F4; mono‐hydroxy CORT118335) accounted for approximately 10% of the administered dose. This was formed by oxidation. Multiple components were detected in urine, but since elimination in urine was minor, none of these accounted for 10% of the administered dose and none were identified. A metabolic pathway in monkeys is provided in Figure 3.

Elimination of administered radioactivity was prolonged, with 80.88 ± 11.60% recovery of radioactivity in male monkeys and 88.08 ± 4.03% in female monkeys by 168 h postdose. Elimination in urine accounted for 0.96 ± 0.08% in male monkeys and 0.74 ± 0.11% in female monkeys. Fecal elimination represented the principal route of elimination with 72.2 ± 11.20% and 78.51 ± 8.77% recovered in this matrix in male and female monkeys, respectively.

Pharmacokinetics, Elimination, and Metabolism in Humans

Six healthy male subjects were enrolled in this study to receive a single dose of 150 mg [¹⁴C]‐miricorilant as an oral solution in caprylic acid. The age range was 32–53 years, and BMI range 22.0–29.5 kg/m².

Maximum plasma concentrations of total radioactivity occurred between 2 and 12 h postdose. Concentrations then declined in a biphasic manner and remained quantifiable for 24–48 h postdose, after which concentrations were below the limit of quantification (79 ng equivalents/mL). Half‐life ranged from 9.9 to 20.1 h. The geometric mean (geometric CV%) C_max and AUC_0‐last were 572 ng equivalents/mL (36.0%) and 6160 ng equivalents × h/mL (25.5%), respectively. The whole blood‐to‐plasma total radioactivity concentration ratios ranged from 0.613 to 0.763, indicating little distribution into the cellular components of whole blood. Additionally, the comparison of total radioactivity in plasma versus parent miricorilant in plasma indicates that parent miricorilant was the main circulating species in the plasma following oral administration (Figure 4). Parent miricorilant achieved maximum plasma concentrations between 2 and 12 h postdose and half‐life ranged from 12.5 to 28.2 h (geometric mean 18.8 h). The geometric mean (geometric CV%) C_max, AUC_0‐last, and AUC_0‐inf were 343 ng/mL (44.8%), 4320 ng h/mL (28.1%), and 4420 ng h/mL (28.1%), respectively.

Figure 4.

Total radioactivity in plasma versus parent miricorilant in plasma. TR, total reactivity.

Only two components, P9 and P10, accounted for at least 10% of total radioactivity in plasma. P10, which accounted for 43%–75%, was confirmed as unchanged miricorilant, and P9 (4.5%–18%) was identified as a mono‐hydroxy metabolite.

A mean ± standard deviation of 93.68 ± 1.63% of the administered radioactivity was recovered in excreta over a 240‐h sampling period, with 19.28 ± 9.01% eliminated within the first 48 h post dose. The majority of total radioactivity (89.12 ± 1.16%) was recovered in feces, suggesting that the predominant route of elimination is hepatic.

Having identified P9 as the only significant metabolite, the concentrations of this metabolite were measured in some subsequent clinical studies, including the DDI perpetrator study described below. A comparison of C_max and AUC_0‐24 values for miricorilant and the P9 metabolite determined on day 10 of the study is provided in Table 1. The geometric means of the metabolite‐to‐parent ratios for C_max and AUC_0–24 were 0.16 and 0.18, respectively.

Table 1.

Pharmacokinetic Parameters for Miricorilant and P9 Metabolite Following Administration of 400 mg Once Daily Miricorilant in the Presence of the Probe Cocktail (ISRCTN10379288) (N = 30).

	Cmax (ng/mL) (%CV)	AUC0‐24 (ng h/mL) (%CV)	Tmax (h) (range)	t1/2 (h) (%CV)	MPR (Cmax) (%CV)	MPR (AUC0‐24) (%CV)
Miricorilant	895 (33.1)	11,400 (39.1)	4.0 (4.0–6.0)	12.25 (34.3)	NA	NA
P9 metabolite	146 (48.4)	2070 (58.6)	5.0 (4.0–6.0)	12.30 (29.8)	0.16 (43.1)	0.18 (49.3)

AUC, area under the concentration versus time curve; MPR, metabolite‐to‐parent ratio; NA, not applicable; %CV, geometric coefficient of variation.

All values are geometric means.

Human Pharmacokinetics

In total, pharmacokinetic data are presented on 122 subjects (107 male, 15 female) who received at least one dose of miricorilant SDD, of which 67 participated in single‐dose studies and 55 in repeated‐dose studies. The age range was 19–60 years, and the BMI range was 19.1–31.8 kg/m². A further 15 subjects received a placebo only.

First‐in‐Human Study

A summary of the pharmacokinetic parameters determined after the administration of single and multiple doses of miricorilant SDD suspension formulation is provided in Tables 2A and 2B, respectively. Following single dose administrations, based on geometric means, there was a close to proportional increase in C_max and AUC_0‐last in the dose range 100–900 mg and a less than proportional increase between 900 and 1500 mg. The slope parameter (β) with its 90% CI for C_max was 0.85 (0.70–0.99) and for AUC was 0.81 (0.67–0.95). Half‐life was approximately 20 h, consistent with once‐a‐day dosing. A comparison between C_max and AUC_0‐last for fed and fasted dosing for the 900 mg dose indicated that dosing with food increased exposure. C_max was increased approximately 2.45‐fold, and AUC_0‐last was increased approximately 3.34‐fold.

Table 2A.

Pharmacokinetic Parameters for Single Doses of Spray‐Dried Dispersion Suspension.

Dose (mg)	Prandial State	Cmax (ng/mL) (%CV)	Tmax (h) Median (range)	AUC0‐96 (ng h/mL) (%CV)	AUC0‐inf (ng h/mL) (%CV)	t1/2 (h) (%CV)
100	Fasted	69.3 (49.2)	2.01 (2.0–4.0)	1090 (44.4)	1190 (40.9)	21.6 (32.1)
300	Fasted	216 (20.5)	3.01 (2.0–4.07)	2940 (25.0)	3080 (25.1)	21.2 (21.7)
900	Fasted	571 (21.5)	4.0 (2.0–4.08)	7360 (35.2)	7640 (36.1)	21.1 (26.9)
900	Fed	1400 (15.4)	2.0 (1.0–4.0)	24,600 (43.0)	25,200 (45.1)	18.5 (17.5)
1500	Fasted	645 (65.8)	4.0 (1.0–4.03)	9420 (61.0)	9680 (61.5)	17.3 (11.8)

AUC, area under the concentration versus time curve; %CV, geometric coefficient of variation.

All values are geometric means.

Table 2B.

Pharmacokinetic Parameters for Multiple Doses of Spray‐Dried Dispersion Suspension.

	Cmax (ng/mL) (%CV)			AUC (ng h/mL) (%CV)			t1/2 (h) (%CV)
Dose (mg)	Day 1	Day 7	Day 14	Day 1	Day 7	Day 14	Day 14
150	100 (28.2)	142 (62.5)	169 (30.1)	896 (38.3)	1730 (44.7)	1940 (39.2)	21.58 (33.2)
450	356 (27.2)	523 (25.5)	469 (37.7)	2940 (30.0)	5600 (24.7)	5700 (32.8)	21.25 (13.5)
900	423 (50.7)	740 (25.6)	935 (38.1)	4760 (49.6)	9750 (28.9)	11,700 (34.2)	19.44 (9.70)

AUC_0‐24 on day 1 and AUC_0‐tau on day 7 and day 14. AUC, area under the concentration versus time curve; %CV, geometric coefficient of variation.

All values are geometric means.

Following once daily administration of miricorilant at doses of 150, 450, and 900 mg for 14 days, C_max and AUC_0‐last increased in a slightly less than dose‐proportional manner, such that a doubling of the dose resulted in an average increase of 1.92‐fold on day 1 (similar results were obtained on days 7 and 14). Accumulation was observed with multiple dosing, with C_max and AUC_0–24 increasing approximately 1.4‐ to 1.8‐fold and 1.78‐ to 2.05‐fold, respectively, on day 7 compared with day 1. Only a slight further increase was seen between day 7 and day 14, indicating that steady state was achieved by approximately day 7.

Plasma concentration versus time profiles following SAD and MAD administrations are provided in Figures S3 and S4.

The administration of 2 × 100 mg SDD tablets with and without food provided the pharmacokinetic parameters summarized in Table 3. Dosing with food increased C_max 1.75‐fold and AUC_0‐last 2.19‐fold compared with dosing after an overnight fast.

Table 3.

Assessment of Food Effect: Pharmacokinetic Parameters for a Single 200‐mg Dose of 100‐mg Spray‐Dried Dispersion Tablets.

Pharmacokinetic parameter	Fed	Fasted	GMR (90% CI)
Cmax (ng/mL) (%CV)	184 (34.1)	105 (55.3)	1.75 (1.29–2.37)
AUC0‐last (ng h/mL) (%CV)	3560 (44.5)	1620 (52.6)	2.20 (1.66–2.91)
t1/2 (h) (%CV)	19.6 (15.3)	21.1 (35.4)	Not applicable

AUC, area under the concentration versus time curve; CI, confidence interval; GMR, geometric mean ratio; %CV, geometric coefficient of variation.

N = 6. All values are geometric means.

Clinical DDI Perpetrator and Victim Studies

In the perpetrator study, rosuvastatin C_max, AUC_0‐last, and AUC_0‐inf were increased approximately 2.6‐, 2.5‐, and 2.4‐fold, respectively, in the presence of miricorilant compared with rosuvastatin dosed alone, indicating that miricorilant is a moderate inhibitor of BCRP. Repaglinide C_max, AUC_0‐last, and AUC_0‐inf were increased approximately 3.7‐, 8.6‐, and 7.8‐fold, respectively, in the presence of miricorilant compared with repaglinide dosed alone, indicating that miricorilant is a strong inhibitor of CYP2C8. Miricorilant did not have any meaningful effect on exposure to the other probe substrates, indicating that it does not inhibit CYP2C9, CYP3A4, or UGT1A1. Key pharmacokinetic parameters are summarized in Table 4.

Table 4.

Probe Substrate Pharmacokinetic Parameters and Statistical Comparisons for Drug–Drug Interaction Studies.

	Probe + Miricorilant	Probe alone
PK parameter	Geometric mean	Geometric mean	GMR (90% CI)
Perpetrator study
Repaglinide (Probe substrate of CYP2C8)
Cmax (ng/mL)	10.8	2.94	3.67 (3.16–4.26)
AUC0‐last (ng h/mL)	57.4	6.68	8.60 (7.86–9.41)
AUC0‐inf (ng h/mL)	57.1	7.27	7.85 (7.19–8.57)
Rosuvastatin (Probe substrate of BCRP)
Cmax (ng/mL)	6.23	2.35	2.65 (2.38–2.95)
AUC0‐last (ng h/mL)	42.3	17.1	2.47 (2.28–2.69)
AUC0‐inf (ng h/mL)	48.8	20.7	2.36 (2.17–2.56)
Dolutegravir (Probe substrate of UGT1A1)
Cmax (ng/mL)	3040	2590	1.17 (1.09–1.26)
AUC0‐last (ng h/mL)	55,800	44,600	1.25 (1.17–1.34)
AUC0‐inf (ng h/mL)	58,700	46,300	1.27 (1.19–1.36)
Tolbutamide (Probe substrate of CYP2C9)
Cmax (ng/mL)	48,000	46,100	1.04 (1.01–1.07)
AUC0‐last (ng h/mL)	637,000	583,000	1.09 (1.06–1.13)
AUC0‐inf (ng h/mL)	665,000	602,000	1.11 (1.07–1.15)
Midazolam (Probe substrate of CYP3A4)
Cmax (ng/mL)	7.75	8.42	0.92 (0.85–1.00)
AUC0‐last (ng h/mL)	32.9	37.5	0.88 (0.82–0.94)
AUC0‐inf (ng h/mL)	34.7	39.5	0.88 (0.82–0.94)

	Probe + Miricorilant	Miricorilant alone
PK parameter	Geometric mean	Geometric mean	GMR (90% CI)
Victim study
Fluvoxamine (Probe inhibitor of CYP2C19)
Cmax (ng/mL)	643	492	1.31 (1.21–1.41)
AUC0‐last (ng h/mL)	11,700	6140	1.90 (1.73–2.09)
AUC0‐inf (ng h/mL)	14,600	6700	2.18 (1.96–2.42)

AUC, area under the concentration versus time curve; BCRP, breast cancer resistance protein; CYP, cytochrome P450; GMR, geometric mean ratio; UGT, uridine diphosphate glucuronosyltransferase.

Units: C_max: ng/mL; AUC: ng h/mL

In the victim study, following coadministration of miricorilant and fluvoxamine, miricorilant C_max, AUC_0‐last, and AUC_0‐inf were increased 1.3‐, 1.9‐, and 2.2‐fold respectively, compared to miricorilant administered alone (see Table 4). These results indicate that miricorilant is a moderately sensitive substrate of CYP2C19.

Summary of Clinical Safety

In phase 1 studies evaluating single doses of miricorilant, healthy subjects received one or more single doses of miricorilant. Treatment‐emergent adverse events (TEAEs) were infrequently observed across these studies; headache was the most commonly reported TEAE. In general, TEAEs were mild or moderate in intensity. No subjects enrolled in single‐dose studies of miricorilant were discontinued from study participation due to TEAEs. One subject in the first‐in‐human study experienced a serious TEAE of acute myocardial infarction 28 days postdose, which resolved with sequelae and was considered unrelated to miricorilant but rather due to underlying genetic factors. No individual laboratory or urinalysis abnormalities were considered clinically significant or reported as TEAEs.

In phase 1 studies evaluating multiple doses of miricorilant, healthy subjects received repeated miricorilant once‐daily dosing for up to 14 days. Within the period studied, no dose‐dependent relationship between the frequency of TEAEs and higher miricorilant doses was noted. TEAEs were mild or moderate in intensity. There were no deaths or treatment‐emergent serious adverse events reported in the repeated‐dose studies. Overall, TEAEs were infrequently observed across these studies; headache was the most commonly reported TEAE. There were no findings of note in laboratory safety tests, electrocardiograms, or vital sign measurements.

Discussion

The overall pharmacokinetic profile of miricorilant has been extensively characterized in preclinical and clinical Phase 1 studies. Following administration of [¹⁴C]‐miricorilant in mice, miricorilant was shown to be distributed in the body with high concentrations of radioactivity in the liver, the tissue of interest in MASH. [¹⁴C]‐miricorilant‐related radioactivity had no affinity for binding to melanin in pigmented mice. The metabolic pathway of miricorilant was characterized in mice and monkeys, and subsequently in humans. Comparing all three species, unchanged miricorilant was the major component in plasma, and oxidation was the main and common route of metabolism in all three species. In mice, two mono‐hydroxy metabolites and one dehydrogenated metabolite were formed, but none exceeded 10% of total circulating radioactivity. In monkeys, however, two metabolites exceeded 10% and both resulted from hydroxylation of miricorilant. One metabolite was a mono‐hydroxy metabolite, and the other was formed by di‐hydroxylation followed by methylation of one of the hydroxyl groups on miricorilant. As the di‐hydroxylated metabolite was not observed in human plasma, no additional characterization was performed. In human plasma, the single mono‐hydroxy metabolite accounted for at least 10% of total circulating radioactivity. Analysis of samples collected in a subsequent clinical study (ISRCTN10379288) provided metabolite‐to‐parent ratios of 0.163 and 0.182 for C_max and AUC, respectively. Collectively, metabolite profiling in all three species suggests that the mono‐hydroxy metabolite represents approximately 10% of total circulating radioactivity and thus measuring this metabolite in future clinical studies is warranted.

In healthy volunteers given single doses of miricorilant, approximately dose‐proportional increases in exposure were observed for doses from 100 mg (the lowest dose evaluated) to 900 mg. The doses used in subsequent DDI studies and the ongoing phase 2 study in patients with MASH fall within this dose range. With repeated daily dosing, steady state exposures were achieved within 7 days with an estimated half‐life of approximately 20 h and showed potential for accumulation with C_max increased by ≈1.5‐fold and AUC by approximately twofold. Administration with food increased C_max by 1.45‐fold and AUC by 2.3‐fold. Based on this observation, miricorilant has been dosed with food in all subsequent clinical studies to maximize exposure. The human ADME study showed that elimination of miricorilant is predominantly hepatic, with 89.12% of the administered dose recovered in feces and only 4.56% recovered in urine. Based on these results, evaluation of miricorilant in patients with hepatic impairment is warranted, and the results of that study will be reported separately.

In vitro studies suggested that miricorilant was a modest inhibitor of CYP3A4, CYP2C8, CYP2C9, and UGT1A1 and a strong inhibitor of BCRP. In subsequent clinical evaluation, CYP2C8 and BCRP inhibition were confirmed, but no clinically meaningful inhibition of CYP2C9, CYP3A4, or UGT1A1 was observed. Accordingly, in the phase 2 clinical study evaluating miricorilant in patients with MASH, administration of miricorilant is prohibited with medications that are moderately sensitive or sensitive substrates of CYP2C8 for which an acceptable dose modification allowing for coadministration with a strong CYP2C8 inhibitor is not an option. Similarly, administration of miricorilant is also prohibited with medications that are substrates of BCRP and have clinically significant in vivo DDIs with BCRP inhibitors, and for which an acceptable dose modification is not an option.

Further in vitro studies suggested that miricorilant is predominantly metabolized by CYP2C19, which led to the expectation that coadministration of miricorilant with a strong CYP2C19 inhibitor would result in increased plasma concentrations of miricorilant. This expectation was confirmed by the results of a clinical victim DDI study, in which coadministration of miricorilant with fluvoxamine resulted in an approximately 2‐fold increase in miricorilant exposure as assessed by AUC. Therefore, the phase 2 clinical study evaluating miricorilant in patients with MASH prohibits medications that are strong inducers of CYP2C19.

Conclusions

The overall pharmacokinetic/ADME profile of miricorilant has been well characterized across several in vitro and in vivo studies. Administration of [¹⁴C]‐miricorilant to mice resulted in high concentrations of radioactivity in the liver. In humans, miricorilant systemic concentrations increased with repeated daily dosing, with accumulation ratios of ≈1.5 for C_max and ≈2.0 for AUC and steady state exposures achieved by day 7. Elimination of miricorilant is predominantly hepatic, with a half‐life of approximately 20 h, and miricorilant is a moderately sensitive substrate of CYP2C19 in vivo. At the total plasma concentrations evaluated, miricorilant is a strong inhibitor of CYP2C8 and a moderate inhibitor of BCRP in vivo. Miricorilant is currently in phase 2 clinical development in patients with MASH.

Authors Contributions

Conceptualization: Hazel J. Hunt, Kirsteen M. Donaldson, Jeevan R. Kunta, and Joseph M. Custodio. Data curation: Hazel J. Hunt, Kirsteen M. Donaldson, Jeevan R. Kunta, and Joseph M. Custodio. Formal analysis: Hazel J. Hunt, Kirsteen M. Donaldson, Jeevan R. Kunta, and Joseph M. Custodio. Funding acquisition: Hazel J. Hunt, Jeevan R. Kunta, and Joseph M. Custodio. Investigation: Hazel J. Hunt, Kirsteen M. Donaldson, Jeevan R. Kunta, and Joseph M. Custodio. Methodology: Hazel J. Hunt, Kirsteen M. Donaldson, Jeevan R. Kunta, and Joseph M. Custodio. Validation: Hazel J. Hunt, Kirsteen M. Donaldson, Jeevan R. Kunta, and Joseph M. Custodio. Writing – original draft: Hazel J. Hunt, Kirsteen M. Donaldson, Jeevan R. Kunta, and Joseph M. Custodio. Writing – review and editing: Hazel J. Hunt, Kirsteen M. Donaldson, Jeevan R. Kunta, and Joseph M. Custodio.

Conflicts of Interest

Hazel J. Hunt: Employee and owns stock in Corcept Therapeutics Incorporated. Kirsteen M. Donaldson: Employee and director of Jade Consultants (Cambridge) Ltd., which provides consultancy services to Corcept. Jeevan R. Kunta: Employee and owns stock in Corcept. Joseph M. Custodio: Employee and owns stock in Corcept.

Funding

This work is funded by Corcept Therapeutics Incorporated, Redwood City, CA. Editorial support was provided by R&R Healthcare Communications, with funding provided by Corcept.

Supporting information

Table S1. Accuracy and precision criteria and measured results in the validation of each probe assay and its subsequent study plasma sample analysis.

Table S2. In vitro transporter and phase 2 enzyme studies.

Figure S1. Plasma radioactivity concentration (µg/mL) profile in male albino CD‐1 mice following a single oral administration of [14C] miricorilant at a nominal dose level of 50 mg/kg (ca 5 MBq/kg).

Figure S2. Concentration of radioactivity in plasma and whole blood in monkeys following a single oral administration of [14C] miricorilant at 80 mg/kg.

Figure S3. Geometric mean plasma concentration versus time profile following single ascending dose administration of miricorilant in healthy subjects.

Figure S4. Geometric mean plasma concentration versus time profile following multiple ascending dose administration of miricorilant in healthy subjects.

Data Availability Statement

De‐identified datasets for the results reported in this publication may be made available to qualified researchers following submission of a methodologically sound proposal to datarequests@corcept.com. Data will be made available for such requests following the online publication of this article and for 1 year thereafter in compliance with applicable privacy laws, data protection, and requirements for consent and anonymization. Data will be provided by Corcept.