Mirikizumab Pharmacokinetics in Patients with Moderately to Severely Active Ulcerative Colitis: Results from Phase III LUCENT Studies

The three clinical trials were designed to evaluate the efficacy, safety, and pharmacokinetics of mirikizumab in inducing (AMAC and LUCENT 1) and maintaining (AMAC and LUCENT 2) remission in patients aged 18–75 years (AMAC) or 18–80 years (LUCENT 1+2) with moderately to severely active UC. Details of the three trials have been reported elsewhere [19‐22].

The AMAC (NCT02589665) trial was conducted at 85 study sites in 14 countries between January 2016 and September 2017. LUCENT 1 (NCT03518086, AMAN) was conducted at 383 study sites in 34 countries from 18 June, 2018 to 21 January, 2021. LUCENT 2 (NCT03524092, AMBG) was conducted at 367 study sites in 34 countries from 19 October, 2018 to 3 November, 2021. These three studies were approved by the applicable ethics review boards and performed in accordance with the Declaration of Helsinki, Council for International Organizations of Medical Sciences International Ethical Guidelines, and the International Council for Harmonisation Guideline for Good Clinical Practice. All patients provided written informed consent [23].

Participating patients had a Mayo endoscopic subscore of ≥2 and a total Mayo score of 6–12 (AMAC) or a modified Mayo score 4–9 (LUCENT 1), and had not responded or were intolerant to conventional UC therapy (AMAC and LUCENT 1), biologic therapy with a target other than IL-23 (LUCENT 1), and/or Janus kinase inhibitors for UC treatment (LUCENT 1). Patients were excluded if they had previous exposure to any other biologic therapy targeting IL-23, with the LUCENT 1 trial also excluding patients who had not responded to three or more different biologic therapies. The LUCENT 2 trial accepted patients who had completed the LUCENT 1 trial.

In the AMAC trial (Fig. 1a of the Electronic Supplementary Material [ESM]), patients were randomized to placebo or mirikizumab 600-mg, 200-mg, or 50-mg induction dose regimens administered intravenously every 4 weeks (Q4W) for 12 weeks. In the mirikizumab 200-mg and 50-mg groups, doses after the first one were adjusted based on exposure. Serum concentrations of mirikizumab were assessed at weeks 2 and 6, and the dose was increased at weeks 4 and 8 according to a prespecified algorithm [21]. The dose increase ranged from 2-fold to 12-fold for patients in the 50-mg arm and from 1.5-fold to 3-fold for patients in the 200-mg arm. The 600-mg arm remained at a fixed dose during the first 12 weeks. No patient was given a dose of > 600 mg in the induction period. The dose adjustments in the 200-mg and 50-mg groups resulted in an average group dose of 250 mg and 100 mg, respectively.

Responders to induction regimens were randomized to receive 200 mg subcutaneously either Q4W or every 12 weeks as a maintenance regimen through 92 weeks, terminating with a final 16-week follow-up period. Non-responders to induction regimens had the option to discontinue from the study or enter the open-label extension period, which consisted of a 12-week induction phase with a fixed intravenous (IV) dose of mirikizumab 600 mg or 1000 mg Q4W (three doses in total), and if they responded to the induction phase, a subsequent 92-week maintenance phase with subcutaneous (SC) mirikizumab 200 mg Q4W. Patients who did not achieve a clinical response at week 12 were discontinued from the study.In the LUCENT 1 trial (Fig. 1b of the ESM), patients were randomized (3:1) to mirikizumab 300 mg or IV placebo Q4W. Once they completed the 12-week induction phase, patients could enter the LUCENT 2 trial and receive treatment based on their response in LUCENT 1.

In the LUCENT 2 trial (Fig. 1b of the ESM), mirikizumab-treated responders from LUCENT 1 (a decrease in the modified Mayo score of ≥ 2 points and a ≥ 30% decrease from baseline, and a decrease of ≥ 1 point in the rectal bleeding subscore from baseline or a rectal bleeding subscore of 0 or 1) were randomized (2:1) to mirikizumab 200 mg or SC placebo Q4W, whereas placebo-treated responders continued to receive placebo Q4W, but with SC administration. Patients who maintained clinical response continued the same regimen until week 40, whereas patients who had a loss of response were given IV mirikizumab 300 mg Q4W for three doses followed by a final assessment. LUCENT 1 trial non-responders received IV mirikizumab 300 mg Q4W in the LUCENT 2 trial. After 12 weeks, if they responded, their dose was changed to SC mirikizumab 200 mg Q4W until week 40; if they did not respond, they discontinued the trial.

Intravenous infusion of mirikizumab or placebo occurred over at least 30 minutes. Subcutaneous administration of mirikizumab or placebo was given in up to four injections (AMAC) or in two injections (LUCENT 2), with a maximum volume of 1.5 mL per injection.

For the AMAC primary and extension studies, blood samples for the PK analysis were collected every second week during the induction phase, every 4 weeks in the first part of the maintenance phase, then every 8 weeks until the end of the study, including the follow-up period. A single sample was collected prior to study drug administration (if occurring on a dosing day), and samples were taken before each IV infusion (trough) and at the end of each IV infusion (maximum plasma drug concentration [C_max]) at weeks 0, 4, and 8 (Table 1 of the ESM).

For the LUCENT trials, a PK sample collection was performed with a total of six samples per patient in LUCENT 1 and four to six samples per patient in LUCENT 2. Blood samples were collected prior to mirikizumab dosing at weeks 0, 4, and 8 and after mirikizumab dosing at weeks 0 and 4. Post-dosing samples were collected up to 2 h after dosing, with the actual time of all dose administrations recorded in the patient’s electronic case report form. Additional samples were collected at week 12, at any unscheduled visits, at early termination visits, and 16 weeks after the last visit (Table 1 of the ESM).

Serum mirikizumab concentrations were measured in blood samples using a validated drug-tolerant quantitative enzyme immunoassay method at ICON Laboratory Services, Inc. (Whitesboro, NY, USA). The lower limit of quantification was 100 ng/mL and the upper limit of quantification was 10,000 ng/mL. Samples above the limit of quantification were diluted to yield results within the calibrated range. The inter-assay accuracy (% relative error) during validation ranged from − 9.09% to 2.30%. The inter-assay precision (% coefficient of variation [CV%]) during validation ranged from 2.18% to 6.57%. Samples were stored at − 70 °C.

A population PK model was initially developed using the data from the phase II AMAC trial. A two-compartment model with first-order absorption for the SC maintenance doses was found to best describe the pharmacokinetics of mirikizumab. The final population PK model was developed using the combined data from LUCENT 1+2 using the same model structure as the phase II study.

Model development consisted of structural model selection, a covariate search, and a final model evaluation (Fig. 2 of the ESM). Key selection criteria were convergence of the estimation and covariance routines, reasonable parameter and variance estimates based on the known pharmacokinetics of mirikizumab, good precision of the parameter and variance estimates (relative standard error < 50%), and graphical methods to ensure the presence of reasonable characterization of data with no obvious model misspecification. For the final model development, an assessment of covariate effects was conducted. Several covariates were investigated (Table 2 of the ESM), including body weight at study entry, age, sex, race, disease severity, prior biologic therapy, concomitant use of corticosteroids or immunomodulators (tested as single and combined covariates), and an antidrug antibody (ADA) titer over time. In particular, age was evaluated as a continuous covariate, and sex, race (White, Asian, and Other [American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, multiple, and missing]), ethnicity, and prior and concomitant therapies were evaluated as categorical covariates. Baseline disease state was evaluated using serum albumin (continuous), modified Mayo score (continuous/categorical), fecal calprotectin (continuous), and C-reactive protein (continuous). Key covariate selection criteria were as per structural model selection. In addition, the criterion for a statistically significant difference in objective function value (OFV) was a ≥ 6.635-point drop in OFV (p < 0.01) for forward inclusion and a ≥ 10.828-point drop in OFV (p < 0.001) for backward elimination. A bootstrap analysis was performed to assess the precision of the final parameter estimates of the final model using the bootstrap routine in Perl-speaks-NONMEM software (Version 4.8.1, ©2018–2019 by Mats Karlsson, Rikard Nordgren, Svetlana Freiberga, Sebastian Ueckert, and Gunnar Yngman), and a visual predictive check was performed to ensure that the model maintained fidelity with the observed data using the visual predictive check algorithm in Perl-speaks-NONMEM.

Missing values of independent variables (patient characteristic data) were imputed within patients using last observation carried forward. Approximately 4% and 2% of the PK samples collected for the AMAC and LUCENT 1+2 studies, respectively, were below the quantifiable limit. Models with and without these samples were compared using a first-order conditional estimation with interaction method and a Laplacian conditional estimation with interaction method when values below the quantifiable limit were included. There were no significant changes on the estimated PK parameters, and no increased uncertainty was noted with the additional samples, so the final analysis excluded these samples.

All analyses were conducted using non-linear mixed-effects modeling [NONMEM] (Version 7.4.2; ICON Development Systems, Gaithersburg, MD, USA), R (Version 4.0.3; R Foundation for Statistical Computing, Vienna, Austria), and Perl-speaks-NONMEM.

A total of 4103 and 7578 serum mirikizumab concentration samples in 233 and 1129 patients were included in the PK analysis for the AMAC and LUCENT 1+2 trials, respectively. In the AMAC PK analysis, 59% of patients were male and 35% were naïve to biologic therapy. The mean age was 42 years (range 17–72 years) with a mean body weight of 75 kg (range 40–122 kg), a mean body mass index (BMI) of 25 kg/m² (range 15–43 kg/m²), and a mean albumin level of 41 g/L (range 24–51 g/L). In the LUCENT 1+2 PK analysis, most patients were male (61%) and 44% were naïve to biologic therapy. The mean age was 43 years (range 18–79 years) with a mean body weight of 73 kg (range 34–152 kg), a mean BMI of 25 kg/m² (range 14–54 kg/m²), and a mean albumin level of 43 g/L (range 21–54 g/L) (Table 1).

For the AMAC trial, the model-estimated apparent total body clearance (CL) of mirikizumab from plasma and the bioavailability of mirikizumab were 0.023 L/h and 42%, respectively (Table 2). For LUCENT 1+2, inter-compartmental CL was fixed to 0.00756 L/h during the model development stage based on the AMAC PK analysis results, and was estimated to be 0.0087 L/h as part of the final PK model. The final model-estimated population-typical values of CL and bioavailability were 0.022 L/h and 47.6% (geometric mean of individual post hoc estimates: 44%; geometric CV% [geoCV%]: 34%), respectively (Table 2). The typical half-life value was estimated to be 9.5 days (geometric mean: 9.33 days; geoCV%: 40%). The parameters estimated for the AMAC and LUCENT 1+2 trials were consistent with each other. A bootstrap analysis (Table 2) and visual predictive check (Fig. 1) demonstrated that the model predictions agreed with the observed data reasonably well and all parameters were estimated with adequate precision.

Comparison of the simulated concentration–time profile following IV mirikizumab 300 mg Q4W and SC 200 mg Q4W (Fig. 2) showed that the overall exposure with the IV regimen was approximately three-fold higher than with the SC regimen, which was consistent with the model-predicted availability of 47.6% (300 mg/(200 mg × 0.476) = 3.2). Specifically, the geometric mean (geoCV%) area under the plasma concentration–time curve during one dosing interval at steady state (AUC_tau,ss) was 538 (34.4%) μg*day/mL for the IV regimen and 160 (57.6%) μg*day/mL for the SC regimen. The largest difference in the concentration profiles was at C_max, with geometric mean steady-state (geoCV%) C_max concentrations of 99.7 (22.7%) μg/mL for the IV regimen and 10.1 (52.1%) μg/mL for the SC regimen. The difference in trough concentrations was smaller with geometric mean steady-state (geoCV%) trough concentrations of 2.75 (101%) μg/mL for the IV regimen and 1.70 (83.3%) μg/mL for the SC regimen.

The covariate evaluation discussed here focuses on the final modeling with phase III data. In the final model based on data from the LUCENT 1+2 trial, body weight and serum albumin level were identified as statistically significant patient factors affecting mirikizumab CL. Higher CL was associated with higher body weights (Fig. 3a) and lower albumin levels (Fig. 3b). Volume of distribution increased with increasing body weight (Fig. 3c, d), whereas bioavailability decreased with increasing BMI (Fig. 3e), both in a statistically significant manner.

To evaluate the potential impact of body weight and albumin on mirikizumab exposure following IV and SC dose regimens, AUC_tau,ss and C_max were compared across the patient covariate quartiles. A significant overlap in the AUC_tau,ss and C_max was observed across quartile groups for weight, BMI, and albumin (Fig. 4). More specifically, with the IV dose regimen, the median AUC_tau,ss in patients in the highest body weight quartile (83–152 kg) was 451 μg*day/mL versus an overall population median AUC_tau,ss of 539 μg*day/mL (Fig. 4a). Similarly, the median C_max in the highest body weight quartile was 84.4 μg/mL versus an overall population median of 99.4 μg/mL (Fig. 4b). The differences in AUC_tau,ss and steady-state C_max between the lowest body weight quartile and population median were also similar in magnitude (Fig. 4a, b). The median AUC_tau,ss in patients in the lowest quartile of albumin levels (21–41 g/L) was 515 μg*day/mL versus an overall population median AUC_tau,ss of 539 μg*day/mL (Fig. 4c). Similarly, the median C_max in the lowest albumin level quartile was 102 μg/mL versus a population median of 99.4 μg/mL (Fig. 4d). With the SC dose regimen, patients with a higher baseline BMI were found to have a lower bioavailability, which would decrease both AUC_tau,ss and C_max (Fig. 4e, f). Because body weight also affected CL, and because body weight and BMI are correlated, AUC and C_max were compared across the quartiles of body weight for the SC regimen. The median AUC_tau,ss in patients in the highest body weight quartile was 124 μg*day/mL versus an overall population median AUC_tau,ss of 165 μg*day/mL. Similarly, the median C_max in the highest body weight quartile was 7.65 μg/mL versus an overall population median of 10.6 μg/mL, respectively. Overall, the differences in AUC_tau,ss and C_max for patients in the highest patient factor quartiles were small relative to the overall range in AUC and C_max values across patients as a result of variability. The effects of body weight, BMI, and albumin levels on mirikizumab exposure were not considered clinically relevant.

In the phase III LUCENT 1+2 studies, 1127, 678, and 195 PK samples were associated with SC injections in the abdomen, arm, and thigh, respectively. A post hoc analysis found that the injection site was not a statistically significant factor affecting bioavailability, with similar bioavailability among the three injection sites (Fig. 5a). Immunogenicity was not found to be a statistically significant factor that affected mirikizumab CL. The post hoc CL values for different ADA titer levels are presented in Fig. 5b. No significant change in CL with ADA titer levels was apparent. The majority of patients who were ADA positive had mirikizumab exposure that was consistent with exposure in patients who were ADA negative (Fig. 5c). For titers of 1:160 or higher, mirikizumab concentrations trended lower in a small number of patients, which limits definitive conclusions. None of the other covariates evaluated showed a meaningful impact on mirikizumab exposure.