ABSTRACT Mirikizumab is a humanized anti–interleukin‐23‐p19 monoclonal antibody approved for both moderately‐to‐severely active ulcerative colitis and moderately‐to‐severely active Crohn's disease (CD). We characterized pharmacokinetics (PK) and exposure‐response (ER) of mirikizumab in relation to efficacy and safety in CD using data from randomized phase 2 SERENITY (NCT02891226) and phase 3 VIVID‐1 (NCT03926130) trials. Patients received 12‐week mirikizumab induction (200, 600, or 1000 mg [SERENITY] or 900 mg [VIVID‐1] intravenously [IV]) or placebo, every 4 weeks (Q4W), then maintenance (200, 600, or 1000 mg IV [SERENITY], 300 mg subcutaneously (SC) [SERENITY and VIVID‐1], or placebo, Q4W) to Week 52. PK and ER for efficacy were analyzed using population PK and logistic regression models for Weeks 12 and 52 endpoints, respectively, and included analyses of covariate effects. Mirikizumab PK was best described by a two‐compartment model, with first‐order absorption for SC maintenance doses. Body weight, body mass index, serum albumin concentration, C‐reactive protein, and disease severity had statistically significant effects on PK, while body weight and disease severity affected ER; these effects were not considered clinically relevant. Efficacy results of 900 mg mirikizumab in VIVID‐1 aligned with SERENITY, which observed near‐maximal efficacy at Week 12 with 600–1000 mg mirikizumab IV. Efficacy at Week 52 did not vary markedly with exposure during maintenance. There was no significant association between exposure and adverse events. These results support the selection of 900 mg mirikizumab IV Q4W for induction and 300 mg SC Q4W for maintenance in patients with CD, with no dose adjustment for patient factors required.

Mirikizumab is a humanized anti-interleukin-23p19 monoclonal antibody being developed for ulcerative colitis (UC) and Crohn's disease. We characterized the relationship of mirikizumab systemic exposure with efficacy and safety end points in patients with UC using phase II (NCT02589665) and III (NCT03518086, NCT03524092) trial data. Exposure-response models were developed for clinical remission, clinical response, endoscopic remission, and change in modified Mayo score following induction (50-1,000 mg i.v. every 4 weeks) and maintenance (200 mg s.c. every 4 or 12 weeks) treatment. These models evaluated observed and pharmacokinetic model-predicted mirikizumab exposures as the exposure measure. Key safety event rates were compared across mirikizumab exposure quartiles in the phase III trial. Mirikizumab efficacy in patients with UC showed an apparent positive association with systemic exposure following both induction and maintenance. However, further analysis found this relationship to be overstated by the presence of confounding factors that were not among the tested patient covariates. While prior biologic experience and baseline disease severity showed statistically significant influences on estimated placebo effect, no patient factors affected the mirikizumab effect parameters in any of the phase III exposure-response models. There was no apparent mirikizumab concentration relationship with any adverse event of special interest. When the phase II and III data and confounding are considered together, efficacy was unlikely to be strongly affected by variation in exposures across individual patients at the phase III dose. Together with the previously demonstrated mirikizumab exposure insensitivity to patient factors, these findings indicate that mirikizumab dose adjustment to patient characteristics is not required.

Abstract Background Mirikizumab (miri) is a humanized anti–interleukin-23-p19 monoclonal antibody approved for the treatment of ulcerative colitis (UC) and under development for Crohn’s disease (CD). This analysis characterises miri pharmacokinetics (PK) and the relationship between miri exposure and efficacy response using data from a phase 2 trial in adults with moderately to severely active CD. Methods AMAG was a randomised, double-blind, placebo-controlled trial conducted in 14 countries. Patients received placebo, miri 200 mg, 600 mg, or 1000 mg as induction regimens administered intravenously (IV) every 4 weeks (Q4W) through Week 12, followed by 36 weeks of maintenance treatment with continuous treatment of miri 200 mg, 600 mg, or 1000 mg IV or miri 300 mg administered subcutaneously (SC) Q4W. PK parameters were analysed by non-linear mixed-effects modelling. Covariate effects on miri exposure were evaluated using simulation-based estimations. Exposure-response (ER) for patients achieving endoscopic response by Simple Endoscopic Score for Crohn’s Disease (SES-CD) at Weeks 12 and 52 were assessed using logistic regression models. Results 186 patients were included. The estimated systemic clearance (CL), central volume of distribution (V), and SC bioavailability (F) were 0.022 L/hr, 3.31 L, and 33.4%, respectively. Lower baseline values for SES-CD (indicative of a less severe CD) were associated with reduced CL. Lower body weight and higher albumin levels were also associated with reduced CL. Higher body weight was associated with higher V and lower baseline body mass index correlated with higher SC F. Impacts on PK parameters were small relative to random variability and not considered clinically relevant. The model-based ER analyses for endoscopic response probability at Week 12 detected a significant treatment effect relative to placebo (p<0.001) and a significant ER (p=0.001) in a dose range of 200-1000 mg. The ER analyses indicated near maximal efficacy for IV dose between 600 mg and 1000 mg during the Induction Period. There was no significant relationship between miri exposure and the probability of achieving endoscopic response by SES-CD at Week 52, indicating exposures produced by the maintenance doses provided similar efficacy. Conclusion Miri PK characteristics in adults with active CD were consistent with miri UC studies. Overall, none of the covariates identified as being significantly correlated with miri PK parameters were considered clinically relevant. No patient factors evaluated in this analysis justify dose adjustment. These findings support the miri induction dose 900 mg IV Q4W and maintenance dose 300 mg SC Q4W selected for phase 3 CD study.

BACKGROUND AND OBJECTIVE:Mirikizumab is a humanized anti-interleukin-23-p19 monoclonal antibody being developed for ulcerative colitis and Crohn's disease. This analysis characterized mirikizumab pharmacokinetics using phase II and III trial data from patients with moderately to severely active ulcerative colitis.METHODS:Serum pharmacokinetic data in patients receiving mirikizumab 50-1000 mg intravenously every 4 weeks as induction treatment and mirikizumab 200 mg subcutaneously every 4 or 12 weeks as maintenance treatment across three trials (N = 1362) were analyzed using non-linear mixed-effects modeling. Covariate effects on mirikizumab exposure were evaluated using simulation-based estimations.RESULTS:Mirikizumab pharmacokinetics was best described by a linear two-compartment model with first-order absorption. Clearance, volume of distribution for central and peripheral compartments, and half-life were estimated at approximately 0.022 L/h (linear), 3.11 L and 1.69 L, and 9.5 days, respectively. Statistically significant effects of body weight and serum albumin levels on clearance, body weight on central and peripheral volumes of distribution, and body mass index on bioavailability were observed but effects were small relative to random inter-individual variability (% coefficient of variation: 18-64%). The subcutaneous bioavailability of mirikizumab was 48%.CONCLUSIONS:Mirikizumab displayed pharmacokinetic characteristics typical of a monoclonal antibody where clearance increased with body weight and decreased with the albumin level, and bioavailability decreased with body mass index. These effects were small relative to random variability, indicating that a dose adjustment for patient factors is not required.CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov: NCT02589665 (28 October, 2015), NCT03518086 (8 May, 2018), NCT03524092 (14 May, 2018).

BACKGROUND & AIMS: Mirikizumab is an antibody against the p19 subunit of interleukin 23 that has demonstrated clinical efficacy and was well tolerated following 12 weeks of induction treatment in a phase 2 trial of patients with moderate to severe ulcerative colitis. We present results of the open-label extended induction period in patients who did not initially respond to treatment with mirikizumab. METHODS: This study was a continuation of I6T-MC-AMAC, a double-blind trial, performed at 75 sites in 14 countries, in which patients with moderate to severe ulcerative colitis were randomly assigned to 12 weeks induction therapy with 50 mg, 200 mg, or 600 mg mirikizumab or placebo. Patients without a clinical response (a 9-point decrease in Mayo subscore of >= 2 points and >= 35% from baseline and either a decrease of rectal bleeding subscore of >= 1 or a rectal bleeding subscore of 0 or 1) at week 12 were offered the opportunity to participate in an open-label, extended induction study for another 12 weeks, in which they received either 600 mg intravenous mirikizumab (n = 20) or, following a protocol amendment, 1000 mg intravenous mirikizumab (n = 64) every 4 weeks. At week 24, patients with a clinical response continued the extension maintenance period and received 200 mg subcutaneous mirikizumab. Endpoints included clinical remission (Mayo subscores of 0 for rectal bleeding, 0 or 1 with a 1-point decrease from baseline), clinical response, endoscopic remission (Mayo endoscopic subscore of 0), or endoscopic improvement (endoscopic subscore of 0 or 1), at study weeks 24 and 52. Data were analysed for patients who received mirikizumab or placebo during the induction phase of the study. RESULTS: Among participants who did not respond to induction mirikizumab, 50.0% of those who received the 12-week extension of 600 mg mirikizumab and 43.8% who received the extension of 1000 mg mirikizumab achieved a clinical response; 15.0% and 9.4% achieved clinical remission, respectively. Endoscopic improvement was achieved by 20.0% of subjects in the 600 mg mirikizumab group and 15.6% subjects in the 1000 mg mirikizumab group. Among initial nonresponders to mirikizumab who had clinical response at study week 24 and continued into maintenance therapy, 65.8% maintained the clinical response, 26.3% achieved clinical remission, and 34.2% had endoscopic improvement at week 52. No new safety concerns were identified. CONCLUSIONS: Extended doses of mirikizumab (600 mg and 1000 mg) for an additional 12 weeks produce a clinical response in up to 50% of patients who did not have a clinical response to 12 weeks of induction doses (50 mg, 200 mg, or 600 mg). Most of the responders to the extended doses maintained clinical response for up to 52 weeks.

Interleukin (IL)-23 is a critical cytokine in inflammatory bowel disease pathogenesis. Mirikizumab (miri), a p19-directed IL-23 antibody, demonstrated efficacy and was well-tolerated during 12 weeks of induction treatment in a Phase 2 randomised clinical trial (AMAC, NCT02589665).1 Maintenance results through Week 52 from this trial are reported. Patients (Mayo score 6–12 with a minimum endoscopic subscore [ES] ≥2) were randomised 1:1:1:1 to receive intravenous (IV) placebo (N = 63), miri 50 mg (N = 63) or 200 mg (N = 62) with possibility of exposure-based (EB) dose increases, or fixed miri 600 mg (N = 61) every 4 weeks (Q4W), with efficacy assessment at Week 12. Patients who achieved a clinical response to miri at Week 12 were re-randomised 1:1 into a double-blind maintenance period to receive miri 200 mg subcutaneously (SC) Q4W (N = 47) or every 12 weeks (Q12W; N = 46), and were treated through Week 52. See Table 1 for definitions of secondary and exploratory outcomes. Missing data were imputed as nonresponse. Abstract OP038 – Table 1. Baseline (BL) characteristics of patients who entered the maintenance period were similar between groups. At BL, 52.7% had previously received a biologic. At Week 52, 46.8% (Q4W) and 37.0% (Q12W) were in clinical remission. Additionally, 80.9% (Q4W) and 76.1% (Q12W) had clinical response, and 57.4% (Q4W) and 47.8% (Q12W) had an ES = 0/1. Among those in clinical remission at Week 12, 61.1% (Q4W) and 38.5% (Q12W) remained in clinical remission at Week 52. Among those in clinical response (but not remission) at Week 12, 37.9% (Q4W) and 36.4% (Q12W) achieved clinical remission at Week 52. Symptomatic scores throughout the maintenance period are shown in Figure 1. During the maintenance period, 1 patient discontinued study due to an adverse event (AE), and similar frequencies of treatment-emergent AEs and serious AEs were reported across both treatment groups. Additional demographic, BL disease characteristics, and outcome data are reported in Table 1. Abstract OP038 – Figure 1 Miri demonstrated durable efficacy (assessed by multiple measures) with no unexpected safety signals and few discontinuations due to AEs throughout the maintenance period. These are the first data demonstrating that a p19-directed IL-23 antibody may be an effective treatment as maintenance therapy in patients with moderately-to-severely active UC.

BACKGROUND & AIMS: Interleukin 23 contributes to the pathogenesis of ulcerative colitis (UC). We investigated the effects of mirikizumab, a monoclonal antibody against the p19 subunit of interleukin 23, in a phase 2 study of patients with UC. METHODS: We performed a trial of the efficacy and safety of mirikizumab in patients with moderate to severely active UC, enrolling patients from 14 countries from January 2016 through September 2017. Patients were randomly assigned to groups given intravenous placebo (N = 63), mirikizumab 50 mg (N = 63) or 200 mg (N = 62) with exposure-based dosing or mirikizumab 600 mg with fixed dosing (N = 61) at weeks 0, 4, and 8. Of assigned patients, 63% had prior exposure to a biologic agent. Clinical responders (decrease in 9-point Mayo score, including >= 2 points and >= 35% from baseline with either a decrease of rectal bleeding subscore of >= 1 or a rectal bleeding subscore of 0 or 1) at week 12 who had received mirikizumab were randomly assigned to groups that received maintenance treatment with mirikizumab 200 mg subcutaneously every 4 weeks (N = 47) or every 12 weeks (N = 46). The primary endpoint was clinical remission (Mayo subscores of 0 for rectal bleeding with 1-point decrease from baseline for stool frequency, and 0 or 1 for endoscopy) at week 12. A multiple testing procedure was used that began with the 600-mg dose group, and any nonsignificant comparison result ended the formal statistical testing procedure. RESULTS: At week 12, 15.9% (P = .066), 22.6% (P = .004), and 11.5% (P = .142) of patients in the 50-mg, 200-mg, and 600-mg groups achieved clinical remission, respectively, compared with 4.8% of patients given placebo. The primary endpoint was not significant (comparison to 600 mg P > .05). Clinical responses occurred in 41.3% (P = .014), 59.7% (P < .001), and 49.2% (P = .001) of patients in the 50-mg, 200mg, and 600-mg groups, respectively, compared with 20.6% of patients given placebo. At week 52, 46.8% of patients given subcutaneous mirikizumab 200 mg every 4 weeks and 37.0% given subcutaneous mirikizumab 200 mg every 12 weeks were in clinical remission. CONCLUSIONS: In a randomized trial of patients with UC, mirikizumab was effective in inducing a clinical response after 12 weeks. Additional studies are required to determine the optimal dose for induction of remission. Mirikizumab showed durable efficacy throughout the maintenance period.

Ixekizumab, a high‐affinity monoclonal antibody, selectively targets interleukin‐17A and has been shown to be efficacious in the treatment of moderate to severe psoriasis. The objective was to describe the relationship between ixekizumab concentrations and efficacy response (static Physician Global Assessment [sPGA] and the Psoriasis Activity and Severity Index [PASI) scores] after 12 weeks of ixekizumab treatment in psoriasis patients from 3 phase 3 studies. Data from 2888 psoriasis patients randomized to receive placebo or 80 mg ixekizumab every 2 weeks or every 4 weeks were analyzed. Separate logistic regression models describing the relationship between ixekizumab concentrations and sPGA or PASI scores at week 12 were used to determine the probability of patients achieving a response and to investigate the impact of various patient factors other than drug concentrations on response rates. Both dosing regimens were efficacious, with higher rates of response achieved with the higher range of observed ixekizumab concentrations after every‐2‐week dosing. Although higher bodyweight, palmoplantar involvement, lower baseline disease state, or high baseline C‐reactive protein were associated with slightly lower response rates, the magnitude of effect of these factors on sPGA(0,1) response was small, with all subgroups able to achieve high levels of response. Other factors tested had no effect including age, sex, and antidrug antibody status. Logistic regression modeling of ixekizumab concentration and efficacy data accurately identified the proportion of responders using sPGA or PASI end points. The higher concentration ranges achieved with 80 mg every 2 weeks versus every 4 weeks were associated with higher response levels.

Table 2. Body weight and body composition.Adjusted means and [95% CI] are estimated in an ANCOVA model including baseline, treatment period, parenteral support and total oral intake at baseline as covariates.DEXA: Dual-

Solanezumab is a monoclonal antibody binding to a mid-domain epitope on soluble Aβ species. Solanezumab has been studied in three double-blind Phase 3 clinical trials (EXPEDITION, NCT00905372; EXPEDITION2, NCT00904683; EXPEDITION3, NCT01900665). EXPEDITION and EXPEDITION2 were conducted in patients with mild- to moderate-AD, without regard to the presence of amyloid pathology. EXPEDITION3 was conducted in mild AD patients with evidence of amyloid pathology. An assessment of the pharmacokinetics (PK) and pharmacodynamics (PD) of solanezumab was incorporated into these trials to determine the extent that patient-specific factors influenced exposure and drug response. Data from EXPEDITION and EXPEDITION2 were combined to develop a population PK model. A two compartment structural model was fit to the data using NONMEM (Version 7.2). Various statistical models were explored to describe inter-patient and residual variability. Clinical and demographic parameters were retained in the model if statistically significant (p<0.01). A mechanistic PK/PD model was developed using equilibrium binding theory to describe the relationship between plasma solanezumab and Aβ1–40 concentrations. Data from EXPEDITION3 were used to evaluate the PK/PD model. Typical population values of clearance (CL) and intercompartmental clearance were estimated as 8.15 mL/hr and 10.3 mL/hr, respectively. The typical population values of central (V1) and peripheral volumes of distribution were determined to be 2780 mL and 2470 mL, respectively. Inter-patient variability in CL and V1 were 23.3% and 46.4%, respectively. The final model suggested that Asian race, body weight, and gender had a statistically significant influence on the PK of solanezumab, although these effects were not large and not thought to be clinically meaningful. The PK/PD model estimated the apparent binding coefficient between solanezumab and Aβ1–40 to be 6.51 ng/mL, suggesting a free plasma Aβ reduction at steady state of ∼91%. The evaluation of PK/PD models using EXPEDITION3 data will be presented. A PK model developed with data from mild and moderate AD patients found no clinically meaningful patient-specific factors influencing solanezumab exposure. This work suggests that exposures and drug effect are generally similar between patients across gender, disease severity, age, body weight, and racial groups.

Anacetrapib, a cholesterol ester transfer protein (CETP) inhibitor, has been reported to have longer elimination half-life after longer treatment. Two pharmacokinetic model-based approaches were used to assess whether evacetrapib, another CETP inhibitor, could behave similarly. Using population pharmacokinetic (PopPK) modeling, evacetrapib and anacetrapib pharmacokinetics were characterized using available concentration-time data, and steady-state conditions were simulated. Published 2-compartment models for each compound were adapted to include a hypothetical third compartment representing a depot into which drug could partition. Physiologically based pharmacokinetic (PBPK) modeling was used to predict steady-state conditions and terminal half-life based on known physicochemical and dispositional properties. The PopPK model described the anacetrapib data well, showing a likely third compartment with estimated apparent volume of 40,700L. Anacetrapib's estimated half-life for this compartment was 550 days. Simulations for evacetrapib using a hypothetical 3-compartment model, the third compartment being consistent with that of the anacetrapib model, produced predictions inconsistent with reported results, indicating that evacetrapib did not substantially accumulate into a large compartment. The PBPK simulations were consistent with PopPK results, predicting accumulation for anacetrapib (but not evacetrapib) followed by very slow elimination. Based on available data and known physicochemical properties, evacetrapib is not expected to accumulate substantially during long-term treatment.

AimsEvacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor under development for reducing cardiovascular events in patients with high risk vascular disease. CETP inhibitors are likely to be utilized as ‘add‐on’ therapy to statins in patients receiving concomitant medications, so the potential for evacetrapib to cause clinically important drug–drug interactions (DDIs) with cytochromes P450 (CYP) was evaluated.MethodsThe DDI potential of evacetrapib was investigated in vitro, followed by predictions to determine clinical relevance. Potential DDIs with possible clinical implications were then investigated in the clinic.ResultsIn vitro, evacetrapib inhibited all of the major CYPs, with inhibition constants (Ki) ranging from 0.57 µm (CYP2C9) to 7.6 µm (CYP2C19). Evacetrapib was a time‐dependent inhibitor and inducer of CYP3A. The effects of evacetrapib on CYP3A and CYP2C9 were assessed in a phase 1 study using midazolam and tolbutamide as probe substrates, respectively. After 14 days of daily dosing with evacetrapib (100 or 300 mg), midazolam exposures (AUC) changed by factors (95% CI) of 1.19 (1.06, 1.33) and 1.44 (1.28, 1.62), respectively. Tolbutamide exposures (AUC) changed by factors of 0.85 (0.77, 0.94) and 1.06 (0.95, 1.18), respectively. In a phase 2 study, evacetrapib 100 mg had minimal impact on AUC of co‐administered simvastatin vs. simvastatin alone with a ratio of 1.25 (1.03, 1.53) at steady‐state, with no differences in reported hepatic or muscular adverse events.ConclusionsTaken together, the extent of CYP‐mediated DDI with the potential clinical dose of evacetrapib is weak and clinically important DDIs are not expected to occur in patients taking concomitant medications.

Evacetrapib is an investigational cholesteryl ester transfer protein inhibitor (CETPi) for reduction of risk of major adverse cardiovascular events in patients with high‐risk vascular disease. Understanding evacetrapib disposition, metabolism, and the potential for drug–drug interactions (DDI) may help guide prescribing recommendations. In vitro, evacetrapib metabolism was investigated with a panel of human recombinant cytochromes P450 (CYP). The disposition, metabolism, and excretion of evacetrapib following a single 100‐mg oral dose of 14C‐evacetrapib were determined in healthy subjects, and the pharmacokinetics of evacetrapib were evaluated in the presence of strong CYP3A or CYP2C8 inhibitors. In vitro, CYP3A was responsible for about 90% of evacetrapib's CYP‐associated clearance, while CYP2C8 accounted for about 10%. In the clinical disposition study, only evacetrapib and two minor metabolites circulated in plasma. Evacetrapib metabolism was extensive. A mean of 93.1% and 2.30% of the dose was excreted in feces and urine, respectively. In clinical DDI studies, the ratios of geometric least squares means for evacetrapib with/without the CYP3A inhibitor ketoconazole were 2.37 for area under the curve (AUC)(0–∞) and 1.94 for Cmax. There was no significant difference in evacetrapib AUC(0–τ) or Cmax with/without the CYP2C8 inhibitor gemfibrozil, with ratios of 0.996 and 1.02, respectively. Although in vitro results indicated that both CYP3A and CYP2C8 metabolized evacetrapib, clinical studies confirmed that evacetrapib is primarily metabolized by CYP3A. However, given the modest increase in evacetrapib exposure and robust clinical safety profile to date, there is a low likelihood of clinically relevant DDI with concomitant use of strong CYP3A or CYP2C8 inhibitors.