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Exposure-response characterization of tofacitinib efficacy in moderate to severe ulcerative colitis: Results from a dose-ranging phase 2 trial.

ABSTRACT: AIMS:Tofacitinib is an oral, small molecule JAK inhibitor being investigated for ulcerative colitis (UC). In a phase 2 dose-ranging study, tofacitinib demonstrated efficacy vs. placebo as UC induction therapy. In this posthoc analysis, we aimed to compare tofacitinib dose and plasma concentration as predictors of efficacy and identify covariates that determined efficacy in patients with UC. METHODS:One- and two-compartment pharmacokinetic models, with first-order absorption and elimination, were evaluated to describe plasma tofacitinib concentration-time data at baseline and week 8. Relationships between tofacitinib exposure (dose, average plasma drug concentration during a dosing interval at steady state [Cav,ss ] and trough plasma concentration at steady state [Ctrough,ss ]) and week 8 efficacy endpoints were characterized using logistic regression analysis. Baseline disease, demographics, prior and concurrent UC treatment were evaluated as covariates. RESULTS:Plasma tofacitinib concentrations increased proportionately with dose and estimated oral clearance, and Cav,ss values were not significantly different between baseline and week 8. Dose, Cav,ss and Ctrough,ss performed similarly as predictors of efficacy based on statistical criteria for model fit and comparison of model predictions for each endpoint. Individual Cav,ss values were similar between clinical remitters and nonremitters at predicted efficacious doses (10 and 15 mg twice daily). Baseline Mayo score was a significant determinant of efficacy. Predicted differences from placebo in clinical remission at 10 mg twice daily for patients with baseline Mayo score >8 and ?8 were 39% (95% CI: 7-70) and 21% (-2-50), respectively. CONCLUSIONS:Exposure-response characterization demonstrated the potential of tofacitinib 10 and 15 mg twice daily as induction therapy for UC without monitoring of plasma drug concentrations for dose optimization.

SUBMITTER: Mukherjee A

PROVIDER: S-EPMC5980553 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Exposure-response characterization of tofacitinib efficacy in moderate to severe ulcerative colitis: Results from a dose-ranging phase 2 trial.

Mukherjee Arnab A Hazra Anasuya A Smith Mike K MK Martin Steven W SW Mould Diane R DR Su Chinyu C Niezychowski Wojciech W

British journal of clinical pharmacology 20180323 6

<h4>Aims</h4>Tofacitinib is an oral, small molecule JAK inhibitor being investigated for ulcerative colitis (UC). In a phase 2 dose-ranging study, tofacitinib demonstrated efficacy vs. placebo as UC induction therapy. In this posthoc analysis, we aimed to compare tofacitinib dose and plasma concentration as predictors of efficacy and identify covariates that determined efficacy in patients with UC.<h4>Methods</h4>One- and two-compartment pharmacokinetic models, with first-order absorption and el ...[more]

PMID: 29377257

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Project description:IntroductionExtraintestinal manifestations (EIMs) in patients with ulcerative colitis (UC) are common. Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of UC. We evaluated the efficacy of tofacitinib in patients with EIMs, and the impact of tofacitinib on EIMs in patients with UC in the OCTAVE clinical program.MethodsData from two 8-week induction studies (OCTAVE Induction 1 and 2) and a 52-week maintenance study (OCTAVE Sustain) were analyzed. The effect of tofacitinib on efficacy outcomes stratified by EIM status, proportion of predefined prior and active EIMs at baseline, and change from baseline in EIMs were determined at the end of the treatment period (weeks 8 or 52), or at early termination.ResultsAt baseline of OCTAVE Induction 1 and 2, and OCTAVE Sustain, 27.0% and 9.0% of patients had a history of EIMs (prior or active), respectively. Patients treated with tofacitinib 10 mg twice daily (BID) achieved remission and had endoscopic improvement in all studies, irrespective of any history of EIMs. A greater proportion of patients had active peripheral arthritis at baseline of OCTAVE Induction 1 and 2 versus OCTAVE Sustain. In OCTAVE Induction 1 and 2, similar proportions of tofacitinib and placebo-treated patients with active peripheral arthritis experienced either no change (81.3% and 85.7%, respectively) or an improvement (15.6% and 14.3%, respectively). By week 52 of OCTAVE Sustain, improvements in active peripheral arthritis were only observed in tofacitinib-treated patients (16.7% and 33.3% with tofacitinib 5 and 10 mg BID, respectively).ConclusionAny history of EIMs did not influence the efficacy of tofacitinib 10 mg BID for induction or maintenance of UC. The most common active EIM was peripheral arthritis, for which many patients in OCTAVE Induction 1 and 2, and OCTAVE Sustain, reported improvement or no change from baseline with tofacitinib treatment.Clinicaltrials.gov:NCT01465763; NCT01458951; NCT01458574.

Project description:BackgroundTofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. We aimed to describe the real-world treatment experience and corticosteroid utilisation of patients treated with tofacitinib in a US claims database.MethodsPatients with a UC diagnosis who initiated tofacitinib, vedolizumab or tumour necrosis factor inhibitor (TNFi) treatment between May 2018 and July 2019 were identified from the Optum Research Database. Demographic and clinical characteristics of patients who initiated tofacitinib, vedolizumab or TNFi were described. Oral corticosteroid use prior to and following tofacitinib initiation was evaluated. Tofacitinib adherence (proportion of days covered) and continuation was assessed for 6 months following initiation. Analyses were descriptive and stratified by prior biologic use (naïve, 1 or ≥ 2; minimum of 12 months prior to tofacitinib initiation).ResultsAmong patients initiating tofacitinib (N = 225), mean age was 45.6 (SD 16.5) years and 50.2% were female. Of these, 43 (19.1%) patients were biologic-naïve and 182 (80.9%) had prior biologic use (92 [40.9%], 1 prior biologic; 90 [40.0%], ≥ 2 prior biologics). Among patients with 1 prior biologic, 82.6% were previously treated with a TNFi. Among patients with ≥ 2 prior biologics, 54.4% were previously treated with vedolizumab and a TNFi, 16.7% with two TNFi and 28.9% with ≥ 3 prior biologics. In the 6 months prior to tofacitinib initiation, 65.8% of patients had received oral corticosteroids (74.4%, 60.9% and 66.7% for biologic-naïve, 1 and ≥ 2 prior biologics, respectively). The proportion of patients with ongoing oral corticosteroid use 3-6 months after tofacitinib initiation decreased to 13.3% (9.3%, 18.5% and 10.0% for biologic-naïve, 1 and ≥ 2 prior biologics, respectively), and 19.6% of patients discontinued oral corticosteroid use during the 6 months after tofacitinib initiation. Overall, tofacitinib adherence, as determined by the mean proportion of days covered during the 6-month follow-up, was 0.7 (median 0.8). During the 6-month follow-up, 84.9% of patients continued tofacitinib.ConclusionsAmong patients with UC initiating tofacitinib, the majority had prior biologic use. Tofacitinib adherence was high, discontinuation was low and oral corticosteroid utilisation decreased irrespective of prior biologic use. Further research with longer follow-up and a larger sample size is required.

Project description:ObjectiveTofacitinib is an oral Janus kinase inhibitor approved for the treatment of ulcerative colitis (UC). The objective of this study was to evaluate the long-term cost-effectiveness of tofacitinib versus current biologics, considering combinations of first-line (1L) and second-line (2L) therapies, from a Japanese payer's perspective in patients with moderate-to-severe active UC following an inadequate response to conventional therapy and in those who were naïve to biologics.MethodsA cost-effectiveness analysis was conducted during the time horizon specified in the Markov model, which considers a patient's lifetime as 60 years and an annual discount rate of 2% on costs and effects. The model compared tofacitinib with vedolizumab, infliximab, adalimumab, golimumab, and ustekinumab. The time of active treatment was divided into induction and maintenance phases. Patients not responding to their biologic treatment after induction or during the maintenance phase were switched to a subsequent line of therapy. Treatment response and remission probabilities (for induction and maintenance phases) were obtained through a systematic literature review and a network meta-analysis that employed a multinomial analysis with fixed effects. Patient characteristics were sourced from the OCTAVE Induction trials. Mean utilities associated with UC health states and adverse events (AEs) were obtained from published sources. Direct medical costs related to drug acquisition, administration, surgery, patient management, and AEs were derived from the JMDC database analysis, which corresponded with the medical procedure fees from 2021. The drug prices were adjusted to April 2021. Further validation through all processes by clinical experts in Japan was conducted to fit the costs to real-world practices. Scenario and sensitivity analyses were also performed to confirm the accuracy and robustness of the base-case results.ResultsIn the base-case, the treatment pattern including 1L tofacitinib was more cost-effective than vedolizumab, infliximab, golimumab, and ustekinumab for 1L therapies in terms of cost per quality-adjusted life year (QALY) gained (based on the Japanese threshold of 5,000,000 yen/QALY [38,023 United States dollars {USD}/QALY]). The base-case results demonstrated that the incremental costs would be reduced for all biologics, and decreases in incremental QALYs were observed for all biologics other than adalimumab. The incremental cost-effectiveness ratio (ICER) was found to be dominant for adalimumab; for the other biologics, it was found to be less costly and less efficacious. The efficiency frontier on the cost-effectiveness plane indicated that tofacitinib-infliximab and infliximab-tofacitinib were more cost-effective than the other treatment patterns. When infliximab-tofacitinib was compared with tofacitinib-infliximab, the ICER was 282,609,856 yen/QALY (2,149,157 USD/QALY) and the net monetary benefit (NMB) was -12,741,342 yen (-96,894 USD) with a threshold of 5,000,000 yen (38,023 USD) in Japan. Therefore, infliximab-tofacitinib was not acceptable by this threshold, and tofacitinib-infliximab was the cost-effective treatment pattern.ConclusionThe current analysis suggests that the treatment pattern including 1L tofacitinib is a cost-effective alternative to the biologics for patients with moderate-to-severe UC from a Japanese payer's perspective.

Project description:BackgroundTofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We aimed to estimate the overall incidence of safety events in patients with UC in a real-life population cohort for comparison with the tofacitinib UC clinical trial program.MethodsClinical trial-like criteria were applied to an IBM MarketScan® claims database population-based cohort (n = 22,967) of patients with UC (October 2010 to September 2015) to identify a UC trial-like cohort treated with tumor necrosis factor inhibitors (TNFi; n = 6366) to compare with the tofacitinib UC clinical trial cohort (n = 1157).ResultsIncidence rates (events per 100 patient-years; [95% confidence interval]) in the UC trial-like cohort were as follows: serious infections, 3.33 (2.73-4.02); opportunistic infections (OIs; excluding herpes zoster [HZ]), 1.45 (1.06-1.93); HZ, 1.77 (1.34-2.29); malignancies (excluding nonmelanoma skin cancer [NMSC]), 0.63 (0.43-0.90); NMSC, 1.69 (1.35-2.10); major adverse cardiovascular events (MACE), 0.51 (0.31-0.79); pulmonary embolism (PE), 0.54 (0.30-0.89); deep vein thrombosis (DVT), 1.41 (1.00-1.93); and gastrointestinal perforations, 0.31 (0.16-0.54). Compared with the UC trial-like cohort, tofacitinib-treated patients had numerically lower incidence rates for serious infections (1.75 [1.27-2.36]), OIs (excluding HZ; 0.16 [0.04-0.42]), NMSC (0.78 [0.47-1.22]), PE (0.16 [0.04-0.41]), and DVT (0.04 [0.00-0.23]), and a higher rate for HZ (3.57 [2.84-4.43]); rates for malignancies (excluding NMSC), MACE, and gastrointestinal perforations were similar.ConclusionsWhen acknowledging limitations of comparing claims data with controlled clinical trial data, incidence rates for HZ among TNFi-treated patients in the UC trial-like cohort were lower than in the tofacitinib UC clinical trial cohort; rates for serious infections, OIs, NMSC, PE, and DVT were numerically higher.Clinicaltrials.govNCT00787202, NCT01465763, NCT01458951, NCT01458574, NCT01470612.

Dataset Information

Exposure-response characterization of tofacitinib efficacy in moderate to severe ulcerative colitis: Results from a dose-ranging phase 2 trial.

Publications

Exposure-response characterization of tofacitinib efficacy in moderate to severe ulcerative colitis: Results from a dose-ranging phase 2 trial.

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