Assessing the economics of biologic and small molecule therapies for the treatment of moderate to severe ulcerative colitis in Japan: a cost per responder analysis of upadacitinib.

AIM: Patients with moderately to severely active ulcerative colitis have an increasing number of advanced therapy options including several biologics and Janus kinase inhibitors. Though data on efficacy and safety of these advanced therapies are available, less is known about the potential economic implications of their utilization in Japan. We evaluated the relative value of these advanced therapies in Japan using a locally developed cost per responder model. METHODS: A model was developed using relevant clinical endpoints and treatment costs to calculate cost per responder of all advanced therapies used for moderately to severely active ulcerative colitis treatment in Japan. Cost per responder was assessed in biologic-naïve and biologic-exposed populations, respectively. The model incorporated induction and maintenance therapy pathways as patients progressed through based on efficacy rates (clinical response, clinical remission and endoscopic improvement). Total costs for induction and maintenance included: drug acquisition, drug administration and serious adverse event management (as necessary) for responders, with additional rescue treatment cost only for non-responders. RESULTS: Upadacitinib showed lower cost per clinical response and cost per clinical remission across both biologic-naïve and biologic-exposed populations with only one exemption in cost per clinical remission in biologic-naïve population. In addition, upadacitinib demonstrated lower cost per endoscopic improvement in both populations. Janus kinase inhibitors outperformed with lower cost per responder than other mediations across all outcomes and patient populations with the exception of tofacitinib for clinical remission in biologic-exposed UC population. LIMITATIONS: Comparative data used in this analysis have been derived from network meta-analysis, not from direct comparison. CONCLUSIONS: The results of this cost per responder analysis suggest upadacitinib is a cost-effective option for the first- and second-line treatment of moderately to severely active ulcerative colitis in Japan.

Efficacy and safety of upadacitinib maintenance therapy for moderately to severely active ulcerative colitis in patients responding to 8 week induction therapy (U-ACHIEVE Maintenance): overall results from the randomised, placebo-controlled, double-blind, phase 3 maintenance study.

BACKGROUND: Upadacitinib is an oral, selective, and reversible JAK inhibitor with demonstrated efficacy in patients with moderately to severely active ulcerative colitis in a phase 2b induction trial, two phase 3 induction trials (U-ACHIEVE Induction and U-ACCOMPLISH), and a primary analysis of the first 451 patients entering a subsequent maintenance trial (U-ACHIEVE Maintenance). Here, we present overall results from the entire U-ACHIEVE Maintenance population. METHODS: In this randomised, placebo-controlled, double-blind, phase 3 maintenance study done across Europe, North and South America, Australasia, Africa, and the Asia-Pacific region at 251 clinical centres in 44 countries, patients aged 16-75 years with moderately to severely active ulcerative colitis (adapted Mayo score 5-9, centrally assessed endoscopic subscore of 2 or 3) for 90 days or more were randomly assigned (2:1) to double-blind upadacitinib 45 mg once daily or placebo induction therapy in the phase 2b induction trial or two phase 3 induction trials. Patients with a clinical response per adapted Mayo score after 8 weeks were randomly reassigned (1:1:1) using web-based interactive response technology to 52 week double-blind maintenance therapy with placebo, upadacitinib 15 mg, or upadacitinib 30 mg once daily. Efficacy was analysed at week 52 in the intention-to-treat population, which included all patients randomly reassigned who received at least one dose of study drug. The primary endpoint was clinical remission per adapted Mayo score. Safety through week 52 was assessed with exposure-adjusted event rates (EAERs; events per 100 patient-years) in upadacitinib 45 mg once daily 8-week induction responders who were enrolled per protocol for 44-week or 52-week maintenance therapy (ie, the intention-to-treat population plus patients who received up to 44 weeks' maintenance therapy under earlier protocol amendments) and received at least one dose of study drug. The study is registered with ClinicalTrials.gov, NCT02819635 and is complete. FINDINGS: Between Sept 3, 2016, and Jan 14, 2021 987 patients received the upadacitinib 45 mg once daily induction therapy in the phase 2b trial, U-ACHIEVE Induction, or U-ACCOMPLISH. 681 patients with a clinical response to the induction therapy (319 from U-ACHIEVE Induction, 341 from U-ACCOMPLISH, and 21 from the phase 2b induction trial) received placebo (n=223), upadacitinib 15 mg once daily (n=225), or upadacitinib 30 mg once daily (n=233) in U-ACHIEVE Maintenance and were included in this analysis. A greater proportion of patients achieved the primary endpoint with upadacitinib 15 mg (40·4%) and 30 mg once daily (53·6%) versus placebo (10·8%; both p<0·0001 vs placebo). For safety, 746 patients were analysed, representing 552·9 patient-years of exposure; the most common grade 3-4 treatment-emergent adverse events were worsening of ulcerative colitis in nine (4%) patients with placebo, and COVID-19 pneumonia and cryptococcal pneumonia in two (1%) patients each with upadacitinib 30 mg once daily. Higher EAERs of the following treatment-emergent events of special interest were observed with upadacitinib versus placebo: herpes zoster (6·0 events per 100 patient-years with upadacitinib 15 mg once daily and 7·3 events per 100 patient-years with upadacitinib 30 mg once daily vs none per 100 patient-years with placebo [12 and 16 vs no events, respectively), hepatic disorders (17·0 and 9·2 vs 5·9 events per 100 patient-years [34 and 20 vs eight events, respectively), creatine phosphokinase elevation (8·0 and 10·1 vs 3·7 events per 100 patient-years [16 and 22 vs five events], respectively), and neutropenia (5·5 and 8·7 vs 5·2 events per 100 patient-years [11 and 19 vs seven events], respectively). One (<1% of patients) adjudicated major adverse cardiovascular event occurred with placebo and one (<1% of patients) with upadacitinib 30 mg once daily (EAERs 0·7 and 0·5 events per 100 patient-years, respectively). Two (1% of patients) venous thromboembolic events occurred with upadacitinib 15 mg once daily and two (1% of patients) with upadacitinib 30 mg once daily (EAERs 1·0 and 0·9 events per 100 patient-years, respectively). All adjudicated major adverse cardiovascular events and venous thromboembolic events with upadacitinib occurred in patients with relevant known risk factors. INTERPRETATION: Consistent with the primary analysis done among a smaller population, both maintenance doses of upadacitinib showed a positive benefit-risk profile in patients with moderately to severely active ulcerative colitis. Upadacitinib represents an effective treatment option for this population, for whom a large unmet need persists. FUNDING: AbbVie.

Correlation of mucosal healing endpoints with long-term clinical and patient-reported outcomes in ulcerative colitis.

BACKGROUND: We evaluated the clinical relevance of achieving histologic endoscopic mucosal improvement (HEMI) and the more stringent target of histologic endoscopic mucosal remission (HEMR) in the phase 3 maintenance trial of upadacitinib for moderately to severely active ulcerative colitis. METHODS: Clinical and patient-reported outcomes were assessed in patients with clinical response after 8- or 16-week upadacitinib induction who received 52-week upadacitinib maintenance treatment. Cross-sectional and predictive analyses evaluated the relationship between HEMR or HEMI at Week 8/16 and Week 52, respectively, and outcomes at Week 52. Adjusted odds ratios (aOR) were derived from logistic regressions for patients achieving HEMR or HEMI without HEMR versus those not achieving HEMI. RESULTS: Cross-sectional analyses showed that patients with HEMR had greater odds of achieving all clinical and patient-reported outcomes at Week 52 than those not achieving HEMI. In predictive analyses, patients with HEMR at Week 8/16 had significantly greater odds of achieving clinical remission (aOR = 3.6, p = 0.001) and endoscopic remission (aOR = 3.9, p < 0.001) at Week 52 than patients not achieving HEMI and HEMR. For patients achieving HEMI without HEMR, these odds were lower: clinical remission (aOR = 3.2, p < 0.001) and endoscopic remission (aOR = 2.4, p = 0.010). The odds of achieving clinically meaningful improvements in most patient-reported outcomes were directionally similar between HEMI and HEMR, but not statistically different to patients not achieving HEMI. No hospitalizations or surgeries were observed in patients with HEMR at Week 52. CONCLUSIONS: Achievement of HEMR or HEMI is clinically relevant with HEMR being associated with greater likelihood of improvement in long-term clinical and patient-reported outcomes. https://www. CLINICALTRIALS: gov NCT02819635.

A Comparative Evaluation of the Measurement Properties of Three Histological Indices of Mucosal Healing in Ulcerative Colitis: Geboes Score, Robarts Histopathology Index and Nancy Index.

BACKGROUND AND AIMS: To inform their future use in regulated clinical trials to evaluate treatment efficacy hypotheses, the measurement properties of three histological indices, Geboes Score [GS], Robarts Histopathology Index [RHI] and Nancy Index [NI], were evaluated among patients with ulcerative colitis. METHODS: Analyses were conducted on data from a Phase 3 clinical trial of adalimumab [M14-033, n = 491] and focused on evaluating the measurement properties of the GS, RHI and NI. Specifically, internal consistency and inter-rater reliability, convergent, discriminant and known-group validity, and sensitivity to change were assessed at Baseline, and at Weeks 8 and 52. RESULTS: Internal consistency for the RHI showed lower alpha [α] values at Baseline [α = 0.62] relative to Weeks 8 [α = 0.82] and 52 [α = 0.81]. The inter-rater reliability values of RHI [0.91], NI [0.64] and GS [0.53] were excellent, good and fair, respectively. Regarding validity, Week 52 correlations were moderate to strong between full and partial Mayo scores and Mayo subscale scores and the RHI and GS, and were weak to moderate for the NI. Significant differences between mean scores of all three histological indices were observed across known-groups based on Mayo endoscopy subscores and full Mayo scores at Weeks 8 and 52 [p < 0.001]. CONCLUSIONS: The GS, RHI and NI are each capable of producing reliable and valid scores that are sensitive to changes in disease activity over time, in patients with moderately to severely active ulcerative colitis. While all three indices demonstrated relatively acceptable measurement properties, the GS and RHI performed better than the NI.

Efficacy and Safety of Advanced Therapies for Moderately to Severely Active Ulcerative Colitis at Induction and Maintenance: An Indirect Treatment Comparison Using Bayesian Network Meta-analysis.

Background: Given rapid innovation in advanced therapies for moderately to severely active ulcerative colitis (UC), we investigated their comparative efficacy and safety during induction and maintenance through network meta-analysis. Methods: Using Bayesian methods, endpoints of clinical remission and clinical response per Full Mayo score, and endoscopic improvement were assessed in bio-naive and -exposed populations. Safety was assessed in overall populations by all adverse events (AEs), serious AEs, discontinuation due to AEs, and serious infections. Phase 3 randomized controlled trials were identified via systematic literature review, including the following advanced therapies: infliximab, adalimumab, vedolizumab, golimumab, tofacitinib, ustekinumab, filgotinib, ozanimod, and upadacitinib. Random effects models were used to address between-study heterogeneity. Intent-to-treat (ITT) efficacy rates were calculated by adjusting maintenance outcomes by likelihood of induction response. Results: Out of 48 trials identified, 23 were included. Across all outcomes and regardless of prior biologic exposure, ITT efficacy rates were highest for upadacitinib, owing to its highest ranking for all efficacy outcomes in induction and for all but clinical remission during maintenance among bio-naive induction responders. For all advanced therapies versus placebo, there were no significant differences in serious AEs or serious infections across therapies. For all AEs, golimumab had higher odds versus placebo during maintenance; for discontinuation due to AEs, upadacitinib had lower odds versus placebo during induction, while ustekinumab and vedolizumab had lower odds versus placebo during maintenance. Conclusions: Upadacitinib may be the most efficacious therapy for moderately to severely active UC based on ITT analyses, with similar safety across advanced therapies.

Upadacitinib Induction and Maintenance Therapy Improves Abdominal Pain, Bowel Urgency, and Fatigue in Patients With Ulcerative Colitis: A Post Hoc Analysis of Phase 3 Data.

BACKGROUND: This post hoc analysis of a large, phase 3 program evaluated the effects of upadacitinib on fatigue, bowel urgency, and abdominal pain in patients with moderately to severely active ulcerative colitis. METHODS: Induction data were pooled from 2 identical studies, the U-ACHIEVE induction and U-ACCOMPLISH studies. Patients in these studies received upadacitinib 45 mg once daily or placebo as induction treatment. Responders to induction treatment were rerandomized in the U-ACHIEVE maintenance study to upadacitinib 15 mg once daily, upadacitinib 30 mg, or placebo. The percentage of patients reporting no abdominal pain and no bowel urgency daily via an electronic diary and a meaningful within-person change (≥5 points) in the Functional Assessment of Chronic Illness Therapy-Fatigue score were evaluated. RESULTS: The results demonstrated a statistically significantly greater percentage of patients reporting no abdominal pain and absence of bowel urgency observed from week 2 (P < .001), with upadacitinib induction treatment and clinically meaningful improvements in Functional Assessment of Chronic Illness Therapy-Fatigue score observed at week 8 (P < .001), when compared with placebo. The maintenance study showed that significant and meaningful improvements in abdominal pain, bowel urgency, and Functional Assessment of Chronic Illness Therapy-Fatigue score achieved during induction were sustained through 52 weeks of maintenance treatment in upadacitinib- vs placebo-treated patients. CONCLUSIONS: The findings of this study support the additional benefit of upadacitinib in treating moderately to severely active ulcerative colitis by demonstrating a statistically significant impact on clinically meaningful symptoms of fatigue, bowel urgency, and abdominal pain.(U-ACHIEVE induction and maintenance studies; NCT02819635; U-ACCOMPLISH induction study; NCT03653026).

A significantly higher percentage of patients with moderately to severely active ulcerative colitis reported no abdominal pain, no bowel urgency, and a meaningful change in fatigue following 8-week upadacitinib induction treatment and 52-week maintenance treatment compared with placebo.

Ulcerative Colitis-Symptom Questionnaire: Valid for Use in Adults with Moderately to Severely Active Ulcerative Colitis.

BACKGROUND: Due to wide-ranging impacts of Ulcerative Colitis (UC), regulatory authorities emphasize the importance of including validated patient-reported symptom severity measures in clinical trials. AIM: To describe the development and validation of the Ulcerative Colitis-Symptom Questionnaire (UC-SQ). METHODS: The UC-SQ was developed in a qualitative study involving a targeted literature review, semi-structured concept elicitation interviews, and combined concept elicitation/cognitive interviews. Measurement properties, including item-level analyses, factor structure, reliability, validity, responsiveness, and clinically meaningful change were evaluated using data from a phase 2b, randomized trial in adults with UC (N = 113). RESULTS: Fourteen symptom concepts were elicited across 22 interviews, with saturation at the fifth interview. Twenty-two items were unmodified as cognitive interview participants interpreted underlying concepts correctly. Instructions were clear and items were relevant, with appropriate response options and recall periods. Reduction to 17 items was completed prior to psychometric testing. Two items (joint pain/constipation) did not contribute to reliability in initial testing and were included as non-scored items. The 15-item UC-SQ showed evidence of internal consistency (α = 0.86) and test-retest reliability (intraclass correlation coefficient = 0.88). The UC-SQ discriminated by disease severity as defined by Mayo and Inflammatory Bowel Disease Questionnaire scores (p < 0.0001). Convergent validity was supported by strong correlations with criterion measures. The UC-SQ was responsive in patients indicating change in other measures. A 10-point decrease from baseline indicated within-patient meaningful improvement. CONCLUSIONS: The UC-SQ is reliable, valid and responsive, with a 10-point improvement estimating within-patient clinically meaningful improvement. The tool is fit-for-purpose as a key endpoint in pivotal UC trials.

Induction and Maintenance Treatment With Upadacitinib Improves Health-Related Quality of Life in Patients With Moderately to Severely Active Ulcerative Colitis: Phase 3 Study Results.

BACKGROUND: We evaluated the health-related quality of life (HRQoL) benefits of upadacitinib (UPA) induction and maintenance treatment in a phase 3 study of patients with ulcerative colitis (UC) across a broad range of patient-centered outcomes. METHODS: Patients received UPA 45 mg once daily or placebo as induction treatment for 8 weeks. Patients who achieved clinical response were rerandomized to receive once daily UPA 15 mg, 30 mg, or placebo as maintenance treatment for 52 weeks. The percentages of patients reporting a clinically meaningful within-person change from baseline in the Ulcerative Colitis Symptoms Questionnaire, Inflammatory Bowel Disease Questionnaire, Work Productivity and Impairment Questionnaire, 36-Item Short Form Survey, and European Quality of Life-5 Dimension 5 Levels were evaluated at weeks 2 and 8 of induction and at weeks 0 and 52 of maintenance. RESULTS: Significant improvements from baseline in all HRQoL measures except the Work Productivity and Impairment Questionnaire-absenteeism were achieved with UPA (P < .001) vs placebo as early as week 2 of induction. These improvements were sustained at week 52 with significantly more patients treated with either 15 mg or 30 mg UPA vs placebo achieving meaningful within-person change in the Ulcerative Colitis Symptoms Questionnaire; Inflammatory Bowel Disease Questionnaire; overall work impairment, presenteeism, and activity impairment; both 36-Item Short Form Survey Physical and Mental Component Summaries; and European Quality of Life-5 Dimension 5 Levels (P < .001). CONCLUSIONS: Induction treatment with UPA 45 mg significantly improved HRQoL measures. A significantly higher percentage of patients who responded to induction treatment with UPA maintained clinically meaningful improvements consistently across a wide range of HRQoL outcomes after 52 weeks of maintenance therapy with UPA (15 mg and 30 mg) compared with placebo. (ClinicalTrials.gov, Numbers: NCT02819635, NCT03653026).

Patients with moderate-to-severe ulcerative colitis who received upadacitinib induction treatment demonstrated clinically meaningful improvements across multiple health-related quality of life assessments, as early as induction week 2, that persisted with maintenance treatment to 52 weeks, compared with placebo.

Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials.

BACKGROUND: There is a great unmet need for advanced therapies that provide rapid, robust, and sustained disease control for patients with ulcerative colitis. We assessed the efficacy and safety of upadacitinib, an oral selective Janus kinase 1 inhibitor, as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. METHODS: This phase 3, multicentre, randomised, double-blind, placebo-controlled clinical programme consisted of two replicate induction studies (U-ACHIEVE induction [UC1] and U-ACCOMPLISH [UC2]) and a single maintenance study (U-ACHIEVE maintenance [UC3]). The studies were conducted across Europe, North and South America, Australasia, Africa, and the Asia-Pacific region at 199 clinical centres in 39 countries (UC1), 204 clinical centres in 40 countries (UC2), and 195 clinical centres in 35 countries (UC3). Patients aged 16-75 years with moderately to severely active ulcerative colitis (Adapted Mayo score 5-9; endoscopic subscore 2 or 3) for at least 90 days were randomly assigned (2:1) to oral upadacitinib 45 mg once daily or placebo for 8 weeks (induction studies). Patients who achieved clinical response following 8-week upadacitinib induction were re-randomly assigned (1:1:1) to upadacitinib 15 mg, upadacitinib 30 mg, or placebo for 52 weeks (maintenance study). All patients were randomly assigned using web-based interactive response technology. The primary endpoints were clinical remission per Adapted Mayo score at week 8 (induction) and week 52 (maintenance). The efficacy analyses in the two induction studies were based on the intent-to-treat population, which included all randomised patients who received at least one dose of treatment. In the maintenance study, the primary efficacy analyses reported in this manuscript were based on the first 450 (planned) clinical responders to 8-week induction therapy with upadacitinib 45 mg once daily. The safety analysis population in the induction studies consisted of all randomised patients who received at least one dose of treatment; in the maintenance study, this population included all patients who received at least one dose of treatment as part of the primary analysis population. These studies are registered at ClinicalTrials.gov, NCT02819635 (U-ACHIEVE) and NCT03653026 (U-ACCOMPLISH). FINDINGS: Between Oct 23, 2018, and Sept 7, 2020, 474 patients were randomly assigned to upadacitinib 45 mg once daily (n=319) or placebo (n=155) in UC1. Between Dec 6, 2018, and Jan 14, 2021, 522 patients were randomly assigned to upadacitinib 45 mg once daily (n=345) or placebo (n=177) in UC2. In UC3, a total of 451 patients (21 from the phase 2b study, 278 from UC1, and 152 from UC2) who achieved a clinical response after 8 weeks of upadacitinib induction treatment were randomly assigned again to upadacitinib 15 mg (n=148), upadacitinib 30 mg (n=154), and placebo (n=149) in the primary analysis population. Statistically significantly more patients achieved clinical remission with upadacitinib 45 mg (83 [26%] of 319 patients in UC1 and 114 [34%] of 341 patients in UC2) than in the placebo group (seven [5%] of 154 patients in UC1 and seven [4%] of 174 patients; p<0·0001; adjusted treatment difference 21·6% [95% CI 15·8-27·4] for UC1 and 29·0% [23·2-34·7] for UC2). In the maintenance study, clinical remission was achieved by statistically significantly more patients receiving upadacitinib (15 mg 63 [42%] of 148; 30 mg 80 [52%] of 154) than those receiving placebo (18 [12%] of 149; p<0·0001; adjusted treatment difference 30·7% [21·7-39·8] for upadacitinib 15 mg vs placebo and 39·0% [29·7-48·2] for upadacitinib 30 mg vs placebo). The most commonly reported adverse events in UC1 were nasopharyngitis (15 [5%] of 319 in the upadacitinib 45 mg group vs six [4%] of 155 in the placebo group), creatine phosphokinase elevation (15 [4%] vs three [2%]), and acne (15 [5%] vs one [1%]). In UC2, the most frequently reported adverse event was acne (24 [7%] of 344 in the upadacitinib 45 mg group vs three [2%] of 177 in the placebo group). In both induction studies, serious adverse events and adverse events leading to discontinuation of treatment were less frequent in the upadacitinib 45 mg group than in the placebo group (serious adverse events eight [3%] vs nine (6%) in UC1 and 11 [3%] vs eight [5%] in UC2; adverse events leading to discontinuation six [2%] vs 14 [9%] in UC1 and six [2%] vs nine [5%] in UC2). In UC3, the most frequently reported adverse events (≥5%) were worsening of ulcerative colitis (19 [13%] of 148 in the upadacitinib 15 mg group vs 11 [7%] of 154 in the upadacitinib 30 mg group vs 45 [30%] of 149 in the placebo group), nasopharyngitis (18 [12%] vs 22 [14%] vs 15 [10%]), creatine phosphokinase elevation (nine [6%] vs 13 [8%] vs three [2%]), arthralgia (nine [6%] vs five [3%] vs 15 [10%]), and upper respiratory tract infection (seven [5%] vs nine [6%] vs six [4%]). The proportion of serious adverse events (ten [7%] vs nine [6%] vs 19 [13%]) and adverse events leading to discontinuation (six [4%] vs ten [6%] vs 17 [11%]) was lower in both upadacitinib groups than in the placebo group. Events of cancer, adjudicated major adverse cardiac events, or venous thromboembolism were reported infrequently. There were no treatment-related deaths. INTERPRETATION: Upadacitinib demonstrated a positive efficacy and safety profile and could be an effective treatment option for patients with moderately to severely active ulcerative colitis. FUNDING: AbbVie.

Higher vs Standard Adalimumab Induction and Maintenance Dosing Regimens for Treatment of Ulcerative Colitis: SERENE UC Trial Results.

BACKGROUND & AIMS: SERENE UC (Study of a Novel Approach to Induction and Maintenance Dosing With Adalimumab in Patients With Moderate to Severe Ulcerative Colitis) evaluated the efficacy of higher adalimumab induction and maintenance dose regimens in patients with ulcerative colitis. METHODS: This phase 3, double-blind, randomized trial included induction and maintenance studies, with a main study (ex-Japan) and Japan substudy. Eligible patients (18-75 years, full Mayo score 6-12, centrally read endoscopy subscore 2-3) were randomized 3:2 to higher induction regimen (adalimumab 160 mg at weeks 0, 1, 2, and 3) or standard induction regimen (160 mg at week 0 and 80 mg at week 2); all received 40 mg at weeks 4 and 6. At week 8, all patients were rerandomized 2:2:1 (main study) to 40 mg every week (ew), 40 mg every other week (eow), or exploratory therapeutic drug monitoring; or 1:1 (Japan substudy) to 40 mg ew or 40 mg eow maintenance regimens. RESULTS: In the main study, 13.3% vs 10.9% of patients receiving the higher induction regimen vs standard induction regimen achieved clinical remission (full Mayo score ≤2 with no subscore >1) at week 8 (induction primary end point; P = .265); among week-8 responders, 39.5% vs 29.0% receiving 40 mg ew vs 40 mg eow achieved clinical remission at week 52 (maintenance primary end point; P = .069). In the integrated (main + Japan) population, 41.1% vs 30.1% of week-8 responders receiving 40 mg ew vs 40 mg eow achieved clinical remission at week 52 (nominal P = .045). Safety profiles were comparable between dosing regimens. CONCLUSION: Although primary end points were not met, a >10% absolute difference in clinical remission was demonstrated with higher adalimumab maintenance dosing. Higher dosing regimens were generally well tolerated and consistent with the known safety profile of adalimumab in ulcerative colitis. CLINICALTRIALS: gov, Number: NCT002209456.

Efficacy and safety of adalimumab in paediatric patients with moderate-to-severe ulcerative colitis (ENVISION I): a randomised, controlled, phase 3 study.

BACKGROUND: Biologic treatment options are limited for children with ulcerative colitis. The aim of this study was to assess the safety and efficacy of adalimumab in children with moderate-to-severe ulcerative colitis. METHODS: The double-blind ENVISION I study was done at 24 hospitals in ten countries. Children (4-17 years) with moderate-to-severe ulcerative colitis despite stable doses of concurrent treatment with oral corticosteroids or immunosuppressants were enrolled. Per the original study design, patients were randomly assigned with an Interactive Voice Response System (IVRS) to receive either high-dose induction adalimumab (2·4 mg/kg [maximum 160 mg] at weeks 0 and 1) or standard-dose induction adalimumab (2·4 mg/kg at week 0 and placebo at week 1); both groups received 1·2 mg/kg (maximum 80 mg) at week 2 and 0·6 mg/kg (maximum 40 mg) at weeks 4 and 6. Patients with partial Mayo score (PMS) response at week 8 (defined as a decrease of two or more points and a decrease of ≥30% from baseline in PMS) were randomly assigned (2:2:1)-using IVRS-to receive either high-dose maintenance adalimumab (0·6 mg/kg weekly), standard-dose maintenance adalimumab (0·6 mg/kg every other week), or placebo up to week 52 (random assignment to the placebo group was ceased mid-trial, as was randomisation in the induction phase with all subsequent patients receiving open-label high-dose induction adalimumab). Coprimary endpoints were the proportion of patients with PMS remission at week 8 (intent-to-treat [ITT]-E population, not including those patients who were not randomised in the induction phase) and full Mayo score (FMS) remission at week 52 in week 8 PMS responders (maintenance ITT-E [mITT-E] population), for which the pooled adalimumab group (patients who received high-dose or standard-dose adalimumab) and the individual dose groups were compared against external adult placebo rates. We report results of the final confirmatory analysis. This trial is registered with ClinicalTrials.gov, NCT02065557. FINDINGS: 93 children were recruited between Oct 13, 2014, and Sept 5, 2018, to the main study (77 [83%] were randomly assigned [double-blind] to receive high-dose or standard-dose induction adalimumab; 16 [17%] received open-label high-dose induction adalimumab after study design change). At week 8, 74 (80%) children who were PMS responders continued to the maintenance period. 62 (84%) patients were randomly assigned to receive high-dose or standard-dose maintenance adalimumab treatment; 12 (16%) patients received placebo. In patients in the ITT-E population who were randomly assigned to receive high-dose induction adalimumab, a significantly higher proportion of patients were in PMS remission at week 8 (28 [60%] of 47) compared with external placebo (19·8%; p=0·0001). 13 (43%) of 30 patients in the standard-dose induction adalimumab group were in PMS remission at week 8 versus an external placebo rate of 19·8%, but this difference was not significant (p=0·38). Similarly, FMS remission at week 52 in children who were week 8 PMS responders was reported in a significantly higher proportion of patients in mITT-E population who received high-dose maintenance adalimumab (14 [45%] of 31 patients) versus external placebo at week 52 (18·4%; p=0·0001). Nine (29%) of 31 patients in the standard-dose maintenance adalimumab group were in FMS remission at week 52 versus an external placebo rate of 18·4%, but this difference was not significant (p=0·38). Remission rates in the pooled adalimumab groups were significantly better compared with external placebo (PMS remission at week 8: 41 [53%] of 77 patients; p<0·0001; FMS remission at week 52: 23 [37%] of 62 patients; p=0·0001). 21 (23%) of 93 patients in the main study had one or more treatment-emergent serious adverse events during any adalimumab exposure. The most common adverse events were headache, anaemia, and ulcerative colitis flare during the induction period and ulcerative colitis flare, headache, and nasopharyngitis during the maintenance period. INTERPRETATION: Clinically meaningful rates of remission and response were reported in children who received adalimumab in this study. No new safety signals were observed, suggesting that adalimumab is an efficacious and safe treatment option for children with moderate-to-severe ulcerative colitis. FUNDING: AbbVie.

Upadacitinib Treatment Improves Symptoms of Bowel Urgency and Abdominal Pain, and Correlates With Quality of Life Improvements in Patients With Moderate to Severe Ulcerative Colitis.

BACKGROUND AND AIMS: Bowel urgency and abdominal pain are impactful, yet under-appreciated ulcerative colitis symptoms and not commonly assessed in clinical trials. We evaluated how these symptoms may improve with upadacitinib treatment and correlate with clinical and health-related quality of life [HRQOL] outcomes in the phase 2b U-ACHIEVE study. METHODS: Patients aged 18-75 years, with moderately to severely active ulcerative colitis, were randomised to receive placebo or upadacitinib (7.5, 15, 30, or 45 mg once daily [QD]). Bowel urgency and abdominal pain were evaluated at baseline and Weeks 2, 4, 6, and 8. Week 8 correlations were evaluated between bowel urgency/abdominal pain with clinical [Mayo subscores and high-sensitivity C-reactive protein and faecal calprotectin measurements] and HRQOL outcomes [Inflammatory Bowel Disease Questionnaire and 36-Item Short Form Health Survey scores]. RESULTS: A greater proportion of patients [n = 250] reported no bowel urgency and less abdominal pain with upadacitinib treatment compared with placebo, with improvements observed as early as 2 weeks. At Week 8, patients receiving the 45-mg QD dose had the greatest improvements versus placebo, with 46% reporting no bowel urgency [vs 9%; p ≤ 0.001] and 38% reporting no abdominal pain [vs 13%; p = 0.015]. At Week 8, moderate correlations were found between bowel urgency or abdominal pain and most clinical and HRQOL outcomes. CONCLUSIONS: Induction treatment with upadacitinib demonstrated significant reductions in bowel urgency and abdominal pain compared with placebo. These symptoms also correlate to clinical and HRQOL outcomes, supporting their use to monitor disease severity and other treatment outcomes.

Quality of Life and Work Productivity Improvements with Upadacitinib: Phase 2b Evidence from Patients with Moderate to Severe Crohn's Disease.

INTRODUCTION: In the phase 2 CELEST study, positive efficacy results were obtained with the Janus kinase 1 inhibitor upadacitinib for adult patients with moderate to severe Crohn's disease. We present the health-related quality of life and work productivity improvement results with upadacitinib from CELEST. METHODS: CELEST (NCT02365649) was a double-blind study where patients were randomized 1:1:1:1:1:1 in the 16-week induction period to placebo or upadacitinib 3 mg twice daily (BID), 6 mg BID, 12 mg BID, 24 mg BID, or 24 mg once daily (QD). Patients completing the induction period were re-randomized 1:1:1 to receive upadacitinib 3 mg BID, 12 mg BID, or 24 mg QD for 36 weeks or 3 mg BID, 6 mg BID, or 12 mg BID (after amendment). Inflammatory Bowel Disease Questionnaire (IBDQ), European Quality of Life-5 Dimensions visual analog scale (EQ-5D VAS), and Work Productivity and Activity Impairment (WPAI) questionnaire outcomes were assessed at baseline and Weeks 8, 16, and 52. RESULTS: At Week 16, a significant percentage (P ≤ 0.05) of patients receiving upadacitinib 6-mg BID dose or higher achieved IBDQ response (IBDQ score change ≥ 16 points; 49%-57% for upadacitinib vs. 24% for placebo) and IBDQ remission, except 24 mg QD (IBDQ score ≥ 170; 26%-39% for upadacitinib vs. 11% for placebo). Greater improvements in IBDQ total score, EQ-5D VAS, and activity impairment from baseline (P ≤ 0.1) versus placebo were also observed. Larger improvements (P ≤ 0.1) in IBDQ response and total score and EQ-5D VAS were observed at Week 8 with 6 and 24 mg BID versus placebo, with improvements for all dosages maintained or greater at Week 52 for IBDQ, EQ-5D VAS, and WPAI endpoints, in particular for the 12-mg BID group. CONCLUSION: Improvements in health-related quality of life and work productivity were achieved and sustained with upadacitinib in patients with moderate to severe Crohn's disease. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02365649.

Addressing HCV Elimination Barriers in Italy: Healthcare Resource Utilization and Cost Impact Using 8 Weeks' Glecaprevir/Pibrentasvir Therapy.

INTRODUCTION: In Italy, hepatitis C virus (HCV) elimination is achievable; however, barriers remain to achieving the World Health Organization's elimination targets, and have become more pronounced with the spread of COVID-19. Glecaprevir/pibrentasvir (G/P) is a direct-acting antiviral therapy for HCV, approved for 8-week treatment in patients without cirrhosis, and with compensated cirrhosis (CC). Previously, 12 weeks of therapy was recommended for patients with CC. Shortened treatment may reduce the burden on healthcare resources, allowing more patients to be treated. This study presents the benefits that 8-week vs 12-week treatment with G/P may have in Italy. METHODS: A multicohort Markov model was used to assess the collective number of healthcare visits and time on treatment with 8-week vs 12-week G/P in the HCV-infected population of Italy from 2019 to 2030, using healthcare resource data from post-marketing observational studies of G/P. Increased treatment capacity and downstream clinical and economic benefits were also assessed assuming the reallocation of saved healthcare visits to treat more patients. RESULTS: Modeled outcomes showed that by 2030, 8-week treatment saved 27,006 years on therapy compared with 12-week treatment, with 21,065 fewer hepatologist visits. Reallocating these resources to treat more patients could increase capacity to treat 5064 (1.4%) more patients with 8 weeks of G/P, all with CC. This increased treatment capacity would further avoid 2257 cases of end-stage liver disease, 893 liver-related deaths, and provide net savings to the healthcare system of nearly €70 million. CONCLUSION: The modeled comparisons between 8- and 12-week treatment with G/P show that shorter treatment duration can lead to greater time and resource savings, both in terms of healthcare visits and downstream costs. These benefits have the potential to enable the treatment of more patients to overcome elimination barriers in Italy through programs aimed to engage and treat targeted HCV populations.

Progress towards hepatitis C virus elimination in high-income countries: An updated analysis.

BACKGROUND & AIMS: Elimination of HCV by 2030, as defined by the World Health Organization (WHO), is attainable with the availability of highly efficacious therapies. This study reports progress made in the timing of HCV elimination in 45 high-income countries between 2017 and 2019. METHODS: Disease progression models of HCV infection for each country were updated with latest data on chronic HCV prevalence, and annual diagnosis and treatment levels, assumed to remain constant in the future. Modelled outcomes were analysed to determine the year in which each country would meet the WHO 2030 elimination targets. RESULTS: Of the 45 countries studied, 11 (Australia, Canada, France, Germany, Iceland, Italy, Japan, Spain, Sweden, Switzerland, and United Kingdom) are on track to meet WHO's elimination targets by 2030; five (Austria, Malta, Netherlands, New Zealand, and South Korea) by 2040; and two (Saudi Arabia and Taiwan) by 2050. The remaining 27 countries are not expected to achieve elimination before 2050. Compared to progress in 2017, South Korea is no longer on track to eliminate HCV by 2030, three (Canada, Germany, and Sweden) are now on track, and most countries (30) saw no change. CONCLUSIONS: Assuming high-income countries will maintain current levels of diagnosis and treatment, only 24% are on track to eliminate HCV by 2030, and 60% are off track by at least 20 years. If current levels of diagnosis and treatment continue falling, achieving WHO's 2030 targets will be more challenging. With less than ten years remaining, screening and treatment expansion is crucial to meet WHO's HCV elimination targets.

Estimating the Year Each State in the United States Will Achieve the World Health Organization's Elimination Targets for Hepatitis C.

INTRODUCTION: Although hepatitis C virus (HCV) infection remains a major clinical, economic, and societal burden, the development of curative antiviral therapy may accelerate the path toward elimination. This analysis assessed the progress of United States (US) states towards achieving the World Health Organization's (WHO) 2030 HCV elimination targets for incidence, mortality, diagnosis, and treatment. METHODS: A previously published Markov model was used to simulate HCV progression over time to estimate the path to HCV elimination in each state based on prevalence, annual treatment, and diagnosis inputs from two large US laboratory datasets from January 2013 to December 2017. State-specific fibrosis stage restrictions on treatment in 2017 were included. The model estimated the year individual states would meet the WHO targets for diagnosing 90% of the HCV-infected population, treating 80% of the eligible population, reducing new HCV infections by 80%, and reducing HCV-related deaths by 65%. The minimum number of annual treatments needed between 2020 and 2030 to achieve the WHO treatment target was also calculated. RESULTS: Overall, the USA is projected to achieve HCV elimination by 2037, with individual targets related to mortality, diagnosis, treatment, and incidence being achieved by 2020, 2027, 2033, and 2037, respectively. Three states (Connecticut, South Carolina, and Washington) are on track to meet all four elimination targets by 2030, and 18 states are not expected to meet these targets before 2040. The estimated annual number of treatments required during 2020-2030 nationally to reach the WHO treatment target is 173,514. CONCLUSION: With the exception of three states, the USA is not on target to meet the WHO 2030 elimination targets and 35% are off track by 10 years or more. Strategies must be implemented to reduce overall prevalence by preventing new infections, increasing rates of screening, improving linkage to care, and implementing unfettered access to curative therapy.

The Economic Value of Improved Productivity from Treatment of Chronic Hepatitis C Virus Infection: A Retrospective Analysis of Earnings, Work Loss, and Health Insurance Data.

INTRODUCTION: Patients with chronic hepatitis C virus infection (HCV) may incur significant indirect costs due to health-related work loss. However, the impact of curative HCV therapy on work productivity is not well characterized. We estimated the economic value of improved productivity following HCV treatment. METHODS: Adults diagnosed with HCV infection (Optum Healthcare Solutions data; Q1 1999 to Q1 2017) were stratified into two cohorts: (1) treated cohort, patients who received HCV therapy and (2) untreated cohort, therapy-naïve patients. For the treated cohort, the index date was set at the end of the post-treatment monitoring period, assumed to be 6 months after the end of treatment for patients with cirrhosis or for those treated with interferon-based therapy, and 3 months after the end of treatment for patients without cirrhosis who received interferon-free therapy. For the untreated cohort, an index date was randomly selected post-HCV diagnosis. Time from the index date to the first work-loss event was assessed using time to event analyses. An economic modeling approach was used to monetize the improved productivity from reduced risk of work-loss event in the 4 years post-index. RESULTS: Patients in the treated cohort had a lower risk of experiencing a work-loss event compared to untreated patients [unadjusted and adjusted hazard ratios and 95% CI 0.72 (0.61-0.86), and 0.68 (0.55-0.85), respectively; p < 0.001 for both]. The mean cumulative added productivity value associated with HCV treatment was US$4511 (CI $2778-$6278) at 1 year post-index and $21,429 (CI $12,733-$30,199) at 4 years post-index. CONCLUSION: HCV treatment reduces the risk of work loss resulting in productivity gains for employers and employees. The monetary value associated with these productivity gains is substantial, and, after about 4 years, it is comparable to the wholesale acquisition cost of some direct-acting antiviral regimens in the United States. Employers may derive economic benefits from adopting HCV elimination strategies.

Global timing of hepatitis C virus elimination in high-income countries.

BACKGROUND & AIMS: Introduction of highly efficacious pan-genotypic therapies for hepatitis C virus (HCV) infection has made the elimination of the disease an attainable goal. This study assessed progress made in 45 high-income countries towards meeting the World Health Organization's targets for HCV elimination by 2030. METHODS: A Markov model developed to forecast annual HCV-infected population was populated with demographic and epidemiological inputs, with historical incidence calibrated to reported prevalence of chronic HCV for each country. Future incidence was assumed to be a linear function of overall prevalence (or prevalence of minimal fibrosis in countries with treatment restrictions). 2017 levels of diagnosis and treatment were assumed constant in the future. The analysis estimated the year countries would meet HCV elimination targets for 80% reduction in incidence, 65% reduction in liver-related deaths, 90% diagnosis coverage and 80% treatment among the treatment-eligible population. RESULTS: Of the 45 countries analyzed, nine (Australia, France, Iceland, Italy, Japan, South Korea, Spain, Switzerland and the United Kingdom) are on track towards meeting the HCV elimination targets by 2030. While Austria, Germany and Malta could also reach the targets with expanded screening efforts, 30 countries are not projected to eliminate HCV before 2050. Incidence was the most difficult target to achieve, followed by liver-related deaths. CONCLUSIONS: Even with introduction of curative therapies, 80% of high-income countries are not on track to meet HCV elimination targets by 2030, and 67% are off track by at least 20 years. Immediate action to improve HCV screening and treatment is needed globally to make HCV elimination attainable.

How Does Treating Chronic Hepatitis C Affect Individuals in Need of Organ Transplants in the United Kingdom?

OBJECTIVES: To estimate the impact of cures for chronic hepatitis C (CHC) infection on organ donation in the United Kingdom. Curing CHC infection reduces the need for liver transplants and enables cured individuals to donate organs of all types. METHODS: We adapted a double-queuing model of organ allocation to estimate the effects of CHC infection cures on liver, lung, heart, and kidney transplants in the United Kingdom. We assumed that cured individuals would donate organs at similar rates as the general population and no longer require liver transplants because of CHC infection. We estimated how curing CHC infection influences waitlist lengths for each organ and the annual net present value to society on the basis of quality-adjusted life-years gained through additional transplants under opt-in and opt-out organ donation policies. RESULTS: Curing CHC generates the most value for patients on the liver waitlist, because it increases the number of transplantable livers and reduces the need for transplants. Under the current opt-in policy, liver waitlist length falls by 24%, generating £34.3 million of annual net present value. Growth in the number of uninfected lungs, hearts, and kidneys generates an additional £19.2 million annually, with £18.7 million from kidneys. Implementing the opt-out policy, liver waitlist length would decrease by 75%, implying that treating CHC eliminates one-third of the excess liver waitlist due to an opt-in policy. CONCLUSIONS: Treating CHC has large positive spillovers to uninfected individuals by reducing the need for liver transplants and allowing cured individuals to donate organs. These spillovers have not been included in traditional value assessments of CHC treatment.

Clinical and Economic Burden of Patients with Chronic Hepatitis C with Versus Without Antiviral Treatment in Japan: An Observational Cohort Study Using Hospital Claims Data.

INTRODUCTION: Japan has one of the highest prevalence rate of chronic hepatitis C (CHC) in the industrialized world. However, the burden of CHC treatment is poorly understood. Thus, the healthcare resource utilization and costs of treated versus untreated patients, and patients with early versus delayed treatment initiation, were assessed in Japan. METHODS: Adult patients with ≥ 2 CHC diagnoses were identified from the Medical Data Vision hospital claims database (1 April 2008-31 May 2016). The presence or absence of antiviral treatment claims was used to form the treated and untreated cohorts, respectively. Among treated patients, the presence of a cirrhosis-related diagnosis was used as an indicator of delayed treatment. The index date was defined as the date of the first antiviral claim for treated patients and randomized to any date with a medical visit for untreated patients. Annualized total healthcare costs and costs associated with hepatic manifestations (HMs) or extrahepatic manifestations (EHMs) were evaluated from the index date to the last observed medical visit. RESULTS: Of 100,125 patients with CHC, 12,984 were treated (early: 8104, delayed: 4880) and 87,141 were untreated. After adjusting for covariates, untreated patients had ¥613,034 ($5456 USD; ¥1 = $0.0089) higher annual medical costs compared with treated patients (P < 0.001), a difference driven by higher inpatient costs. Between 65% (treated patients) and 70% (untreated patients) of medical costs were EHM-related and between 14% (untreated patients) and 15% (treated patients) were HM-related. Patients in the delayed treatment cohort had ¥114,347 ($1018) higher annual medical costs (P < 0.001) versus those in the early treatment cohort. About 95% of these costs were EHM-related, and 64% were HM-related. CONCLUSION: Withholding or delaying antiviral treatment initiation for Japanese patients with CHC increases the clinical and economic burden associated with HMs and EHMs. FUNDING: AbbVie.