BACKGROUND & AIMS:The efficacy and safety of extended induction treatment with risankizumab, an interleukin-23 p19 inhibitor, in patients with moderately to severely active ulcerative colitis (UC) who, per site evaluation, did not achieve clinical response to 12 weeks of risankizumab induction was evaluated. METHODS:In the phase 3 INSPIRE induction study, 209 initial nonresponders to 12 weeks of 1200 mg intravenous (IV) risankizumab induction were rerandomized to receive 12 weeks of additional 1200 mg risankizumab (weeks 12, 16, and 20) or 180 mg or 360 mg subcutaneous [SC] risankizumab (weeks 12 and 20) in a double-blind fashion. Patients from both phase 2b and 3 with week 24 clinical response to SC risankizumab (delayed responders) continued to receive blinded risankizumab at their assigned dose in the phase 3 COMMAND maintenance study. Efficacy and safety were evaluated at week 24 of induction and week 52 of maintenance. RESULTS:Initial nonresponders (1200 mg IV [n = 68], 180 mg SC [n = 71], or 360 mg SC [n = 70]) had week 24 clinical response rates of 50%, 56.3%, and 57.1%, respectively; patients also achieved clinical remission, histologic endoscopic mucosal improvement (8.8%, 12.7%, and 15.7% for both endpoints), endoscopic improvement (17.6%, 18.3%, and 24.3%), and endoscopic remission (1.5%, 8.5%, and 5.7%). Efficacy rates were generally highest with 360 mg. In maintenance, delayed responders demonstrated sustained rates of clinical remission and increased rates of endoscopic outcomes and histologic endoscopic mucosal improvement at week 52. The safety with extended risankizumab treatment was consistent with the known risankizumab safety profile. CONCLUSIONS:Over 50% of initial nonresponders achieved clinical response with extended risankizumab treatment. Additional clinical and endoscopic outcomes were also achieved, with sustained or improved efficacy observed following maintenance. Extended treatment was well tolerated with no new safety risks identified. ClincialTrials.gov, Numbers. NCT03398148 (INSPIRE), NCT03398135 (COMMAND).

BACKGROUND AND AIMS:Treating ulcerative colitis (UC) in patients with prior advanced therapy (AT) exposure may be challenging. We report the efficacy and safety of risankizumab, a monoclonal interleukin 23p19 antibody, in patients with UC and prior inadequate response or intolerance to AT (AT-IR). METHODS:In the 12-week phase 3 INSPIRE induction study, patients were randomized to intravenous risankizumab 1200 mg or placebo. Clinical responders were randomized to subcutaneous risankizumab 180 mg, risankizumab 360 mg, or placebo (risankizumab withdrawal) in the 52-week phase 3 COMMAND maintenance study. This post hoc analysis assessed outcomes by AT-IR status, number, and mechanism of action. AT included biologics, Janus kinase inhibitors, and sphingosine-1-phosphate receptor modulators. RESULTS:Efficacy analyses included 472 non-AT-IR and 503 AT-IR patients (induction), and 137 non-AT-IR and 411 AT-IR patients (maintenance). More patients achieved clinical remission per Adapted Mayo score with risankizumab 1200 mg versus placebo at induction week 12 (non-AT-IR, 29.7% versus 8.4%, nominal P < .0001; AT-IR, 11.4% versus 4.3%, nominal P = .0083); consistent with risankizumab 180 mg or risankizumab 360 mg versus placebo (withdrawal) at maintenance week 52 (non-AT-IR, 50.9% or 61.7% versus 31.1%, nominal P = .057 or P = .0033, respectively; AT-IR, 36.6% or 29.5% versus 23.2%, nominal P = .0159 or P = .2334, respectively). Risankizumab had increased efficacy over placebo, regardless of AT-IR number or mechanism of action, with higher efficacy rates for non-AT-IR compared to AT-IR. Safety results in non-AT-IR and AT-IR patients were generally comparable in both induction and maintenance. CONCLUSIONS:Risankizumab was effective and well tolerated, regardless of prior AT-IR status. CLINICAL TRIAL REGISTRATION NUMBERS:INSPIRE [NCT03398148], COMMAND [NCT03398135].

Importance The clinical effects of risankizumab (a monoclonal antibody that selectively targets the p19 subunit of IL-23) for the treatment of ulcerative colitis are unknown. Objective To evaluate the efficacy and safety of risankizumab when administered as an induction and a maintenance therapy for patients with ulcerative colitis. Design, Setting, and Participants Two phase 3 randomized clinical trials were conducted. The induction trial was conducted at 261 clinical centers (in 41 countries) and enrolled 977 patients from November 5, 2020, to August 4, 2022 (final follow-up on May 16, 2023). The maintenance trial was conducted at 238 clinical centers (in 37 countries) and enrolled 754 patients from August 28, 2018, to March 30, 2022 (final follow-up on April 11, 2023). Eligible patients had moderately to severely active ulcerative colitis; a history of intolerance or inadequate response to 1 or more conventional therapies, advanced therapies, or both types of therapies; and no prior exposure to risankizumab. Interventions For the induction trial, patients were randomized 2:1 to receive 1200 mg of risankizumab or placebo administered intravenously at weeks 0, 4, and 8. For the maintenance trial, patients with a clinical response (determined using the adapted Mayo score) after intravenous treatment with risankizumab were randomized 1:1:1 to receive subcutaneous treatment with 180 mg or 360 mg of risankizumab or placebo (no longer receiving risankizumab) every 8 weeks for 52 weeks. Main Outcomes and Measures The primary outcome was clinical remission (stool frequency score <= 1 and not greater than baseline, rectal bleeding score of 0, and endoscopic subscore <= 1 without friability) at week 12 for the induction trial and at week 52 for the maintenance trial. Results Among the 975 patients analyzed in the induction trial (aged 42.1 [SD, 13.8] years; 586/973 [60.1%] were male; and 677 [69.6%] were White), the clinical remission rates at week 12 were 132/650 (20.3%) for 1200 mg of risankizumab and 20/325 (6.2%) for placebo (adjusted between-group difference, 14.0% [95% CI, 10.0%-18.0%], P < .001). Among the 548 patients analyzed in the maintenance trial (aged 40.9 [SD, 14.0] years; 313 [57.1%] were male; and 407 [74.3%] were White), the clinical remission rates at week 52 were 72/179 (40.2%) for 180 mg of risankizumab, 70/186 (37.6%) for 360 mg of risankizumab, and 46/183 (25.1%) for placebo (adjusted between-group difference for 180 mg of risankizumab vs placebo, 16.3% [97.5% CI, 6.1%-26.6%], P < .001; adjusted between-group difference for 360 mg of risankizumab vs placebo, 14.2% [97.5% CI, 4.0%-24.5%], P = .002). No adverse event signals were detected in the treatment groups. Conclusion and Relevance Compared with placebo, risankizumab improved clinical remission rates in an induction trial and in a maintenance trial for patients with moderately to severely active ulcerative colitis. Further study is needed to identify benefits beyond the 52-week follow-up.

OBJECTIVE:To assess the efficacy and safety of ABBV-3373, a novel antibody-drug conjugate (ADC) composed of the anti-tumor necrosis factor (anti-TNF) monoclonal antibody adalimumab linked to a glucocorticoid receptor modulator (GRM), compared to adalimumab, in patients with rheumatoid arthritis (RA).METHODS:In this randomized, double-blind, active-controlled, proof-of-concept trial (ClinicalTrials.gov identifier: NCT03823391), adults with moderate-to-severe RA receiving background methotrexate were administered intravenously (IV) ABBV-3373 100 mg every other week for 12 weeks, followed by placebo for 12 weeks, or subcutaneous adalimumab 80 mg every other week for 24 weeks. The primary end point was change from baseline in the Disease Activity Score in 28 joints using C-reactive protein (DAS28-CRP) at week 12, with 2 prespecified primary comparisons of ABBV-3373 versus historical adalimumab (80 mg every other week or equivalent dose) and versus combined in-trial/historical adalimumab. Secondary end points included change from baseline in the Clinical Disease Activity Index, Simplified Disease Activity Index, and DAS28 using erythrocyte sedimentation rate, as well as the proportion of patients achieving a DAS28-CRP of ≤3.2 and the American College of Rheumatology 50% improvement criteria.RESULTS:Forty-eight patients were randomized to receive either ABBV-3373 (n = 31) or adalimumab (n = 17). At week 12, ABBV-3373 demonstrated a reduction in DAS28-CRP compared to historical adalimumab (-2.65 versus -2.13; P = 0.022) and compared to combined in-trial/historical adalimumab (-2.65 versus -2.29; probability 89.9%), with numerically greater improvement than in-trial adalimumab (-2.51). For secondary end points, greater efficacy was observed with ABBV-3373 compared to historical adalimumab; ABBV-3373 was predicted with 79.3-99.5% probability to be more effective than adalimumab based on combined in-trial/historical adalimumab data. Of the ABBV-3373-treated patients who achieved DAS28-CRP ≤3.2 at week 12, 70.6% maintained this response at week 24 despite switching to placebo. Four serious adverse events (SAEs) were reported with ABBV-3373 (noncardiac chest pain, pneumonia, upper respiratory tract infection, and anaphylactic shock) and 2 SAEs with adalimumab (breast abscess and bronchitis). After increasing the duration of IV ABBV-3373 administration from 3 minutes to 15-30 minutes, no similar events of anaphylactic shock were reported.CONCLUSION:Data from this proof-of-concept trial support the continued development of a TNF-GRM ADC for the treatment of RA, with the potential to achieve superior outcomes compared to currently available therapies.

SummaryBackgroundUpadacitinib is an oral, selective Janus kinase inhibitor.AimTo assess the efficacy and safety of upadacitinib in patients with moderate‐to‐severe ulcerative colitis following 16‐week extended induction therapy, and 52‐week maintenance therapy in patients achieving clinical response after 16‐week extended induction therapyMethodsPatients without clinical response to 8 weeks' upadacitinib 45 mg once daily induction therapy in two induction trials were eligible for an additional 8 weeks of therapy. Patients achieving clinical response at Week 16 were subsequently re‐randomised (1:1) to upadacitinib 15 or 30 mg once daily for 52‐week maintenance therapy. Efficacy was assessed at induction Week 16 (integrated) and maintenance Week 52; safety was assessed throughout.ResultsOverall, 127/663 (19.2%) patients did not achieve clinical response to upadacitinib 45 mg at Week 8 and received an additional 8 weeks of therapy; 75/127 (59.1%) subsequently achieved clinical response at Week 16 and entered the maintenance trial. At Week 52, 26.5% of patients receiving upadacitinib 15 mg, and 43.6% receiving 30 mg, achieved clinical remission; efficacy was observed across all other endpoints with both doses. Herpes zoster rates increased with longer duration (16 weeks) of exposure to upadacitinib 45 mg during induction compared with the same population during the first 8 weeks. No other new safety signals were observed, and results are otherwise consistent with the known safety profile of upadacitinib.ConclusionsPatients without clinical response after 8 weeks' upadacitinib 45 mg induction therapy, may benefit from an additional 8 weeks of therapy.Clinical trial registration: NCT02819635; NCT03653026

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 (404%) and 30 mg once daily (536%) versus placebo (108%; both p<00001 vs placebo). For safety, 746 patients were analysed, representing 5529 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 (60 events per 100 patient-years with upadacitinib 15 mg once daily and 73 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 (170 and 92 vs 59 events per 100 patient-years [34 and 20 vs eight events, respectively), creatine phosphokinase elevation (80 and 101 vs 37 events per 100 patient-years [16 and 22 vs five events], respectively), and neutropenia (55 and 87 vs 52 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 07 and 05 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 10 and 09 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.

Introduction: Risankizumab (RZB), a monoclonal antibody neutralizing interleukin (IL)-23p19, was evaluated for efficacy and safety of induction therapy in patients with moderately to severely active ulcerative colitis (UC) in a large phase 3 trial, INSPIRE (NCT03398148). Methods: Eligible patients (18-80 years) with moderately to severely active UC (Adapted Mayo score of 5–9 points) and an endoscopic subscore of 2-3 (per central review) were enrolled. Patients were required to have a diagnosis of UC for at least 3 months prior to baseline, and demonstrated intolerance or inadequate response to conventional and/or advanced therapies (biologics, JAK inhibitors, and S1P receptor modulators). Patients (N=975) were randomized 2:1 to receive either RZB 1200 mg intravenously (IV) or placebo (PBO) at Weeks (Wks) 0, 4, and 8. The primary endpoint was clinical remission (per Adapted Mayo score) at Wk 12 (see Figure 1 legend for definitions). Key, ranked secondary endpoints included clinical response, endoscopic improvement, endoscopic remission, histologic-endoscopic mucosal improvement (HEMI), and histologic-endoscopic mucosal remission (HEMR), which were measured at Wk 12, unless otherwise noted. Results: Baseline characteristics were similar between treatment groups. Significantly more patients receiving RZB achieved clinical remission vs PBO (20.3% vs 6.2%, adjusted treatment difference 14.0% [95% CI, 10.0%-18.0%], P< .00001, Figure 1A). All ranked secondary endpoints were met. RZB attained higher rates of clinical response (per Adapted Mayo score at Wk 12 and per Partial Adapted Mayo score at Wk 4), endoscopic improvement, endoscopic remission, HEMI, and HEMR, compared to PBO (P< .00001 for all endpoints, Figure 1B). Adverse event (AE) rates were 42.1% in RZB vs 49.7% PBO, serious AEs (2.3% vs 10.2%), severe AEs (2.5% vs 10.2%), AEs leading to discontinuation of study drug (0.6% vs 3.7%), and serious infections (0.6% vs 1.2%) were numerically lower in the RZB arm. No adjudicated major adverse cardiovascular events, adjudicated anaphylaxis, or serious hepatic events were reported. One death occurred in the RZB group due to COVID-19 pneumonia. Conclusion: In patients with moderately to severely active UC, RZB was superior to PBO as an induction therapy for clinical remission and all secondary clinical, endoscopic, and endoscopic-histologic endpoints. RZB was well-tolerated, and no new safety risks were observed.Figure 1.: Primary and Key Secondary Endpoints All patients in this dataset were included here within the ITT population. Endpoints were assessed at Week 12 unless otherwise noted. Clinical Remission per Adapted Mayo score: Stool frequency subscore ≤ 1 and not greater than baseline, rectal bleeding subscore of 0, and endoscopic subscore ≤ 1 without friability Clinical Response per Adapted Mayo: Decrease from baseline ≥ 2 points and ≥ 30%, in addition to a decrease in RBS ≥ 1 or an absolute rectal bleeding score (RBS) ≤ 1 Clinical Response per Partial Adapted Mayo: Decrease from baseline ≥ 1 point and ≥ 30% a decrease in RBS ≥ 1 or an absolute RBS ≤ 1 Endoscopic Improvement: Endoscopic subscore of 0 or 1 without friability Endoscopic Remission: Endoscopic subscore = 0 Histologic-Endoscopic Mucosal Improvement (HEMI): Endoscopic subscore of 0 or 1 without friability and Geboes score ≤ 3.1 Histologic-Endoscopic Mucosal Remission (HEMR): Endoscopic subscore of 0 and Geboes score < 2.0 Results were stratified by baseline corticosteroid use (yes vs no), baseline Adapted Mayo score (≤ 7 vs > 7), and the number of advanced therapy failures (0, 1, >1). Results are based on non-responder imputation incorporating multiple imputation (NRI-MI) to handle missing data due to COVID-19 or due to geopolitical conflict in Ukraine or surrounding areas. ***P-value <.00001 vs PBO. P-value for treatment difference between RZB 1200 mg IV and PBO, using Cochran-MantelHaenszel (CMH) test for categorical endpoints, controlling for stratification factors. IR, inadequate response.

Objectives. To evaluate the inhibition of progression of structural joint damage through week 48 in patients with moderately to severely active RA receiving upadacitinib as monotherapy or in combination with MTX. Methods. Radiographic progression was assessed in two phase 3 randomized controlled trials. MTX-naive patients were randomized to upadacitinib 15 or 30 mg once daily or MTX monotherapy (SELECT-EARLY, n = 9 45), while MTX inadequate responders (IRs) were randomized to upadacitinib 15 mg once daily or adalimumab 40 mg every other week or placebo added to background MTX (SELECT-COMPARE, n = 1629). The mean changes from baseline in modified total Sharp score (mTSS), joint space narrowing and erosion scores were determined. Data were analysed both by linear extrapolation for missing data imputation and treatment switching and as observed. Results. In patients naIve or with limited exposure to MTX (SELECT-EARLY), mean changes from baseline to week 48 in mTSS were 0.03 for upadacitinib 15 mg, 0.14 for upadacitinib 30 mg and 1.00 for MTX based on linear extrapolation (P < 0.001 for both upadacitinib doses vs MTX). Among patients with an inadequate response to MTX (SELECT-COMPARE), the mean change from baseline in mTSS was significantly reduced in the upadacitinib 15 mg plus MTX group vs placebo plus MTX (0.28 vs 1.73; P < 0.001). The mean change from baseline in the adalimumab plus MTX group was 0.39. Conclusion. Upadacitinib monotherapy or in combination with background MTX was effective in inhibiting the progression of structural joint damage through week 48 in MTX-naive and MTX-IR patients with RA.

Real-world data (RWD) is playing an increasingly important role in drug development from early discovery throughout the life-cycle management. This includes leveraging RWD in randomized clinical trial (RCT) design and study conduct. In many scenarios, a concurrent control arm may not be viable for ethical or practical considerations, and inclusion of an external control arm can greatly facilitate the decision-making and interpretation of findings. We summarize the strengths and limitations of typical external data sources including historical RCT, aggregated data at study level from literature, patient registry, health insurance claims, electronic health records in terms of fit-for-purpose data selection. To address the inherent confounding due to lack of randomization, propensity score matching method has the advantages of separating the design from analysis and providing the ability to explicitly examine the degree of overlap in confounders. Within the framework of causal inference, however, many alternatives have been proposed with desirable theoretical properties. In this article, we review key steps from study design conceptualization to data source selection, and focus on several methods for evaluation of performance in the context of creating external control for clinical trials. We conducted a focused simulation studies to assess bias reduction and statistical properties when underlying assumptions are violated or models are mis-specified. The results support that analysis using matched group improve bias reduction when sample size is not a limiting factor, and targeted maximum likelihood estimation coupled with super learner is robust when estimating both average treatment effects and average treatment effects among treated.

The cost of clinical research for new drug development has been increasing rapidly. An effective approach to reduce the cost of clinical trials is to use a synthetic control arm to substitute a concurrent control arm. Synthetic control arms are usually created with propensity-score-based methods from historical or external patient-level control data. Although there is much literature discussing how to create synthetic control arms, little is known about how synthetic control arms perform compared to concurrent control arms in real clinical trials. In this paper, we take a real randomized controlled clinical trial and create a synthetic control arm for it using propensity-score-based methods from the control data in other randomized clinical trials. The goal is to demonstrate validity of using synthetic control arms by comparing the performance of synthetic control arms to the concurrent control arm. Four propensity-score-based methods, stratification, matching, inverse probability of treatment weighting, and covariate adjustment are applied to create the synthetic control group. Our results show that the synthetic control arm created with the stratification or matching method could provide an estimate of treatment effect that is as accurate as that of a real randomized clinical trial. This suggests a good opportunity to expedite drug development with reduced cost. We encourage use of these methods in clinical research for drug development when patient-level control data from comparable historical randomized clinical trials are available.

Background: ABBV-3373 is a novel antibody drug conjugate composed of adalimumab (ADA) linked to a proprietary and highly potent glucocorticoid receptor modulator (the anti-inflammatory payload) currently evaluated for the treatment of rheumatoid arthritis (RA). Objectives: To assess the efficacy and safety of ABBV-3373 vs ADA in RA patients (pts). Methods: This was a 24-week (wk) randomized, double-blind, double-dummy, active-controlled Phase 2a study of intravenously (IV)-administered ABBV-3373 100 mg (for 12 wks followed by placebo [PBO] for 12 wks) vs subcutaneous injections of ADA 80 mg every other wk (for 24 wks) in pts on background methotrexate. The primary endpoint was the change from baseline (BL) in DAS28(CRP) at Wk 12. Pre-planned statistical methods incorporating pre-specified historical ADA data both alone (pre-specified success criterion, 2-sided P ≤0.1) and supplemented with in-trial ADA data (pre-specified success criterion, probability >95%) were used to achieve adequate statistical power with a reduced trial size. Assay sensitivity was evaluated through construction of a synthetic PBO arm by propensity score matching, using individual pt-level PBO data from 3 recent sponsor-run trials of similar populations and trial settings. Secondary endpoints at Wk 12 included 1) mean change from BL in CDAI, SDAI, DAS28(ESR), HAQ-DI; 2) proportion of pts achieving DAS28(CRP)≤3.2, ACR20/50/70 responses, HAQ-DI≤-0.22. Continuous and categorical efficacy variables were analyzed using mixed effect model repeated measurements and Cochran-Mantel-Haenszel test, respectively; non-responder imputation was applied to missing categorical data. Treatment-emergent adverse events were summarized through Wk 12. Results: A total of 48 pts were randomized and treated (ABBV-3373: 31; ADA: 17); 46 pts (96%) completed 12 wks of study treatment. BL demographics and disease characteristics were indicative of established RA and similar among the 2 treatment arms and the synthetic PBO arm. ABBV-3373 demonstrated significant improvement in mean DAS28(CRP) at Wk 12 vs the pre-specified historical ADA (-2.65 vs -2.13; P =0.022) and numerically greater improvement vs the combined in-trial and historical ADA arm (-2.65 vs -2.29; probability 90%; Figure). Comparable improvements in disease activity and targets were observed for ABBV-3373 and in-trial ADA. Assay sensitivity was supported by the fact that both ABBV-3373 and ADA arms were superior to synthetic PBO ( P <0.001). For secondary endpoints, greater efficacy was observed with ABBV-3373 vs historical ADA; ABBV-3373 was predicted with 79-99% probability to be better than ADA based on the combined in-trial and historical ADA data. 2 serious infections were reported with ABBV-3373 (pneumonia, upper respiratory tract infection) and none with ADA through Wk 12 (Table). 1 event of anaphylactic shock reaction was reported with ABBV-3373. After increasing the duration of IV administration from 3 min to 15-30 min, no similar events were observed. Table 1. Treatment Emergent Adverse Events up to Week 12 Event, n (% ) ADA (N = 17 ) ABBV-3373 (N = 31 ) Adverse event (AE) 12 (70.6) 11 (35.5) AE with reasonable possibility of being drug related $ 3 (17.6) 2 (6.5) Severe AE 0 1 (3.2) Serious AE 0 4 (12.9) # AE leading to Discontinuation of Study Drug 1 (5.9) 1 (3.2) Serious infections 0 2 (6.5) Opportunistic infection excluding Tuberculosis 0 0 Allergic Reactions Including Hypersensitivity, Angioedema, and Anaphylaxis 2 (11.8) & 1 (3.2) ^ Systemic glucocorticoid events 0 0 All deaths 0 0 $ As assessed by investigator. # Serious AEs: 1 non-cardiac chest pain, 1 pneumonia, 1 upper respiratory tract disease and 1 anaphylactic shock. & 1 Type I hypersensitivity, 1 Pruritus ^ 1 Anaphylactic shock Conclusion: These data demonstrate the clinical efficacy of ABBV-3373 and its potential to provide improved outcomes for RA pts compared to ADA. The safety profile of ABBV-3373 was generally similar to ADA. Acknowledgements: AbbVie and the authors we thank the patients, trial sites, and investigators who participated in this clinical trial. AbbVie, Inc was the trial sponsor, contributed to trial design, data collection, analysis & interpretation, and to writing, reviewing, and approval of final version. No honoraria or payments were made for authorship. The authors thank Yang Yang of AbbVie Inc for supporting the statistical analysis and data reporting. Medical writing support was provided by Ramona Vladea, PhD of AbbVie, Inc. Disclosure of Interests: Frank Buttgereit Consultant of: AstraZeneca, AbbVie, Grünenthal, Horizon Pharma, Pfizer, and Roche, Grant/research support from: AbbVie, Horizon Pharma, Pfizer, and Roche, Jacob Aelion Grant/research support from: AbbVie, Amgen, AstraZeneca, BMS, Celgene, Eli Lilly, Galapagos/Gilead, Genentech, GlaxoSmithKline, Horizon, Janssen, Mallinckrodt, Nektar, Nichi-Iko, Novartis, Pfizer, Regeneron, Roche, Sanofi-Aventis, Selecta, UCB, Bernadette Rojkovich: None declared, Anna Zubrzycka-Sienkiewicz Consultant of: Astellas and Roche, Grant/research support from: AbbVie, Astellas, Galapagos NV, Gilead Sciences, Janssen, Lilly, Mabion, Pfizer, Roche, and UCB SA, Timothy Radstake Shareholder of: AbbVie, Employee of: AbbVie, Su Chen Shareholder of: AbbVie, Employee of: AbbVie, Dilek Arikan Shareholder of: AbbVie, Employee of: AbbVie, Hartmut Kupper Shareholder of: AbbVie, Employee of: AbbVie, Howard Amital Consultant of: Abbvie, Janssen, Novartis, Roche, Perrigo, Pfizer, Neopharm, Elly Lilly, Gilead, Sanofi, Teva and Rafa, Grant/research support from: Yansen, Pfizer

OBJECTIVE:Adalimumab is approved for treatment of Crohn's disease and ulcerative colitis. Thus, we postulated that exacerbation or new-onset of inflammatory bowel disease (IBD) would be rare events in patients treated with adalimumab for non-IBD indications. The objective was to evaluate the incidence of IBD adverse events (AEs) across adalimumab trials.METHODS:IBD AE rates in 75 adalimumab clinical trials in rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, pediatric enthesitis-related arthritis, uveitis, hidradenitis suppurativa, adult and pediatric psoriasis, psoriatic arthritis, nonpsoriatic arthritis peripheral spondyloarthritis (SpA), axial SpA, including nonradiographic axial SpA, and ankylosing spondylitis, were analyzed. Search terms for IBD AEs (new onset or worsening/flare) included IBD, ulcerative colitis, Crohn's disease, and ulcerative proctitis.RESULTS:This analysis included 24,114 patients, representing 36,508 patient-years of adalimumab exposure. The overall rate of IBD AEs in adalimumab-treated patients was 0.1 (95% confidence interval [95% CI] 0.1-0.2)/100 patient-years (41 events), ranging from no events (psoriatic arthritis, uveitis, and pediatric trials) to 0.8 (95% CI 0.2-2.2)/100 patient-years in peripheral SpA. The rate of IBD in axial SpA was 0.6 (95% CI 0.4-1.0)/100 patient-years. During placebo-controlled trials, the overall IBD rate was 0.1 (95% CI 0.0-0.3)/100 patient-years for adalimumab groups (3 events in 6,781 patients; 2,752 patient-years of exposure) and 0.1 (95% CI 0.0-0.4)/100 patient-years for placebo groups (1 event in 3,493 patients; 1,246 patient-years of exposure). IBD rates in axial SpA were 0.5 (95% CI 0.1-1.4)/100 patient-years for adalimumab and 0.6 (95% CI 0.0-3.1)/100 patient-years for placebo.CONCLUSION:The rates of IBD AEs in adalimumab clinical trials were generally low across the evaluated diseases, including axial SpA; all events occurred in adult patients.

Objective To assess upadacitinib monotherapy versus methotrexate (MTX) in MTX-naive Japanese patients with rheumatoid arthritis (RA) from the Phase 3 SELECT-EARLY study. Methods Japanese patients were randomized 2:1:1:1 to upadacitinib 7.5, 15, or 30 mg daily or MTX 7.5 mg/week (titrated to <= 15 mg/week). Efficacy endpoints included the proportion of patients reporting 20% improvement in American College of Rheumatology criteria (ACR20) at week 12 and change from baseline in modified Total Sharp Score (mTSS) at week 24. Other efficacy outcomes were also assessed at weeks 12 and/or 24. Safety was assessed over 24 weeks. Results Of 138 Japanese patients enrolled, significantly more patients treated with upadacitinib 7.5 and 15 mg, but not 30 mg, reported ACR20 responses versus MTX at week 12. Significantly smaller changes from baseline in mTSS were observed with upadacitinib 15 and 30 mg, but not 7.5 mg, versus MTX at week 24. Upadacitinib demonstrated an acceptable safety profile; herpes zoster occurred in 3.6%, 7.4%, and 7.1% of patients treated with upadacitinib 7.5, 15, and 30 mg, respectively. Conclusion Similar to the global study population, upadacitinib demonstrated clinical efficacy superior to placebo in the Japanese subpopulation. Among upadacitinib-treated patients, herpes zoster was least common with 7.5 mg.