Exposure-adjusted Event Rates Research Articles

Long-term safety profile and secondary effectiveness of canakinumab in pediatric rheumatic diseases: a single-center experience

ABSTRACT Background To demonstrate the long-term safety profile of canakinumab over a nine-year period by documenting adverse events in patients with various pediatric rheumatic diseases. Research design and methods This retrospective observational study was conducted at the Pediatric Rheumatology Department of Istanbul University Cerrahpasa between 2015 and 2023. The analysis concerned individuals who had been administered canakinumab treatment for at least six months. The exposure-adjusted event rates were calculated as adverse events per 100 patient days and were compared among three groups based on the cumulative canakinumab dose of <35 mg/kg, 35–70 mg/kg, and >70 mg/kg. Results Among 189 patients, the median exposure time to canakinumab was 2.9 (1.5–4.1) years, corresponding to 573.4 patient years. The median cumulative dose of canakinumab was 2205 (1312–3600) mg. The most common adverse event was upper respiratory tract infection (0.76), followed by urinary tract infection (0.02), pneumonia (0.009), latent tuberculosis (0.009) and lymphadenitis (0.004). A total of 55 serious adverse events (0.025) were reported, 12 (0.006) of which led to drug discontinuation. The event rate of macrophage activation syndrome and disease exacerbation was statistically higher in patients receiving <35 mg/kg cumulative canakinumab dose (p < 0.05). Conclusions An increase in side effect was not observed with the increasing cumulative doses of canakinumab. Canakinumab demonstrated long-term safety with appropriate indication and monitoring.

Safety Profile of Upadacitinib up to 5 Years in Psoriatic Arthritis, Ankylosing Spondylitis, and Non-radiographic Axial Spondyloarthritis: An Integrated Analysis of Clinical Trials.

This integrated analysis of the phase 2/3 and phase 3 SELECT trials describes the safety profile of upadacitinib, an oral Janus kinase inhibitor, for up to 5years of exposure across psoriatic arthritis (PsA), ankylosing spondylitis (AS), and non-radiographic axial spondyloarthritis (nr-axSpA) (including pooled axial spondyloarthritis [axSpA]). Safety data from five trials of upadacitinib in PsA (2 trials), AS (2 trials), and nr-axSpA (1 trial) were analyzed up to a data cut-off of August 15, 2022. One PsA study included adalimumab as an active comparator. Treatment-emergent adverse events (TEAEs) were summarized for PsA (pooled upadacitinib 15mg once daily and adalimumab 40mg biweekly), AS (pooled upadacitinib 15mg), nr-axSpA (upadacitinib 15mg), and pooled axSpA (pooled upadacitinib 15mg from axSpA trials). TEAEs were reported as exposure-adjusted event rates per 100 patient-years (E/100 PY). A total of 1789 patients (PsA, n = 907; AS, n = 596; nr-axSpA, n = 286) received ≥ 1 dose of upadacitinib 15mg for 3689 PY of exposure or adalimumab (n = 429) for 1147 PY of exposure. Overall TEAEs and serious TEAEs were highest in PsA and numerically higher with upadacitinib versus adalimumab; rates were similar between AS and nr-axSpA. In PsA, higher rates of serious infection, herpes zoster (HZ), lymphopenia, and nonmelanoma skin cancer (NMSC) were observed with upadacitinib versus adalimumab. Rates of malignancy excluding NMSC, adjudicated major adverse cardiovascular events, and adjudicated venous thromboembolic events were comparable between upadacitinib and adalimumab in PsA and were similar across diseases. Higher rates of serious infection, HZ, lymphopenia, and NMSC were observed with upadacitinib versus adalimumab in PsA; slightly elevated rates for most of these TEAEs were seen with upadacitinib in PsA versus axSpA. Upadacitinib 15mg demonstrated a generally consistent safety profile across disease states with no new safety signals identified. SELECT-AXIS 1: NCT03178487; SELECT-AXIS 2: NCT04169373; SELECT-PsA 1: NCT03104400; SELECT-PsA 2: NCT03104374.

P1008 Efficacy and safety of retreatment with upadacitinib after treatment interruption in ulcerative colitis: Data from the phase 3 open-label extension study U-ACTIVATE

Abstract Background Upadacitinib (UPA) is an oral reversible Janus kinase (JAK) inhibitor designed to preferentially inhibit JAK1 approved for the treatment of moderately to severely active ulcerative colitis (UC). UPA may be temporarily discontinued for many reasons including adverse events (AEs) and lack of efficacy.1 As clinical consequences of discontinuing and restarting UPA are yet to be characterised, here, we assess the efficacy and safety of UPA retreatment in patients (pts) who lost response following UPA treatment withdrawal. Methods Pts with a clinical response to 8 weeks’ (wks) UPA 45 mg once daily (QD; UPA45) induction therapy in the Phase 3 U-ACHIEVE or U-ACCOMPLISH studies were re-randomised to placebo (PBO), UPA 15 mg QD (UPA15) or UPA 30 mg QD (UPA30) for the 52-wk maintenance phase of U-ACHIEVE. Pts randomised to PBO who lost response could enter the long-term extension (LTE), U-ACTIVATE, and be retreated with UPA15. Efficacy was analysed (i) at wk 4 of the LTE and (ii) at wk 48 of the LTE among pts with an inadequate response to UPA15 who dose escalated to UPA30 between wks 2 and 36. Exposure-adjusted event rates (EAERs) of treatment-emergent AE (TEAE) were assessed throughout. Results Of 223 pts with a clinical response to UPA45 induction randomised to PBO during maintenance, 112 (50.2%) lost response (mean [standard deviation (SD)] days to loss of response: 135.4 [84.6]) and 110 subsequently entered the LTE. Pts with loss of response vs those without were more likely to have a history of inadequate response, loss of response, or intolerance to ≥1 biologic (57.1% vs 46.8%, respectively) or corticosteroid use at baseline (42.0% vs 33.3%). After 4 wks of retreatment with UPA15, 75/108 (69.4%) and 39/108 (36.1%) pts achieved clinical response and remission, respectively (Figure A). In total, 38 (34.5%) pts dose escalated to UPA30 (mean [SD] days to escalation: 80.3 [57.8]); 30/31 (96.8%) and 22/31 (71.0%) achieved clinical response and remission at wk 48 of retreatment, respectively (Figure B). For safety during maintenance, 225 pts with 128.7 patient-years (PYs) of exposure (loss of response [n=112], 42.6 PYs; no loss of response [n=113], 86.1 PYs) were analysed. Generally, the EAERs of serious TEAEs were numerically lower in patients with vs without loss of response. However, patient years of exposure were low, restricting interpretation. During the LTE, EAERs were generally similar in pts who underwent dose escalation vs all pts. Conclusion In pts who experience loss of response following UPA withdrawal, efficacy can be recaptured following retreatment with UPA15 and UPA30. No new safety signals were identified. Reference 1. Sandborn WJ, et al. Gastroenterology. 2020;158(8):2139−2149.e14.

Impact of Upadacitinib on Laboratory Parameters and Related Adverse Events in Patients with RA: Integrated Data Up to 6.5 Years.

Upadacitinib (UPA) is a Janus kinase inhibitor that has demonstrated efficacy in moderate-to-severe rheumatoid arthritis (RA) with an acceptable safety profile. We investigated laboratory parameter changes in UPA RA clinical trials. Pooled data from six randomized trials in the SELECT phase 3 program were included. Key laboratory parameters and safety data were measured for UPA 15 and 30mg once daily (QD), adalimumab (ADA) 40mg every other week + methotrexate (MTX), and MTX monotherapy. Exposure-adjusted event rates (EAERs) of adverse events were calculated. A total of 3209 patients receiving UPA 15 mg QD (10 782.7 patient-years [PY]), 1204 patients receiving UPA 30mg QD (3162.5 PY), 579 patients receiving ADA + MTX (1573.2 PY), and 314 patients receiving MTX monotherapy (865.1 PY) were included, representing up to 6.5years of total exposure. Decreases in mean levels of hemoglobin, neutrophils, and lymphocytes, and increases in mean levels of liver enzymes and creatinine phosphokinase were observed with UPA, with grade 3 or 4 changes observed in some patients. Mean low- and high-density lipoprotein cholesterol ratios remained stable for patients receiving UPA 15 mg QD. EAERs of anemia and neutropenia occurred at generally consistent rates between UPA and active comparators (3.1-4.3 and 1.7-5.0 events [E]/100 PY across treatment groups, respectively). Rates of hepatic disorder were higher with MTX monotherapy, UPA 15mg and UPA 30mg (10.8, 9.7, and 11.0 E/100 PY, respectively) versus ADA + MTX (6.4 E/100 PY). Rates of lymphopenia were highest with MTX monotherapy (3.2 E/100 PY). Treatment discontinuations due to laboratory-related events were rare, occurring in 1.1% and 2.2% of patients treated with UPA 15 and 30mg QD, respectively. The results of this integrated long-term analysis of laboratory parameters continue to support an acceptable safety profile of UPA 15 mg QD for moderate-to-severe RA.

Analysis of Ventricular Arrhythmias and Sudden Death with Acalabrutinib from 5 Prospective Clinical Trials

Background: The approval of ibrutinib, the first covalent Bruton tyrosine kinase inhibitor (BTKi), provided an effective non-chemotherapy option for the treatment of B-cell malignancies, such as chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). While generally well tolerated, ibrutinib demonstrated significant toxicities in clinical studies, particularly cardiovascular adverse events such as hypertension, atrial fibrillation, and ventricular arrhythmias (VAs). Post hoc analysis of the phase 3 FLAIR trial in patients with previously untreated CLL reported an unexplained sudden or cardiac death rate of 0.5 patients per 100 patient-years with ibrutinib plus rituximab (Hillmen et al. Lancet Oncol. 2023). Acalabrutinib is a next-generation, more selective, irreversible BTKi approved to treat CLL/SLL and relapsed/refractory mantle cell lymphoma. Herein, the rates of nonfatal and fatal VAs and sudden deaths (SDs) from 5 acalabrutinib clinical trials of patients with CLL were analyzed. Methods: Incidence and relative risk of nonfatal and fatal VAs and SDs were analyzed using pooled data from 5 prospective acalabrutinib clinical trials (nonrandomized trials: CL-001 [acalabrutinib monotherapy], CL-003 [acalabrutinib + obinutuzumab]; randomized trials: CL-006 [acalabrutinib vs ibrutinib], CL-007 [acalabrutinib ± obinutuzumab vs chlorambucil + obinutuzumab], CL-309 [acalabrutinib vs idelalisib + rituximab OR bendamustine + rituximab]). Acalabrutinib-containing arms were pooled as a single group; comparators, which were standard-of-care therapies, were pooled as a separate group. Events were identified by comprehensive data extraction of terms capturing nonfatal and fatal VAs and SDs (terms are defined in Table 1 footnote). Nonfatal events were analyzed with and without the inclusion of premature ventricular contractions (PVCs). A subset of fatal events also was analyzed after adjudication through manual clinical review by the sponsor's medical, clinical, and safety leadership. Results: In total, 1299 patients received acalabrutinib (cumulative exposure, 4568.4 patient-years) and 585 received standard-of-care therapies (comparator group) (941.3 patient-years). Considering only fatal VAs and SDs, 5 (0.4%) and 3 (0.5%) patients had an event in the acalabrutinib and comparator groups, respectively, via comprehensive data extraction ( Table 1). Based on exposure-adjusted event rates per 100 patient-years, fatal VAs and SDs were numerically less frequent for acalabrutinib versus comparators; however, relative risks did not statistically favor either group. This trend persisted when events were adjudicated through manual clinical review. After adjudication, 2 of 5 patients in the acalabrutinib group and 2 of 3 patients in the comparator group were determined to have fatal VA or cardiac-related SD. Nonfatal VAs were reported in 11 (0.8%) patients in the acalabrutinib group and 3 (0.5%) patients in the comparator group. When PVCs were excluded, 2 patients in each group (acalabrutinib, 0.2%; comparator, 0.3%) had nonfatal VAs. These nonfatal VAs consisted of ventricular fibrillation (acalabrutinib, n=2 [grades 2 and 4]; comparator, n=1 [grade 4]) and unspecified VA (comparator, n=1 [grade 1]). Although the acalabrutinib group had a lower exposure-adjusted event rate per 100 patient-years than the comparator group, relative risk did not favor either group. With both fatal and nonfatal VAs (with or without PVCs), time to event was notably longer with acalabrutinib than with comparators ( Table 1). A sensitivity analysis excluding the ibrutinib-treated patients from the comparator cohort yielded overall similar results (data not shown). Conclusions: This pooled analysis of prospective acalabrutinib clinical trials demonstrates that the risk of VA and SD with acalabrutinib is low and similar to that of standard-of-care therapies when adjusted for exposure. The current analysis with more than 1200 patients treated with acalabrutinib points to favorable safety outcomes and no specific trend with SDs and VAs. Additional analyses with larger cohorts from the clinical development program and all postmarketing sources will continue to further characterize the safety profile of acalabrutinib.

Malignancy in the Upadacitinib Clinical Trials for Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, and Non-radiographic Axial Spondyloarthritis.

This article aims to describe malignancies in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), or non-radiographic axial spondyloarthritis (nr-axSpA) treated with upadacitinib (UPA) or active comparators. This integrated safety analysis includes data from 11 phase3 UPA trials across RA (6 trials), PsA (2 trials), AS (2 trials; one phase2b/3), and nr-axSpA (1 trial). Treatment-emergent adverse events (TEAEs) were summarized for RA (pooled UPA 15mg [UPA15], pooled UPA 30mg [UPA30], adalimumab 40mg [ADA], methotrexate monotherapy [MTX]), PsA (pooled UPA15, pooled UPA30, ADA), AS (pooled UPA15), and nr-axSpA (UPA15). TEAEs were reported as exposure-adjusted event rates (events/100 patient-years). Median treatment duration ranged from 1.0 to 4.0years (with a maximum of 6.6years in RA). Across treatments and indications, rates of malignancy excluding nonmelanoma skin cancer (NMSC) ranged from 0.2 to 1.1, while NMSC ranged from 0.0 to 1.4. In RA, rates of malignancy excluding NMSC were generally similar between UPA15, UPA30, ADA, and MTX (breast and lung cancer were the most common). In RA and PsA, Kaplan-Meier analyses revealed no differences in event onset of malignancy excluding NMSC with UPA15 versus UPA30 over time. In RA, NMSC rates were higher with UPA30 than UPA15; both UPA15 and UPA30 were higher than ADA and MTX. In PsA, rates of malignancy excluding NMSC and NMSC were generally similar between UPA15, UPA30, and ADA. In AS and nr-axSpA, malignancies were reported infrequently. Few events of lymphoma were reported across the clinical programs. Rates of malignancy excluding NMSC were generally similar between UPA15, UPA30, ADA, and MTX and were consistent across RA, PsA, AS, and nr-axSpA. A dose-dependent increased rate of NMSC was observed with UPA in RA. ClinicaTrials.gov identifier: NCT02706873, NCT02675426, NCT02629159, NCT02706951, NCT02706847, NCT03086343, NCT03104400, NCT03104374, NCT03178487, and NCT04169373.

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

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. 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. 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. 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. AbbVie.

P119 The Use of Exposure-Adjusted Event Rates versus Exposure-Adjusted Incidence Rates in Adverse Event Reporting: Insights from Filgotinib Integrated Safety Data in Rheumatoid Arthritis

Abstract Background/Aims Reporting of treatment-emergent adverse events (TEAEs) in rheumatoid arthritis (RA) clinical trials can be summarized as exposure-adjusted incidence rates (EAIRs) or exposure-adjusted event rates (EAERs). Censored EAIR (EAIR), weighing exposure up to a patient’s first event, is commonly reported; uncensored EAIR (EAIRu), using total exposure time for all patients, can also be used. For EAIR, exposure time can vary by event. In contrast to EAIR(u), the total number of events are used to calculate EAER. The three methods account for different exposures and/or multiple events, which can impact the outcome evaluation. Studies of filgotinib (FIL) in RA report safety data as EAIR/100 patient-years of exposure (PYE) for TEAEs, which is uncensored. Objective: To describe the outcome of long-term FIL integrated safety data in RA by applying different statistical methodologies: EAER, EAIRu and EAIR. Methods Integrated FIL safety data from seven clinical trials were assessed. Predefined adverse events of special interest (AESI) included serious infections (any), herpes zoster (HZ), major adverse cardiac events (MACE), malignancies (excluding nonmelanoma skin cancer [NMSC]), NMSC and venous thromboembolism (VTE). The number of patients with an event, number of events, EAER, EAIRu and EAIR were summarized. The data extraction date was January 2021 for the DARWIN 3 (NCT02065700) long-term extension (LTE) and November 2020 for the FINCH 4 (NCT03025308) LTE. Results In total, 3691 patients received ≥1 FIL dose for 8085 PYE. In this population, 176 serious infections were reported in 137 patients, 125 HZ events were reported in 112 patients, 39 MACE were reported in 33 patients, 20 cases of VTE were reported in 15 patients, 60 malignancies excluding NMSC were reported in 49 patients and 21 cases of NMSC were reported in 20 patients. Within each treatment arm (FIL 200 mg [FIL200], FIL 100 mg [FIL100] or combined FIL), rates for most AESI were similar when reported as EAER, EAIRu or EAIR. For serious infections, EAER was higher than EAIRu or EAIR. The total exposure time to first event (censored PYE) was high and comparable to total exposure (PYE) (&amp;gt;2700 years and &amp;gt;5100 years for the total populations in the FIL100 and FIL200 groups, respectively). Conclusion These data confirm that using different methods to analyze FIL safety data (EAER, EAIRu, EAIR) does not result in different safety outcomes, reinforcing the previously reported FIL safety profile in patients with RA. As the AESI reported in the long-term safety database with FIL are rare, patients commonly have long exposure times before experiencing an event, which are often associated with end of treatment. As such, EAIRu, EAIR and EAER are similar. Disclosure P. Durez: Member of speakers’ bureau; AbbVie, Galapagos, Lilly. E. Feist: Consultancies; AbbVie, Galapagos, Lilly, Novartis, Pfizer, Roche, and Sobi. Member of speakers’ bureau; AbbVie, Galapagos, Lilly, Pfizer, Roche, Novartis and Sobi. Grants/research support; Lilly, Pfizer and Roche. R. Blanco: Consultancies; AstraZeneca, Galapagos, Janssen, Novartis and Pfizer. Member of speakers’ bureau; AbbVie, Amgen, Bristol-Myers, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, Roche and Sanofi. Grants/research support; AbbVie, Roche. V. Rajendran: Other; Galapagos. N. Verbruggen: Other; Galapagos. K. Van Beneden: Shareholder/stock ownership; Galapagos. Other; Galapagos. J. Galloway: Consultancies; AbbVie, Galapagos, Gilead, Janssen, Lilly, Novartis and Pfizer. Member of speakers’ bureau; AbbVie, Biogen, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, Roche and UCB. Grants/research support; AstraZeneca, Celgene, Gilead, Janssen, Medicago, Novavax and Pfizer.

P135 Efficacy and safety of upadacitinib in TNFi inadequate responders with rheumatoid arthritis from three Phase 3 clinical trials

Abstract Background/Aims For patients with RA who are refractory to biologic disease-modifying antirheumatic drugs (bDMARDs), such as tumor necrosis factor inhibitors (TNFis), optimal disease control is less likely to be achieved with subsequent therapy. In line with recommendations from EULAR and ACR, switching to a treatment with a different mechanism of action is appropriate for these patients. Objectives To describe the efficacy and safety of upadacitinib (UPA) 15 mg once daily in patients with RA and an inadequate response or intolerance to TNFis (TNFi-IR). Methods A post hoc subgroup analysis was conducted in TNFi-IR patients who were treated with UPA 15 mg once daily in three Phase 3 clinical trials: SELECT-BEYOND, -CHOICE, and -COMPARE. For COMPARE, only patients treated with adalimumab and switched to UPA as rescue therapy were included. ≥20/50/70% improvement in ACR criteria, DAS28-CRP, Clinical Disease Activity Index, and Simple Disease Activity Index, as well as change from baseline in HAQ-DI and other patient-reported outcomes (PROs) were reported through 24 weeks. Non-responder imputation was used for all missing categorical outcomes; as observed (COMPARE) or multiple imputation (CHOICE, BEYOND) were used for missing continuous outcomes. Pooled safety results were presented as exposure-adjusted event rates (EAERs) with a cut-off of June 30, 2021. Results 568 TNFi-IR patients were included: 146 from BEYOND, 263 from CHOICE, and 159 from COMPARE. Mean duration since RA diagnosis was longer for BEYOND and CHOICE versus COMPARE; CV risk factors were common among this refractory population. ACR20/50/70 and disease activity outcomes observed in the TNFi-IR population were generally consistent with the overall BEYOND and CHOICE bDMARD-IR populations, and consistent across the three studies in the TNFi-IR subgroups. Improvements in PROs including HAQ-DI, fatigue, pain, and morning stiffness over 24 weeks were observed (data not shown). Pooled safety results reporting 1574.8 PY of exposure in the TNFi-IR subgroup showed similar results to the overall BEYOND and CHOICE bDMARD-IR study populations, with EAERs of 3.1 events/100 PY for herpes zoster and 0.8 events/100 PY for adjudicated major adverse CV events and venous thromboembolism, and malignancy excluding non-melanoma skin cancer. The EAER of any AE leading to death was 1.4 events/100 PY. Conclusion In this post hoc subgroup analysis, TNFi-IR patients treated with UPA 15 mg achieved clinically meaningful efficacy responses over 24 weeks, with safety consistent with the overall bDMARD-IR patient population in the Phase 3 program. Disclosure R. Fleischmann: Consultancies; Consultant for AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Galvani, Gilead, GSK, Janssen, Novartis, Pfizer Inc, and UCB. Grants/research support; Grant/research support from AbbVie, Amgen, Biosplice, Bristol-Myers Squibb, Flexion, Gilead, Horizon, Eli Lilly, Galvani, Janssen, Novartis, Pfizer Inc, Sanofi-Aventis, Selecta, Teva, UCB, Viela, and. L. Bessette: Consultancies; AbbVie, Amgen, Bristol-Meyers Squibb, Celgene, Eli Lilly, Fresenius Kabi, Gilead, Janssen, Merck, Novartis, and Pfizer, Roche, Sanofi-Aventis, Teva, and UCB. Member of speakers’ bureau; AbbVie, Amgen, Bristol-Meyers Squibb, Celgene, Eli Lilly, Fresenius Kabi, Gilead, Janssen, Merck, Novartis, and Pfizer, Roche, Sanofi-Aventis, Teva, and UCB. Grants/research support; AbbVie, Amgen, Bristol-Meyers Squibb, Celgene, Eli Lilly, Fresenius Kabi, Gilead, Janssen, Merck, Novartis, and Pfizer, Roche, Sanofi-Aventis, Teva, and UCB. S. Hall: Consultancies; AbbVie, Amgen, Bristol-Meyers Sqibb, Eli Lilly, Gilead, Janssen, Merck, Novartis, and UCB. Grants/research support; AbbVie, Amgen, Bristol-Meyers Sqibb, Eli Lilly, Gilead, Janssen, Merck, Novartis, and UCB. J. Sparks: Consultancies; Consulted for AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer. M. Jain: Consultancies; Amgen, Abbvie, Eli Lilly, Pfizer, and Novartis. Grants/research support; Amgen, Abbvie, Eli Lilly, Pfizer, and Novartis. A. Kakehasi: Consultancies; Amgen, Janssen, UCB, AbbVie, Pfizer, Eli Lilly, Novartis, Sandoz, Fresenius Kabi. Member of speakers’ bureau; Amgen, Janssen, UCB, AbbVie, Pfizer, Eli Lilly, Novartis, Sandoz, Fresenius Kabi. Grants/research support; Amgen, Janssen, UCB, AbbVie, Pfizer, Eli Lilly, Novartis, Sandoz, Fresenius Kabi. Y. Song: Shareholder/stock ownership; full-time employees of AbbVie and may own stock or options. S. Meerwein: Shareholder/stock ownership; full-time employees of AbbVie and may own stock or options. R. DeMasi: Shareholder/stock ownership; full-time employees of AbbVie and may own stock or options. J. Suboticki: Shareholder/stock ownership; full-time employees of AbbVie and may own stock or options. A. Rubbert-Roth: Consultancies; AbbVie, AbbVie Deutschland, Amgen, Bristol-Myers Squibb, Chugai Pharmaceuticals, Eli Lilly, F. Hoffman-La Roche, Gilead Sciences, Janssen Global Services, Novartis, and Sanofi Pasteur.

Predictors of&amp;nbsp;bioprosthetic valve dysfunction after transcatheter aortic valve implantation

Recently, the Valve Academic Research Consortium (VARC)-3 criteria redefined bioprosthetic valve dysfunction (BVD) after transcatheter aortic valve implantation (TAVI). However, the rate of BVD is scarcely reported in current practice. We aimed to evaluate the rate and predictors of BVD after TAVI based on the VARC-3 criteria. We retrospectively analysed patients who had undergone TAVI using single-centre data. BVD was reported as exposure-adjusted event rates with a patient-year unit (per 100 patient-years). Predictors of BVD after TAVI were analysed using Fine-Gray competing risk regression to account for the competing risk of death. Among 514 patients, the rate of BVD was 7.5 events per 100 patient-years (n=74) at a median follow-up of 1.9 years. The main cause of BVD was moderate or severe prosthesis-patient mismatch (PPM; n=59). The Fine-Gray model demonstrated that predilatation was associated with a lower rate of BVD, mainly moderate or severe PPM (adjusted subdistribution hazard ratio [sub-HR] 0.42, 95% confidence interval [CI]: 0.21-0.88). In a subgroup analysis, the patients with a small aortic annulus (area <400 mm2 or perimeter <72 mm) tended to benefit from predilatation (p for interaction=0.03). The same regression model also demonstrated that a small balloon-expandable valve (BEV; ≤23 mm) was associated with a higher rate of BVD (adjusted sub-HR 2.46, 95% CI: 1.38-4.38). Our study suggested that the rate of BVD in patients undergoing TAVI is relatively low at midterm follow-up. Predilatation, particularly in small annuli and small BEV might have an impact on BVD, mainly caused by moderate or severe PPM, after TAVI.

Safety profile of upadacitinib over 15 000 patient-years across rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and atopic dermatitis

ObjectiveTo evaluate the long-term safety profile for upadacitinib across rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS) and atopic dermatitis (AD).MethodsSafety data from clinical trials of upadacitinib 15 mg...

P518 Safety of upadacitinib in ulcerative colitis: Long-term data from the phase 3 open-label extension study (U-ACTIVATE)

Abstract Background Upadacitinib (UPA), an oral reversible and selective JAK inhibitor, has demonstrated efficacy, with a well-characterised safety profile, in two replicate induction studies of UPA 45 mg once daily (QD; U-ACHIEVE induction and U-ACCOMPLISH), and a maintenance study of UPA 15 mg or UPA 30 mg QD (U-ACHIEVE maintenance).1 Here, we report safety data from the ongoing, Phase 3, open-label, 288-week long-term extension (LTE) study in patients with ulcerative colitis (UC) who previously participated in the induction studies. Methods Rates of treatment-emergent adverse events (TEAEs) and TEAEs of special interest were calculated by treatment sequence in patients who received ≥1 dose of UPA in the induction studies, maintenance study, or by the data cut-off of 13 December 2021 in the LTE study. Rates are presented as exposure-adjusted event rates (EAERs; events/100 patient-years [PYs]), except for events that typically occur as a single instance, which are presented as exposure-adjusted incidence rates (EAIRs; n/100 PYs). PYs were calculated from the first dose of UPA 45 mg received during induction through to the last UPA dose received or the data cut-off date for ongoing patients. Results Overall, 1,308 patients representing 2,350.2 PYs of UPA exposure were evaluated (mean age: 43 years; female: 38%). Across treatment groups, EAERs of serious TEAEs, severe TEAEs, TEAEs leading to UPA discontinuation, TEAEs with reasonable possibility of being related to UPA, or TEAEs leading to death were numerically similar across all UPA treatment sequences (Table 1). EAERs of serious infections, herpes zoster, neutropenia, hepatic disorder, and creatine phosphokinase elevation were numerically higher with UPA 15 mg and 30 mg vs placebo; and creatine phosphokinase elevation with UPA 30 mg vs UPA 15 mg (Table 2). The EAER of anaemia was numerically lower with UPA 30 mg vs UPA 15 mg and placebo. Of note, no remarkable differences were observed in EAIRs of adjudicated major adverse cardiovascular events, adjudicated venous thromboembolic events, or malignancy (excluding non-melanoma skin cancer). Conclusion: Long-term use of UPA 15 or 30 mg among patients with UC continuing to benefit from prolonged therapy representing 2,350.2 PYs of exposure was well tolerated. The ongoing safety profile of UPA is consistent with previous analyses, with no new safety signals identified compared with previous UC analyses following 52 weeks’ maintenance therapy,1,2 or other immune-mediated indications for which UPA is approved.3,4

1135P Adverse event (AE) burden of nivolumab-based immuno-oncology (IO) therapy with/without chemotherapy (chemo) for first-line (1L) advanced non-small cell lung cancer (aNSCLC)

Nivolumab + ipilimumab (N + I) alone or with limited chemo (LC; up to 6 weeks [wks]) provide new 1L treatment (tx) options for aNSCLC; but the relative contributions of the different agents to the AE profile over time have not been assessed. Here, we quantified the AE rates and associated costs for N + I, N + I + LC, and N + chemo (C; 12+ wks) over time during tx for 1L aNSCLC. Exposure-adjusted event rates (EAERs) were calculated as the number of occurrences of all-cause grade 3–5 AEs per patient-year (PY), using individual patient data from the CheckMate 227 Parts 1 and 2 and CheckMate 9LA trials (minimum follow-up: 48, 38, and 23 months, respectively). EAERs were estimated for the overall trial period and at 5 pre-specified time periods (wks 0–6, 7–12, 13–24, 25–48, and 49+) to assess the impact of tx on AE burden. AE costs per patient were estimated as the rates of grade 3–5 AEs (with any-grade incidence ≥15%) multiplied by the corresponding unit hospitalization costs for AE management obtained from the 2019 US Healthcare Cost and Utilization Project National Inpatient Sample database. EAERs of all-cause grade 3–5 AEs per PY were lower with N + I (4.8) vs N + I + LC (7.0) and N + C (6.1) at wks 0–6 and lower with N + I (4.0) and N + I + LC (3.1) vs N + C (5.2) at wks 7–12, when chemo was administered; EAERs for the total exposure time period were similar in the N + I (2.6), N + I + LC (2.5), and N + C (2.5) tx groups (Table). EAERs continued to decline in subsequent wks in all 3 tx groups. Overall AE costs were lower with N + I ($6560) and N + I + LC ($7492) vs N + C ($11,731); similar trends were seen per time period.Table: 1135PTime period, wksEAERaAE costb, $N 3 mg/kg Q2W + I 1 mg/kg Q6W n = 576N 360 mg Q3W + I 1 mg/kg Q6W + LC Q3W, up to 2 cycles n = 358N 360 mg Q3W + C Q3W, 4+ cycles n = 547N 3 mg/kg Q2W + I 1 mg/kg Q6W n = 576N 360 mg Q3W + I 1 mg/kg Q6W + LC Q3W, up to 2 cycles n = 358N 360 mg Q3W + C Q3W, 4 + cycles n = 5470–64.87.06.12033315537157–124.03.15.216501157332813–242.52.22.79441080237425–481.71.71.210571423118049+1.51.11.08756761134Overall2.62.52.56560749211,731aPer PY (defined as the total exposure time [time between date of first dose and the earliest among last dose date + 30 days, cutoff date, and date of death] for each patient at risk of AE); bPer patient. 1 cycle = 3 wks; Q2W, every 2 wks; Q3W, every 3 wks; Q6W, every 6 wks. Open table in a new tab aPer PY (defined as the total exposure time [time between date of first dose and the earliest among last dose date + 30 days, cutoff date, and date of death] for each patient at risk of AE); bPer patient. 1 cycle = 3 wks; Q2W, every 2 wks; Q3W, every 3 wks; Q6W, every 6 wks. Higher incidence of AEs and AE costs associated with N + I + LC and N + C vs N + I correlated with the time when chemo was administered during tx; toxicities and costs declined over time after chemo was completed. Results imply an overall lower AE cost burden with 1L N + I compared with IO + chemo-based tx regimens for aNSCLC.

865-P: Long-Term Ertugliflozin Treatment and Incidence of Hypoglycemia: Analyses from VERTIS CV

This analysis assessed the incidence and total events of hypoglycemia in VERTIS CV (NCT01986881) , the cardiovascular (CV) outcome trial for ertugliflozin (ERTU) in patients (pts) with type 2 diabetes and atherosclerotic CV disease. Hypoglycemia was categorized as level 1, a documented symptomatic event with plasma glucose (PG) ≤70 mg/dL (prespecified) ; level 2, a documented event with PG &amp;lt;54 mg/dL (post hoc) ; level 3, a severe event requiring assistance (prespecified) . Time to first HYPO-broad (levels 1+2+3) and HYPO-strict (levels 2+3) were analyzed by a Cox proportional hazards model. Kaplan-Meier estimates were plotted. Exposure-adjusted event rates for total (first + recurrent) HYPO-broad and -strict were analyzed. Overall, 8246 pts were randomized, mean follow-up was 3.5 yrs. The incidence rate (ERTU vs PBO) of first HYPO-broad was 14.3 vs. 16.2/100 pt-yrs; adjusted hazard ratio [aHR], 95% CI: 0.93 [0.85, 1.00] and HYPO-strict was 9.5 vs. 11.1/100 pt-yrs; aHR: 0.89 [0.81, 0.97] [Figure A]. Exposure-adjusted event rates were lower in ERTU vs PBO [Figure B]. The increase in percentage of insulin users (end of study vs. baseline) was less with ERTU (3.5% 5 + 15 mg) compared with PBO (6.2%) . In VERTIS CV, pts randomized to ERTU had a lower risk of hypoglycemia, including first and recurrent events, than PBO-treated pts. This may in part be due to the lesser increase in insulin users with ERTU vs. PBO. Disclosure S.Dagogo-jack: Consultant; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Medtronic, Merck &amp; Co., Inc., Sanofi. R.E.Pratley: Other Relationship; Bayer AG, Corcept Therapeutics, Dexcom, Inc., Hanmi Pharm. Co., Ltd., Merck &amp; Co., Inc., Metavention, Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. C.P.Cannon: Advisory Panel; Alnylam Pharmaceuticals, Inc., Amarin Corporation, Amgen Inc., Amryt Pharma Plc, Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck &amp; Co., Inc., Pfizer Inc., Rhoshan, Sanofi, Research Support; Amgen Inc., Better Therapeutics, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novo Nordisk, Pfizer Inc. D.Cherney: Other Relationship; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Research &amp; Development, LLC, Lilly, Maze, BMS, CSL-Behring, Merck, Otsuka, Novartis and Novo-Nordisk , Mitsubishi Tanabe Pharma Corporation, Sanofi, Research Support; Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca and Novo-Nordisk. F.Cosentino: Advisory Panel; Merck Sharp &amp; Dohme Corp., Pfizer Inc., Speaker's Bureau; AstraZeneca, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Lilly, Merck Sharp &amp; Dohme Corp., Novo Nordisk. D.K.Mcguire: Consultant; AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, ESPERION Therapeutics, Inc., Lexicon Pharmaceuticals, Inc., Lilly, Merck &amp; Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi. J.Liu: Employee; Merck &amp; Co., Inc. C.Liu: Employee; Merck &amp; Co., Inc., Stock/Shareholder; Merck &amp; Co., Inc. R.Frederich: Employee; Pfizer Inc., Stock/Shareholder; Bristol-Myers Squibb Company, Pfizer Inc. J.P.Mancuso: Employee; Pfizer Inc., Stock/Shareholder; Pfizer Inc. Funding This study was sponsored by Merck Sharp &amp; Dohme Corp., a subsidiary of Merck &amp; Co., Inc., Kenilworth, NJ, USA, and Pfizer Inc., New York, NY, USA.

POS0683 EFFICACY AND SAFETY OF UPADACITINIB IN TNFi-IR PATIENTS WITH RHEUMATOID ARTHRITIS FROM THREE PHASE 3 CLINICAL TRIALS

BackgroundFor patients with RA who are refractory to biologic DMARDs (bDMARDs), such as tumor necrosis factor inhibitors (TNFis), optimal disease control is less likely to be achieved with subsequent therapy.1 In line with recommendations from EULAR and ACR, switching to a treatment with a different mechanism of action is appropriate for these patients.ObjectivesTo describe the efficacy and safety of upadacitinib (UPA) 15 mg once daily in patients with RA and an inadequate response or intolerance to TNFis (TNFi-IR).MethodsA post hoc subgroup analysis was conducted in TNFi-IR patients who were treated with UPA 15 mg once daily in three Phase 3 clinical trials: SELECT-BEYOND,2 -CHOICE,3 and -COMPARE.4 For COMPARE, only patients treated with adalimumab and switched to UPA as rescue therapy were included. ≥20/50/70% improvement in ACR criteria, DAS28(CRP), CDAI, and SDAI, as well as change from baseline in HAQ-DI and other patient-reported outcomes (PROs) were reported through 24 weeks. Non-responder imputation was used for all missing categorical outcomes; as observed (COMPARE) or multiple imputation (CHOICE, BEYOND) were used for missing continuous outcomes. Pooled safety results were presented as exposure-adjusted event rates (EAERs) with a cut-off of June 30, 2021.Results568 TNFi-IR patients were included: 146 from BEYOND, 263 from CHOICE, and 159 from COMPARE. Mean duration since RA diagnosis was longer for BEYOND and CHOICE versus COMPARE; cardiovascular (CV) risk factors were common among this refractory population (Table 1). ACR20/50/70 and disease activity outcomes observed in the TNFi-IR population were generally consistent with the overall BEYOND2 and CHOICE3 bDMARD-IR populations, and consistent across the three studies in the TNFi-IR subgroups (Figure 1). Improvements in PROs including HAQ-DI, fatigue, pain, and morning stiffness over 24 weeks were observed (data not shown). Pooled safety results reporting 1574.8 patient-years (PY) of exposure in the TNFi-IR subgroup showed similar results to the overall BEYOND2 and CHOICE3 bDMARD-IR study populations, with EAERs of 3.1 events/100 PY for herpes zoster and 0.8 events/100 PY for adjudicated major adverse CV events, adjudicated venous thromboembolism (VTE), and malignancy excluding non-melanoma skin cancer. The EAER of any AE leading to death was 1.4 events/100 PY.Table 1.Baseline characteristics of TNFi-IR patients treated with UPA 15 mgn (%), unless specifiedSELECT-BEYOND (n=146)SELECT-CHOICE (n=263)SELECT-COMPARE (ADA → UPA) (n=159)Female122 (83.6)219 (83.3)133 (83.6)Mean (SD) age, years56.6 (11.0)55.5 (11.1)53.9 (10.6)Mean (SD) duration of RA diagnosis, years13.2 (9.5)12.5 (9.4)8.2 (8.5)Concomitant csDMARDs MTX alone100 (70.4)195 (74.1)159 (100.0) MTX and other csDMARDs20 (14.1)25 (9.5)0 csDMARDs other than MTX22 (15.5)38 (14.4)0Concomitant oral steroids73 (50.0)140 (53.2)98 (61.6)1 prior bDMARD68 (46.6)172 (65.4)142 (89.3)2 prior bDMARDs40 (27.4)62 (23.6)17 (10.7)a≥3 prior bDMARDs38 (26.0)29 (11.0)0Failed ≥1 prior TNFi due to lack of efficacyb131 (89.7)223 (84.8)159 (100.0)History of VTE / CV event3 (2.1) / 28 (19.2)6 (2.3) / 20 (7.6)4 (2.5) / 14 (8.8)CV risk factors Hypertension72 (49.3)109 (41.4)68 (42.8) Diabetes mellitus22 (15.1)34 (12.9)17 (10.7) Smoking (current former past)68 (46.6)109 (41.5)55 (34.6) Elevated LDL-C (≥3.36 mmol/L)38 (26.0)52 (20.0)48 (30.2) Low HDL-C (≤1.55 mmol/L)80 (54.8)171 (65.0)88 (55.3)aThese patients received one bDMARD before entry into SELECT-COMPARE.bRemaining patients were intolerant to ≥1 prior TNFi.ConclusionIn this post hoc subgroup analysis, TNFi-IR patients treated with UPA 15 mg achieved clinically meaningful efficacy responses over 24 weeks, with safety consistent with the overall bDMARD-IR patient population in the Phase 3 program.

A37 EFFICACY AND SAFETY OF RISANKIZUMAB AS MAINTENANCE THERAPY IN PATIENTS WITH CROHN’S DISEASE: 52 WEEK RESULTS FROM THE PHASE 3 FORTIFY STUDY

BackgroundRisankizumab (RZB), an anti-IL-23 p19 inhibitor, was well-tolerated and superior to placebo (PBO) in inducing clinical remission and endoscopic response in patients (pts) with moderate-to-severe Crohn’s disease (CD) in two phase 3 studies at 12 weeks.AimsFORTIFY (NCT03105102), was a 52-week (wk) phase 3 double-blind, re-randomized responder withdrawal study that evaluated the efficacy and safety of continuing RZB as subcutaneous (SC) maintenance therapy versus withdrawal to placebo in pts achieving induction response to RZBMethodsWeek 12 IV RZB responders were re-randomized 1:1:1 to: RZB SC 360mg (N=141), RZB 180mg (N=157), or PBO (withdrawal from IV RZB; N=164) every 8wks for 52wks. Co-primary endpoints were clinical remission (per CD Activity Index [CDAI] (US); or stool frequency/abdominal pain score [SF/APS] (OUS) and endoscopic response at wk52. Other clinical and endoscopic endpoints, inflammatory biomarkers, RZB serum levels, and safety were assessed over time.ResultsRates of clinical remission (CDAI, SF/APS) and clinical response were similar for RZB and PBO groups through wk24, with rates lower for PBO thereafter. At wk52, clinical remission (CDAI, SF/APS) and endoscopic response rates were significantly higher with RZB 360mg than PBO ( P<0.01); RZB 180mg was superior to PBO for clinical remission per CDAI and endoscopic response ( P<0.01). Endoscopic remission and deep remission rates increased over time with 360mg, remained steady with 180mg, and decreased with PBO. Mean fecal calprotectin (FCP) and C-reactive protein (CRP) levels decreased with SC RZB, but increased with PBO, over 52wks. Exposure-adjusted event rates (per 100 pts-years) of serious adverse event (AE) were generally similar among groups (360mg, 21.0 E/100PY and 180mg, 19.5 E/100PY vs PBO, 19.3 E/100PY), as were AEs leading to drug discontinuation (4.8 E/100PY and 2.4 E/100PY vs 3.7 E/100PY), and serious infections (6.0 E/100PY and 3.0 E/100PY vs 5.0 E/100PY).ConclusionsIn pts with moderate-to-severe CD, a robust pharmacodynamic effect on the IL-23 pathway after 12wks RZB IV induction was maintained with RZB SC maintenance therapy. The durability of RZB was demonstrated with high rates of efficacy over the 52-wk study. RZB was superior to PBO for achieving clinical remission and endoscopic response at wk52. Results for the more stringent endpoints (endoscopic remission\\deep remission) and persistent improvements in inflammatory biomarkers are consistent with a dose response relationship. Continued RZB SC maintenance treatment was generally safe and well-tolerated.Funding AgenciesAbbVie

P573 The safety profile of upadacitinib maintenance therapy in ulcerative colitis in the Phase 3 U-ACHIEVE study is consistent with that in approved indications

Abstract Background The oral, small-molecule, selective and reversible Janus kinase inhibitor upadacitinib (UPA) is approved for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), moderate-to-severe atopic dermatitis (AD) and ankylosing spondylitis, and is under investigation in ulcerative colitis (UC). This assessment reviewed adverse event (AE) data for UPA maintenance therapy in UC in the context of the known long-term safety profile of UPA in its approved indications. Methods Safety data were collated from patients with UC who responded to 8 weeks’ induction treatment with UPA 45 mg once daily (QD) and were enrolled in U-ACHIEVE to receive maintenance treatment (UPA 15 mg, 30 mg QD or placebo) for ≤52 weeks. Treatment-emergent AEs (TEAEs) were defined as AEs with an onset on or after the first dose, and ≤30 days after the last dose, of study drug. Safety data were also collected from two AD (15 and 30 mg doses), six RA (15 mg dose in all, 30 mg dose in four) and two PsA (15 and 30 mg doses) Phase 3 trials. Exposure-adjusted event rates were calculated for TEAEs and AEs of special interest (AESIs). Results Data were available for 746 patients with UC who received 8 weeks’ induction with UPA 45 mg and were randomised to maintenance treatment as follows: placebo, n=245; UPA 15 mg, n=250; UPA 30 mg, n=251. Rates of any AEs, serious AEs, severe AEs and AEs leading to treatment discontinuation were lower with both UPA doses versus placebo (Table 1). No deaths occurred. Rates of the above AE categories in patients with UC who received maintenance treatment with UPA 15 or 30 mg were within the ranges previously reported in AD, RA and PsA, apart from neutropenia (Table 1). AESI rates in UC were generally similar with UPA and placebo, except for higher rates of herpes zoster, creatine phosphokinase elevation, hepatic disorder, and venous thromboembolism (VTE), but lower rates of anaemia, with UPA (Table 2). Non-melanoma skin cancer was reported only with UPA 30 mg. One adjudicated major cardiovascular event was reported in each of the placebo and UPA 30 mg arms. VTE only occurred with UPA treatment (two events per arm). Based on the limited number of patients exposed, and apart from a higher VTE rate, AESI rates in the UC maintenance study were generally similar to those reported in patients receiving long-term treatment with UPA 15 or 30 mg QD in AD, RA or PsA. Conclusion The safety profile of UPA maintenance treatment in UC is consistent with that in its approved indications. Although VTE rates were higher in UC, background VTE risk is known to be increased in UC versus AD, RA and PsA. This review identified no new important safety risks.

Safety Profile of Upadacitinib up to 3 Years in Psoriatic Arthritis: An Integrated Analysis of Two Pivotal Phase 3 Trials.

IntroductionThis integrated analysis describes the safety profile of upadacitinib, an oral Janus kinase inhibitor, at 15 and 30 mg once daily for up to 3 years of exposure in patients with active psoriatic arthritis (PsA) who had a prior inadequate response or intolerance to ≥ 1 non-biologic or biologic disease-modifying antirheumatic drug.MethodsSafety data were pooled and analyzed from two randomized, placebo-controlled phase 3 trials. Both trials evaluated upadacitinib 15 mg and 30 mg once daily, and one trial also evaluated adalimumab 40 mg every other week. Treatment-emergent adverse events (TEAEs) and laboratory data were summarized for four groups: pooled placebo, pooled upadacitinib 15 mg, pooled upadacitinib 30 mg, and adalimumab. TEAEs were reported as exposure-adjusted event rates (events per 100 patient-years [E/100 PY]) up to a data cut-off of June 29, 2020.ResultsA total of 2257 patients received ≥ 1 dose of upadacitinib 15 mg (N = 907) or 30 mg (N = 921) for 2504.6 PY of exposure or adalimumab (N = 429) for 549.7 PY of exposure. Upper respiratory tract infection, nasopharyngitis, and increased creatine phosphokinase (CPK) were the most common TEAEs with upadacitinib. Rates of malignancies, adjudicated major adverse cardiovascular events (MACEs) and venous thromboembolic events (VTEs), and deaths were similar across treatment groups. Rates of herpes zoster (HZ) and opportunistic infections (OI; excluding tuberculosis, HZ, and oral candidiasis) were higher with upadacitinib versus adalimumab. Serious infection, anemia, and CPK elevations were most frequent with upadacitinib 30 mg. Potentially clinically significant laboratory abnormalities were uncommon.ConclusionsUpadacitinib 15 mg and adalimumab had similar safety profiles with the exception of HZ and OIs, consistent with what was observed in rheumatoid arthritis. Rates of malignancies, MACEs, VTEs, and deaths were comparable among patients receiving upadacitinib and adalimumab. No new safety risks emerged with longer-term exposure to upadacitinib.Trial Registration NumbersSELECT-PsA 1: NCT03104400; SELECT-PsA 2: NCT03104374.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-021-00410-z.

Risk of herpes zoster (shingles) in patients with rheumatoid arthritis under biologic, targeted synthetic and conventional synthetic DMARD treatment: data from the German RABBIT register

ObjectiveTo compare event and incidence rates of herpes zoster (HZ), also known as shingles, in patients with rheumatoid arthritis under treatment with conventional synthetic (cs), targeted synthetic (ts) or biologic...

OP04 Safety analysis of filgotinib for Ulcerative Colitis: Results from the phase 2b/3 SELECTION study and phase 3 SELECTIONLTE long-term extension study

Abstract Background Filgotinib (FIL) is an oral preferential Janus kinase (JAK) 1 inhibitor in development for the treatment of inflammatory diseases. FIL for the treatment of moderately to severely active ulcerative colitis (UC) was evaluated in the phase 2b/3, double-blind, placebo (PBO)-controlled SELECTION study (NCT02914522) and its long-term extension (LTE) study (NCT02914535). Here we report safety results from the FIL UC program. Methods Patients received FIL 100 mg, FIL 200 mg or PBO (2:2:1) once daily orally for up to 11 weeks for induction (cohort 1). At week 11, FIL induction responders were rerandomized 2:1 to continue FIL or receive PBO maintenance for 47 weeks (cohort 2). Week 10 non-responders and patients with worsening disease during the maintenance study were eligible for open-label FIL in the LTE. Patients completing the maintenance study could continue blinded dosing in the LTE. Cohort 3 comprised cohorts 1 and 2 and the LTE. Exposure-adjusted incidence rates (EAIRs) and exposure-adjusted event rates (EAERs) per 100 patient-years (PYs) were calculated for treatment-emergent adverse events (AEs) by treatment group in cohorts 1 and 2 (EAIR) and cohort 3 (EAER). Results In cohort 1, 1069 patients received FIL and 279 patients received PBO; baseline characteristics were generally similar across treatment groups (overall mean age, 43 years; mean UC duration, 8.4 years; mean Mayo Clinic Score, 9.0). EAIRs for AEs of interest were similar across treatment groups in cohorts 1 and 2 (Table 1). Treatment exposure for PBO, FIL 100 mg or FIL 200 mg in cohort 3 (i.e. cohorts 1 + 2 + the LTE) was 318, 360 and 1207 PYs, and median treatment duration was 12, 11 and 67 weeks, respectively. One case of pulmonary embolism occurred with FIL 200 mg induction and three venous thrombosis cases occurred with PBO maintenance/LTE (cohort 3) (Table 2). EAERs for all infections were similar across treatment groups, the most common being nasopharyngitis (Table 2). Opportunistic infections were rare. EAERs for serious infections were low across treatment groups (2.2 [PBO], 3.5 [FIL 100 mg], 2.2 [FIL 200 mg]), the most common being appendicitis (Table 2). EAERs for herpes zoster (HZ) were low in all treatment groups (0.3 [PBO], 0.3 [FIL 100 mg], 1.8 [FIL 200 mg]) (Table 2). HZ infections were cutaneous only and only one was serious. EAIRs for all infections in cohorts 1 and 2 were generally numerically higher for both PBO and FIL in patients over (vs under) 65 years old and in those with (vs without) biologic treatment failure (Figure 1). Conclusion FIL was well tolerated in patients with UC. Aggregation of AEs typical for pan-JAK inhibition was not observed, consistent with preferential JAK-1 inhibition with FIL.