Prior Tumor Necrosis Factor Inhibitor Research Articles

Efficacy and safety of guselkumab in patients with active psoriatic arthritis who had inadequate efficacy and/or intolerance to one prior tumor necrosis factor inhibitor: study protocol for SOLSTICE, a phase 3B, multicenter, randomized, double-blind, placebo-controlled study

BackgroundTumor necrosis factor inhibitors (TNFi) are frequently chosen as the first biologic for patients with psoriatic arthritis (PsA). Given that many patients with PsA are TNFi inadequate responders (TNF-IR; either inadequate efficacy or intolerance), treatments utilizing alternative mechanisms of action are needed. In phase 3 studies, the fully human interleukin (IL)-23p19 subunit-inhibitor, guselkumab, was efficacious in patients with active PsA, including TNFi-IR. Efficacy was generally consistent between TNFi-naïve and TNFi-experienced cohorts; however, in the latter, higher response rates have been observed with the Q4W dosing regimen relative to the Q8W dosing regimen for some endpoints, suggesting the need to evaluate whether more frequent dosing may provide an incremental clinical benefit for TNFi-IR patients.MethodsThe phase 3b SOLSTICE study will assess guselkumab efficacy and safety in TNFi-IR PsA patients. Eligibility criteria include a PsA diagnosis for ≥ 6 months; active disease (≥ 3 swollen, ≥ 3 tender joints, C-reactive protein ≥ 0.3 mg/dL); and inadequate efficacy with, and/or intolerance to, one prior TNFi. Participants will be randomized 1:1:1 to guselkumab Q4W or Q8W or placebo→guselkumab Q4W (at Week 24). The primary endpoint is the proportion of patients achieving ≥ 20% improvement in the American College of Rheumatology criteria (ACR20) at Week 24. Major secondary endpoints include ACR50, ACR70; an Investigator’s Global Assessment (IGA) of psoriasis score of 0/1 plus ≥ 2-grade reduction and ≥ 90% improvement in Psoriasis Area and Severity Index (both among patients with ≥ 3% body surface area affected by psoriasis and baseline IGA ≥ 2); minimal/very low disease activity; and changes from baseline in Health Assessment Questionnaire-Disability Index, the 36-item Short-Form Health Survey Physical Component Summary, and Functional Assessment of Chronic Illness Therapy-Fatigue scores. The target sample size (N = 450) is estimated to provide > 90% power in detecting differences between each guselkumab group and the placebo group for the primary endpoint assuming a 2-sided α = 0.05. Cochran-Mantel–Haenszel testing and analyses of covariance will be used to compare efficacy for binary and continuous endpoints, respectively.DiscussionFindings from the phase 3b SOLSTICE study, the design of which was informed by results from previously conducted phase 3 studies, is expected to provide important efficacy and safety information on guselkumab therapy in TNFi-IR patients with PsA.Trial registrationThis trial was registered at ClinicalTrials.gov, NCT04936308, on 23 June 2021.

P167 Bimekizumab achieved sustained improvements in efficacy outcomes in patients with axial spondyloarthritis, regardless of prior tumour necrosis factor inhibitor treatment: week 52 pooled results from the phase 3 studies BE MOBILE 1 and BE MOBILE 2

Abstract Background/Aims Bimekizumab (BKZ) is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL17A. In the phase 3 BE MOBILE 1 and 2 studies, BKZ treatment resulted in rapid and sustained improvements in efficacy outcomes through 52 weeks (wks) in patients with active nonradiographic axial spondyloarthritis (nr-axSpA) and radiographic (r)axSpA (i.e., ankylosing spondylitis [AS]). Here, we assess the efficacy of BKZ in tumour necrosis factor inhibitor (TNFi)-naïve or -inadequate responder (IR) patients with active nr-axSpA and raxSpA through Wk52. Methods In BE MOBILE 1 (nr-axSpA; NCT03928704) patients met Assessment of SpondyloArthritis international Society (ASAS) classification criteria and in BE MOBILE 2 (r-axSpA; NCT03928743) patients fulfilled modified New York and ASAS criteria. Patients were randomised to receive subcutaneous BKZ 160mg every 4wks (Q4W) or placebo (PBO) then BKZ 160mg Q4W from Wk16. This post-hoc analysis reports pooled mean efficacy data, including disease activity, MRI inflammation, physical function, and quality of life (QoL), through Wk52, stratified by TNFi status (naïve/IR). TNFi-IR patients were defined as those who experienced intolerance, or IR, to prior treatment given at an approved dose for ≥12wks. Results This pooled analysis included 505 TNFi-naïve and 81 TNFi-IR patients. 302/505 (59.8%) TNFi-naïve and 47/81 (58.0%) TNFi-IR patients were randomised to BKZ. Higher proportions of BKZ-randomised patients vs PBO achieved Wk16 ASAS40 (TNFinaïve: 46.0% vs 23.2%, TNFi-IR: 44.7% vs 14.7%; multiple imputation) and AS Disease Activity Score (ASDAS) <2.1 or low disease activity (47.9% vs 20.3%, 30.2% vs 15.6%; observed case). In continuous BKZ-treated patients, responses increased to Wk52 (ASAS40: 59.9%, 55.3%; ASDAS<2.1: 62.0%, 54.1%). Greater reductions from baseline in ASDAS-CRP and MRI inflammation by Wk16 were achieved with BKZ vs PBO in both TNFi-naïve/-IR patients; in continuous BKZ-treated patients this was sustained or further improved through 52wks. Comparable improvements in physical function, nocturnal spinal pain and ASQoL were observed through 52wks with BKZ in TNFinaïve/-IR patients (Table). Conclusion Across the full axSpA disease spectrum, BKZ treatment resulted in clinically relevant improvements in key efficacy outcomes vs PBO, including suppression of inflammation and improvements in physical function and QoL, regardless of prior TNFi exposure. Improvements were sustained to Wk52. Disclosure M. Magrey: Consultancies; AbbVie, BMS, Eli Lilly, Novartis, Pfizer and UCB Pharma. Grants/research support; AbbVie, BMS and UCB Pharma. M. Van de Sande: Consultancies; AbbVie, Novartis and UCB Pharma. Member of speakers’ bureau; Janssen, Novartis and UCB Pharma. Grants/research support; Eli Lilly, Novartis and UCB Pharma. M. Breban: Consultancies; Novartis and UCB Pharma. Grants/research support; MSD. F. Van den Bosch: Consultancies; AbbVie, Amgen, Eli Lilly, Galapagos, Janssen, Novartis, Pfizer and UCB Pharma. Member of speakers’ bureau; AbbVie, Amgen, Janssen, Merck, Novartis, Pfizer and UCB Pharma. C. Fleurinck: Other; Employee of UCB Pharma. U. Massow: Other; Employee of UCB Pharma. N. de Peyrecave: Other; Employee of UCB Pharma. T. Vaux: Other; Employee of UCB Pharma. X. Baraliakos: Consultancies; AbbVie, BMS, Chugai, Eli Lilly, Galapagos, Gilead, Novartis, Pfizer and UCB Pharma. Member of speakers’ bureau; AbbVie, BMS, Chugai, Eli Lilly, Galapagos, MSD, Novartis, Pfizer and UCB Pharma. Grants/research support; Novartis and UCB Pharma. Other; Paid instructor for AbbVie, BMS, Chugai, Eli Lilly, Galapagos, MSD, Novartis, Pfizer and UCB Pharma. H. Marzo-Ortega: Consultancies; AbbVie, Biogen, Eli Lilly, Janssen, Moonlake, Novartis, Pfizer, Takeda and UCB Pharma. Honoraria; AbbVie, Biogen, Eli Lilly, Janssen, Moonlake, Novartis, Pfizer, Takeda and UCB Pharma. Grants/research support; Janssen, Novartis and UCB Pharma.

Efficacy and Safety of Secukinumab in US Patients with Psoriatic Arthritis: A Subgroup Analysis of the Phase 3 FUTURE Studies.

The aim of this work is to evaluate secukinumab vs. placebo in a challenging-to-treat and smaller US patient subpopulation of the international FUTURE 2-5 studies in patients with psoriatic arthritis (PsA). Data were pooled from US patients enrolled in the phase 3 FUTURE 2-5 studies (NCT01752634, NCT01989468, NCT02294227, and NCT02404350). Patients received secukinumab 300 or 150 mg with subcutaneous loading dose, secukinumab 150 mg without subcutaneous loading dose, or placebo. Categorical efficacy and health-related quality-of-life (QoL) outcomes and safety were evaluated at week 16. Subgroup analyses were performed based on tumor necrosis factor inhibitor (TNFi) status and body mass index (BMI). For hypothesis generation, odds ratios (ORs) for American College of Rheumatology (ACR) 20/50/70 and Psoriasis Area and Severity Index (PASI) 75/90/100 responses by treatment were estimated using logistic regression without adjustment for multiple comparisons. Of 2148 international patients originally randomized, 279 US patients were included in this pooled analysis. Mean BMI was > 30 kg/m2 and 55.2% had prior TNFi treatment. ORs for ACR20/50/70 significantly favored patients receiving secukinumab 300 mg and 150 mg with loading dose vs. placebo (P < 0.05), but not those receiving secukinumab 150 mg without loading dose vs. placebo. For PASI75, ORs favored all secukinumab groups over placebo (P < 0.05); for PASI90 and PASI100, only the secukinumab 300-mg group was significantly favored over placebo (P < 0.05). In this challenging sub-population of US patients with PsA, secukinumab provided rapid improvements in disease activity and QoL. Patients with PsA and active psoriasis might benefit more from secukinumab 300mg than 150mg.

Real-World Use and Effectiveness Outcomes in Patients with Rheumatoid Arthritis Treated with Upadacitinib: An Analysis from the CorEvitas Registry.

Data assessing longer-term real-world effectiveness and treatment patterns with upadacitinib (UPA), a Janus kinase inhibitor, in rheumatoid arthritis (RA) are lacking. We assessed improvement in clinical and patient-reported outcomes and treatment patterns for up to 12months among adult patients with RA initiating UPA. Data were collected from the CorEvitas® RA Registry (08/2019-04/2022). Eligible patients had moderate to severe RA (Clinical Disease Activity Index [CDAI] > 10) and follow-up visits at 6 or 12months after UPA initiation. Outcomes were mean change from baseline, percentage achieving minimal clinically important differences (MCID) in clinical and patient-reported outcomes, and disease activity at follow-up. We evaluated clinical outcomes and therapy changes among patients with tumor necrosis factor inhibitor (TNFi) experience and among those receiving UPA as first-line therapy, as well as those receiving UPA as monotherapy versus as part of combination therapy. We further evaluated whether outcomes were similar among those that remained on therapy. Patients treated with UPA (6-month cohort, N = 469; 12-month cohort, N = 263) had statistically significant improvements (p < 0.001) in mean CDAI, tender/swollen joint counts, pain, and fatigue at follow-up. At 12months, 46.0% achieved MCID in CDAI and 40.0% achieved low disease activity/remission. Overall, 43.0% discontinued UPA at 12months; of those receiving combination treatment (N = 90) with conventional therapies and UPA, 42.2% (N = 38) discontinued conventional therapy. Findings were similar in the 6-month cohort and among subgroups. Changes from baseline and proportions of patients achieving MCID or clinical outcomes tended to be numerically lower among patients with TNFi experience and numerically higher among those receiving UPA as first-line therapy. UPA initiation was associated with improvements in clinical and patient-reported outcomes, with meaningful clinical improvements regardless of prior TNFi experience, line of therapy, or concomitant use of conventional therapies. Further research is needed to better understand sustained response of UPA over longer treatment periods.

Early recapture of response with tofacitinib 10mg twice daily in patients with ulcerative colitis in OCTAVE Open following dose reduction or treatment interruption in OCTAVE Sustain.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis. These post hoc analyses evaluated early improvement in patient-reported outcomes with tofacitinib 10mg twice daily (BID) in OCTAVE Open among patients with ulcerative colitis who experienced treatment failure with placebo (retreatment subpopulation) or tofacitinib 5mg BID (dose escalation subpopulation) during maintenance. Endpoints based on Mayo subscores (rectal bleeding improvement, stool frequency improvement, and symptomatic [both rectal bleeding and stool frequency] improvement) were analyzed overall and by prior tumor necrosis factor inhibitor (TNFi) failure status from month (M)1-M6 in OCTAVE Open. Changes from baseline in partial Mayo score, rectal bleeding subscore, and stool frequency subscore at M1 were also analyzed, by M2 clinical response status. At M1 of OCTAVE Open, 83.2%, 70.3%, and 64.4% of patients in the retreatment subpopulation (n=101) had rectal bleeding improvement, stool frequency improvement, and symptomatic improvement, respectively. Corresponding values in the dose escalation subpopulation (n=57) were 59.6%, 50.9%, and 38.6%. For both subpopulations, results were generally consistent regardless of prior TNFi failure. In the dose escalation subpopulation, mean decrease from baseline in partial Mayo score and stool frequency subscore at M1 was greater in patients with versus without a clinical response at M2. Rectal bleeding improvement and stool frequency improvement were achieved by M1 in many patients receiving tofacitinib 10mg BID in both subpopulations, with no apparent difference by prior TNFi failure. Analyses were limited by small sample sizes for some subgroups.

Efficacy and safety of upadacitinib in patients with ankylosing spondylitis refractory to biologic therapy: 1-year results from the open-label extension of a phase III study

BackgroundUpadacitinib, a Janus kinase inhibitor, has demonstrated efficacy and an acceptable safety profile in patients with ankylosing spondylitis (AS) in the phase III SELECT-AXIS programs. We report the 1-year efficacy and safety in patients with AS and an inadequate response to biologic disease-modifying antirheumatic drugs (bDMARD-IR) from the SELECT-AXIS 2 study.MethodsPatients ≥ 18 years with active AS who met the modified New York criteria for AS and were bDMARD-IR received double-blind upadacitinib 15 mg once daily (QD) or placebo for 14 weeks. Patients who completed 14 weeks could enter an open-label extension and receive upadacitinib 15 mg QD for up to 2 years. Efficacy endpoints included the percentage of patients achieving ≥ 40% improvement in Assessment of SpondyloArthritis international Society response (ASAS40), Ankylosing Spondylitis Disease Activity Score (ASDAS) low disease activity (LDA), and ASDAS inactive disease (ID); and change from baseline in total and nocturnal back pain, and Bath Ankylosing Spondylitis Functional Index (BASFI). Subgroup analyses (bDMARD lack of efficacy versus intolerance, and prior tumor necrosis factor inhibitor [TNFi] versus interleukin-17 inhibitor [IL-17i] exposure) were conducted. Binary and continuous efficacy endpoints were assessed using non-responder imputation with multiple imputation (NRI-MI) and as observed (AO) analyses; and mixed-effects model repeated measures (MMRM) and AO, respectively. Safety was assessed based on adverse events. Data through week 52 are reported.ResultsOf 420 randomized patients, 366 (continuous upadacitinib: n = 181; placebo to upadacitinib: n = 185) completed 52 weeks of treatment. At week 52, in the continuous upadacitinib and placebo to upadacitinib groups, ASAS40, ASDAS LDA, and ASDAS ID were achieved by 66% and 65%, 57% and 55%, and 26% and 25% (all NRI-MI); and change from baseline in total back pain, nocturnal back pain, and BASFI was -4.5 and -4.3, -4.6 and -4.4, and -3.6 and -3.5 (all MMRM), respectively. No new safety risks were identified. Subgroup analyses were consistent with the overall study population.ConclusionsUpadacitinib 15 mg QD demonstrated sustained improvement up to 52 weeks in bDMARD-IR patients with AS. Efficacy was generally similar in patients with lack of efficacy versus intolerance to bDMARDs and prior TNFi versus IL-17i exposure.Trial registrationNCT02049138.

One-Year Medication Adherence and Persistence in Rheumatoid Arthritis in Clinical Practice: A Retrospective Analysis of Upadacitinib, Adalimumab, Baricitinib, and Tofacitinib.

This study evaluated 12months adherence and persistence among Janus kinase inhibitors (upadacitinib, baricitinib, tofacitinib) and adalimumab, a tumor necrosis factor inhibitor (TNFi), in patients with rheumatoid arthritis (RA). This retrospective analysis used administrative claims data from the Merative™ MarketScan® Research Databases (2018-2022). Eligible adults had≥1 RA diagnosis before the index date,≥1 pharmacy claim for index medication, and≥12months of continuous insurance enrollment pre- and post-index. Adherence to treatment [defined as proportion of days covered (PDC)≥80%], risk of treatment discontinuation, and mean time to discontinuation were assessed during the 12months follow-up. Adjusted odds ratios (aOR), adjusted hazard ratios (aHR), and 95% confidence intervals (CI) were reported. In total, 6317 patients were included (683 upadacitinib, 3732 adalimumab, 132 baricitinib, 1770 tofacitinib). Compared with upadacitinib, patients initiating adalimumab [aOR (95% CI): 0.82 (0.69, 0.96)], baricitinib [0.46 (0.31, 0.68)], and tofacitinib [0.74 (0.62, 0.88)] were significantly less likely to achieve PDC≥80%. Risk of treatment discontinuation was significantly higher in patients treated with adalimumab [aHR (95% CI): 1.14 (1.01, 1.29)], baricitinib [1.48 (1.16, 1.90)], and tofacitinib [1.22 (1.07, 1.38)] compared with upadacitinib. Mean time to discontinuation was 256 (upadacitinib), 249 (adalimumab), 221 (baricitinib), and 239 (tofacitinib) days. Similar results were observed in patients with prior TNFi use. Patients with RA, regardless of recent TNFi experience, initiating upadacitinib were significantly more likely to be adherent and less likely to discontinue therapy compared to adalimumab, baricitinib, and tofacitinib in the first 12months of treatment.

Long-Term Durability of Certolizumab Pegol in Patients with Rheumatoid Arthritis Over 5 Years: An Analysis of Pooled Clinical Trial Data.

There is a paucity of data on how patient characteristics may affect the long-term durability of certolizumab pegol (CZP) in patients with rheumatoid arthritis (RA). This study therefore aimed to investigate CZP durability and reasons for discontinuation over 5years between different subgroups of patients with RA. Data were pooled from 27 clinical trials in RA patients. Durability was defined as the percentage of patients randomized to CZP at baseline who were still on CZP treatment at a given timepoint. Post hoc analyses of clinical trial data on CZP durability and reasons for discontinuation among different patient subgroups were conducted using Kaplan-Meier curves and Cox proportional hazards modeling. Patient subgroups included: age (18- < 45/45- < 65/ ≥ 65years), gender (male/female), prior tumor necrosis factor inhibitor (TNFi) use (yes/no), and disease duration (< 1/1- < 5/5- < 10/ ≥ 10years). Among 6927 patients, the durability of CZP was 39.7% at 5years. Patients aged ≥ 65years had a 33% greater risk of CZP discontinuation than patients 18- < 45years (hazard ratio [95% confidence interval]: 1.33 [1.19-1.49]) and patients with prior TNFi use had a 24% greater risk of discontinuing CZP than patients without (1.24 [1.12-1.37]). Conversely, greater durability was observed among patients who had a baseline disease duration of ≥ 1year. Durability did not differ in the gender subgroup. Of the 6927 patients, the most common reason for discontinuation was inadequate levels of efficacy (13.5%); followed by adverse events (11.9%); consent withdrawn (6.7%); lost to follow-up (1.8%); protocol violation (1.7%); other reasons (9.3%). CZP durability was comparable with durability data on other bDMARDs in RA patients. Patient characteristics that were associated with greater durability included younger age, TNFi-naïvety, and disease duration ≥ 1year. Findings may be helpful in informing clinicians on a patient's likelihood of discontinuing CZP, based on their baseline characteristics.

Multidomain Efficacy and Safety of Guselkumab Through 1 Year in Patients With Active Psoriatic Arthritis With and Without Prior Tumor Necrosis Factor Inhibitor Experience: Analysis of the Phase 3, Randomized, Placebo-Controlled DISCOVER-1 Study.

To evaluate efficacy and safety of the interleukin-23p19-subunit inhibitor, guselkumab, in DISCOVER-1 patients with active psoriatic arthritis (PsA) by prior use of tumor necrosis factor inhibitor (TNFi). The phase 3, randomized, placebo-controlled DISCOVER-1 study enrolled patients with active PsA (swollen joint count ≥3, tender joint count ≥3, and C-reactive protein level ≥ 0.3 mg/dl) despite standard therapies; approximately one-third could have received two or fewer prior TNFi. Patients were randomized to 100 mg of guselkumab every 4 weeks (Q4W); 100 mg of guselkumab at week 0, at week 4, and every 8 weeks (Q8W); or placebo with crossover to guselkumab Q4W at week 24. Efficacy end points of ≥20% and ≥50% improvement in individual American College of Rheumatology (ACR) criteria and achieving the minimal disease activity (MDA) components were summarized by prior TNFi status. In DISCOVER-1, 118 (31%) patients previously received one or two TNFi. As previously reported, rates for acheiving ≥20%improvement in the composite ACR response at week 24 and week 52 were similar in TNFi-naive and TNFi-experienced patients randomized to guselkumab Q4W (76% and 68%, respectively) and Q8W (61% and 58%, respectively). Similar trends were observed for response rates of ≥20% and ≥50% improvement in individual ACR criteria and for achieving individual MDA components at week 24; TNFi-naive patients were more likely to achieve end points related to physical function and pain than TNFi-experienced patients. Overall, response rates were maintained or increased through week 52 regardless of prior TNFi use. Through week 60 in guselkumab-treated TNFi-naive and TNFi-experienced patients, 62% and 64%, respectively, reported one or more adverse events (AEs); 4% and 6% had serious AEs, respectively. Through 1 year, 100 mg of guselkumab Q4W and Q8W provided sustained improvements across multiple domains in both TNFi-naive and TNFi-experienced patients with active PsA.

Impact of Concomitant Corticosteroids on Tofacitinib Induction Efficacy and Infection Rates in Ulcerative Colitis

BackgroundTofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis.AimTo report efficacy and infection rates in patients receiving tofacitinib induction treatment, by baseline corticosteroid status.MethodsWe evaluated efficacy and safety data from OCTAVE Induction 1&2 in patients with moderately-to-severely active ulcerative colitis who received tofacitinib 10 mg twice daily or placebo for 8 weeks, based on induction baseline oral corticosteroid use (Corticosteroid-Yes/No) and dose (< 20/ ≥ 20 mg/day). Infections of interest included serious infections, herpes zoster (HZ), and adjudicated opportunistic infections (OIs).ResultsAt OCTAVE Induction 1&2 baseline, 478/1092 (43.8%) patients were receiving corticosteroids. Tofacitinib demonstrated significant induction efficacy versus placebo for both Corticosteroid-Yes and Corticosteroid-No. With adjustment for prior tumor necrosis factor inhibitor and immunosuppressant failure, there were no statistically significant differences in remission and clinical response rates for Corticosteroid-Yes versus Corticosteroid-No. Among tofacitinib-treated patients, HZ and OIs occurred more frequently in Corticosteroid-Yes versus Corticosteroid-No, regardless of dose (< 20 mg vs. ≥ 20 mg). Infection incidence rates (regardless of severity/seriousness) during tofacitinib induction were generally similar regardless of baseline corticosteroid use. The proportion of tofacitinib-treated patients with HZ was 0.2% for Corticosteroid-No versus 1.1% for Corticosteroid-Yes < 20 mg and 1.0% for Corticosteroid-Yes ≥ 20 mg. Two out of three patients had HZ OIs.ConclusionsTofacitinib induction efficacy (clinical response and remission) was similar in baseline corticosteroid subgroups. Infections of interest were rare; HZ and OIs occurred more frequently among those receiving tofacitinib and corticosteroids versus those receiving tofacitinib without corticosteroids.Trial Registrationhttp://www.clinicaltrials.gov (NCT01465763[21/10/2011]; NCT01458951[21/10/2011]).

P781 Treatment outcome of tofacitinib dose reduction to 5 mg BID vs remaining on 10 mg BID in patients with Ulcerative Colitis who were in stable remission on 10 mg BID: Updated 30-month data from the double-blind, randomised RIVETING study

Abstract Background Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis. The long-term, Phase 3b/4 RIVETING study (NCT03281304) assessed the efficacy and safety of tofacitinib dose reduction from tofacitinib 10 mg twice daily (BID) maintenance therapy to 5 mg BID in patients (pts) in stable remission.1 We present a final analysis of the RIVETING study after ≥30 months of treatment. Methods RIVETING was a double-blind, randomised, parallel-group study with a 42-month (M) duration. Eligible pts had received tofacitinib 10 mg BID for ≥2 consecutive years in an open-label, long-term extension study (NCT01470612), had been in stable remission for ≥6 months and corticosteroid-free for ≥4 weeks prior to baseline. The primary efficacy endpoint was remission at M6 based on modified Mayo (mMayo) score (endoscopic and stool frequency subscores of ≤1 and rectal bleeding subscore of 0).1 RIVETING was terminated (primary objective met) when all pts had passed M30 (or discontinued); some pts had already completed all visits up to M42. Here, we assess efficacy at M30 and safety throughout. Results Overall, 140 pts were randomised (1:1) to tofacitinib 5 or 10 mg BID; 50.0% and 62.9% were in remission based on mMayo score at M30 in the 5 and 10 mg BID dose groups, respectively, with consistent findings observed for other secondary efficacy endpoints (Table 1). At M30, observed differences for mMayo remission between tofacitinib 10 and 5 mg BID were generally greater in the subgroup with a baseline endoscopic subscore of 1 vs 0 and in the subgroup with vs without prior tumour necrosis factor inhibitor (TNFi) failure (Table 1). The percentage of pts who experienced loss of remission by M30, as estimated from Kaplan-Meier curves, was numerically higher in the 5 vs the 10 mg BID dose group (28.1%; 95% confidence interval [CI], 17.68–39.49 vs 21.7%; 95% CI, 12.21–32.95, respectively). Table 2 shows adverse events of special interest, by dose group. One death occurred due to fatal coronavirus disease 2019 pneumonia (10 mg BID). Conclusion These long-term data showed that most pts in stable remission on tofacitinib 10 mg BID maintenance therapy maintained mMayo score remission through M30 after dose reduction to 5 mg BID. Dose group difference in remission at M30 was consistent with that at M6.1 Differences in remission between the tofacitinib 5 and 10 mg BID groups were greater in subgroups with an endoscopic subscore of 1 vs 0 and in subgroups with vs without prior TNFi failure. Overall, safety findings were consistent with tofacitinib’s known safety profile; incidence of serious infections and herpes zoster was numerically higher in the tofacitinib 10 vs 5 mg BID group. 1. Vermeire S et al. J Crohns Colitis 2021;15:1130-41.

Presence of risk factors associated with colectomy among patients with ulcerative colitis: a post hoc analysis of data from the tofacitinib OCTAVE ulcerative colitis clinical program.

Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). To assess colectomy incidence rates (IRs) and baseline characteristics for the presence of identified colectomy risk factors among patients in the tofacitinib OCTAVE UC clinical program. This post hoc analysis evaluated patients in the 8-week OCTAVE Induction 1 and 2, 52-week OCTAVE Sustain, and OCTAVE Open (open-label, long-term extension) studies. IRs [95% confidence interval (CI)] for colectomy were analyzed. Baseline risk factors based on clinical guidelines: aged <40 years at diagnosis, extensive colitis, severe endoscopic disease [Mayo endoscopic subscore (MES) = 3], hospitalization for UC within 12 months, C-reactive protein (CRP) >3 mg/L, and serum albumin <3.5 g/dL. Baseline risk factors were evaluated in patients who underwent colectomy by study and summarized descriptively. Over a maximum of 7.8 years of tofacitinib exposure, 14 patients underwent colectomy: 3/1139 (0.3%) in OCTAVE Induction 1 and 2 [tofacitinib 10 mg twice daily (BID): n = 2; placebo: n = 1], 3/593 (0.5%) in OCTAVE Sustain (placebo: n = 3), and 8/944 (0.8%) in OCTAVE Open (tofacitinib 10 mg BID: n = 8). Colectomy IR per 100 patient-years for all patients who received ⩾1 tofacitinib dose was 0.34 (95% CI: 0.16-0.63). All patients who underwent colectomy had ⩾1 risk factor and prior tumor necrosis factor inhibitor (TNFi) failure, among which the most common risk factors were a MES of 3 (n = 13), CRP >3 mg/L (n = 11), and aged <40 years at diagnosis (n = 9). Among patients with moderate to severe UC receiving tofacitinib, colectomies were infrequent; all patients undergoing colectomy had prior TNFi failure, and most had multiple additional risk factors. This provides important information to discuss with patients and inform management decisions. NCT01465763; NCT01458951; NCT01458574; and NCT01470612.

Assessment of Safety and Efficacy of Tofacitinib, Stratified by Age, in Patients from the Ulcerative Colitis Clinical Program.

In patients with ulcerative colitis (UC), risks of infection and malignancies increase with age. Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of UC. This analysis assessed age as a risk factor for adverse events of special interest (AESI) in the tofacitinib UC clinical program. Data were from phase 2 and 3 induction studies, a phase 3 maintenance study, and an open-label, long-term extension study. Efficacy and/or safety outcomes were analyzed in the Induction, Maintenance, and Overall Cohorts (patients who received ≥ 1 dose of tofacitinib), stratified by age. The effects of baseline demographic and disease-related factors on AESI incidence were assessed by Cox proportional-hazards regression analysis. In the Overall Cohort (1157 patients with ≤ 6.8 years' tofacitinib treatment), age was a statistically significant predictor of herpes zoster (HZ), malignancies excluding nonmelanoma skin cancer (NMSC), and NMSC. Other statistically significant predictors included prior tumor necrosis factor inhibitor failure for HZ, NMSC, and opportunistic infection events, and prior duration of UC for malignancies excluding NMSC. In the Induction and Maintenance Cohorts, a higher proportion of tofacitinib-treated than placebo-treated patients (numerical difference) achieved the efficacy endpoints (endoscopic improvement, clinical remission, clinical response) across all age groups. Older individuals receiving tofacitinib as induction and maintenance therapy to treat UC may have an increased risk of HZ, malignancies (excluding NMSC), and NMSC versus similarly treated younger patients, consistent with findings from the general population. Across all age groups, tofacitinib demonstrated greater efficacy than placebo as an induction and maintenance therapy. NCT00787202; NCT01465763; NCT01458951; NCT01458574; NCT01470612.

Health-Related Quality of Life Outcomes With Tofacitinib Treatment in Patients With Ulcerative Colitis in the Open-Label Extension Study, OCTAVE Open.

Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis. We report health-related quality of life (HRQoL) outcomes in patients with ulcerative colitis in the phase 3 open-label, long-term extension study, OCTAVE Open. The Inflammatory Bowel Disease Questionnaire (IBDQ), EuroQoL-5 Dimensions Health Questionnaire, and 36-Item Short Form Survey scores were analyzed up to month (M) 72 in 4 subpopulations: patients in remission at baseline (maintenance remitters) assigned tofacitinib 5 mg twice daily and patients not in remission at baseline (maintenance nonremitters, maintenance treatment failures, and induction nonresponders [IndNRs]) assigned tofacitinib 10 mg twice daily in OCTAVE Open. Data were analyzed overall and stratified by corticosteroid use at baseline, prior tumor necrosis factor inhibitor failure, and prior immunosuppressant failure. Among maintenance remitters and nonremitters, HRQoL outcomes were maintained up to M72: 80.0% and 100.0% of patients had an IBDQ total score ≥170, respectively. At baseline, 7.4% of maintenance treatment failures had an IBDQ total score ≥170, and this increased to 54.3% and 75.0% at M2 and M72, respectively. Corresponding values for IndNRs were 22.6%, 51.0%, and 86.0%. HRQoL outcomes were independent of treatment history. Among patients not in remission at baseline, improvement in EuroQoL-5 Dimensions Health Questionnaire and 36-Item Short Form Survey scores was maintained or achieved by M2, and steady to M72 or M33, with maintenance treatment failures and IndNR subpopulations undergoing the biggest improvements from baseline. A continued favorable impact on HRQoL was revealed with long-term tofacitinib treatment in OCTAVE Open, regardless of baseline remission status or treatment history. (ClinicalTrials.gov; number: NCT01470612).

S780 Impact of Ozanimod on Fecal Calprotectin Levels and the Association With Efficacy in Patients With Moderately to Severely Active Ulcerative Colitis: Results From the Phase 3 True North Study

Introduction: Ozanimod (OZA) is approved in the USA and EU for the treatment of moderate/severe ulcerative colitis (UC). OZA demonstrated efficacy in the phase 3 True North (TN) trial in patients (pts) with moderate/severe UC (NCT02435992). Infiltration of neutrophils in intestinal mucosa contributes to inflammation in inflammatory bowel diseases. Calprotectin, which is released by neutrophils, is a neutrophilic activity marker that is useful in monitoring UC disease activity. Methods: We assessed the effect of OZA on fecal calprotectin (FCP) levels and association with OZA efficacy in TN. During the 10-week (W) induction period, pts were randomized to double-blind (DB) OZA 0.92 mg or placebo (PBO) once daily (Cohort 1) or received open-label (OL) OZA once daily (Cohort 2). Pts with clinical response (CRS) to OZA at W10 were rerandomized to DB OZA or PBO for maintenance through W52. Efficacy endpoints (clinical remission, CRS, endoscopic improvement, mucosal healing, and histologic remission) and FCP levels were assessed at W10 and W52. Results: Change in FCP from baseline (BL) to W10 was assessed in 517 pts who received DB OZA (n=347) or PBO (n=170) and 293 who received OL OZA. Pts on OZA demonstrated reductions from BL in FCP at W10; this was significant vs PBO (P< .001, both cohorts) (Table). FCP reductions were significantly greater in pts with vs without CRS at W10 in all treatment groups (P< .001, all groups). Change in FCP from BL to W52 was assessed in 149 pts remaining on OZA and 109 who switched to PBO. FCP levels remained low through W52; pts on continuous OZA had significantly greater FCP reductions at W52 vs pts who switched to PBO (P=.0002). FCP reductions were significantly greater in pts with vs without CRS at W52 in OZA-OZA and OZA-PBO groups (P< .01, for both). Significantly greater reductions from BL in FCP occurred with OZA vs PBO at W10 and W52 regardless of prior biologic or tumor necrosis factor inhibitor exposure (P< .05, all groups). BL FCP level was predictive for CRS and histologic remission at W10 (P< .05, both endpoints). Reduction from BL in FCP at W10 was predictive and prognostic for all endpoints except CRS at W52 (P< .05, all endpoints). Conclusion: OZA treatment led to FCP reductions, indicative of decreases in intestinal neutrophil levels. BL FCP was predictive for OZA response. FCP reductions were predictive for OZA response and prognostic for UC. These findings may support use of FCP as a predictive biomarker for OZA response and prognostic biomarker in UC. Table 1. - Change from baseline in FCP at Weeks 10 and 52 FCP adjusted mean percent change (95% CI) Induction (Week 10) Maintenance (Week 52) Cohort 1 Cohort 2 Placebo (n=170) Ozanimod (n=347) Ozanimod (n=293) Ozanimod-placebo (n=109) Ozanimod-ozanimod (n=149) All patients 18.8 (-11.6, 59.6) -59.3 (-67.1, -49.7) -71.6 (-77.2, -64.5) -70.7 (-79.6, -57.7) -87.7 (-91.0, -83.3) Responders a -48.7 (-68.7, -16.0) -83.9 (-87.8, -78.8) -86.2 (-89.5, -81.8) -81.5 (-87.8, -71.7) -91.0 (-93.7, -87.1) Nonresponders b 54.9 (12.4, 113.5) -12.1 (-32.4, 14.4) -33.3 (-50.9, -9.5) -10.5 (-53.6, 72.9) -75.4 (-85.9, -57.2) aResponders during induction are pts who achieved CRS at W10, and responders during maintenance are pts who achieved CRS at W52.bNonresponders during induction are pts who did not achieve CRS at W10 and nonresponders at W52 did not achieve CRS at W52.

OP0255 BIMEKIZUMAB IN PATIENTS WITH ACTIVE PSORIATIC ARTHRITIS AND AN INADEQUATE RESPONSE TO TUMOUR NECROSIS FACTOR INHIBITORS: 16-WEEK EFFICACY &amp; SAFETY FROM BE COMPLETE, A PHASE 3, MULTICENTRE, RANDOMISED PLACEBO-CONTROLLED STUDY

OP0255 BIMEKIZUMAB IN PATIENTS WITH ACTIVE PSORIATIC ARTHRITIS AND AN INADEQUATE RESPONSE TO TUMOUR NECROSIS FACTOR INHIBITORS: 16-WEEK EFFICACY &amp; SAFETY FROM BE COMPLETE, A PHASE 3, MULTICENTRE, RANDOMISED PLACEBO-CONTROLLED STUDY

P607 Efficacy and safety of tofacitinib in Ulcerative Colitis patients with extraintestinal manifestations in OCTAVE Open

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Data from OCTAVE Induction 1&amp;2 and OCTAVE Sustain demonstrated that a history of extraintestinal manifestations (EIMs) was shown not to influence the efficacy of tofacitinib 10 mg twice daily (BID).1 We explored the efficacy and safety of tofacitinib in patients (pts) with and without a history of EIMs in the open-label, long-term extension study, OCTAVE Open. Methods Efficacy and safety (treatment-emergent serious adverse events of interest) data from OCTAVE Open (NCT01470612) were analysed by history of EIMs. Tofacitinib dose in OCTAVE Open was based on baseline remission status; pts in remission received tofacitinib 5 mg BID; all others received 10 mg BID. The frequency of pre-defined prior and active EIMs at OCTAVE Open baseline (peripheral arthritis [PA]; sacroiliitis; ankylosing spondylitis [AS]; myopathy; pyoderma gangrenosum; erythema nodosum; scleritis, episcleritis; uveitis, iritis; oral ulcer/stomatitis; and thromboembolic disorder) and new occurrences of EIMs at Month (M)36, or at early termination, were evaluated in pts with non-missing data. Results In OCTAVE Open, 113/935 (12.1%) had EIMs at baseline (7/174 [4.0%] tofacitinib 5 mg BID; 106/761 [13.9%] tofacitinib 10 mg BID). Pts with EIMs were more likely to be female (61.1%), have a total Mayo score of ≥3 (93.8%) at OCTAVE Open baseline and have disease duration ≥6 years (60.2%), prior tumour necrosis factor inhibitor failure (61.9%), prior immunosuppressant treatment (86.7%) or corticosteroid use (54.0%) at induction study baseline, compared to those without EIMs (38.8%, 78.7%, 49.6%, 50.9%, 74.5% and 43.9%, respectively). There was no consistent trend in the proportions of pts with and without EIMs at baseline who met the OCTAVE Open efficacy endpoints (Table 1). Tofacitinib 5 and 10 mg BID had comparable safety in pts with or without EIMs at baseline (Table 2). In pts with EIMs at baseline, the most frequent active EIMs were PA (51/113 [45.1%]), sacroiliitis (6/113 [5.3%]), oral ulcer/stomatitis (5/113 [4.4%]), myopathy (4/113 [3.5%]) and AS (4/113 [3.5%]). At M36, 4/428 [0.9%] had new occurrences of PA and there were no new occurrences of sacroiliitis (0/468 [0%]), oral ulcer/stomatitis (0/460 [0%]), myopathy (0/469 [0%]) or AS (0/469 [0%]). Conclusion The presence or absence of a history of EIMs at baseline did not impact the long-term efficacy and safety of tofacitinib in pts with UC. New occurrences of EIMs were infrequent. Reference 1. Rubin DT et al. Therap Adv Gastroenterol 2021; 14: 1–12.

P286 Sustained improvement in health-related quality of life outcomes in patients with Ulcerative Colitis with long-term tofacitinib treatment in the open-label extension study, OCTAVE Open

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Tofacitinib induction and maintenance therapy has previously been shown to improve health-related quality of life (HRQoL) outcomes. Here, we present HRQoL data from patients (pts) with UC who received tofacitinib 5 or 10 mg twice daily (BID) in the Phase 3 open-label, long-term extension (OLE) study (OCTAVE Open; NCT01470612), up to Month (M)72. Methods Proportions of pts with an Inflammatory Bowel Disease Questionnaire (IBDQ) total score ≥170, and EuroQol-5D (EQ-5D) and Short Form-36 Health Survey (SF-36) scores were analysed up to M72 in 4 subpopulations in the OLE study: ‘maintenance remitters’ completed OCTAVE Sustain in remission and received tofacitinib 5 mg BID in the OLE study; in contrast, ‘maintenance treatment failures’ (induction responders who experienced treatment failure), ‘maintenance non-remitters’ and ‘induction non-responders (IndNR)’ received tofacitinib 10 mg BID in the OLE study (Figure 1). Data were analysed for each subpopulation overall and stratified by prior tumour necrosis factor inhibitor (TNFi) failure, prior immunosuppressant failure and baseline corticosteroid use. Results Baseline demographics and clinical characteristics for each subpopulation are shown in Table 1. Among the 163 maintenance remitters, HRQoL outcomes were maintained up to M72: 80.0% of pts had an IBDQ total score ≥170 (Figure 1); changes from baseline in EQ-5D scores up to M72 and SF-36 scores up to M33 were minimal (eg M72 EQ-5D utility score -0.07 [standard deviation 0.10]; M33 SF-36 physical functioning score -1.3 [8.3]). Among pts continuing long-term tofacitinib treatment, improvement in IBDQ total score was maintained/achieved by M2 (first post-baseline assessment), and was stable up to M72, with maintenance treatment failures and IndNR subpopulations experiencing the largest improvements from baseline (Figure 1). Similar trends were observed for improvement in EQ-5D and SF-36 scores. Improvements in HRQoL outcomes were independent of prior TNFi failure, prior immunosuppressant failure or baseline corticosteroid use, eg in maintenance remitters with prior TNFi failure, 90.9% of pts had IBDQ total score ≥170 at M60 vs 88.9% of pts without prior TNFi failure. Conclusion Sustained beneficial effects in HRQoL were observed among pts continuing long-term tofacitinib treatment in OCTAVE Open. In maintenance remitters, improvements in all HRQoL outcomes were maintained with tofacitinib therapy. In pts who entered the OLE study not in remission and received tofacitinib 10 mg BID, HRQoL improvements were observed within the first 2 months, and were maintained up to M72, regardless of treatment history including prior TNFi failure.

P477 Rectal bleeding and stool frequency improvement with tofacitinib retreatment in patients with Ulcerative Colitis after treatment interruption: Results from OCTAVE Open

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Patients may require retreatment following treatment interruption for reasons such as adverse events or pregnancy.1 In the tofacitinib UC clinical programme, patients who responded to tofacitinib 10 mg BID during induction, and experienced treatment failure whilst receiving placebo during maintenance (OCTAVE Sustain) and subsequently received tofacitinib 10 mg BID in the open-label, long-term extension (OLE) study (OCTAVE Open; NCT01470612), comprised the retreatment subpopulation. The efficacy and safety of tofacitinib in the retreatment subpopulation have previously been reported.1 Here, we evaluated patient-reported outcomes to assess rectal bleeding and stool frequency improvement in the retreatment subpopulation in OCTAVE Open. Methods The following efficacy endpoints based on the Mayo subscores were analysed in the overall retreatment subpopulation and by prior tumour necrosis factor inhibitor (TNFi) failure status: rectal bleeding improvement (≥1 point decrease in rectal bleeding subscore [RBS] from OLE study baseline), and stool frequency improvement (≥1 point decrease in stool frequency subscore [SFS] from OLE study baseline), up to Month (M)6 in the OLE study (full analysis set, non-responder imputation). Changes from baseline in partial Mayo score (PMS), RBS and SFS at M1, by M2 clinical response status, were also analysed (as observed). Results In OCTAVE Open, 101 patients were included in the retreatment subpopulation, of which 46 (45.5%) had prior TNFi failure. Overall, at M1 and M6 of OCTAVE Open, 83.2% and 76.2% of patients had rectal bleeding improvement, respectively (Figure 1). Corresponding values for stool frequency improvement were 70.3% and 75.2%. At most time points, rates of rectal bleeding and stool frequency improvements were similar in patients with and without prior TNFi failure. Mean decrease from baseline in PMS, RBS and SFS at M1 was similar in patients with and without a clinical response at M2 (Figure 2). Conclusion In this post hoc analysis, in patients with UC who had loss of response after 8–52 weeks of treatment interruption, retreatment with tofacitinib 10 mg BID resulted in rectal bleeding and stool frequency improvement in the majority of patients by M1, which was maintained to M6, regardless of prior TNFi failure status. Reference 1. Panés J et al. J Crohns Colitis 2021. Epub ahead of print.

P378 Rectal bleeding and stool frequency improvement with tofacitinib dose escalation to, 10 mg BID in patients with Ulcerative Colitis following loss of response on tofacitinib, 5 mg BID maintenance therapy: Results from OCTAVE Open

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). In the tofacitinib UC clinical programme, patients who responded to tofacitinib, 10 mg BID during induction, and experienced treatment failure whilst receiving tofacitinib, 5 mg BID during maintenance (OCTAVE Sustain) and subsequently received tofacitinib, 10 mg BID in the open-label, long-term extension (OLE) study (OCTAVE Open; NCT01470612), comprised the dose escalation subpopulation. The efficacy and safety of tofacitinib in the dose escalation subpopulation have been previously reported.1 Here, we evaluated patient-reported outcomes to assess rectal bleeding and stool frequency improvement in the dose escalation subpopulation in OCTAVE Open. Methods The following efficacy endpoints based on the Mayo subscores were analysed in the overall dose escalation subpopulation and by prior tumour necrosis factor inhibitor (TNFi) failure status: rectal bleeding improvement (≥1 point decrease in rectal bleeding subscore [RBS] from OLE study baseline) and stool frequency improvement (≥1 point decrease in stool frequency subscore [SFS] from OLE study baseline), up to Month (M)6 in the OLE study (full analysis set, non-responder imputation). Changes from baseline in partial Mayo score (PMS), RBS and SFS at M1, by M2 clinical response status, were also analysed (as observed). Results In OCTAVE Open, 57 patients were included in the dose escalation subpopulation, of which, 28 (49.1%) had prior TNFi failure. Overall, at M1 and M6, of OCTAVE Open, 59.6% and, 66.7% of patients had rectal bleeding improvement, respectively (Figure, 1). Corresponding values for stool frequency improvement were, 50.9% and, 64.9%. At most time points, rates of rectal bleeding and stool frequency improvements were similar in patients with and without prior TNFi failure. Patients with a clinical response at M2 had a numerically greater mean decrease from baseline in PMS, RBS and SFS at M1 than those without (Figure 2). Conclusion In this post hoc analysis, in patients with UC who had loss of response after, 8–52 weeks of treatment with tofacitinib, 5 mg BID (following reduction from induction tofacitinib, 10 mg BID), dose escalation back to, 10 mg BID generally resulted in rectal bleeding and stool frequency improvement in the majority of patients by M1, which was maintained to M6, regardless of prior TNFi failure status. Furthermore, early improvement in RBS and/or SFS at M1 may indicate likelihood of recapturing response at M2 with dose escalation from tofacitinib, 5 to, 10 mg BID. Reference 1. Sands BE et al. Aliment Pharmacol Ther, 2020;, 51:, 271–280.