Ghosh, Subrata

Abstract Background and Aims Previously published long-term safety data reported a favourable ustekinumab safety profile for the treatment of inflammatory bowel disease [IBD]. We present the final cumulative safety data from pooled ustekinumab IBD phase 2/3 clinical studies through 5 years in Crohn’s disease [CD] and 4 years in ulcerative colitis [UC]. Methods In phase 3 studies, patients received a single intravenous placebo or ustekinumab [130 mg or ~6 mg/kg] induction dose followed by subcutaneous maintenance doses of placebo or ustekinumab [90 mg q8w or q12w]. Analyses included all patients who received one dose of study treatment and included patients who were biologic-naïve and patients with a history of biologic failure. Safety outcomes are summarized and presented using number of events per 100 patient-years of follow-up and corresponding 95% confidence intervals. Results In this final pooled safety analysis, 2575 patients were treated with ustekinumab with 4826 patient-years of follow-up. Rates of key safety events, including major adverse cardiac events and malignancies, were similar between placebo and ustekinumab or not higher for ustekinumab. Opportunistic infections, including tuberculosis, and malignancies were reported infrequently. Rates of key safety events in the IBD group were no higher in the ustekinumab group than in the placebo group for both patients who were biologic-naïve or who had a history of biologic failure. No lymphomas or cases of posterior reversible encephalopathy syndrome [formerly known as reversible posterior leukoencephalopathy syndrome] were reported. Conclusion The final cumulative ustekinumab safety data through 5 years in CD and 4 years in UC demonstrated favourable safety compared to placebo and continue to support the well-established safety profile across all approved indications. Clinical trials.gov numbers NCT00265122, NCT00771667, NCT01369329, NCT01369342, NCT01369355, NCT02407236

Abstract Background Ustekinumab (UST) is an approved treatment for adults with inflammatory bowel disease (IBD: Crohn’s disease [CD] and ulcerative colitis [UC]), psoriasis (PsO), and psoriatic arthritis (PsA). Here, we present pooled safety analyses in these approved indications of patients (pts) with active tuberculosis (TB) and opportunistic infections (OIs) through 5 years (yrs) of UST treatment. Methods Pooled data included 13 Phase 2/3 UST studies through 5 yrs of CD and PsO, 2 yrs of UC, and 1 yr of PsA. OIs were identified by clinician review. Herpes zoster (HZ) was evaluated separately. Event rates per 100 pt yrs (PYs) are presented. Concomitant immunomodulators/corticosteroids were permitted in IBD and PsA pts. All pts who received ≥1 UST dose were included. In IBD, placebo (PBO) pts included data up to the first UST dose for pts initially treated with PBO, or >16 weeks after the last UST dose for UST pts who switched to PBO. Results Across all approved indications, 19 OIs including TB were reported, with rates in PBO of 0.40 and UST of 0.10 through 5 yrs in 13807 PYs of follow-up (Table 1); rates of HZ were 1.21 and 0.63, respectively. Of 19 OIs, 18 were in IBD pts and 1 in a PsO pt. Overall, 14/16 pts (12/13 UST) with OIs excluding TB were also receiving confounding concomitant medications. A total of 3 active TB cases (2 pts with CD and 1 pt with UC) were reported in PBO (n=2; 1 in a Hungarian CD pt 10 months after receiving last UST dose) and UST (n=1) pts (Table 1). One active TB case was reported in an asymptomatic South African CD pt treated with UST who had a positive QuantiFERON®-TB Gold test on routine screening and bronchial brushings positive for M. tuberculosis. Both CD pts completed TB treatment with disease resolution. The most common OIs were esophageal candidiasis (UST n=3; PBO n=2) and cytomegalovirus colitis (UST n=3; PBO n=1). Conclusion Rates of OIs, including active TB, in UST-treated pts were low across approved indications through up to 5 yrs with 13807 PYs of follow-up and not higher in UST pts vs PBO pts, suggesting no increased risk of OI with long-term UST treatment.

Abstract Background Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Efficacy and safety of tofacitinib were demonstrated in the OCTAVE clinical programme.1,2 Here, we present an analysis of the number and causes of UC-related hospitalisations during the OCTAVE clinical programme. Methods This descriptive analysis comprised patients (pts) hospitalised for UC who received placebo or tofacitinib 10 mg twice daily (BID) in OCTAVE Induction 1&2 (NCT01465763; NCT01458951)1, and pts who received placebo, or tofacitinib 5 or 10 mg BID in OCTAVE Sustain (NCT01458574)1, or ≥1 dose of tofacitinib in OCTAVE Open (NCT01470612)2; it includes data from pts with ≤7.8 years of tofacitinib exposure. We examined the demographic and clinical characteristics, proportions, causes and other aspects of UC-related hospitalisations in pts treated with placebo or tofacitinib in the OCTAVE clinical programme. Results Overall, 1139 pts with UC were included in this analysis. Demographic and disease characteristics of pts with UC-related hospitalisations were generally similar across treatment groups in each study; most pts were <40 years old, had pancolitis, a mean total Mayo score >8, prior treatment with oral corticosteroids and immunosuppressants (Table 1). Ninety-five pts had UC-related hospitalisations; of whom 92 had one UC-related hospitalisation and 3 pts were hospitalised twice (Table 2). In OCTAVE Induction 1&2, OCTAVE Sustain and OCTAVE Open, 2.1%, 1.0% and 6.6% of pts, respectively, had UC-related hospitalisations with tofacitinib 10 mg BID vs 1.0% and 2.9% of pts receiving tofacitinib 5 mg BID in OCTAVE Sustain and OCTAVE Open, and 3.4% and 4.0% of pts receiving placebo in OCTAVE Induction 1&2 and OCTAVE Sustain, respectively. UC-related hospitalisations did not lead to temporary treatment discontinuations in most pts (Table 2). The most frequent cause of UC-related hospitalisations in tofacitinib- and placebo-treated pts was non-surgical UC-related events (ie, UC flares; Table 2). Conclusion UC-related hospitalisations were infrequent in the OCTAVE clinical programme, and rates were generally lower than those reported in a real-world assessment of pts with UC treated with biological therapies.3 Most hospitalised pts were aged <40 years with severe disease and prior corticosteroid and immunosuppressant exposure. The most common cause of hospitalisation was non-surgical UC-related events. References: 1. Sandborn WJ et al. N Engl J Med 2017;376:1723-1736. 2. Sandborn WJ et al. Aliment Pharmacol Ther 2022;55:464-478. 3. Bressler B et al. J Crohn’s Colitis 2021;15:1694-1706.

SummaryBackgroundCrohn's disease has a substantial negative impact on health‐related quality of life (HRQoL).AimTo examine the effects of risankizumab on HRQoL in Crohn's diseaseMethodsWe analysed data from patients with Crohn's disease from 12‐week induction trials ADVANCE (N = 850) and MOTIVATE (N = 569) with risankizumab 600 mg or 1200 mg intravenous (IV) versus placebo IV and a 52‐week maintenance trial FORTIFY (N = 462) with risankizumab 180 or 360 mg subcutaneous (SC) versus placebo SC. Outcomes included Inflammatory Bowel Disease Questionnaire (IBDQ), Functional Assessment of Chronic Illness Therapy‐Fatigue (FACIT‐F), 36‐item Short Form Health Survey (SF‐36), EuroQol 5‐Dimension‐5‐Level (EQ‐5D‐5L) and work productivity. The mean change and percentages of patients achieving clinically meaningful improvement in all outcomes were determined at weeks 12 and 52.ResultsAt week 12, more patients in the risankizumab 600 or 1200 mg groups achieved IBDQ response than with placebo (ADVANCE: 70.2%, 75.5% vs. 47.8%, p ≤ 0.001; MOTIVATE: 61.7%, 68.5% vs. 48.2%, p ≤ 0.01) and FACIT‐F response (ADVANCE: 51.3%, 48.0% vs. 35.7%, p ≤ 0.01; MOTIVATE: 44.2%, 49.1% vs. 33.7%, p < 0.05). These improvements persisted at week 52 with risankizumab maintenance treatment. Similar trends were observed for SF‐36 physical and mental component summary scores, EQ‐5D‐5L and activity impairment within work productivity measures.ConclusionsRisankizumab induction therapy (600 or 1200 mg IV) led to clinically meaningful improvements in disease‐specific and general patient‐reported outcomes, including fatigue, in patients with moderate to severe Crohn's disease. These improvements were sustained after 52 weeks of risankizumab (180 or 360 mg SC) maintenance therapy.

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

Abstract Background Risankizumab (RZB), an IL-23 inhibitor, is being investigated for Crohn’s disease (CD). MOTIVATE (NCT03105128) and ADVANCE (NCT03104413) were two double-blind, randomised, placebo (PBO)-controlled phase 3 trials evaluating the efficacy and safety of RZB as induction therapy for CD after inadequate response or intolerance to biologic treatment, or conventional or biologic treatment. We investigated the effect of RZB on patient-reported outcomes (PROs) in these two trials. Methods Patients with moderately to severely active CD (CD activity index of 220–450, Simple Endoscopic Score for CD excluding the narrowing component ≥ 6 or ≥ 4 for isolated ileal disease, and average daily stool frequency ≥ 4 and/or average daily abdominal pain score ≥ 2) were randomised 1:1:1 (MOTIVATE; N=569) or 2:2:1 (ADVANCE; N=850) to intravenous RZB 600 mg, RZB 1200 mg or PBO at Weeks 0, 4 and 8. PROs assessed were Inflammatory Bowel Disease Questionnaire (IBDQ), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and 36-Item Short Form Health Survey (SF 36). Least-squares mean change from baseline to Week 4 and 12 were assessed for each PRO. Additionally, the proportion of patients achieving IBDQ remission (IBDQ total score ≥ 170 points) was evaluated. Comparisons between RZB dosage groups and PBO were based on Cochran-Mantel-Haenszel or chi-square/Fisher’s exact tests; missing data were reported using non-responder imputation. Results In the MOTIVATE (100% biologic inadequate responder [bio-IR]) and ADVANCE (57% bio-IR) trials, significant (P&lt;0.05) improvements in nearly all PROs evaluated were seen as early as Week 4 (Figures 1–4). At Week 12, significant improvements in all PROs were reported for both doses of RZB compared with PBO in both trials, except for the SF-36 Mental Component Summary score (RZB 1200 mg in MOTIVATE), which improved, but not significantly. In MOTIVATE, at Week 4 and 12, IBDQ remission was achieved by significantly (P&lt;0.05) more patients taking RZB (600 mg, 25.1%/38.3%; RZB 1200 mg, 31.9%/44.6%) than PBO (15.5%/26.8%). Results were similar in ADVANCE: RZB 600 mg 30.9%/44.5%, RZB 1200 mg 33.7%/51.5%, and PBO 18.4%/29.8% at weeks 4 and 12, respectively (P&lt;0.001 for both RZB groups compared to PBO). Conclusion Patients with active CD and an inadequate response to conventional or biologic treatment who received RZB (600 mg or 1200 mg) induction therapy reported significant improvements in disease-specific (IBDQ) and general health-related PROs (FACIT and SF-36) compared with PBO, with improvements seen as early as Week 4. Funding statement: Study was funded by AbbVie. Acknowledgement: Medical writing support was provided by Joann Hettasch of Fishawack Facilitate Ltd, and was funded by AbbVie.