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 Long-term efficacy of ustekinumab (UST) has been reported in Crohn’s disease (CD) through 5 years (yrs)1 and in ulcerative colitis (UC) through 4 yrs.2 A previous pooled analysis of long-term safety data reported a favorable UST safety treatment profile for inflammatory bowel disease (IBD).3 Here, we present results of the final cumulative analysis of long-term safety data from UST studies through up to 5 yrs in CD and 4 yrs in UC. Methods Data from 6 phase 2/3 UST IBD studies were pooled. In phase 3, patients (pts) received a single IV placebo (PBO) or UST (130mg or ~6mg/kg) induction dose followed by SC maintenance doses of PBO or UST (90mg q8w or q12w). Concomitant immunomodulators and corticosteroids were permitted. All pts who received ≥1 dose of UST were included. Safety outcomes are summarized and presented using number of events per 100 patient-years (PY) of follow-up and corresponding 95% confidence interval (CI). Results In this final pooled UST IBD safety data, 2575 pts were treated with UST with 4826 PYs of follow-up. Rates of key safety events, including MACE and malignancies, were similar between PBO and UST or not higher for UST (Table 1). The most frequently occurring adverse events (AEs) in either group (excluding diseases under study) were headache (PBO 16.66 vs. UST 11.60), arthralgia (PBO 15.91 vs. UST 11.23), abdominal pain (PBO 13.79 vs. UST 9.86), nausea (PBO 11.35 vs. UST 7.13), and pyrexia (PBO 11.35 vs. UST 5.91); infections were nasopharyngitis (PBO 17.82 vs UST 19.10) and upper respiratory tract infection (PBO 11.78 vs UST 9.80). The most frequently reported serious infections of anal abscess, pneumonia, cellulitis, and abdominal abscess were no higher in the UST group than PBO, except gastroenteritis (PBO 0.11 vs UST 0.25). No lymphomas were reported. Nine deaths were reported in UST-treated pts (0.00 [0.00, 0.32] PBO vs. 0.19 [0.09, 0.35] UST), 6 in CD and 3 in UC (all considered unrelated to study agent). Conclusion The final compilation of cumulative UST IBD safety data through 5 yrs in CD and 4 yrs in UC showed a safety profile that continued to be favorable and supports the well-established UST safety experience across all approved indications. References: 1. Sandborn WJ, et al. Five-Year Efficacy and Safety of Ustekinumab Treatment in Crohn's Disease: The IM-UNITI Trial. Clin Gastroenterol Hepatol. 2022;20(3):578-590.e4. 2. Afif W, et al. Efficacy and Safety of Ustekinumab for Ulcerative Colitis Through 4 Years: Final Results from The UNIFI Long-term Extension. UEGW 2023. 3. Sandborn WJ, et al. 129 Safety of Ustekinumab In IBD: Pooled Safety Analysis through 5 years in CD and 2 Years in UC. Gastroenterology. 2021;Supplement:S-35-S-36.

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 Ustekinumab (UST) is an approved biologic for the treatment of adults with inflammatory bowel disease (IBD: Crohn’s disease [CD] and ulcerative colitis [UC]). Previously, an integrated analysis of safety data through up to 5 years (yrs) showed a favourable safety profile for UST that was generally similar to placebo (PBO) in patients (pts) with IBD, and to the well-established safety profile across other approved indications. Several treatment options exist for newly diagnosed pts with moderate to severe IBD; therefore, long-term safety data from bionaive pts are important to help inform treatment selection in this population. Here, we present an integrated analysis incorporating UST Phase 2/3 long-term safety data from IBD studies through up to 5 yrs in CD and 2 yrs in UC for bionaive pts. Methods Data from 4 Phase 2/3 UST IBD studies were pooled. In Phase 3, pts received a single IV PBO or UST (130mg or ~6mg/kg) induction dose followed by SC maintenance doses of PBO or UST (90mg q8w or q12w). Patients identified as bionaive (never treated with a biologic) were included in the analysis of data through up to 5 yrs in CD and up to 2 yrs in UC. Concomitant immunomodulators and corticosteroids were permitted. All pts who received ≥1 UST dose were included. Safety outcomes are presented as event rates per 100 patient yrs (PY) of follow-up and 95% confidence interval (CIs). Bionaive UST data from the SEAVUE study (N=191) adjusted for exposure with events per 100 PY, will be shown for comparison. Results Through up to 5 yrs, 425 bionaive IBD pts received PBO (376 PYs) and 771 pts received UST (1511 PYs). Mean duration of follow-up (weeks) for PBO and UST was similar through 1 yr, and >2-fold longer for UST though 5 yrs. Rates per 100 PY for adverse events (AEs), serious AEs, infections, serious infections, major adverse cardiac events (MACE), and malignancies were similar between PBO and UST through up to 1 yr in bionaive IBD pts (Table 1). Rates per 100 PY for AEs, serious AEs, infections, serious infections, and MACE were similar and/or numerically lower for UST vs PBO through up to 5 yrs (Table 2). Overall, malignancies were infrequently reported through up to 5 yrs. Malignancy rates in bionaive UST pts were not significantly different than PBO through 1 yr (PBO: 0.44; UST: 0.34) or through 5 yrs (PBO: 0.27; UST: 0.46). A total of 2 deaths were reported in bionaive pts treated with UST through up to 5 yrs (0.13/100 PY); both assessed as unrelated (Table 3). Conclusion The safety profile of UST in the long-term IBD pooled safety dataset was favourable among bionaive pts and consistent with the well-established safety profile across approved indications.

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. 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. 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). 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.

Background:While no adverse developmental outcomes were observed in preclinical animal studies, limited data exist regarding effects of ustekinumab on human pregnancies. Previously, no data have been reported for women treated with ustekinumab in inflammatory bowel disease (IBD) clinical trials and corresponding pregnancy outcomes. Here, we present pregnancy outcomes from IBD clinical trials, incorporating 5 years of treatment in Crohn's disease (CD) and 2 in ulcerative colitis (UC).Methods:All patients in the clinical trials agreed to use adequate birth control and were discontinued from treatment upon pregnancy confirmation. Nonetheless, 39 pregnancies occurred with maternal ustekinumab exposure from 4 CD and 1 UC study. Maternal and neonatal outcomes and data are presented with summary statistics, where available.Results:Of 1289 women who received ≥1 dose of ustekinumab, 39 maternal pregnancies with outcomes were reported (pregnancy cohort). Median maternal age was 28.0 years and median duration of ustekinumab treatment before pregnancy was 63.7 weeks with the last dose of ustekinumab administered prior to or during the first trimester (terminal half-life of ~3 weeks). Outcomes for the 39 pregnancies were: 26 live births (all normal newborns), 8 spontaneous abortions, and 5 elective abortions. No congenital anomalies were reported among normal newborns and no safety signals emerged with neonatal outcomes.Conclusions:Based on this series of 39 pregnancies with outcomes from IBD clinical trials, mothers treated with ustekinumab (limited to up to the first trimester) did not demonstrate a risk of negative outcomes. More data are needed to characterize the safety profile of ustekinumab use during pregnancy.

claim post-CDI index. Outcomes included mortality, healthcare resource utilization (HRU), and per-patient-per-month (PPPM) cost. Results: Of 497,489 individuals with CDI, 36,059 (7.2%) had IBD (27.3% CD; 72.7% UC). CDI patients with IBD were somewhat younger, more likely female, less likely dual eligible for Medicaid (i.e., low income), and had similar Charlson Comorbidity Index scores compared to patients without IBD (Table 1). Mortality was higher among CDI patients without IBD compared to those with IBD (CD 42.9% vs 34.7%; UC42.7% vs 40.0%; p, 0.0001). Mortality was higher for IBD patients with pCDI (CD 37.6% and UC 44.6%) compared to rCDI (CD 28.7%; UC 31.1%; p, 0.001). Post CDIindex, all cohorts had high hospitalization use (86%-99%, p, 0.0001), but IBD patients had higher HRU than those without, including more hospitalizations with longer length of stay and higher 30day readmissions. Adjusted costs for CDI patients with UC who died were significantly higher (pCDI 1$2,192 PPPM, p, .0001; rCDI 1$2366 PPPM, p, 0.0001) than those without UC. Adjusted costs for CDI patients with CD who died were similar to those without CD but higher in those with CD who survived (pCDI 1$213, p50.0061; rCDI 1$273, p50.0306). Conclusion: CDI patients with IBD had lower mortality rates but higher HRU and costs compared to patients without IBD. Specifically, CDI patients with UC who died had significantly higher monthly costs. CDI patients with IBD are likely identified more rapidly given their higher risk, but also require more resources to stabilize the CDI and IBD. This could explain the lower mortality with higher HRU. Clinicians should be more aggressive and treat all patients earlier to diminish the risks of poor outcomes.

Introduction: Pediatric patients (pts) with inflammatory bowel disease (IBD) being treated with infliximab (IFX) may undergo dose escalation. DEVELOP is a multicenter, global, prospective, observational registry of long-term safety and clinical status of 6069 pts with IBD. We evaluated the efficacy, safety, pharmacokinetics (PK), and immunogenicity of IFX among pts with Crohn’s disease (CD) or ulcerative colitis (UC) who had dose escalation from 5 to 10 mg/kg q8w. Methods: In DEVELOP, data are collected every 6 months (mos). This analysis included pts (≤ 18 years) who received ≥ 1 escalated IFX dose of 10 mg/kg after ≥ 2 doses of 5 mg/kg. Data were collected within 12 mos before escalation and after escalation in the first 3 mos and at 12 (± 3) mos. Efficacy was assessed by the proportions of pts in response or remission using the Pediatric Crohn’s Disease Activity Index (PCDAI) criteria for CD and partial Mayo for UC (Table 1). Safety was assessed by adverse events (AEs). Results: Of the 262 dose-escalated pts (221 CD, 41 UC; 44% female; 83% white; median age 15 years), the majority (62% CD; 77% UC) were in remission at the time of dose escalation, with small changes in remission noted at 3 mos and 12 mos after escalation (Table 1). In a subgroup of 71 CD pts with active disease (PCDAI ≥ 10) within 60 days before escalation and ≥ 1 post dose escalation PCDAI measurement, approximately 34% had clinically meaningful improvement (PCDAI improvement ≥ 10 points) after escalation (Figure 1), with 37% in remission at 12 mos after escalation. The numbers of pts/100 pt-years experiencing AEs, infections, and serious AEs were generally similar before/after escalation. Infusion reactions increased from 0.34% (1/294) of infusions within 3 mos before to 2.33% (13/558) within 3 mos after escalation. For 39 dose escalated pts in a PK/immunogenicity substudy, median trough IFX levels increased slightly from 1.18 μg/mL before to 3.21 μg/mL after escalation; 74% of pts with samples had antibodies to IFX (ATI) before (n=23, ≤ 1:3200; n=3, > 1:3200) and 76% after (n=20, ≤ 1:3200; n=2, > 1:3200) escalation. Conclusion: These real-world data reveal that many pts treated with IFX were positive for ATI before dose escalation and were dose escalated while in clinical remission. There appears to be some clinical benefit of IFX dose escalation in pediatric pts with CD that is evident 12 mos later, although of modest magnitude, with a slight increase in infusion reactions and little change in immunogenicity.Figure 1.: Distribution of Change in Pediatric Crohn’s Disease Activity Index (PCDAI) Scores for Crohn’s Disease Patients With Active Disease at Infliximab (IFX) Dose Escalation (N = 71). Change measured from last visit before escalation to first visit after escalation. Includes pts who received ≥ 1 escalated IFX dose of 10 mg/kg after ≥ 2 maintenance IFX doses of 5 mg/kg plus PCDAI score ≥ 10 within 60 days before escalation and ≥ 1 post dose escalation PCDAI measurement. Note: a decrease in PCDAI score represents an improvement of disease activity, whereas an increase in PCDAI score represents a worsening of disease activity.Table 1.: Proportions of Pediatric Patients in Clinical Response or Clinical Remission At and After Infliximab (IFX) Dose Escalation From 5 mg/kg to 10 mg/kg.

Introduction: Ustekinumab (UST) is a well-established therapy and was approved for treatment of adults with psoriasis (PsO) in 2009, psoriatic arthritis (PsA) in 2013, Crohn’s disease (CD) in 2016, and ulcerative colitis (UC) in 2019. An integrated analysis of safety data through 1 year1 and the more recently presented 2020 IBD Pooled Safety Dataset showed a favorable safety profile for UST across indications that was generally similar to placebo (PBO). Here, we present an integrated analysis of the pooled safety data incorporating phase 2/3 long-term safety data from IBD studies through up to 5 years in CD and 2 years in UC and psoriatic disease studies through up to 5 years in PsO and 1 year in PsA. Methods: Data from 13 phase 2/3 studies in approved indications were pooled. Concomitant immunomodulators and corticosteroids were permitted for IBD and PsA pts, but not PsO pts. All pts who received ≥1 dose of UST were included in this analysis. Safety outcomes are presented as events per 100 patient-years (PY) of follow-up and 95% confidence interval (CIs). Of note, the PBO-controlled period in most PsO studies was 12 wks, and 16 wks in PSA. Results: Across all indications, 2501 pts were treated with PBO with 1244 PYs of follow-up and 6710 pts were treated with UST with 13807 PYs of follow-up. Rates of key events per 100 PYs and corresponding 95% CIs were generally similar between UST and PBO groups (Table 1). In pooled indications in the PBO and UST groups, respectively, the most frequent adverse events (AEs; excluding preferred terms of CD and UC) were nasopharyngitis (20.83 vs 20.87), upper respiratory tract infection (13.51 vs 14.53), arthralgia (13.99 vs 7.01), abdominal pain (10.77 vs 4.01), and diarrhea (6.67 vs 3.88). Anal abscess (PBO 0.72 vs UST 0.17), pneumonia (PBO 0.32 vs UST 0.14), and cellulitis (PBO 0.16 vs UST 0.11) were the most frequently reported serious infections. Events of malignancy and death were less frequently reported, particularly in the PBO group and as such, CIs were wide. Conclusion: The safety profile of UST across pooled indications was favorable through up to 5 yrs, confirming the well-established safety profile of UST in psoriatic and IBD indications.Table 1.: Key Safety Events in CD, UC, PsO, and PsA Studies Through Up to 5 Years

Objectives: Guselkumab, an interleukin-23 antagonist, is approved for self-administration with the UltraSafe Plus (TM) syringe to treat moderate-to-severe plaque-type psoriasis. We evaluated the efficacy, safety, pharmacokinetics, and acceptability of guselkumab administered using a novel patient-controlled injector (One-Press) in psoriasis patients. Materials and methods: This Phase 3, multicentre, double-blind, placebo-controlled study (ORION, Clinicaltrials.gov identifier-NCT02905331) randomized adults with moderate-to-severe psoriasis (4:1) to guselkumab 100 mg at Weeks 0/4/12/20/28 or placebo at Weeks 0/4/12 with crossover to guselkumab 100 mg at Weeks 16/20/28. Week 16 co-primary endpoints were the proportions of patients achieving Investigator Global Assessment (IGA) cleared/minimal (IGA 0/1) and Psoriasis Area and Severity Index 90% improvement (PASI90) responses. One-Press usability/acceptability was evaluated using the Self-Injection Assessment Questionnaire (SIAQ) and Patient-Controlled Injection Device Questionnaire. Final assessments occurred at Week 40. Results: At Week 16, significantly higher proportions of guselkumab-treated (N = 62) than placebo-treated (N = 16) patients achieved IGA 0/1 (80.6% vs. 0.0%, p < .001) and PASI90 (75.8% vs. 0.0%, p < .001) responses. Adverse events were comparable between treatments. SIAQ results demonstrated 99% (68/69) of patients were satisfied/very satisfied with One-Press at Week 28. Conclusions: Guselkumab administered using the One-Press patient-controlled injector was efficacious and well-tolerated in moderate-to-severe psoriasis patients, consistent with previously reported Phase-3 studies of guselkumab administered using UltraSafe Plus. One-Press was highly acceptable to patients.

Background: Ustekinumab is currently approved globally in Crohn's disease (CD) and psoriatic diseases. Recent phase 3 data demonstrate safety/efficacy in ulcerative colitis (UC). Crohn's disease and UC phase 3 programs had similar study designs, facilitating integrated safety analyses. Methods: Data from 6 ustekinumab phase 2/3 CD and UC studies were pooled, and safety was evaluated through 1 year. Patients received 1 placebo or ustekinumab (generally 130 mg or similar to 6 mg/kg) intravenous induction, then subcutaneous (90 mg) maintenance every 8/12 weeks. Analyses incorporated all patients who received >= 1 ustekinumab dose. Safety outcomes are presented as percentages of patients (induction) and as number of patients with events per 100 patient-years of follow-up (through 1 year). For key safety events, 95% confidence intervals (CIs) are provided, as appropriate. Hazard ratios with 95% CIs from time-to-event analyses for serious adverse events and serious infections were also performed. Results: Through 1 year, 2574 patients received ustekinumab (1733 patient-years of follow-up). The number of patients with adverse events per 100 patient-years (placebo 165.99 [95% CI, 155.81-176.67] vs ustekinumab 118.32 [95% CI, 113.25-123.55]), serious AEs (27.50 [95% CI, 23.45-32.04] vs 21.23 [95% CI, 19.12-23.51]), infections (80.31 [95% CI, 73.28-87.84] vs 64.32 [95% CI, 60.60-68.21]), serious infections (5.53 [95% CI, 3.81-7.77] vs 5.02 [95% CI, 4.02-6.19]), and malignancies excluding nonmelanoma skin cancer (0.17 [95% CI, 0.00-0.93] vs 0.40 [95% CI, 0.16-0.83]) were similar between placebo and ustekinumab. Conclusions: The safety profile of ustekinumab across the pooled inflammatory bowel disease population through 1 year was favorable and generally comparable to placebo. These data are consistent with the established safety profile of ustekinumab across indications.