Safety Of Ustekinumab Research Articles

P615 The safety and efficacy of ustekinumab combined with sphincter-preserving surgery for perianal fistulizing Crohn’s disease:a single-center retrospective study

Abstract Background To assess the clinical efficacy and safety of ustekinumab(UST) combined with sphincter-preserving surgery in the treatment of perianal fistulizing Crohn’s disease(pfCD). Methods A single-center retrospective study. The baseline data of pfCD patients who met the inclusion and exclusion criteria and visited the Anorectal Department of the Affiliated Hospital of Nanjing University of Traditional Chinese Medicine from January 2020 to March 2022 were collected. Patients were assessed for fistula response and remission by rectal magnetic resonance image(MRI) and perianal disease activity index(PDAI). Patients' fistula response and remission were assessed by rectal MRI and PDAI. Patients were assessed for clinical response and remission by using Crohn's disease activity Index( CDAI). Patients' anal function was assessed by using the Wexner score. The differences in CDAI,PDAI and inflammatory parameters, including C-reactive protein(CRP) and erythrocyte sedimentation rate(ESR), at 0 week, 8 weeks and 16 weeks were statistically analyzed. Results A total of 64 pfCD patients were included. Fistula response was 23.4% (8 weeks), 40.6% (16 weeks), and 51.6% (follow-up endpoint); fistula remission was 21.9% (follow-up endpoint); fistula MRI remission was 9.3% (follow-up endpoint); clinical response was 68.8% (8 weeks) and 79.7% (16 weeks); and clinical remission was 46.9% (8 weeks) and 59.4% (16 weeks). CDAI, PDAI and inflammatory parameters at the 8th and 16th week of treatment were significantly lower than those before treatment (p<0.05). There was no significant difference in postoperative anal function (p<0.05). The incidence of adverse events was 1.6%. Conclusion UST combined with sphincter-preserving surgery is safe and effective in the treatment of pfCD.This therapy can effectively improve the fistula condition and systemic manifestations.

P500 Real life 2 year experience with ustekinumab in a Spanish open-label cohort of ulcerative colitis patients.

Abstract Background Ustekinumab has been recently approved for the treatment of moderately to severe ulcerative colitis (UC). Data from the UNIFI clinical trial are encouraging; nevertheless, real-world assessment is needed. We assess the effectiveness, safety and pharmacokinetics of ustekinumab in a cohort of refractory UC patients. Methods Multicentre and observational study of UC patients who received ustekinumab for active disease. Values for Partial Mayo Score (PMS), endoscopic activity, C reactive protein (CRP) and faecal calprotectin (FC) were recorded at baseline and at weeks 8, 24 and 52 weeks and at 18 and 24 months when was possible. Demographic and clinical data, previous treatments, adverse events (AEs), surgeries and hospitalizations were documented. Possible predictors of response were examined. Results One hundred and eight patients were analyzed (Table 1). Two patients only received the first IV dose. During follow-up, 58 patients (54%) required interval reduction (every 4 weeks (76%) and every 6 weeks (24%)) after a median of 22.3 weeks [11.6, 41.2]. Intravenous reinduction doses were administered to 20 (18.5%) after 27.7 weeks [6.64, 56.3]. Three patients required a maintenance therapy with IV administration. The clinical remission (PMS≤ 2) rates were 39.6%, 41%, 51% at 8, 24 and 52 weeks, respectively, and 61%, and 57.7% at 18 and 24 months, respectively. FC levels returned to normal (<250 μg/g) in the 39.6%, 41%, 51%, 61%, 58% of the patients at weeks 8, 24 and 52 and at 18 and 24 months respectively. CRP returned to normal (<3 mg/L) in the 79%, 75%, 76.5%, 71% and 70% of the patients at weeks 8, 24 and 52 and at 18 and 24 months respectively. PMS, FC and CRP values and ustekinumab through levels over time are shown in Figure. Fewer previous anti-TNF agents and the loss of response to anti-TNF were associated with clinical response and with normalization of FC respectively. No variables at baseline (body mass index, serum albumin, and lymphocytes count) were associated with ustekinumab through levels. Of the 17 patients with endoscopy before and after treatment, 6 were in remission and 3 with mild activity. The AEs were recorded in 5 (4.6%) patients, 12 (11%) were hospitalized and 9 (8.3%) had surgery. A total of 23 patients (21%) discontinued ustekinumab over time, the persistence rates were 98%, 91%, 83% and 81% at 8, 24, 48 and 96 weeks respectively. Conclusion This is the first study to show the real-world long-term effectiveness, persistence, endoscopic improvement and safety of ustekinumab in a cohort of highly refractory UC patients. The clinical remission preceded the FC normalization. Ustekinumab through levels and their pharmacokinetic require further investigations.

P742 Real-world evidence comparison on the effectiveness of ustekinumab vs anti-TNF or vedolizumab in ulcerative colitis: induction phase results from the prospective, observational RUN-UC study

Abstract Background Observational real-world evidence (RWE) studies on the effectiveness and safety of ustekinumab (UST) in ulcerative colitis (UC) are required in addition to RCTs, which are usually confined to selected patients and thus may not represent distinct treatment patterns and everyday clinical practice. For this reason, the prospective, controlled, propensity score (PS)-adjusted RUN-UC study was conducted in UC patients starting a newly initiated biologics therapy with a follow-up period of 3 years. The aim of the present analysis was to investigate the induction phase effectiveness of UST vs anti-TNF vs vedolizumab (VEDO) in UC in terms of clinical and steroid-free remission. Methods Between 2020-2022, 507 UC patients starting a new therapy with UST or other biologics were enrolled in 34 IBD-experienced centres across Germany. After exclusion of small molecules and missing outcomes, the final sample consisted of 317 patients. Response modified (reduction of partial Mayo score (pMayo) by ≥ 3 points from baseline to week-16 and a reduction of at least 30% or reaching remission at week-16), clinical remission (pMayo ≤ 1 plus a bleeding subscore=0), and steroid-free remission (pMayo ≤ 1, bleeding subscore=0 and no systemic use of steroids or oral budesonide during the last 8 weeks) were considered as outcomes. To reduce the effect of confounders, PS adjustment with inverse probability of treatment weighting (IPTW) was implemented. A weighted logistic regression was used, and the results were reported as odds ratio (OR) and 95% confidence interval (CI). Health-related quality of life was assessed by using the self-reported visual analogue scale (EQ-VAS) of the EQ-5D. Changes in EQ-VAS from baseline to week-16 were assessed with a linear model. Results 101 UST (bio-naïve: 6), 106 anti-TNF (ADA: 24.5%, IFX: 65.1%, GOL: 10.4%) (bio-naïve: 70) and 110 VEDO (bio-naïve: 73) UC-patients were included. PS adjustment removed systematic differences between the three groups (UST/anti-TNF/VEDO: 44.9/43.8/48.1% males, 6.7/9.9/5.5% smokers, 7.9/12.5/9.3% EIM). The effectiveness of UST in terms of response, clinical and steroid-free remission was comparable to that of anti-TNF and VEDO at week 16 (Tab. 1). We observed a significant increase in EQ-VAS within all three groups (Tab. 2). The increase in the UST group was significantly higher than in the VEDO group and numerically higher than in the anti-TNF group. Conclusion In this prospective RUN-UC study, with propensity score weighted groups, UST showed similar induction phase effectiveness in comparison with anti-TNF and VEDO. Quality of life was significantly improved in the UST group vs VEDO and was numerically higher than anti-TNF after the induction phase.

OP36 Real-world evidence on comparative effectiveness of Ustekinumab vs anti-TNF in Crohn’s disease with propensity score adjustment: two-year maintenance phase results from the prospective observational RUN-CD study

Abstract Background Within the framework of the prospective real-world RUN-CD registry on the effectiveness and safety of ustekinumab (UST) in Crohn’s disease (CD), a total of 901 CD-patients undergoing a newly initiated biologics therapy were enrolled in 44 IBD-experienced centers from all over Germany between 2017-2020 with a follow-up of 3 years. Here, the results on the effectiveness of the maintenance therapy over 24 months are presented as a real-world evidence (RWE) comparison of CD-patients with UST vs anti-TNF. Methods After exclusion of other biologics than UST and anti-TNF and missing outcomes (HBI), the final sample consisted of 550 CD patients. Clinical remission (HBI ≤ 4) was the predefined endpoint at month 24 and additionally, switching of biologics therapy was considered as an outcome failure. Patients were analysed on a modified intent-to-treat basis (mITT; switchers considered as outcome failure). To reduce the effect of confounders, propensity score (PS) adjustment with inverse probability of treatment weighting (IPTW) was implemented. A weighted logistic regression was used, and the results were reported as odds ratio (OR) and 95% confidence interval (CI). Quality of life was assessed using the self-reported visual analogue scale (EQ-VAS) of the EQ-5D with changes from baseline to 2 years. Results 308 UST (naïve: 27) and 242 anti-TNF (naïve: 162) CD-patients were included (ADA: 61.2%, IFX: 38.8%). The number of switches within 24 months was significantly lower with UST than with anti-TNF (27.6% vs 37.1%; p=0.038), and especially with IFX, whereby the difference between UST and IFX (27.6% vs 46.7%; p=0.003) proves to be statistically significant (Fig. 1). Clinical remission at two years was not statistically different for the overall UST vs anti-TNF groups (51.2% vs 54.4) (numerically higher in biologic-naïve UST- vs anti-TNF-patients, without statistically significance) (Tab. 1). Remission rates were similar for UST vs ADA, while they were significantly higher for UST vs IFX (54.4% vs 37.9%; p=0.008) (Tab. 2), and also significantly higher for ADA vs. IFX (58.2% vs 37.9%; p=0.003). As a sign of an improved QoL we observed a significant increase in EQ-VAS within both treatment groups. However, a similar increase in EQ-VAS was observed with UST and anti-TNF (+14.2 vs +12.3; p=0.147). Conclusion In this prospective two-year RWE comparison clinical remission was, also due to more frequent switches within the IFX group, significantly higher with UST when compared with IFX and higher with ADA than with IFX. Considering the effectiveness results of UST and the proven favourable safety profile, UST can be considered a first-line targeted therapy for CD.

P796 Effectiveness and safety of ustekinumab for patients with ulcerative colitis: A single-centre retrospective study

Abstract Background Ustekinumab, a monoclonal antibody directed against the interleukin 12/23 p40 subunit, was approved worldwide in 2020 for the treatment of ulcerative colitis. The efficacy of ustekinumab in inducing and maintaining remission in moderate to severe ulcerative colitis was demonstrated in the phase 3 clinical study, the UNIFI trial; however, real-world data on the effectiveness and safety of ustekinumab for patients with ulcerative colitis is still scarce. We aimed to investigate the real-world effectiveness and safety of ustekinumab in patients with ulcerative colitis. Methods This was a single-centre retrospective study enrolling patients with ulcerative colitis who were aged 16 years or more and administered ustekinumab between March 2022 and March 2022 at Toho University Sakura Medical Center, a tertiary center. Data were extracted by chart review. Ustekinumab was administered as a single intravenous infusion (approximately 6 mg/kg) followed by 90mg subcutaneous injection at week 8 and then by 90mg subcutaneous injection every 8-12 weeks. The endpoints were 1) the proportion of patients achieving symptomatic remission, defined as a rectal bleeding score of 0 and a stool frequency score of 0 or 1 in patient-reported outcome-2 (PRO-2), at week 8, 2) time to discontinuation, and 3) safety during the observation periods. Results We enrolled 53 patients in this study, with a median age of 45 years (interquadrant range: 27-57). Thirty patients (56.6%) were male and 23 (43.4%) were female. The majority of patients (n=39; 73.6%) had extensive colitis. Notably, 21 (38.9%) patients were naïve to advanced therapies. Thiopurines had been administered to 24 (45.3%) patients. Twenty-one (39.6%) patients achieved symptomatic remission at week 8 after a single intravenous infusion. The proportion of patients with symptomatic remission was numerically higher in advanced therapy-naïve patients compared with advanced therapy-experienced patients (47.6% versus 34.4%) (Figure 1). Univariate analysis failed to identify clinical predictors for symptomatic remission at week 8. The time to discontinuation were significantly longer in advanced-therapy naïve patients compared with advanced therapy experienced patients, with a median observation period of 296 days (Figure 2). As for safety, one patient discontinued ustekinumab due to skin disorder. One death due to pneumonia was observed, which was unrelated to ustekinumab. Conclusion Ustekinumab was effective and safe in the real-world setting. Advanced-therapy naïve patients were more likely to continue ustekinumab compared with advanced therapy experienced patients.

P525 Real-world effectiveness and safety of ustekinumab in patients with ulcerative colitis: a systematic review and meta-analysis

Abstract Background Knowledge of the real-world effectiveness and safety of tofacitinib for ulcerative colitis (UC) is relevant to confirm the benefit observed in clinical trials. The aim of this systematic review was to summarize reported evidence on the real-world outcomes of ustekinumab for UC and to conduct a meta-analysis of effectiveness and safety data. Methods A systematic search was conducted in electronic databases PubMed, Web of Science, EMBASE, and Science Direct, and conference proceedings until 15 September 2022 for real-world studies evaluating ustekinumab for UC. A random-effects meta-analysis model was used to calculate the pooled rates of clinical and safety outcomes. We evaluated the outcomes at week 8, week 12 to 16, month 6, and month 12. Need for colectomy and adverse events (AE) were reported as percentages and incidence rates (IRs) per 100 patients-year (PY) of exposure. Results Of the 254 citations identified, 19 studies were included with 3786 patients. Sixteen studies reported prior exposure to biologics or JAK inhibitors and included 1003 patients, of whom 92.3% were previously treated with any biologic, 61.1% with both anti-TNF and vedolizumab, and 16.4% with any biologic and tofacitinib (Figure 1). Remission was achieved in 45.4% of patients at week 8 (95% confidence interval 30.1-60.6%), 43.8% (38.4-49.2%) at weeks 12 to 16, 44.6% (35.9-53.3%) at month 6, and 50.6% (36.3-64.8%) at month 12 (Figure 2). Response was achieved in 61.2%, 59.4%, 65.2%, and 76.8% of patients at week 8, weeks 12 to 16, month 6, and month 12, respectively (Figure 3). Corticosteroid-free remission was achieved in 18.7%, 36.8%, 34.5%, and 39% of patients at week 8, weeks 12 to 16, month 6, and month 12, respectively. Endoscopic improvement was achieved in 29.9%, 24.3% %, and 58.2% of patients at weeks 12 to 16, month 6, and month 12, respectively. Almost 30% of the patients needed dose escalation, which was effective in 40% of these patients. The pooled rate of persistence with ustekinumab was 76.9% and 73.3% at month 9 and month 12, respectively. The IRs of colectomy, AE, serious AE, and serious infections were 5.1, 7.9, 1 and 0.5 per 100 PY, respectively (Figure 4). Conclusion The results of this systematic review and meta-analysis of real-world studies confirm the effectiveness of ustekinumab in a highly treatment-refractory population of patients with active moderate-to-severe UC. The acceptable safety data presented here support the positive long-term benefit-risk profile of ustekinumab in the treatment of UC. These real-world effectiveness and safety results were consistent with clinical trials and provide a broader perspective that can be used to aid treatment decisions in a more heterogeneous clinical setting.

P782 Ustekinumab in Ulcerative colitis: a real-life effectiveness study across multiple Belgian centers (SULTAN)

Abstract Background Ulcerative colitis (UC) is a chronic inflammatory disease affecting the colon.1 Ustekinumab (UST), a monoclonal antibody against the p40 subunit of interleukin (IL) 12 and 23 has shown in the UNIFI trials to be effective and safe in patients with moderate-to-severe UC.2 Real-life data are still limited.3 The aim of this study was to assess the real-world effectiveness and safety of UST in patients with UC across Belgian hospitals. Methods In this multicentric, retrospective observational study, patients with UC who received UST from September 2020 onwards were included. Clinical and biochemical response was assessed at baseline, week 8, 16 and 52. The primary endpoint was steroid-free remission defined as partial Mayo score of ≤ 2 with no subscore > 1 at week 16. Secondary endpoints included clinical and biochemical response (defined respectively as a decrease in partial Mayo score ≥ 3 points and ≥ 3 plus a decrease in rectal bleeding score ≥ 1 or an absolute rectal bleeding score ≤ 1 and a decline of 50% or more in CRP and/or fecal calprotectin). Results 107 patients with moderate-severe UC (86% patients with ≥ S2 severity) were included across 16 participating centers. Median disease duration was 10 years (1-73y) and 69 (64%) of patients had previously failed 2 or more biologicals. At week 16, 35 patients reached the primary endpoint of steroid-free clinical remission (33%), while 67 had a clinical response (62.6%) (Fig 1). There was a statistically significant decline in partial mayo score (median at baseline 6.0 range (1-9); W16 2.0 (0-9, p<.001), CRP (3.85 mg/L (0.4-181) vs 3.15 (0.88-10.3); p<.001) and calprotectin (1040 (13-6000) vs 300 (3.8-2980); p<.001) (Fig 2 and 3). Biochemical response was seen in 41 patients (38%). No predictors for steroid-free remission could be identified. At the end of follow-up at week 52, 75 patients were still treated with UST (70%). Reasons for discontinuation were primary non-response (N=18 (17%), loss of response (N=8 (7.5%) and adverse events (N=2 (1.9%)). No predictor for UST failure could be identified. Eight patients needed to be referred for colectomy (7.5%). In 7 patients dose optimization via IV reinduction occurred. No difference in occurrence of extra-intestinal manifestations was noted during treatment, severe infections occurred in 1 patient (0.9%). No other new safety signals were observed. Conclusion In this multi-centric, real-life cohort with highly refractory UC patients, UST was associated with a clinical response rate of 63% at 16 weeks while steroid-free remission was achieved in 33% of patients. No important new safety signals were observed.

OP39 Safety of ustekinumab in IBD: Final pooled long-term safety analysis through 5 years in CD and 4 years in UC

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.

P438 Efficacy and safety of ustekinumab for Ulcerative Colitis through 4 years in Asian patients: Final results from the sub-population of UNIFI long-term extension

Abstract Background Ustekinumab (UST) is an interleukin-12/23 p40 antagonist approved for the treatment of moderately to severely active ulcerative colitis (UC). Here, we report the final efficacy and safety results of UST in the Asian subpopulation in the UNIFI long-term extension (LTE) through 4 years (Week [WK] 200). Methods Overall, 87 intravenous (IV) UST induction WK8 responders were randomised to subcutaneous (SC) maintenance therapy: 34 placebo (PBO); 24 UST 90 mg every 12 weeks (q12w); 29 UST 90 mg q8w. The nonrandomised patients (pts) included 22 IV UST induction nonresponders who received SC UST at WK8, responded at WK16, and continued on SC UST q8w; and 12 responders to IV PBO induction who received SC PBO.1,2 Pts who completed WK44 continued on SC UST q8w or PBO treatment in the LTE, and PBO pts were discontinued after unblinding. Starting at WK56, randomised pts with UC worsening could adjust to SC UST 90 mg q8w. Efficacy was evaluated in UST-randomised pts (n=53) using symptomatic remission (Mayo stool frequency subscore of 0 or 1 and rectal bleeding subscore of 0). Safety was evaluated for all pts treated in the LTE, including randomised and nonrandomised populations until WK220. Results Among all UST-randomised pts at maintenance baseline WK0 (intent-to-treat population with nonresponder imputation for missing data and treatment failure criteria), 49.1% were in symptomatic remission at WK200 (biologic naïve 77.8.%; failures 34.4%); 49.1% of pts were in corticosteroid-free symptomatic remission at WK200 (Table 1; Fig. 1-2). Overall, 43.5% of biologic failure and 0% of biologic naïve pts who were randomised to UST and treated in the LTE discontinued treatment between WK44 and WK200. Among randomised pts who continued UST in the LTE, 63.4% were in symptomatic remission at WK200; 78.6% of pts with observed data at WK200 were in symptomatic remission (Table 1; Fig. 3); and 80.0% of those in clinical remission at WK44 were in symptomatic remission at WK200. Safety events were similar among UST-treated pts compared with PBO. From maintenance baseline WK0 through WK220, pts receiving UST (combined UST) and PBO had 241.8 and 56.5 total pt-years of follow-up, respectively. Safety events per 100 pt-years of follow-up for combined UST vs PBO were AEs: 222.48 vs 320.29, SAEs: 11.58 vs 7.08, and serious infections: 1.65 vs 1.77. During the final year of the LTE, no deaths or major cardiovascular events were reported in UST-treated Asian pts. Conclusion Consistent with the overall study population in UNIFI LTE1,2, Asian pts receiving SC UST generally maintained clinical benefit through 4 years. No new safety signals were observed. 1Afif W, et al. UEGW. Vienna, Austria, October 8-11, 2022. 2Sands BE, et al. ACG. Charlotte, NC, October 21-26, 2022

Meta-analysis: Real-world effectiveness and safety of ustekinumab in patients with ulcerative colitis.

Evidence on real-world outcomes of ustekinumab for ulcerative colitis (UC) patients is needed. To summarise evidence on the real-world outcomes of ustekinumab for UC and conduct a meta-analysis of effectiveness and safety data. A systematic search was conducted through September 2022 in electronic databases for observational studies evaluating ustekinumab for UC. A random-effects meta-analysis model was used to calculate the pooled effect sizes (percentages or incidence rates [IRs]) of effectiveness and safety outcomes. In all, 19 studies were included with 3786 patients. More than 92% of patients were previously treated with any biologic, 61.1% with both anti-TNF and vedolizumab and 16.4% with any biologic and tofacitinib. Clinical remission was achieved in 45.4% at week 8 (95% CI: 30.1%-60.6%), 43.8% (38.4%-49.2%) at weeks 12-16, 44.6% (35.9%-53.3%) at month 6, and 50.6% (36.3%-64.8%) at month 12. Response was achieved in 61.2%, 59.4%, 65.2% and 76.8% at weeks 8, 12-16, month 6 and 12, respectively. CS-free remission was achieved in 18.7%, 36.8%, 34.5% and 39% at weeks 8, 12-16, month 6 and 12, respectively. Overall, 58.2% of patients had endoscopic improvement at month 12. Almost 30% of the patients needed dose escalation, which was effective in 40% of these patients. The IRs of colectomy, adverse events (AEs), serious AEs and serious infections were 4.8, 7.9, 0.8 and 0.3 per 100 patient-years, respectively. This meta-analysis confirms the effectiveness and safety of ustekinumab in a highly treatment-refractory population of UC patients.

Effectiveness and safety of ustekinumab in bio-naïve Crohn's disease patients: a multicentre observational retrospective study.

Clinical trials have demonstrated the efficacy and safety of ustekinumab in Crohn's disease (CD). However, more data are necessary on the effectiveness of ustekinumab in bio-naïve patients in real-life studies. The aim of our study was to evaluate the effectiveness and safety of ustekinumab in patients with CD refractory or intolerant to conventional therapy and without previous exposure to biological drugs. We performed a nationwide, observational, retrospective, multicentre study including patients with CD, in which ustekinumab was used as the first biological drug. The corticosteroid-free clinical and biological response and remission were analysed at weeks 16, 24, 52 and 72. Clinical remission was defined as Harvey-Bradshaw index ⩽ 4 and biological remission as a faecal calprotectin (FC) <250 mg/g and C-reactive protein (CRP) <5 mg/L. Moreover, the persistence of the treatment and any adverse events were assessed. In all, 84 patients were included in the study, males and females were equally distributed, with a median age of 63 years [interquartile range (IQR): 51-75] and a median disease duration of 6.8 years [IQR: 3.6-17.0]. The majority (86.9%) of patients were treated with ustekinumab as monotherapy, without concomitant immunosuppressive medication. The proportion of patients in corticosteroid-free clinical remission or response at weeks 16, 24, 52 and 72 was 93.3% (56/60), 86.8% (46/53), 82.2% (37/45) and 71.4% (30/42), respectively. CRP returned to normal values in 47.6%, 43.2%, 50% and 52.4% of patients at weeks 16, 24, 52 and 72, respectively. Similarly, FC was normalized in 45.5%, 45.5%, 48.6% and 50% of patients at weeks 16, 24, 52 and 72, respectively. The cumulative probability of remaining on ustekinumab treatment was 84.8% (95% confidence interval: 73.3-91.6) after 72 weeks. Ustekinumab was discontinued in 10 patients (11.9%) within 72 weeks of follow-up. Reasons for discontinuing treatment were lack of response (n = 4), adverse events (n = 4) and death (n = 2). There were no discontinuations because of stable remission. Ustekinumab was effective and safe in Spanish bio-naïve CD patients, showing a quicker and more durable response than obtained in patients with previous biological treatment. In this cohort of bio-naïve patients starting on ustekinumab, the average age was high. Effectiveness and safety of ustekinumab in Crohn's disease patients not previously exposed to other biological therapies Evidence on the use of ustekinumab in biological naïve real-world patients is scarce. Here, we present real-world data evaluating the effectiveness and safety of ustekinumab in 84 bio-naïve patients from 17 Spanish hospitals. We report high rates of both clinical and biological remission. Moreover, after 1 year, 90.4% of patients remained being treated with ustekinumab. The safety profile of ustekinumab in these patient population was favourable. In conclusion, our results show that in patients with CD, ustekinumab could be considered as first-line therapy.

Two-year real-world outcome data from a single tertiary centre shows reduced ustekinumab persistence in a non-bio-naïve Crohn's disease cohort with penetrating disease, -ostomies and sarcopenia.

Ustekinumab was approved in 2016 for the treatment of moderate-severe Crohn's disease (CD). Clinical trials and real-world studies have suggested ustekinumab to be a safe and effective treatment; however, studies to date infrequently use imaging techniques to predict response to biologics in CD. We assessed the 2-year real-world effectiveness and safety of ustekinumab in a tertiary CD cohort with the use of novel imaging techniques. Retrospective cohort study. Retrospective data were collected between 2016 and 2021. Study end points included ustekinumab persistence, biological and/or clinical response and remission at 12, 18 and 24 months. Statistical analysis included demographic and inferential analyses. In all, 131 CD patients [57.3% female, median age of 26.0 (21.0-37.0)] were included. Patients were non-bio naïve, and the majority received ustekinumab as third- or fourth-line treatment. At 24 months, 61.0% (80/131) persisted with ustekinumab [52.7% (69/131) steroid free]. Clinical response was reported in 55.2% (37/67), clinical remission in 85.7% (57/67), biological response in 46.8% (22/47) and biological remission in 31.9% (15/47) of patients at 24 months. The low outcome numbers were attributable to missing data. Improvements in routine disease markers, including C-reactive protein and Harvey-Bradshaw Index, were also reflected in magnetic resonance imaging-derived disease scores. The presence of penetrating CD, an -ostomy and sarcopenia were all predictors of poorer ustekinumab outcomes (p < 0.05). Ustekinumab is effective in non-bio-naïve CD patients with non-stricturing, non-penetrating disease with an unremarkable safety profile but may be less effective in those with penetrating disease, -ostomies and sarcopenia.

Real-World Effectiveness and Risk Factors for Discontinuation of Ustekinumab in Ulcerative Colitis

Introduction: Ustekinumab (UST) has been approved for the treatment of moderate-to-severe ulcerative colitis (UC). Real-world data showing the effectiveness and safety of UST are necessary to confirm the results of clinical trials for applicability in daily clinical practice. Although some studies have reported real-world evidence of UST, only few studies have confirmed its effectiveness in the real world. The aim of this study was to assess the short- and long-term effectiveness, durability, safety, and risk factors for discontinuation of UST in UC in clinical practice. Methods: This was a retrospective, single-center, observational study. From March 2020 to January 2023, all consecutive patients with active UC who were treated with UST at Nagoya University Hospital were included. The primary outcome was the clinical remission rate at weeks 2–8 and weeks 24–48. The secondary outcomes included clinical response, persistence of UST therapy, endoscopic changes during follow-up, risk factors for UST discontinuation, and occurrence of any adverse events. The clinical effectiveness was evaluated using the Lichtiger score. Results: A total of 31 patients were included in this study. The clinical remission rates were 9.7%, 29.0%, 54.8%, and 64.5% at weeks 2, 8, 24, and 48, respectively. Twelve (38.7%) patients discontinued UST during the follow-up period. The probability of continuing UST was 93.5%, 80.6%, 77%, and 70% at weeks 2, 8, 24, and 48, respectively. The major reason for discontinuation of UST was primary failure (75.0%). A high baseline C-reactive protein (CRP) level was a significant risk factor for the discontinuation of UST. No adverse events were observed in this study. Conclusion: UST is effective for patients with UC. High CRP levels were identified as a risk factor for UST discontinuation. The findings of this study would help clinicians to select appropriate treatment options for patients with UC by identifying the risk factors for treatment discontinuation.

Real-World Evidence Comparing Vedolizumab and Ustekinumab in Antitumor Necrosis Factor-Experienced Patients With Crohn's Disease.

Many patients with Crohn's disease (CD) lose response or become intolerant to antitumor necrosis factor (TNF) therapy and subsequently switch out of class. We compared the effectiveness and safety of ustekinumab to vedolizumab in a large, geographically diverse US population of TNF-experienced patients with CD. We conducted a retrospective cohort study using longitudinal claims data from a large US insurer (Anthem, Inc.). We identified patients with CD initiating vedolizumab or ustekinumab with anti-TNF treatment in the prior 6 months. Our primary outcome was treatment persistence for >52 weeks. Secondary outcomes included (i) all-cause hospitalization, (ii) hospitalization for CD with surgery, (iii) hospitalization for CD without surgery, and (iv) hospitalization for infection. Propensity score fine stratification was used to control for demographic and baseline clinical characteristics and prior treatments. Among 885 new users of ustekinumab and 490 new users of vedolizumab, we observed no difference in treatment persistence (adjusted risk ratio 1.09 [95% confidence interval 0.95-1.25]). Ustekinumab was associated with a lower rate of all-cause hospitalization (adjusted hazard ratio 0.73 [0.59-0.91]), nonsurgical CD hospitalization (adjusted hazard ratio 0.58 [0.40-0.83]), and hospitalization for infection (adjusted hazard ratio 0.56 [0.34-0.92]). This real-world comparative effectiveness study of anti-TNF-experienced patients with CD initiating vedolizumab or ustekinumab showed similar treatment persistence rates beyond 52 weeks, although secondary outcomes such as all-cause hospitalizations, nonsurgical CD hospitalizations, and hospitalizations for infection favored ustekinumab initiation. We, therefore, advocate for individualized decision making in this medically refractory population, considering patient preference and other factors such as cost and route of administration.

Comparative Safety of Ustekinumab and Vedolizumab in Older Patients with Inflammatory Bowel Disease: A Bicentric Cohort Study.

Data about the safety of vedolizumab and ustekinumab are lacking in older patients with inflammatory bowel disease. The objective was to compare the safety of vedolizumab and ustekinumab therapies in older patients (&gt;60 years) with inflammatory bowel disease. This retrospective study included patients with Crohn's disease or ulcerative colitis initiating vedolizumab, ustekinumab or anti-TNF therapy at &gt;60 years of age. We examined the occurrence of adverse events within one year after therapy. This study included 182 patients: 53 were treated with vedolizumab (22 patients with Crohn's disease and 31 with ulcerative colitis), 31 with ustekinumab (30 Crohn's disease and one ulcerative colitis) and 98 with anti-TNF (63 Crohn's disease and 35 ulcerative colitis). At one year, there was no difference in terms of safety in patients with Crohn's disease between vedolizumab and ustekinumab considering the number of adverse events per year of follow-up (p = 0.258). For ulcerative colitis and Crohn's disease, the occurrence of adverse events per year of follow-up was similar between vedolizumab and anti-TNF (p = 0.274 and p = 0.876, respectively). Safety was similar between vedolizumab and ustekinumab in older patients with inflammatory bowel disease.

Comparison of Pharmacokinetic Similarity, Immunogenicity, and Safety of Ustekinumab and BAT2206 in Healthy Chinese Male Subjects in a Double-Blind, Randomized, Single-Dose, Parallel-Group Phase I Trial.

We aimed to evaluate the similarity of BAT2206 to its originator, ustekinumab, including pharmacokinetic profiles, immunogenicity, and safety in healthy Chinese male subjects. This was a double-blinded, randomized, single-dose, parallel-group clinical trial, in which 270 healthy male subjects were enrolled to receive a single subcutaneous injection (45 mg) of either BAT2206 or ustekinumab (European Union or USA) at a 1:1:1 ratio. The pairwise pharmacokinetic similarities and the safety and immunogenicity of both drugs were evaluated and compared. The results showed that the 90% confidence interval of the geometric mean ratio for primary pharmacokinetic parameters (maximum plasma concentration and area under the plasma concentration-time curve from time zero to infinity) among BAT2206 and ustekinumab (USA or European Union sourced) groups were all within the predefined equivalent interval of 80-125%. Furthermore, all the groups had similar incidences of treatment-emergent adverse events, in which the majority of cases belonged to Common Terminology Criteria for the Classification of Adverse Events Grade 1 or 2. Anti-drug antibodies were detected in 54 (20.1%) subjects, namely 24 (26.7%), 13 (14.8%), and 17 (18.9%) patients in the BAT2206, ustekinumab (European Union), and ustekinumab (USA) groups, respectively. In contrast, the incidences of positive neutralizing antibodies were similar among the three groups. Pharmacokinetic similarity between BAT2206 and ustekinumab (USA or European Union sourced) was confirmed. The three groups had similar safety profiles, and the investigational drugs were well tolerated by subjects. This study was registered with ClinicalTrials.gov (NCT04371185).

Ustekinumab Safety in Pregnancy: A Comprehensive Review.

Chronic inflammatory conditions, including inflammatory bowel diseases (IBD), psoriasis, and psoriatic arthritis, are prevalent among women of reproductive age; patients with active disease during pregnancy may be at an increased risk of adverse birth outcomes. For this reason, physicians are focused on approaches to controlling disease activity prior to and during pregnancy. The safety profile of many therapies used for these conditions has been relatively well established, though evidence on newer therapies is lacking. Ustekinumab is a relatively new interleukin-12/23 inhibitor approved for IBD, psoriasis, and psoriatic arthritis, whose safety in pregnancy is not yet fully understood. In this comprehensive review, we critically assess the available evidence on ustekinumab in pregnancy across animal studies and human case reports, case series, observational studies, and clinical practice guidelines. We show that, to date, studies have not identified an excess risk of adverse pregnancy outcomes among women exposed to ustekinumab in pregnancy, with few exposed pregnancies and potential for some bias. Clinical guidelines are conflicted regarding whether they recommend continuing or discontinuing ustekinumab, highlighting the paucity of data and need for more research on this issue.

Effectiveness and Safety of Ustekinumab for Moderate to Severely Active Crohn's Disease: Results from an Early Access Program in Brazil.

This prospective, observational, open-label study aimed to provide access to ustekinumab prior to market authorization and assess its safety and effectiveness in patients with Crohn's disease (CD) refractory to anti-tumor necrosis factor-α and conventional drugs in Brazil. Patients with a diagnosis of moderate-to-severe active CD for ≥3 months before screening received ustekinumab in a single intravenous induction dose (~6 mg/kg) at week 0, and a 90 mg maintenance dose, subcutaneously, every 8 or 12 weeks, from week 8 through to 80. Serious adverse events (SAE), adverse drug reactions (ADR), clinical response (per CD Activity Index and Harvey Bradshaw Index (HBI) scores), remission (per HBI scores), biomarkers (C-reactive protein (CRP) and fecal calprotectin (FC)) and endoscopic improvement rate over 80 weeks were assessed. Patients with a mean age of 39.9 years were assessed. Discontinuation rate was low (23%) and most adverse events were mild (68.7%). The SAE rate was 21% (mostly infections/infestations or gastrointestinal disorder), and ADR rate was 44%. The CD Activity Index and HBI scores decreased (by 74% and 81%, respectively) with 50% of patients showing normalized CRP and FC, and 63% achieved endoscopic improvement. Ustekinumab was fairly safe, well tolerated and effective in a Brazilian cohort of CD patients.

S743 Efficacy and Safety of Ustekinumab for Ulcerative Colitis Through 4 Years: Final Results From the UNIFI Long-Term Extension

S743 Efficacy and Safety of Ustekinumab for Ulcerative Colitis Through 4 Years: Final Results From the UNIFI Long-Term Extension

S738 Real World Evidence Comparing Vedolizumab and Ustekinumab in Anti-TNF Experienced Patients With Crohn’s Disease

Introduction: Many patients with Crohn’s disease (CD) lose response or become intolerant to anti-TNF therapy. Newer classes of biologics have demonstrated efficacy in anti-TNF experienced patients, but real-world comparative effectiveness studies are limited and have yielded conflicting results. We sought to compare the effectiveness and safety of ustekinumab to vedolizumab in a large, geographically diverse United States (U.S.) population of adult patients with CD previously treated with TNF inhibitors. Methods: We conducted a retrospective cohort study using longitudinal claims data from a large national U.S. insurance company (Anthem, Inc.). We identified CD patients initiating vedolizumab or ustekinumab with evidence of anti-TNF treatment in the prior 6 months. Our primary outcome was treatment persistence > 52 weeks. Select secondary outcomes included: 1) all-cause hospitalization; 2) hospitalization for CD with surgery; 3) hospitalization for CD without surgery, and 4) hospitalization for infection. Propensity score fine stratification was used to control for confounding by demographic and clinical characteristics and prior treatments at baseline. Results: We identified 885 new users of ustekinumab and 490 new users of vedolizumab who met criteria for our primary analysis. We observed no difference in treatment persistence [adjusted RR 1.09 (95% CI 0.95 -1.25)]; however, ustekinumab was associated with lower all-cause hospitalization (adjusted HR 0.73 [0.59-0.91]) and non-surgical CD hospitalizations (adjusted HR 0.58 [0.40-0.83]) (Figure). Ustekinumab initiators were also less likely to be hospitalized for infection (adjusted HR 0.56 [ 0.34-0.92]). Conclusion: This real-world comparative effectiveness study of anti-TNF experienced CD patients initiating vedolizumab or ustekinumab showed similar treatment persistence rates beyond 52 weeks, although secondary outcomes such as all-cause hospitalization, non-surgical CD hospitalizations, and hospitalizations for infection favored ustekinumab initiation. We therefore advocate for individualized decision making in this medically refractory population, considering patient preference, prior Anti-TNF experience and other factors such as cost and route of administration.Figure 1.: Incidence and Effect Estimates for Primary and Secondary Endpoints in New Users of Ustekinumab vs Vedolizumab