P40 Subunit Research Articles

Efficacy and safety of risankizumab for the treatment of patients with plaque type psoriasis.

Risankizumab (Skyrizi®, Abbvie, North Chicago, IL, USA) is a humanized immunoglobulin (Ig) G1 monoclonal antibody targeting the p19 subunit of IL-23, thereby inhibiting IL-23-dependent releasing of proinflammatory cytokines in plaque psoriasis. Risankizumab is licensed is most countries for the treatment of patients with moderate-to-severe plaque psoriasis, and in Japan for generalized pustular psoriasis, erythrodermic psoriasis and palmoplantar pustulosis. Risankizumab showed higher efficacy and favorable safety profiles in patients with moderate-to-severe plaque psoriasis, compared with adalimumab, secukinumab and ustekinumab in several randomized controlled phase 3 pivotal studies and among real-life data in large retrospective studies. Furthermore, its high efficacy even in patients with prior biologic failure, better drug survival, less need for biologic switch and longer drug-free remission durations have also been shown in real-life settings and in long-term follow up. In addition, reports of both reduced dosing and increased (bolus) dosing exist which increase our ability to use risankizumab more flexibly in an era of personalized medicine. Also, the use of risankizumab in several special population, such as elderly, Asian people, erythrodermic psoriasis, patients with high induction doses, pregnancy and human immunodeficiency virus group are discussed.

Managing the Overlap: Therapeutic Approaches in Patients with Concomitant Psoriasis and Atopic Dermatitis—A Case Series

Introduction: Psoriasis (PSO) and atopic dermatitis (AD) have traditionally been considered distinct diseases, respectively, mediated by T-helper 1 (Th1) and the T-helper 2 (Th2) immune pathway. In recent years, there has been a growing body of evidence highlighting an overlap between the two conditions, such as Asian AD, pediatric PSO, or “psoriasis dermatitis/PSOREMA”. Moreover, psoriasis dermatitis can be induced by therapeutic interventions. For instance, anti-IL-4/IL-13 monoclonal antibodies, commonly used to treat AD, can induce psoriasiform reactions by inhibiting the Th2 pathway, thereby unmasking Th1/Th17-driven PSO. Conversely, anti-TNFα and anti-IL-17 therapies, effective for PSO, may induce eczematous reactions promoting a switch toward Th2-driven inflammation. Janus Kinase Inhibitors (JAK-i) and IL-23 antagonists may represent valid therapeutic options for managing psoriasis dermatitis. JAK-i exert broader immunomodulatory effects, inhibiting both Th1 and Th2 pathways; however, they require careful monitoring due to potential adverse events. In contrast, IL-23 antagonists specifically suppress the IL-23/IL-17 axis inhibiting the p19 subunit of IL-23 and could represent a safer option for patients with psoriasis dermatitis. Materials and Methods/Results: We present a series of five cases of psoriasis dermatitis, including both patients who had the condition from the onset and those who developed it during treatment, with tailored therapeutic strategies based on individual patient profiles, comorbidities, and the specific characteristics of their overlapping disease presentation. Conclusions: JAK-i and IL-23 antagonists are both valid therapeutic options for managing psoriasis dermatitis, but with different immunomodulatory effects and safety profiles. Future research should focus on a better understanding of the immune pathway and identifying specific biomarkers of psoriasis dermatitis, to optimize therapeutic strategies.

P1100 Effectiveness of Risankizumab in Crohn’s Disease, our real-world experience: Clinical, Biochemical and Ultrasonographic responses. A single centre, observational, retrospective study

Abstract Background Risankizumab (RZB) is the first monoclonal antibody targeting IL-23 (p19 subunit) approved for moderate-to-severe Crohn’s disease (CD) patients. Clinical remission at week 12 has been reported 42-45% in the induction trials (ADVANCE, MOTIVATE), and up to 52% by week 52 at the maintenance trial (FORTIFY). Real world evidence is necessary to confirm these data. Methods We conducted an observational, retrospective, unicentric study including all adult patients with active CD who have initiated treatment with RZB. Primary endpoint is clinical remission defined as Harvey-Bradshaw Index (HBI) ≤4 for CD, both at week 12 and at the end of follow up. Secondary endpoints are: Steroid-free clinical remission, biochemical remission (defined as fecal calprotectin [FC] <250μg/g, or c reactive protein [CRP] <5mg/L), ultrasound response (defined using Ilvemark JFKF, et al 2021 Consensus Statement), and adverse events. Data are represented with median (range), and percentage. Wilcoxon, Student t-test (paired), and McNemar tests were used as appropriate. Results 34 patients were included. Full demographic description can be found in Table 1. End of follow up for HBI was on day 132.5 (93, 210). Clinical remission both at week 12 and at the end of follow up was 58.82%, steroid-free clinical remission both at week 12 and at the end of follow up was 52.94%. HBI decreased significantly from 5 (3, 9) at baseline, to 4 (2, 6) at week 12 (p=0.0471), and down to 3 (2, 6) at the end of follow up (p=0.0203). Fecal calprotectin decreased from baseline 2098.5 (490, 3003.8), to 1357.8 (805, 3077.7) at week 12 (p=0.2386), and to 1300.5 (515, 2940.7) by the end (p=0.1056). No statistically significant differences were found in the FC remission rate, nor in the CRP values and its remission rate. Transmural response assessed with ultrasound was 40% (2/5) at week 12, and 50% (4/8) at the end of follow up; transmural remission was 20% (1/5) at week 12, and 25% (2/8) at the end. There were not found differences in the intestinal ultrasound activity scores for CD. RZB was stopped in 9 (26.47%) patients, due to: primary failure 5 (2 of them required intestinal resection), secondary failure 1, and adverse events 3. Adverse events occurred in 7 (20.59%) patients: 2 arthralgias, 1 mild-moderate infusion reaction, 1 worsening of atopic dermatitis, 1 renal function impairment, 1 mild urinary tract infection, and 1 device failure. Conclusion Real world RZB effectiveness seems comparable to the efficacy reported in clinical trials. References -D’Haens G, Panaccione R, Baert F, et al. Risankizumab as induction therapy for Crohn’s disease: results from the phase 3 ADVANCE and MOTIVATE induction trials. Lancet. 2022;399(10340):2015-2030. doi:10.1016/S0140-6736(22)00467-6. -Ferrante M, Panaccione R, Baert F, et al. Risankizumab as maintenance therapy for moderately to severely active Crohn’s disease: results from the multicentre, randomised, double-blind, placebo-controlled, withdrawal phase 3 FORTIFY maintenance trial. Lancet. 2022;399(10340):2031-2046. doi:10.1016/S0140-6736(22)00466-4. -Ilvemark JFKF, Hansen T, Goodsall TM, et al. Defining Transabdominal Intestinal Ultrasound Treatment Response and Remission in Inflammatory Bowel Disease: Systematic Review and Expert Consensus Statement. J Crohns Colitis. 2022;16(4):554-580. doi:10.1093/ecco-jcc/jjab173. -Barreiro-de Acosta M, Nieto García L, Poncela M, et al. OP043 Real-world short-term effectiveness of Risankizumab in refractory Crohn’s disease: RISANCROHN study from the ENEIDA registry. UEG Week 2024 Oral Presentations. United European Gastroenterol J. 2024;12(Suppl 8): 2050-6406. doi.org/10.1002/ueg2.12614.

P1130 Real-life histological remission in Ulcerative Colitis patients treated with Ustekinumab: results from the Belgian SULTAN trial

Abstract Background Histological remission is an aspirational therapeutic target in Ulcerative Colitis (UC) associated with lower relapse rates.1Ustekinumab (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. However, real-life data on histological remission rates are sparse. The aim of the study was to assess the real-life histological response and remission rates of UST in patients with UC across Belgian hospitals. Methods In this multicentric, retrospective observational study, patients with UC who initialised UST treatment between September 2020 and July 2023 were included. Histological remission was defined as Nancy score = 0, response as Nancy ≤ 1 and assessed at week 16 and 52 by the local pathologist. Other endpoints included steroid-free clinical remission (partial Mayo ≤ 2 with no subscore >1), endoscopic remission (endoscopic Mayo = 0), endoscopic response (Mayo score ≤ 1) and clinical response (decrease in partial Mayo score ≥ 3 points and ≥ 30% plus a decrease in rectal bleeding score ≥ 1 or an absolute rectal bleeding score ≤ 1). UST drug persistence was analyzed by Cox regression analysis, predictors of other endpoints by logistic regression. Results 120 patients with moderate to severe UC (86% patients with ≥S2 severity) were included across 16 participating centers. Median disease duration was 11 years (IQR 9) and 81 (68%) of patients had previously failed 2 or more biologicals. Histological remission was achieved in 3/37 (8%) and 5/45 (11%) at W16 and W52, while histological response was seen in 10.8% (4/37) and 26.7% (12/45) respectively. Steroid-free clinical remission rates were 41/120 (34%) and 38/85 (44%) while endoscopic remission was seen in 23/120 (19%) and 13/52 (25%) at W16 and 52 respectively. Two patients (40%) in histological remission at W52 had an endoscopic Mayo 0 score, while 3 had a Mayo 1 (60%) at the time of evaluation. Active smoking was a negative predictor for achieving steroid-free remission (OR 0.412, p=0.011). No significant predictors for histological remission or response could be identified. UST drug persistence by week 52 was 70.8%. Active smoking (OR 3.058, p=0.02), vedolizumab non-response (OR 2.592, p=0.03) and a high Nancy baseline score (OR 2.46, p=0.04)) were associated with UST failure Conclusion In this multi-centric, real-life cohort with highly refractory UC patients, UST shows acceptable clinical and endoscopic remission rates, but histological remission rates remain low after one year of treatment.

P0717 Real-world data of Mirikizumab in the induction and maintenance therapy for ulcerative colitis

Abstract Background Mirikizumab, a humanized IgG4 monoclonal antibody binding subunit p19 of interleukin 23, has been approved for the therapy of ulcerative colitis since May 2023. Phase 3 studies showed significant efficacy in both inducing and sustaining clinical remission in patients with moderate to severe active ulcerative colitis. Methods All patients with active ulcerative colitis who began induction therapy with Mirikizumab at our outpatient clinic between July 2023 and June 2024 were analyzed retrospectively with a follow-up period until October 2024. Patients with prednisolone therapy exceeding 20 mg, loperamide intake or deviation of standard clinical application period were excluded. The primary endpoints were defined as achieving clinical remission following the completion of intravenous induction (at weeks 12, 16 or 24) and the maintenance of clinical remission at any time between week 8 and week 49 following the initiation of subcutaneous application. Secondary endpoints included rates of clinical remission and relapse in patients previously treated with Ustekinumab, a monoclonal antibody targeting the p40 subunit of interleukin-12 and -23. Results A total of 40 patients started Mirikizumab induction therapy, with 23 meeting the inclusion criteria. Seventeen patients were observed in the maintenance period. After completion of induction, 20 out of 23 patients (87.0%) achieved clinical remission. Among these, 12 (60.0%) had previously been treated with Ustekinumab. During the maintenance period, 6 out of 17 patients (35.3%) experienced a relapse, of whom 5 (83.3%) had prior therapy with Ustekinumab. Within the Ustekinumab subgroup, 5 out of 10 patients (50.0%) suffered relapse after initially achieving clinical remission. Conclusion Mirikizumab is an effective therapy in patients with active ulcerative colitis, including those who had a prior loss of response to Ustekinumab therapy. Patients with prior Ustekinumab therapy exhibited a higher rate of relapse during the maintenance phase.

P0861 Comparative effectiveness and safety of ustekinumab versus anti-tumour necrosis Factor agents as first- or second-line biologics in Crohn´s disease: a real-world multicentric observational study

Abstract Background Ustekinumab (UST), an antibody targeting the p40 subunit of interleukin-12/23, has demonstrated efficacy in patients with Crohn’s disease (CD). However, comparative real-world data regarding the positioning of biologic therapies, particularly UST versus anti-tumour necrosis factor (TNF) agents, remain limited. This study aimed to compare the effectiveness and safety of UST and anti-TNF agents in biologic-naïve and biologic-failure CD patients. Methods A multicentre retrospective cohort study was conducted, including patients with moderate to severe CD initiating first- or second-line biologic treatment with UST or anti-TNF agents [infliximab (IFX) or adalimumab (ADA)]. Propensity score adjustment (1/PS) was applied to address confounders. Primary endpoints were clinical remission (Harvey-Bradshaw Index ≤3), endoscopic remission (SES-CD ≤3 or Rutgeerts score I0), and steroid-free clinical remission at week 52. Secondary outcomes included clinical response, primary/secondary loss of response, treatment persistence, biochemical remission, adverse events (AEs), hospitalisation, and surgeries. Results A total of 536 CD patients (172 IFX, 132 ADA, 236 UST) were analysed. Clinical remission at week 52 was achieved by 78.1% of UST and 75.7% of anti-TNF patients in the biologic-naïve group (p=0.25), and 52.2% of UST and 50.5% of anti-TNF in biologic-failure patients (p=0.31). Steroid-free clinical remission rates were similar between UST and anti-TNF groups: 80.5% vs 80.1% (p=0.99) in biologic-naïve and 81.2% vs 77.3% (p=0.46) in biologic-failure patients. Endoscopic remission was observed in 74.8% of UST vs 68.8% of anti-TNF patients (p=0.81) in biologic-naïve, and 50.6% vs 46.8% (p=0.72) in biologic-failure. Serious AEs were more frequent with anti-TNF agents in biologic-failure patients (28.3% vs 12.5%; p<0.01). UST demonstrated higher treatment persistence in biologic-naïve patients (96.9% vs 80.8%; p=0.029) and lower CD relapse rates (3.08% vs 11.11%; p=0.01). Conclusion UST and anti-TNF agents exhibit comparable effectiveness for CD treatment regardless of prior biologic exposure. UST showed superior treatment persistence and a better safety profile, particularly in biologic-naïve patients.

P1303 A machine – learning approach of therapeutic response prediction for Ustekinumab in ulcerative colitis

Abstract Background Ustekinumab, a monoclonal antibody targeting the p40 subunit of interleukin (IL)-12 and IL-23, is a promising therapeutic approach in patients with ulcerative colitis (UC), but predicting treatment response remains a challenge. In the present study, we focused to identify prognostic response markers to ustekinumab in patients with active UC, utilizing mucosal transcriptome information and machine-learning approaches. Methods We used 36 drug naive UC patients initiating treatment with ustekinumab. Colonic mucosal biopsies were obtained before treatment initiation. The gene expression analysis was performed using a microarray panel of 84 inflammation related genes. A differential gene expression analysis (DGEA), correlation analysis, and network centrality analysis on co-expression networks were performed to identify potential biomarkers. Additionally, machine learning (ML) models were employed to predict treatment response based on gene expression data. Results The genes BCL6, CXCL5, and FASLG, were among the significantly upregulated, while IL23A and IL23R were downregulated in non-responders compared to responders. The co-expression analysis revealed distinct patterns between responders and non-responders. The ML algorithms demonstrated a high predictive power, emphasizing the significance of the IL23R, IL23A, and BCL6 genes. Conclusion Through a variety of computational approaches, our study indicates the predictive power of mucosal expression data in predicting patient response to ustekinumab treatment.

P0809 Higher Ustekinumab Concentrations in Induction are associated With Better Endoscopic Outcomes in Inflammatory Bowel Disease

Abstract Background Ustekinumab (UST) is a monoclonal antibody targeting the p40 subunit of interleukin-12/23. Evidence suggests a relationship between UST concentrations and therapeutic outcomes. This study aimed to evaluate the association between UST trough concentrations during the induction phase and clinical and especially endoscopic outcomes at week 24 in patients with Crohn’s disease (CD) and ulcerative colitis (UC). Methods Patients with CD and UC were included from the start of UST treatment. Intensification and maintenance regimens were based on standard clinical practice. UST trough concentrations were measured at weeks 8,16, and 24 after induction. The primary objective was to assess endoscopic remission at week 24, defined as a simple-endoscopic-score (SES-CD) ≤2 for CD and a Mayo endoscopic score (MES) ≤1 for UC. Secondary endpoints included clinical remission, and endoscopic improvement. Quartile analysis and logistic regression assessed the relationship between UST concentrations and endoscopic outcomes, while logistic and Cox proportional hazards regressions identified variables associated with endoscopic remission and treatment discontinuation, respectively. The diagnostic performance of UST concentrations was assessed with receiver operating characteristic (ROC) curve analysis. Results Seventy patients (45 with CD) were enrolled. Those achieving endoscopic response and remission at week 24 had higher UST levels at week 8 (4.0 μg/mL vs. 2.5 μg/mL, p=0.002; 3.9 μg/mL vs. 2.9 μg/mL, p=0.047). Patients with UST concentrations in the fourth quartile (Q4) at week 8 (> 4.5 μg/mL) had higher rates of endoscopic remission (69% [Q4] vs. 23% [Q1], p=0.014; 24% [Q2], p=0.003; 31% [Q3], p=0.024). A UST concentration threshold of 4.5 μg/mL at week 8 was the best predictor of endoscopic remission (AUC=0.678, sensitivity 52.5%, specificity 84.6%), while 3.5 μg/mL predicted endoscopic response (AUC=0.732, sensitivity 63.6 %, specificity 73.1 %). Logistic regression did not reveal other predictive factors for endoscopic response/remission other than higher through concentrations at week 8. Longer disease duration correlated with a higher risk of UST discontinuation (OR 1.034, 95% CI 1.002-1.068, p=0.035). Fourteen (20%) patients discontinued UST after a median of 15.50 months. Higher UST concentrations in Q4 did not result in greater drug persistence (p=0.319). Conclusion UST concentrations at week 8 were positively associated with endoscopic outcomes at week 24, with a threshold of 4.5 μg/mL reliably predicting endoscopic remission. Further randomized clinical trials are warranted to explore whether optimizing UST treatment based on post-induction concentrations can enhance therapeutic outcomes. References K. Papamichael, E.H. Vogelzang, J. Lambert, G. Wolbink, A.S. Cheifetz, Therapeutic drug monitoring with biologic agents in immune mediated inflammatory diseases, Expert Rev Clin Immunol 15 (2019) 837–848. https://doi.org/10.1080/1744666X.2019.1630273. D. Alsoud, G. De Hertogh, G. Compernolle, S. Tops, J. Sabino, M. Ferrante, D. Thomas, S. Vermeire, B. Verstockt, Real-world Endoscopic and Histological Outcomes Are Correlated with Ustekinumab Exposure in Patients with Ulcerative Colitis, J Crohns Colitis 16 (2022) 1562–1570. https://doi.org/10.1093/ECCO-JCC/JJAC067. C. Mcdonald, H. Kerr, E. Gibbons, T. Lukose, D. Cheriyan, G. Harewood, S. Patchett, A. O’toole, O. Kelly, K. Boland, Higher Ustekinumab Levels in Maintenance Therapy are Associated with Greater Mucosal Healing and Mucosal Response in Crohn’s Disease: An Experience of 2 IBD Centers, Inflamm Bowel Dis 30 (2024) 423–428. https://doi.org/10.1093/ibd/izad073. T. Straatmijer, V.B.C. Biemans, D.J.A.R. Moes, F. Hoentjen, R. ter Heine, P.W.J. Maljaars, R. Theeuwen, M. Pierik, M. Duijvestein, A.E. van der Meulen-de Jong, Ustekinumab Trough Concentrations Are Associated with Biochemical Outcomes in Patients with Crohn’s Disease, Dig Dis Sci 68 (2023) 2647. https://doi.org/10.1007/S10620-023-07822-7.

P1114 Engineering and Development of a Novel Bispecific Antibody Targeting IL-23 and TL1A

Abstract Background Both IL23 and TL1A are clinically validated targets with genetical linkage to various human autoimmune diseases. Here we engineered and produced HXN-1003, a bispecific antibody (bsAb) simultaneously targeting both IL23 and TL1A, with the aim to further enhance clinical efficacy, and to overcome refractory and resistance associated with single-target based therapies. Methods The binding and blocking efficacy of HXN-1003 for each target were assessed using various in vitro assays, including IL23 reporter and mouse splenocyte activation assays for IL23, and TF-1 apoptosis and DR3-NFκB-Luc reporter assays for TL1A. The synergistic effect of dual targeting was measured by IL22 secretion in mouse splenocytes co-stimulated with IL23 and TL1A. In vivo efficacy was evaluated in hIL23/hTL1A transgenic mice with DSS-induced colitis and IMQ-induced psoriasis models, as well as in SD rats with subcutaneous injections of hTL1A and hIL23 to induce dermatitis. Results HXN-1003 features a tetravalent structure, with the anti-IL23 arm specifically binds to the p19 subunit of IL23, demonstrating superior affinity and blocking activity compared to benchmark Risankizumab. For TL1A, HXN-1003 binds to both the TL1A trimer and monomer with sub-nanomolar affinity, exhibiting similar blocking activity to its parent antibody HXN-1001 and RVT-3101. In the mouse splenocyte activation assay induced by IL23 and TL1A, HXN-1003 showed greater activity than each individual antibody and was equally active to their combination. In animal models, HXN-1003 significantly alleviated symptoms of DSS-induced colitis, and demonstrated superior therapeutic effects in the IMQ-induced psoriasis model compared to the IL23 monoclonal antibody. Additionally, in the dermatitis model induced by hTL1A and hIL23, the bsAb outperformed each individual antibody and their combination. Conclusion HXN-1003 simultaneously blocks IL23 and TL1A, with each arm exhibiting activity comparable to the parent monoclonal antibodies. It has demonstrated synergistic/additive therapeutic effects in both in vitro and in vivo experiments, highlighting its potential to enhance clinical efficacy and benefit autoimmune patients in multiple clinical settings.

P1030 Efficacy and safety of subcutaneous guselkumab in East Asian participants with moderately to severely active Crohn’s disease: Subgroup analysis of the Phase 3 GRAVITI study

Abstract Background Guselkumab (GUS) is a dual-acting interleukin-23 p19 subunit inhibitor that was efficacious in phase 3 trials of participants (pts) with Crohn’s disease (CD) using either intravenous (IV; GALAXI 2/3) or subcutaneous (SC; GRAVITI) induction and SC maintenance.1,2 We evaluated the efficacy and safety of GUS SC induction and SC maintenance in a post hoc subgroup analysis of East Asian (China, Japan, Korea, and Taiwan) pts from GRAVITI, a phase 3 treat-through trial in pts with moderately to severely active CD. Methods The GRAVITI study (NCT05197049) included pts with CD with a history of inadequate response or intolerance to oral corticosteroids, AZA, 6-MP, MTX, or biologics (BIO-IR). Randomization was stratified by baseline Crohn’s Disease Activity Index (CDAI), Simple Endoscopic Score for Crohn’s Disease (SES-CD), and BIO-IR status, and pts were allocated 1:1:1 in a treat-through design to GUS 400mg SC every 4 weeks (q4w) (x3)→GUS 200mg SC q4w, GUS 400mg SC q4w (x3)→GUS 100mg SC every 8 weeks (q8w), or placebo (PBO). Participants in the placebo group who met rescue criteria received GUS 400mg SC at Wk16, Wk20, and Wk24 followed by GUS 100mg SC q8w; GUS pts stayed on GUS per treat-through design (sham rescue). The co-primary endpoints were clinical remission at Wk12 and endoscopic response at Wk12. Additional endpoints were patient-reported outcome 2 (PRO-2) remission at Wk12, clinical response at Wk12, clinical remission at Wk24, clinical remission at Wk48, and endoscopic response at Wk48. All endpoints assessed through Wk12 compared the combined GUS 400mg SC treatment arm to PBO; assessments after Wk12 compared each GUS SC maintenance regimen to PBO. All pts who met rescue criteria were considered not to have met efficacy endpoints after Wk16. Safety was assessed through Wk48. Results This analysis included 71 East Asian pts. At Wk12, higher proportions of pts in the GUS 400mg SC cohort achieved clinical remission, clinical response, endoscopic response, and PRO-2 remission relative to PBO pts. At Wk24 and Wk48, higher proportions of pts achieved clinical remission in both GUS SC maintenance dose regimens compared with PBO. Endoscopic response at Wk48 was achieved in a higher proportion of pts in both GUS SC maintenance dose regimens compared with PBO (Figure 1). Key safety event rates through Wk48 were similar among treatment groups (Table 1). No deaths were reported in East Asian pts. Conclusion Efficacy of GUS as SC induction followed by SC maintenance therapy in the subgroup of East Asian pts from GRAVITI was consistent with that observed in the overall study population. The safety profile was consistent with the known safety profile of GUS in approved indications and with the overall study population.

P0609 Real-world short and long-term effectiveness of risankizumab in refractory Crohn’s disease: RISANCROHN study from the ENEIDA Registry

Abstract Background Phase III trials have demonstrated the efficacy of risankizumab (RZB), this being the first humanized monoclonal IgG1 antibody which targets the interleukin 23 p19 subunit, in Crohn’s disease (CD). However, real-world data with this drug is limited. The aim of our study was to assess the real-world effectiveness of RZB in patients with CD. Methods Adult CD patients that had received treatment with RZB in the ENEIDA registry —a large prospectively maintained Spanish database promoted by the Spanish Working Group of Crohn’s and Colitis (GETECCU)— were included. Clinical and demographical data including number of previous biologics and advanced therapies were included. The primary endpoints were steroid-free clinical remission (SFCR) after induction period (Harvey-Bradshaw score <5) and long-term SFCR at the end of follow-up. Influence of previous use of ustekinumab (UST) and number of previous advanced therapies in short- and long-term efficacy was also evaluated. Statistical analysis was performed using the Chi-square/Student-t test and multivariate analysis with logistic regression. Results 857 CD patients (60% male) were included: median age 50 (18-84) years, median disease duration 14 years, 27% smokers. 50% were L1, 8% L2, 38% L3, and 4% exclusively L4. B1 phenotype was present in 42%, 37% B2, 21% B3. Perianal disease was present in 28%, 46% had previously CD-related surgery and 39% extraintestinal manifestations. Only 3% were biological naïve, 50% had been exposed to 1-2 advanced therapies, and 47% to 3 or more. Following induction 56% of the patients achieved SFCR. Remission was more frequent in patients who had not previously been treated with UST (64% vs. 53% in those previously exposed to UST, p<0.01). In the multivariate analysis, a higher number of prior advanced therapies was associated with lower remission rates (p<0.01). Long-term efficacy was evaluated in 652 patients (median follow-up 7 months). At the end of the follow-up 61.2% of patients maintained SFCR. Long-term remission rate in patients non-exposed to UST was 72%, and 55% exposed to UST (p<0.01). In the multivariate analysis, younger age was associated with higher long-term remission rates (p<0.01). 11% needed dose optimization/reinduction during follow-up. 68 patients (7.9%) presented adverse events but only 18 (2%) needed to give up the treatment. Conclusion This study represents the largest cohort of real-world data on RZB in CD, including highly refractory patients with multiple prior drug failures. RZB induced SFCR in 56% of patients after induction and 61% in the long term. Higher remission rates were observed in patients who had never been exposed to UST. Younger age and fewer previous advanced therapies were associated with better outcomes.

P1112 Pharmacokinetic comparability and safety between original and citrate-free mirikizumab formulations for subcutaneous injections: Results from three clinical trials in healthy participants

Abstract Background Mirikizumab (miri), a humanized IgG4 monoclonal antibody which selectively binds to the p19 subunit of human IL-23, is administered via subcutaneous (SC) injection. Since injection site pain (ISP) may be negatively affected by formulation buffer excipients such as citrate1, a citrate-free (CF) formulation of miri has been developed. We assessed the bioequivalence, ISP, and overall safety of the CF formulation of miri. Methods Three phase 1, two-arm, randomised, single-dose, subject-blind, parallel design studies were conducted in healthy subjects: one pilot relative bioavailability (RBA) study A (NCT04548219), and two bioequivalence (BE) studies B (NCT05515601) and C (NCT05644353). Subjects were randomised 1:1 to CF or original miri in all studies. The primary endpoint in all studies was to assess the comparability between CF and original formulations via Cmax, area under the concentration versus time curve (AUC) (0-∞), and AUC(0-tlast). Study A assessed the RBA of a single 200 mg SC dose, Study B assessed the BE of a single 200 mg SC dose, and Study C assessed the BE of a single 300 mg SC dose. The 200 mg and 300 mg doses are proposed for ulcerative colitis and Crohn’s disease, respectively. The secondary endpoint was safety assessment by spontaneous treatment-emergent adverse events and serious adverse events. In addition, in Study A, ISP was also quantified prospectively using the 100-mm validated visual analogue scale (VAS) assessment form2. Injection site reactions (ISRs) were prospectively assessed in Study A. Results The number of subjects who received miri were 60 in Study A, 396 in Study B, and 450 in Study C. Baseline characteristics were similar across studies and treatment groups. There was no statistically significant difference in exposure between the formulations in Study A. Figure 1 shows that the CF formulation demonstrated BE in Studies B and C, with the 90% confidence intervals (CIs) of the ratios of geometric least squares means (LSM) within the pre-specified equivalence limits. Figure 2 shows a statistically significant difference of 13.43 in the VAS Pain Score LSM at 1-minute post-dose for Study A, which is also considered clinically relevant3. Overall, CF and original miri demonstrated an acceptable safety profile consistent with previous work in healthy participants. Conclusion The CF formulation of mirikizumab is bioequivalent to the original formulation and is associated with a lower VAS pain score which may positively affect treatment experience.

P1149 Guselkumab improves health-related quality of life as measured by PROMIS-29 in participants with moderately to severely active Crohn’s disease: Phase 3 GRAVITI study

Abstract Background Patients (pts) with Crohn’s disease (CD) suffer from symptoms that impair health-related quality of life (HRQoL).1-3 The Phase 3 GRAVITI treat-through trial evaluated the efficacy and safety of SC induction and maintenance of guselkumab (GUS), an interleukin (IL)-23 p19 subunit antagonist, in pts with moderately to severely active CD who had demonstrated a history of inadequate response or intolerance to oral corticosteroids, AZA, 6-MP, MTX, or biologics. Here we report HRQoL as measured by the Patient-Reported Outcomes Measurement Information System (PROMIS)-29 through Week (Wk) 48. PROMIS-29 consists of 7 domains (symptom domains: anxiety, depression, fatigue, pain interference, and sleep disturbance; functional domains: physical function and social participation) and a pain intensity item. Methods The GRAVITI programme for GUS in CD (NCT05197049) employs a treat-through design in which pts were allocated 1:1:1 to GUS 400mg SC every 4 weeks (q4w) (x3)→GUS 200mg SC q4w, GUS 400mg SC q4w (x3)→GUS 100mg SC every 8 weeks (q8w), or placebo (PBO). Pts in the placebo group who met the criteria for rescue therapy received guselkumab 400 mg SC at Wk16, Wk20, and Wk24 followed by guselkumab 100 mg SC q8w; GUS pts stayed on GUS per treat-through design (sham rescue). PROMIS-29 uses standardized T-scores, with a general population mean of 50 and standard deviation (SD) of 10. The physical component summary (PCS) and mental component summary (MCS) scores were calculated based on the domain T-scores. Clinically meaningful improvement (CMI) was according to previously defined thresholds for each domain, and the MCS and PCS.4 Higher scores indicate better health outcomes for the functional domains and two summary scores (PCS and MCS), and worse symptoms for the symptom domains, including the pain intensity item, which uses a numeric rating scale (NRS; 0 [no pain] to 10 [worst pain]). Results In the full analysis population, baseline mean PROMIS-29 domain scores were similar among all treatment groups in functional domain scores, symptom domain scores, and pain intensity scores. All baseline values were indicating impaired HRQoL (Table 1). GUS-treated pts achieved a greater improvement from baseline at Wk12 and Wk48 in each domain T-score, the pain intensity NRS score, and the PCS and MCS than PBO-treated pts. Additionally, the percentage of pts achieving CMI through Wk12 and Wk48 was greater for GUS vs PBO in each domain, the pain intensity NRS score, and the PCS and MCS scores (Figure 1). Conclusion Pts with moderately to severely active CD treated with GUS SC induction and maintenance experienced broad and clinically meaningful improvements in HRQoL compared with placebo pts as measured by PROMIS-29 through Wk12 and through Wk48.

P0587 Effectiveness and safety of Risankizumab in Crohn’s disease patients from a large Italian cohort: preliminary results from the RESOLVE IgIBD study

Abstract Background Risankizumab has been recently approved for the treatment of moderate-to-severe Crohn's disease (CD). It is a humanized IgG1 monoclonal antibody that binds to the p19 subunit of IL-23, selectively inhibiting IL-23. Due to the limited available real-world data on its effectiveness, this study aims to assess the short-term effectiveness and safety of risankizumab induction in a large, real-life Italian cohort of CD patients. Methods From September 2023, following AIFA reimbursement, until now, all consecutive CD patients treated with risankizumab in 14 Italian centers were retrospectively enrolled. Only patients who completed the induction phase of risankizumab, with at least a 12-weeks follow-up were included in the final analysis. Clinical characteristics, disease activity scores, steroid usage, and adverse effects were collected. The primary endpoint was steroid-free clinical remission (SFCR) (Harvey Bradshaw Index [HBI] <5) at 12 weeks. Secondary endpoints included clinical response (≥3 point decrease in HBI and/or HBI <5), biochemical remission (CRP≤ 5 mg/L), remission of extra-intestinal manifestations (EIMs), occurrence of disease complications, and adverse events. Results To date, 147 patients have been enrolled, with 67 completing the 12-week follow-up. Of these, 34 (50.7%) patients had received ≥3 biologics, and 38 (56.7%) had previous intestinal resections. Fifty-four patients underwent colonoscopy within the last 6 months before starting risankizumab, exhibiting a mean SES-CD of 10.9±6.0 and a mean Rutgeerts score of 3.1±1.4. The rates of SFCR and clinical response at week 12 were 58.2% (39/67) and 76.1% (51/67) respectively, while 53.7% (22/41) and 65.9% (27/41) in ustekinumab exposed patients. Fecal calprotectin levels decreased from 963.6±1346.0 to 311.8±403.0 at week 12. Thirty-eight patients (56.7%) achieved normal CRP levels at week 12. Clinical remission of rheumatological and dermatological EIMs was observed at week 12 in 16.7% (3/18) and 75.0% (6/8) of patients, respectively. Two patients developed disease complications, including one case of worsening of the disease and one of new fistula development. This latter patient discontinued treatment before week 12. Additionally, two patients (3.0%) experienced minor adverse events after risankizumab administration. No patients underwent surgery during the 12-weeks follow-up. Conclusion In a large cohort of refractory CD patients with multiple prior drug failures, including frequent failures with ustekinumab, nearly 60% achieved SFCR following risankizumab induction. Risankizumab demonstrated good effectiveness in managing dermatological EIMs, but less effectiveness in rheumatological EIMs. The safety profile of risankizumab was consistent with existing literature.

DOP099 Prolonged Pharmacodynamic Effects of Risankizumab Following Withdrawal in Patients with Moderately to Severely Active Ulcerative Colitis

Abstract Background Risankizumab (RZB) is a high-affinity humanized IgG1 monoclonal antibody that selectively binds to the p19 subunit of human IL-23 cytokine, thereby inhibiting its interaction with the IL-23 receptor.1 RZB was intentionally designed with modifications to the antibody that could contribute to prolonged half-life, low immunogenicity, and increased stability and bioavailability.1 The objective of this post-hoc analysis was to characterise the pharmacokinetic (PK) and pharmacodynamic (PD) effects of RZB following withdrawal in patients with moderately to severely active ulcerative colitis (UC). Methods In the UC maintenance trial (COMMAND, NCT03398135), 272 patients who responded to 12 weeks of intravenous (IV) RZB 1200 mg induction therapy were re-randomised to receive subcutaneous (SC) RZB maintenance dosing (180 mg or 360 mg) or placebo (PBO; RZB withdrawal).2 This analysis evaluated clinical endpoints, PK, and biomarkers of the SC PBO/withdrawal. Change from baseline in partial modified Mayo score, serum RZB concentrations and levels of high-sensitivity C-reactive protein (hs-CRP) and fecal calprotectin (FCP) were assessed at each predetermined study visits throughout the maintenance trial. Results A total of 90 patients were re-randomised to receive PBO (withdrew from RZB induction) in COMMAND. Predicted PK profiles of exposure over time in the PBO/withdrawal group showed that, following the third and final RZB induction dose, residual RZB concentrations lasted for at least 16 weeks before complete washout.3 The PBO/withdrawal group did not have meaningful increases from baseline in partial modified Mayo score until after about week 24 of maintenance (36 weeks since the last dose of RZB) (Figure). Levels of hs-CRP and FCP in the PBO/withdrawal patients remained low throughout maintenance and did not meaningfully increase until week 52. Conclusion Patients with moderately to severely active UC who received IV RZB 1200 mg induction therapy and were re-randomised to PBO exhibited continued response to RZB as demonstrated by disease activity and biomarkers for at least 6 months, exceeding the time of PK washout. hs-CRP and FCP did not increase until week 52 of maintenance and remained below baseline values. This durability of response may have important clinical implications and warrants continued investigation.

Takayasu arteritis: a geographically distant but immunologically proximal MHC-I-opathy.

Takayasu arteritis, a granulomatosis vasculitis with a pathogenesis that is poorly defined but known to be associated with HLA-B*52, shares many features with other MHC-I-opathies. In addition to the shared clinical features of inflammatory bowel diseases, cutaneous inflammation, and HLA-B*52, is shared association of an IL12B single- nucleotide polymorphism encoding the common IL-12 and IL-23 p40 subunit, which might affect not only type 17 cytokine responses, but also IFNγ and TNF production-the cardinal type 1 cytokines in granuloma formation. Considering the translational context of responses to TNF inhibition in Takayasu arteritis, in this Personal View we propose Takayasu arteritis as a type 1 MHC-I-opathy. Additionally, type 1 and type 17 T-cell immune responses show immune plasticity, which connects the overlapping features of Takayasu arteritis and spondyloarthritis spectrum disorders, providing a basis for shared anti-TNF responses, and points to p40 and IFNγ cytokine antagonism and potential selective CD8 T-cell repertoire ablation.

Characterization for the Similarity Assessment Between the Proposed Biosimilar SB17 and Ustekinumab Reference Product Using State-of-the-Art Analytical Methods.

SB17 is being developed as a biosimilar to ustekinumab reference product (RP), a human monoclonal antibody (IgG1 kappa immunoglobulin) that binds to the common p40 subunit of cytokines interleukin (IL)-23 and IL-12. Binding to this subunit prevents interaction with their receptor, resulting in modulation in the immune system responses that play a key role in inflammatory disease. The objective of this study was to demonstrate structural, physicochemical, and biological similarity between ustekinumab RP and SB17 using various state-of-the-art analytical methods. Comprehensive analytical characterization was conducted by the quality range and side-by-side comparison approach for SB17 versus the European Union (EU) and US ustekinumab RP using various analytical methods. Comparisons included purity, product-related impurity, charge heterogeneity, primary structure, posttranslational modification, higher-order structure, quantity, Fab-related biological activities (potency and binding activity), and Fc-related biological activities. On the basis of the analytical similarity assessment, the structural, physicochemical, and biological characterization results demonstrated that SB17 is comparable to the ustekinumab RP. In the structural aspects, it was confirmed that there is no clinically meaningful difference between posttranslational modification profiles and higher-order structures of SB17 compared with the ustekinumab RP. Product-related impurities in the form of aggregates were also confirmed to be similar. SB17 has lower acidic and basic variants compared with ustekinumab RP, owing to the difference in the producing cell line. Ustekinumab RP is expressed in an Sp2/0 cell line, whereas SB17 is expressed in CHO cell line. However, the difference between SB17 and ustekinumab RP in the charge variants is not considered to be clinically meaningful, since equivalent biological activity was observed. In the case of mechanism of action (MoA)-related biological activities, SB17 is highly similar to the EU and US ustekinumab RP with respect to overall critical and noncritical quality attributes analyzed. Moreover, similarity or lack of activity in Fc-related biological activities was also confirmed. On the basis of these results, SB17 is expected to have comparable safety and efficacy as compared with ustekinumab RP. In summary, the overall analytical characterization and similarity assessment results show that SB17 is comparable to the EU and US ustekinumab RP in terms of structural, physicochemical, biophysical, and biological attributes.

Efficacy and Safety of Mirikizumab in the Treatment of Moderately to Severely Active Ulcerative Colitis Regardless of Baseline Modified Mayo Score: Results From the Phase 3 LUCENT Trials

Abstract Background The modified Mayo score (mMS) is a measure for ulcerative colitis (UC) disease activity. Recent US Food and Drug Administration guidance for moderately to severely active UC trials suggests that patients should have baseline mMS of 5–9 including an endoscopy score of at least 2, opposed to the previous range of 4–9. This disclosure reports results from patients with UC with baseline mMS of 5–9 who received mirikizumab, a monoclonal antibody directed against the interleukin-23 p19 subunit, or placebo in the phase 3 LUCENT trials. Methods Mirikizumab was evaluated in the randomized, double-blind, placebo-controlled LUCENT-1 (NCT03518086) and LUCENT-2 (NCT03524092) trials, and the ongoing long-term LUCENT-3 (NCT03519945) trial, which use mMS 4-9. Analyses for patients with baseline mMS of 5-9 (excluding patients with mMS of 4) were conducted according to LUCENT trial statistical analysis plans. Categorical efficacy endpoints were summarized using proportions and confidence intervals. Continuous efficacy endpoints are presented as least-squares mean (standard error) changes from baseline. Results Mirikizumab demonstrated efficacy for the primary endpoint of clinical remission and major secondary endpoints including clinical response, endoscopic improvement, histologic–endoscopic mucosal improvement/remission, bowel urgency remission, and corticosteroid-free remission. Importantly, mirikizumab exhibited greater improvements versus placebo in the Inflammatory Bowel Disease Questionnaire, fatigue, symptomatic remission, and work productivity. Finally, mirikizumab demonstrated long-term (104-week) sustained, durable efficacy across all studied endpoints. No new safety signals were identified during 2-year follow-up. Conclusions Mirikizumab delivered significant clinical benefit for patients with baseline mMS of 5-9 and demonstrated a favorable safety profile.

Targeting the Interleukin 23 Pathway in Inflammatory Bowel Disease.

Interleukin (IL) 23, a member of the IL12 family of cytokines, maintains intestinal homeostasis, but is also implicated in the pathogenesis of inflammatory bowel diseases (IBDs). IL23 is a heterodimer composed of disulfide-linked p19 and p40 subunits. Humanized monoclonal antibodies selectively targeting the p19 subunit of IL23 are poised to become prominent drugs in IBDs. In this review, we discuss the pharmacodynamic and pharmacokinetic properties of the currently available IL23p19 inhibitors and discuss the mechanistic underpinnings of their therapeutic effects, including the mechanism of action, epitope affinity, potency, and downstream signaling. Furthermore, we address available data on the efficacy, safety, and tolerability of IL23p19 inhibitors in the treatment of IBDs and discuss important studies performed in other immune-mediated inflammatory diseases. Finally, we evaluate the potential for combining classes of biological therapies and provide future directions on the development of precision medicine-guided positioning of IL23p19 inhibitors in IBD.

Guselkumab for the treatment of moderate-to-severe plaque psoriasis in pediatric patients: results of the phase 3, randomized, placebo-controlled PROTOSTAR study.

No currently approved treatment for pediatric plaque psoriasis selectively targets interleukin (IL)-23. In adults, guselkumab (a selective IL-23 inhibitor targeting the p19 subunit) demonstrated substantial efficacy with a favorable safety profile in treating moderate-to-severe plaque psoriasis. PROTOSTAR (NCT03451851) evaluated the efficacy and safety of guselkumab in pediatric patients with moderate-to-severe plaque psoriasis. This phase 3, randomized, placebo-controlled study enrolled patients ≥6 to <18 years of age with moderate-to-severe plaque psoriasis. In Part 1 (Week [W]0-W16), patients were randomized to receive guselkumab, placebo, or open-label etanercept (active reference arm). At W16, Part 1 patients entered a guselkumab withdrawal/retreatment period or continued/crossed over to receive guselkumab (W16-W52). Co-primary endpoints were Investigator's Global Assessment (IGA) 0/1 and Psoriasis Area and Severity Index (PASI)75 (or United States Food and Drug Administration-required PASI90 co-primary endpoint) responses at W16 of Part 1. Part 2 evaluated continuous open-label guselkumab treatment (W0-W52). Of 92 and 28 patients enrolled in Parts 1 and 2, respectively, 86% and 96% continued treatment through W52. In Part 1, at W16, significantly higher proportions of guselkumab-treated than placebo-treated patients achieved IGA 0/1 (66% vs 16%; P<0.001), PASI75 (76% vs 20%; P<0.001), and PASI90 (56% vs 16%; P<0.01). More than one-third of guselkumab-treated patients achieved clear skin (IGA 0: 39% vs 4% placebo; PASI100: 34% vs 0% placebo; both P<0.01). In Part 2, at W52, 86%, 93%, and 82% of guselkumab-treated patients achieved IGA 0/1, PASI75, and PASI90, respectively. Through W16 of Part 1, 42%, 68%, and 58% of guselkumab-, placebo-, and etanercept-treated patients, respectively, had adverse events (AEs). Rates of AEs with guselkumab were similar through W52 in Parts 1 and 2; common AEs included nasopharyngitis, upper respiratory tract infection, and COVID-19. No serious or opportunistic infections occurred. Guselkumab demonstrated significant and clinically meaningful responses in pediatric patients with moderate-to-severe plaque psoriasis and all co-primary and major secondary endpoints were met. Guselkumab safety outcomes were similar to placebo; no new safety signals were identified. These findings support the use of guselkumab to treat pediatric patients with moderate-to-severe plaque psoriasis.