Introduction

Janus kinase inhibitors (JAKi), including tofacitinib (TOFA, a pan-JAK inhibitor) and filgotinib (FILGO, a selective JAK1 inhibitor), represent an emerging class of orally administered agents for moderate-to-severe ulcerative colitis (UC). Comparative real-world data on their effectiveness and safety are limited.

Aims & Methods

We conducted a multicenter, real-world, propensity score-weighted cohort study using data from the Sicilian Network for Inflammatory Bowel Diseases (SN-IBD). All adult UC patients treated with TOFA or FILGO with ≥16 weeks of follow-up were included. The primary outcomes were steroid-free clinical remission and clinical response at weeks 8 and 24. Treatment persistence and adverse events were also assessed. Inverse Probability of Treatment Weighting (IPTW) was applied to adjust for baseline differences.

Results

A total of 263 patients were included (TOFA: n=171; FILGO: n=92). At week 8, steroid-free clinical remission was achieved in 53.2% of patients treated with TOFA and 43.4% of those treated with FILGO (IPTW-adjusted OR: 1.51; 95% CI: 0.88–2.61; p=0.14). Clinical response at 8 weeks was reported in 75.4% of TOFA-treated patients versus 69.6% in the FILGO group (IPTW-adjusted OR: 1.34; 95% CI: 0.73–2.46; p=0.34). At week 24, steroid-free clinical remission was observed in 58.8% of the TOFA group and 44.9% of the FILGO group (IPTW-adjusted OR: 1.37; 95% CI: 0.76–2.49; p=0.30). Clinical response rates at 24 weeks were 63.6% for TOFA and 59.0% for FILGO (IPTW-adjusted OR: 1.13; 95% CI: 0.62–2.08; p=0.69). IPTW-adjusted Kaplan–Meier and Cox proportional hazards analyses showed no statistically significant difference in the likelihood of treatment discontinuation (log-rank p=0.294; IPTW-adjusted HR for TOFA: 0.78; 95% CI: 0.49–1.25; p=0.30). Adverse event rates were 12.7 and 5.4 per 100 person-years for TOFA and FILGO, respectively, with no significant difference (p=0.152).

Conclusion

In this real-world, IPTW-based study, TOFA and FILGO were well tolerated and demonstrated comparable and high effectiveness and treatment persistence in patients with moderate-to-severe UC, supporting their use as viable oral options in routine clinical practice.

Disclosure

FSM served as an advisory board member and/or received lecture grants from AbbVie, Ferring, Galapagos, Giuliani, Janssen, Lilly, Liohealth s.r.l., Pfizer, Sandoz, Takeda Pharmaceuticals. WF served as an advisory board member and/or received lecture grants from Abbvie, MSD, Takeda, Pfizer, Biogen, Sandoz, Zambon, Ferring, Sofar. AV received lecture grants from Pfizer. MC served as an advisory board member for AbbVie, MSD, Takeda Pharmaceuticals, and received lecture grants from AbbVie, MSD, Chiesi, and Takeda Pharmaceuticals. MC served as an advisory board member for AbbVie, MSD, Takeda Pharmaceuticals, and received lecture grants from AbbVie, MSD, Chiesi, and Takeda Pharmaceuticals. FM served as an advisory board member for Janssen and Galapagos, and received lecture grants from Takeda Pharmaceuticals. SR served as an advisory board member for AbbVie, Janssen, and MSD Pharmaceuticals, and received lecture grants from AbbVie, Galapagos, Janssen, MSD, Pfizer, and Takeda Pharmaceuticals. AO served as an advisory board member for AbbVie, Ferring, Galapagos, Lilly, MSD, Janssen, Pfizer, Samsung Bioepis, and Takeda Pharmaceuticals, and received lecture grants from AbbVie, Fresenius Kabi, Galapagos, Lionheath s.r.l., MSD, Sofar, Chiesi, Janssen, Pfizer, and Takeda Pharmaceuticals. All other authors: nothing to disclose.

Introduction

Ustekinumab has pioneered IBD treatment by targeting the p40 subunit shared by IL- 12 and IL-23, crucial cytokines in gut inflammation. Despite its lower binding affinity compared to more recent anti-IL-23 antibodies targeting the p19 subunit, ustekinumab achieves comparable remission rates in IBD. This unexpected efficacy likely stems from its dual action; IL-12 neutralization suppresses the initiation of new inflammatory gut lesions, while IL-23 inhibition maintains disease control (Eftychi et al., 2019). However, ustekinumab's sub-optimal binding affinity and immunogenicity (3-12% neutralizing ADA per Stelara Prescribing Information), presents clear opportunities to develop MVP-523 as a next-generation, bio-better therapeutic. Discovered 25 years ago, ustekinumab predates our current understanding of IBD pathology and antibody optimization techniques. Its sub-optimal performance characteristics present opportunities for improvement. Moreover, ustekinumab's extensive patient years of data and favorable safety profile make it an ideal template for next-generation drug development.

Aims & Methods

Computational protein design enabled by CCG Molecular Operating Environment and Epimatrix software.
Variants were expressed, purified and tested experimentally biochemically, in vitro cell models and in vivo in mice.

Results

Our optimization efforts have yielded MVP-523, featuring increased binding affinity/potency and reduced immunogenicity, while having the potential to extend halflife and dosing intervals. CDR amino acid substitutions in both heavy and light chains reduced KD from ~300 pM to ~50 pM, significantly improving IC50 in cell-based assays and enhancing in vivo IL-12 neutralization. Concurrently, computational protein design combined with EpiVax's ISPRI (Interactive Screening and Protein Reengineering Interface) was employed for in-silico deimmunization. This process successfully reduced the anti-drug antibody (ADA) score from 10.4% (which correlates with 3-12% observed clinically) to a predicted score of 1.5%. Considering that the majority of ustekinumab-induced ADAs are neutralizing, this substantial improvement could potentially lead to significantly enhanced outcomes in clinical trials and increased treatment durability.

Conclusion

MVP-523 represents a novel, bio-better therapeutic, built on ustekinumab's reliability and offers a de-risked clinical development candidate for IBD and other diseases. Furthermore, it provides an intriguing platform for engineering trispecifics (IL-12, IL-23, other target) while maintaining the preferred bivalent structure of classical IgG.

Disclosure

JHS BLB AFH are shareholders in Multiverse Pharma

Introduction

While three JAK inhibitors are now available in Ulcerative Colitis (UC), no direct comparison exists between these drugs making difficult the hierarchization of these therapeutic options.

Aims & Methods

We performed a systematic review and network meta-analysis to compare the short and long-term efficacy of the three available JAK inhibitors (JAKi) (Tofacitinib/TOFA, filgotinib/FILGO, upadacitinib/UPA) in patients with moderat-to-severe UC.
We performed a systematic review and network meta-analysis (PRISMAguidelines) of randomized controlled trials (including post-hoc analyses) conducted in adults, evaluating the efficacy of JAKi in moderate-to-severe UC.
The outcome mesures were 1) steroid-free clinical remission (CFREM) after induction therapy (partial Mayo score ≤ 2), 2) CFREM with endoscopic improvement (endoscopic Mayo score ≤ 1) after induction therapy, 3) CFREM at one year among induction-responders, 4) CFREM at one year among patients in clinical remission after induction.
The network meta-analysis was carried out according to a random effects model. The results are presented as relative risk (RR) with 95% confidence interval. The risk of bias of the studies was assessed according to the Cochrane risk-of-bias tool for randomized trials and overall statistical heterogeneity between studies was assessed using τ .
The SUCRA ranking method (surface under the cumulative ranking) was used to rank the treatments.

Results

Nine studies were included in this network meta-analysis, including a total of 2015 patients.
TOFA 10mg bid, FILGO 200 mg qd and UPA 45mg qd were more effective than placebo to induce CFREM and CFREM with endoscopic improvement. Side-by-side comparisons between JAKi found a higher efficacy of UPA 45 mg qd versus FILGO 200 mg qd (RR=0.22[0.10; 0.45]) for induction but no other significant difference between JAKi. SUCRA ranking hierarchizes induction therapies as following : UPA 45 mg qd (0.99), TOFA 10mg bid (0.75), FILGO 200 mg qd (0.27) and placebo (0.01).
Among induction-responders, all JAKi maintenance regimen (TOFA 10mg bid, TOFA 5mg, bid, FILGO 200mg qd, FILGO 100 mg qd, UPA 30 mg qd, UPA 15 mg qd) were more effective than placebo to achieve CFREM at one year with the following SUCRA ranking : UPA 30mg qd (0.85), TOFA 10mg bid (0.80), FILGO 200 mg qd (0.64), TOFA 5mg bid (0.56), UPA 15 mg (0.44), and placebo (0.01).
Among patients in CFREM after induction phase, all JAKi maintenance regimen (TOFA 10mg bid, TOFA 5mg, bid, FILGO 200mg qd, FILGO 100 mg qd, UPA 30 mg qd, UPA 15 mg qd) were more effective than placebo to achieve CFREM at one year with a different ranking (SUCRA) : TOFA 10 mg bid (0.84), FILGO 200 mg bid (0.74), TOFA (5mg bid) (0 .66), UPA 30mg qd (0.63), UPA 15 mg (0.44) and placebo (0.09).

Conclusion

While this network meta-analysis confirms the efficacy of JAKi to induce and maintain CFREM in moderate-to-severe UC, UPA seems to be the most effective JAKi to induce and maintain CFREM. However, once CFREM achieved after induction, continuing the same dose than during induction such as TOFA (10mg bid) or FILGO 200 mg seems to be more effective than reducing the dose (UPA 30 mg or UPA 15 mg) to maintain remission highlighting the dose-efficacy relationship of JAKi.

Disclosure

Consulting fees from: Abbvie, Amgen, Arena, Biocon, Biogen, Celltrion Healthcare, CTMA, Ferring, Galapagos/AlfaSigma, GutyCare/Resilience Janssen, Lilly, MSD, Nexbiome, Pfizer, Roche, Sandoz, Takeda et Tillotts
Lecture fees from: Abbvie, Amgen, Biogen, Celltrion Healthcare Galapagos/AlfaSigma, Ferring, Janssen, Lilly, Mayoli-Spindler, MSD, Nordic Pharma, Norgine, Pfizer, Roche, Takeda, Tillotts and Vifor Pharma
Research grants/fundings from: Abbvie, Celltrion Healthcare, Janssen, Lessaffre, Lilly, Pfizer, Sandoz and Takeda

Introduction

Mirikizumab is a humanized IgG4 monoclonal, anti-interleukin-23p19 antibody. VIVID-2 (NCT04232553), an ongoing open-label study, has demonstrated sustained clinical and endoscopic efficacy at 2 years of treatment of mirikizumab for Crohn’s disease (CD).¹ Here we present the long-term quality of life (QoL) up to 2 years from VIVID-2.

Aims & Methods

Patients enrolled in the phase 3 VIVID-1 study who achieved an endoscopic response to mirikizumab continued maintenance treatment in VIVID-2, while endoscopic non-responders received mirikizumab induction therapy followed by maintenance treatment. Quality of life was assessed using the Inflammatory Bowel Disease Questionnaire (IBDQ). The proportion of patients who achieved IBDQ response/remission, as well as mean changes from VIVID-1 baseline in IBDQ total scores at W64 and104 were reported. EQ-5D-5L Visual Analog Scale (VAS) scores (range 0-100, with 100 being best imaginable health state) were assessed at W64. Work productivity was assessed at W64 using Work Productivity and Activity Impairment Questionnaire in Crohn's Disease (WPAI:CD) (4 scores including absenteeism, presenteeism, work productivity loss and activity impairment are derived as percentages with higher values indicating greater impairment). Modified non-responder imputation (mNRI) was used for binary missing data imputation, and modified baseline observation carried forward (mBOCF) was used for continuous missing data imputation. Estimates of mean changes from baseline were calculated with analysis of covariance (ANCOVA).

Results

Analysis of endoscopic responders showed IBDQ response and IBDQ remission were maintained through W104 (85.0% and 71.3%, respectively) while endoscopic non-responders also maintained IBDQ response and remission through the same time (72.6% and 60.8%, respectively). (Table 1) Mean change from baseline in IBDQ total score was maintained through W104 for endoscopic responders and non-responders (least squares mean (standard error); 57.2 (2.1) and 46.8 (2.4), respectively). Similarly, EQ-5D-5L VAS improvement was observed for both groups at W64 (27.0 (1.0) and 22.3 (1.2), respectively). WPAI:CD improvements in both groups ranged from −13.9 (1.8) to −34.3 (1.5) for the different scores collected at W64.

Conclusion

Patients continuing mirikizumab maintenance and those receiving reinduction achieved meaningful long-term QoL improvement that was maintained at 2 years of treatment.

References

1. Barnes E, Sands B, D'Haens G, et al. Long-term efficacy and safety of mirikizumab following 104 weeks of continuous treatment for Crohn's disease: results from the VIVID-2 open-label extension study. Gastroenterology. 2025;168(3 Suppl):S14-S15. doi:10.1053/j.gastro.2025.01.073.

Introduction

​Post-ERCP pancreatitis (PEP) is still the most common major complication of ERCP despite technical advancements and meticulous patient selection. The efficacy of the existing techniques is conflicting.

Aims & Methods

We aimed to compare the efficacy of peripapillary epinephrine injection in combination with rectal diclofenac for the prevention of PEP in high-risk patients .
Methods Between January 2023 and August 2023, a total of 378 patients were enrolled. We calculated that 189 patients in each group (rectal diclofenac – Group A and peripapillary epinephrine injection plus rectal indomethacin – Group B) would suffice based on a previous study by our group (α:0.05, 80% power). Patients with a non-naive papillae, ampulla of Vater cancer, biliary pancreatitis, altered anatomy, pregnancy, and pancreatic diseases such as chronic pancreatitis were excluded. Patients were assigned in a 1:1 simple randomized fashion. The primary outcome was the rate of PEP. Secondary outcomes were the rate of hyperamylasemia and rates of other adverse events.

Results

​Demographic characteristics, indications, and procedure-related risk factors were similar between the groups. The overall success rate of selective cannulation was 99.2% in Group A and 99.3% in Group B (p=0.997). PEP occurred in 9 of the 189 (4.8%) patients in Group A and 2 of the 189 (0.5%) patients in Group B. All cases were mild and managed conservatively. The rate of post-procedure 4th-hour hyperamylasemia was significantly higher in Group A (19% vs 5%, p<0.001). Postsphincterotomy-related bleeding developed in 5 patients in Group A (2.64%) but none of the patients had bleeding in Group B. Stapfer type-II perforation occurred in two patients in each group. No major cardiac adverse events-related to epinephrine injection were detected in Group B.

Conclusion

Compared to rectal diclofenac, peripapillary epinephrine injection significantly reduced the incidence of PEP, post-procedure hyperamylasemia, and sphincterotomy-related bleeding.

Introduction

Clinical remission of symptoms and endoscopic disease activity were the primary endpoints of two phase-3 studies (LUCENT-1 and -2; NCT03518086 and NCT03524092) in patients with moderately-to-severely active ulcerative colitis (UC) treated with the anti-IL23p19 monoclonal antibody, mirikizumab (miri)(1). This outcome was reached in 24.2% and 49.9% of miri-treated patients at week (W) 12 and 52, respectively. 
In clinical practice, access to endoscopic evaluation can be limited. Measurement of faecal calprotectin (FCP) can be a surrogate biomarker for endoscopic disease activity and therapy response in patients with UC(2). Combined symptom and FCP remission may serve as a surrogate for clinical and endoscopic remission in real-world clinical practice.

Aims & Methods

This post-hoc analysis evaluates the proportion of patients in LUCENT-1/-2 who achieved combined symptom and biomarker remission.
Patients in LUCENT-1 (N=1162) were randomised to receive either 300mg miri (n=868) or placebo (PBO; n=294) intravenously (IV) every 4W (Q4W) for 12W. In LUCENT-2, patients from LUCENT-1 with no clinical response to miri at W12 (N=272) received an extended induction therapy of 300mg miri IV Q4W for 12W (W24 of continuous treatment), while miri-responders (N=544) were randomised to either subcutaneous (SC) 200mg miri (n=365) or PBO (n=179), Q4W for 40W (W52 of continuous treatment).
At W4, W12, W24, and W52, patient symptoms and FCP levels were reported as combined endpoints of symptomatic response or remission (defined in Table 1), with FCP remission (FCP ≤250µg/g). The Cochran-Mantel-Haenszel test compared the treatment groups a) miri and PBO at W4 and W12 from LUCENT-1, and b) miri and PBO at W52 from LUCENT-1 miri-responders. The risk difference and its associated confidence intervals and p-values were reported in Table 1. Non-responder imputation was used for binary variables, while modified baseline observation carried forward was used for continuous variables.

Results

At W4 and W12, 14.2% and 33.2% of the miri group compared to 8.5% and 18.7% of PBO (p=0.0113 and <0.0001, respectively) achieved the combined symptomatic response and biomarker remission endpoint, while 7.3% and 23.7% of the miri group compared to 3.7% and 11.2% of PBO (p=0.0282 and <0.0001, respectively) achieved the combined remission endpoints. At W52, 54.3% of the miri group compared to 27.4% of PBO (p=<0.0001) achieved the combined symptomatic response and biomarker remission endpoint, while 48.5% of the miri group compared to 21.8% of PBO (p=<0.0001) achieved the combined remission endpoints. At W12 and W24, 2.9% and 23.5% of the extended induction group achieved combined symptomatic response and biomarker remission endpoints, respectively, while 1.1% and 13.2% achieved the combined remission endpoints.

Conclusion

In moderate-severe UC, patients treated with miri demonstrated improved efficacy compared to PBO in combined symptomatic and biomarker response and remission endpoints. Additionally, the data from this post-hoc analysis is consistent with the clinical remission data from LUCENT studies, indicating that this is a suitable endpoint measure in real-world practice.

References

1. D'Haens G, Dubinsky M, Kobayashi T, Irving PM, Howaldt S, Pokrotnieks J, et al. Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med. 2023;388(26):2444-55.
2. Bressler B, Panaccione R, Fedorak RN, Seidman EG. Clinicians' guide to the use of fecal calprotectin to identify and monitor disease activity in inflammatory bowel disease. Can J Gastroenterol Hepatol. 2015;29(7):369-72.
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Disclosure

MCF reports payment or honorarium for speaker events: Eli Lilly and Company, Pfzier, AbbVie, Alfa-Sigma, Johnson & Johnson, and Takeda; meeting/travel support: AbbVie, Takeda, and Johnson & Johnson. JG reports grants/contracts: MSD, Janssen, Takeda, Kern Pharma, Sandoz, AbbVie, and GE Healthcare consulting fees: AbbVie, MSD, Jassen, Takeda, Roche, Eli Lilly and Company, Celltrion, Pfizer, Galapagos, GoodGut, and GE Healthcare; payment or honorarium for speaker events: AbbVie, MSD, Janssen, Kern Pharma, Bülhmann, GoodGut, GE Healthcare, Takeda, Eli Lilly and Company, Pfizer, and Galapagos; meeting/travel support: AbbVie, MSD, Janssen, Jern Pahrma, Bülhmann, GE Healthcare, Eli Lilly and Company, and Pfizer. EDM reports grants/contracts: Adacyte Therapeutic; consulting fees: Roche; payment or honorarium for speaker events: Eli Lilly and Company and Adacyte; travel/meeting support Adacyte, Pfizer, Kern Pharma, and AbbVie. CWL reports consulting fees: AbbVie, Janssen, Takeda, Pfizer, Galapagos, GSK, Gilead, Vifor Pharma, Ferring, Dr Falk Pharma, BMS, Boehringer Ingelheim, Eli Lilly and Company, Merck, Novartis, Sandoz, Celltrion, Cellgene, Amgen, Samsung Bioepis, Fresenius Kabi, Tillotts, Kuma Health, and Trellus Health and Iterative Health; payment or honorarium for speaker events: AbbVie, Janssen, Takeda, Pfizer, Galapagos, GSK, Gilead, Vifor Pharma, Ferring, Dr Falk Pharma, BMS, Boehringer Ingelheim, Eli Lilly and Company, Merck, Novartis, Sandoz, Celltrion, Cellgene, Amgen, Samsung Bioepis, Fresenius Kabi, Tillotts, Kuma Health, and Trellus Health and Iterative Health. GS reports consulting fees: AbbVie, Takeda, Johnson & Johnson, Eli Lilly and Company, BMS, Pfizer, and Celltrion; payment or honorarium for speaker events: AbbVie, Takeda, Johnson & Johnson, Eli Lilly and Company, BMS, Pfizer, and Celltrion; participation on data safety monitoring or advisory board: AbbVie, Takeda, Eli Lilly and Company, BMS, and Pfizer; leadership or fiduciary role in committees: ACG training committee, ACG FDA committee, AGA Government Affairs committee, and Crohn’s and Colitis Foundation National Scientific Advisory Committee. ES reports consulting fees: Janssen-Cilag of Johnson & Johnson, Pharmacosmos, Takeda Pharma, AbbVie Deutschland, Pfizer, Tillotts Pharma, AstraZeneca, Galapagos Biopharma, Eli Lilly and Company, Celltrion, DGVS, Dr. Falk Pharma, BMS, Kompetenznetz Darmerkrankungen, and STADA; payment or honorarium for speaker events: Janssen-Cilag of Johnson & Johnson, Pharmacosmos, Takeda, AbbVie Deutschland, Pfizer, Tillotts Pharma, AstraZeneca, Galapagos Biopharma, Eli Lilly and Company, Celltrion, DGVS, Dr. Falk Pharma, BMS, Kompetenznetz Darmerkrankungen, and STADA. DPH reports grants/contracts: Johnson & Johnson and Pfizer; consulting fees: Eli Lilly and Company, AbbVie, Abivax, BMS, Johnson & Johnson, Prometheus, Sanofi, Pfizer, CorEvitas, Fresenius Kabi, Biocon, and Takeda. HG, IR, and ED are employees and minor shareholders in Eli Lilly and Company. AK is an employee of HaaPACS GmBH and a contractor for Eli Lilly and Company.