Introduction

Tulisokibart is a monoclonal antibody that targets tumor necrosis factor-like cytokine 1A (TL1A), a regulator of inflammation and fibrosis in inflammatory bowel disorders. In the Phase 2 ARTEMIS-UC study, a significantly higher proportion of participants on tulisokibart compared to placebo achieved clinical remission after 12 weeks of induction treatment in patients with moderate to severe active ulcerative colitis (UC) and conventional or advanced treatment failure.¹ In a post hoc analysis from ARTEMIS-UC, re-induction and delayed induction treatment with tulisokibart were effective in participants who did not respond during the initial induction period.² We explored the efficacy and safety of tulisokibart maintenance therapy up to 1 year during the open-label extension of ARTEMIS-UC among patients who responded to induction, re-induction, and delayed induction.

Aims & Methods

Participants (≥18 years) were randomized to intravenous (IV) tulisokibart 1000 mg on day 1 and 500 mg at weeks 2, 6, and 10 or placebo. The study population consisted of 2 cohorts based on a genetic diagnostic test (Dx) assessing likelihood for responding to anti-TL1A treatment. Cohort 1 included participants stratified by Dx results while Cohort 2 included only Dx positive participants. Cohort 1 is the population used in this analysis. Participants were classified as induction responders (defined as reduction of ≥2 points and ≥30% in modified Mayo score from baseline, accompanied by a reduction ≥1 in rectal bleeding subscore or absolute rectal bleeding subscore ≤1 at week 12) or induction nonresponders. Induction non-responders in the tulisokibart and placebo groups were assigned to an open label 12-week re-induction with the aforementioned tulikosibart induction dosing regimen. Cohort 1 induction, re-induction, and delayed induction responders were randomized (stratified by Dx status) to open-label IV tulisokibart 100 mg or 250 mg every 4 weeks.

Results

In Cohort 1, 47 tulisokibart induction responders, 13 re-induction responders, and 29 delayed induction responders were randomized to open-label maintenance treatment with tulisokibart 100 mg or 250 mg every 4 weeks. Maintenance of treatment effect was generally similar with a trend for higher efficacy with tulisokibart 250 mg vs 100 mg maintenance treatment observed across the 3 groups. The safety profile of tulisokibart maintenance treatment was similar across the 3 groups, with no new safety signals being observed.

Conclusion

Tulisokibart was effective as a maintenance treatment in patients with moderate to severe UC. The effect was generally similar across Cohort 1 tulisokibart induction responders, re-induction responders, and delayed induction responders. Tulisokibart maintenance treatment was well tolerated across the 3 groups, with no identified safety signals. Altogether, this suggests that a second induction regimen in tulisokibart non-responders may result in a long-term efficacy benefit without increased safety risk. Larger trials are needed to confirm these findings.

Table: Efficacy and fecal calprotectin

As observed	Tulisokibart induction	Tulisokibart induction responders				Tulisokibart induction non-responders who responded to re-induction with tulisokibart			Placebo induction non-responders who responded to delayed induction with tulisokibart
	Week 12	Week 34		Week 50		Week 26	Week 48		Week 26	Week 48
		100 mg	250 mg	100 mg	250 mg​		100 mg	250 mg		100 mg	250 mg
Endoscopic improvement, n/N (%)	25/68 (36.8)	N/A	N/A	8/22 (36.4)	12/25 (48.0)	N/A	3/6 (50.0)	1/7 (14.3)	N/A	4/17 (23.5)	3/12 (25.0)
Clinical response, n/N (%)	45/68 (66.2)	N/A	N/A	13/22 (59.1)	17/25 (68.0)	N/A	3/6 (50.0)	4/7 (57.1)	N/A	7/17 (41.2)	6/12 (50.0)
Symptomatic response, n/N (%)	60/68 (88.2)	17/22 (77.3)	23/25 (92.0)	15/22 (68.2)	22/25 (88.0)	13/21 (61.9)	4/6 (66.7)	5/7 (71.4)	31/41 (75.6)	11/17 (64.7)	10/12 (83.3)
Symptomatic improvement, n/N (%)	N/A	17/22 (77.3)	21/25 (84.0)	15/22 (68.2)	20/25 (80.0)	10/21 (47.6)	3/6 (50.0)	5/7 (71.4)	26/41 (63.4)	11/17 (64.7)	9/12 (75.0)
Mean (SD) fecal calprotectin, µg/g Baseline Timepoint	1219.1 (1381.5) N=67 594.4 (926.9) n=55	1103.9 (855.7) n=22 628.5 (995.2) n=13	1204.2 (1614.9) n=24 239.2 (367.7) n=19	1103.9 (855.7) n=22 785.0 (1270.5) n=13	1204.2 (1614.9) n=24 636.7 (916.1) n=18	1228.9 (1548.3) n=21 906.3 (936.8) n=18	531.7 (565.0) n=6 791.8 (1473.2) n=4	1377.9 (1075.4) n=7 399.8 (280.2) n=4	1230.4 (1209.3) N=41 691.4 (902.6) n=36	877.9 (934.9) n=17 476.2 (837.5) n=12	1671.9 (1481.4) n=12 594.5 (968.4) N=10
GM fecal calprotectin fold change from baseline	0.21	0.30	0.21	0.31	0.23	0.48	0.22	0.25	0.41	0.47	0.17
Endoscopic improvement is defined as endoscopy subscore ≤ 1 with no friability. The 3-component Modified Mayo Score clinical response is defined as reduction from baseline ≥ 2 points and ≥ 30% in 3-component Modified Mayo Score, accompanied by a reduction ≥ 1 in RB subscore or absolute RB subscore ≤ 1. Symptomatic response is defined as a reduction of PRO-2 score ≥ 1 point from baseline. Symptomatic improvement is defined as RB subscore = 0 or SF subscore = 0 or 1 with a reduction of ≥ 1 point from baseline. GM, geometric mean; N/A, not assessed at that timepoint.

References

1. Sands et al. N Engl J Med 2024; 26;391:1119-1129
2. Hoque et al. J Crohns Colitis 2025; 19(suppl 1):i1158-i1159

Disclosure

Sami Hoque: ​Received Lecture fees and research grants from Tillotts, Ferring and Eli Lilly.
Bruce E. Sands: Travel fees from Eli Lilly and Company, Janssen Research & Development, LLC, Takeda Development Center Americas, Inc.; Received food & beverage from AnX Robotica Corp.; Grant from Janssen Research & Development, LLC; Owns stock options in Ventyx Biosciences; Consulting fees from AbbVie, Abivax, Aclaris Therapeutics, Adiso Therapeutics, Agomab Therapeutics, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, Artizan Biosciences, Artugen Therapeutics, AstraZeneca, Biora Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb Company, Celltrion Healthcare, Celltrion Healthcare, Connect Biopharm, Cytoki Pharma, Eli Lilly and Company, Entera, Enveda Biosciences, Equilium, Evommune, F. Homann-La Roche AG, Ferring, Fresenius Kabi USA, LLC, Galapagos, Genentech USA, Inc., Gilead Sciences , GlaxoSmithKline, GossamerBio, HMP Acquisition, Imhotex, Immunic, Immunyx Pharma Ltd., Index Pharmaceuticals, Innovation Pharmaceuticals, Janssen Biotech, Inc., Janssen Scientific Affairs, LLC, Johnson & Johnson Health Care Systems Inc., Kaleido, Kallyope, Kyowa Kirin Co., Ltd, Merck & Co., Inc., Microba, Microbiotica Limited, MiroBio, Mobius Care, Morphic Therapeutic, MRM Health, Nexus Therapeutics, Nimbus Therapeutics, Odyssey Therapeutics, Pfizer, Progenity Inc., Prometheus Biosciences, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Pharma, Recludix Pharma, SANOFI US SERVICES INC., Spyre Therapeutics, Surrozen, Synlogic Operating Company, Takeda Pharmaceuticals International, Inc., Target RWE, Teva Branded Pharmaceutical Products R&D, Theravance Biopharma Inc., TLL Pharmaceutical, VectivBio AG, Ventyx Biosciences
Brian G. Feagan: Consulting fees from Abbvie, Adiso Therapeutics, Agomab, Alimentiv Inc, Allianthera, Amgen Canada, AnaptysBio, Applied Molecular Transport, Arena Pharma, Biora Therapeutics, Blackbird Laboratories, Boehringer Ingelheim AB, Bristol-Myers Squibb, Celgene, Celsius Therapeutics, Connect BioPharma, Duality, Eli Lilly and Company, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen Global Services, LLC, JapanTobacco, Klick Health, Mage Biologics, Mestag Therapeutics, Mobius Therapeutics, LLC, Monte Rosa Therapeutics, Nexys Therapeutics, Nimbus Discovery Inc, Orphagen Inc., PFIZER CANADA INC, Prometheus, SANOFI US SERVICES INC., Seres Therapeutics, Sobi, Inc, Spyre Therapeutics, Surrozen, Synedgen, Takeda Canada, Takeda Development Center Americas, Inc., Televant, Tillotts, Triastek Inc.
Mark Yen: Employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Bin Dong: Employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Wen Zhou: Employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Silvio Danese: Consulting fees from AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion Healthcare, Ferring, Gilead Sciences, Hospira, Inc., Janssen Biotech, Johnson & Johnson Health Care Systems Inc., Pfizer, Sandoz, UCB Inc., Vifor (International) Ltd.

Introduction

The need for effective therapies in moderate to severe Crohn's disease (CD) drives the comparative evaluation of biologic treatments. The current work uses an anchored Matching-Adjusted Indirect Comparison (MAIC) to assess the efficacy of guselkumab (GUS) relative to risankizumab (RZB) during the treatment induction phase. This MAIC is using data from five phase 3 placebo-controlled blinded clinical trials (GRAVITI, GALAXI 2, GALAXI 3, ADVANCE, MOTIVATE).

Aims & Methods

Adult patients with moderate to severe CD, as defined in GRAVITI, GALAXI 2/3, ADVANCE and MOTIVATE trials were included. An anchored MAIC was utilized, leveraging placebo as common comparator and following guidance from the National Institute for Health Care Excellence in UK. The analysis aligned pooled individual patient data for GUS with published data for RZB by matching exclusion criteria and patient baseline characteristics that could be treatment effect modifiers (eg Age, Sex, BMI, CDAI, disease location or prior biologic treatment failure). During induction, patients received GUS 200 mg intravenous or 400 mg subcutaneous at weeks 0, 4, and 8 or RZB 600 mg intravenous at weeks 0, 4, and 8. The endpoints of interest were symptomatic endpoints such as clinical remission, PRO-2 remission, clinical response, abdominal pain and stool frequency remission, as well as endoscopic response at week 12, which marks the end of the induction period.

Results

After matching, baseline characteristics were balanced between the GUS and RZB cohorts. In a mixed population of bio-naïve and bio-experienced patients, GUS demonstrated statistically significant results in comparison to RZB for PRO-2 remission, clinical response and abdominal pain remission (table 1). Clinical remission showed a trend in favor of GUS, endoscopic response and stool frequence remission were comparable to RZB. In patients with biologic treatment failure versus the MOTIVATE trial, results had been generally more in favor of GUS, while maintaining positive outcomes seen across mixed populations (ADVANCE & MOTIVATE). Results were also mostly consistent whether analyzing pooled GUS data or individual trials, eg from GRAVITI, against RZB.

Table 1: Results of GUS from pooled GRAVITI, GALAXI 2/3 vs. RZB for induction period at week 12

Endpoint	RE measure	Mixed population (ADVANCE & MOTIVATE)		Bio-failure population (MOTIVATE)
		BC	SA	BC	SA
Clinical response	OR [95%CI]	1.78* [1.06; 2.99]	1.42 [0.76; 2.64]	1.71 [0.82; 3.57]	1.23 [0.49; 3.04]
Endoscopic response	OR [95%CI]	1.05 [0.56; 1.97]	1.05 [0.53; 2.09]	1.57 [0.59; 4.18]	1.56 [0.49; 5.01]
Clinical remission	OR [95%CI]	1.51 [0.84; 2.70]	1.22 [0.60; 2.46]	1.52 [0.65; 3.51]	1.08 [0.39; 3.01]
PRO-2 remission	OR [95%CI]	1.96* [1.13; 3.38]	1.85* [1.03; 3.33]	2.89* [1.29; 6.49]	2.97* [1.11; 7.94]
AP score remission	OR [95%CI]	1.68 [1.00; 2.82]	1.37 [0.75; 2.52]	2.02 [0.97; 4.20]	1.68 [0.69; 4.09]
SF score remission	OR [95%CI]	0.99 [0.62; 1.59]	0.93 [0.55; 1.58]	1.14 [0.59; 2.19]	1.04 [0.48; 2.26]

Footnotes: clinical response= ≥100-point reduction from baseline in CDAI OR CDAI <150; endoscopic response= ≥50% improvement from baseline in SES-CD OR SES-CD ≤2; clinical remission= CDAI <150; PRO-2 remission=AP mean daily score at or below 1 [AP≤1] AND SF mean daily score at or below 3 [SF≤3], and no worsening of AP or SF from baseline; AP score remission=Abdominal Pain mean daily score at or below 1 [AP≤1];
SF score remission= number of liquid or very soft stools mean daily score at or below 3 [SF≤3];
BC=baseline risk-adjusted; SA=sensitivity analysis; *p<0,05

Conclusion

The anchored MAIC analysis demonstrates comparable to even superior efficacy of guselkumab over risankizumab in inducing symptomatic improvements in Crohn's disease patients. It also suggests that subcutaneous induction seems to be preferential over iv induction.

Disclosure

van Sanden S, Trevisan M, Strobl A and Wirth D are employees of J&J Innovative Medicines

Introduction

Upadacitinib (UPA) is an oral, reversible Janus kinase inhibitor (JAKi) approved for the treatment of patients with moderate-to-severe ulcerative colitis (UC).^1-2 Despite substantial evidence from clinical trials supporting the use of UPA for treating UC, real-world (RW) data on its effectiveness and safety remain limited.³ The Prospective Real-World Study of UPA in UC (PROFUNDUS) is an ongoing multi-country, open-label, noninterventional, observational study aimed to evaluate the effectiveness and safety of UPA in patients with moderate-to-severe UC in RW practice (initiated 15 Aug 2022).

Aims & Methods

PROFUNDUS recruited 785 adult patients (18 to 75 years [yrs] of age) with moderate-to-severe UC initiating UPA in 16 countries worldwide. UPA was administered in accordance with the terms of the local marketing authorization, with patient treatment determined by the investigator, and patients followed for up to 3 yrs (156 weeks [wk]). This analysis represents data available after the first 500 patients completed 6 months of treatment or discontinued before 6 months, with a data cut-off of 28 Feb 2025. Of the first 500 patients who provided informed consent and met the inclusion criteria, the full analysis set (FAS) included 490 patients who initiated a once-daily UPA dosing regimen. This analysis reported baseline demographics and disease characteristics among FAS; the time to achievement of first clinical response per daily Partial Adapted Mayo Score (pAMS) and the percentage of patients achieving clinical response per pAMS at the end of UPA induction (wk 8) or extended induction (wk 16) were reported among evaluable patients who took at least 1 dose of UPA and had available scores to define the outcomes, a subset of FAS. Safety outcomes were analysed through week 26 (6 months), with treatment-emergent adverse events (TEAEs) presented as patient numbers and percentages.

Results

Among FAS, the patient age range was 18 to 79 yrs; 43.3% were female. At baseline (defined as the last available assessment on or before the first dose date of UPA), pAMS were as follows: < 2: 26.5%; 2-4: 48.1%; > 4-5: 18.8%; > 5-6: 6.6%; with score 0 indicative of inactive disease, while a score of 6 indicates active disease and spontaneous bleeding.⁴ At baseline, 51.3% of patients had a history of intolerance or inadequate response (IR) to advanced therapies (AT-IR), with 13.1% of patients who failed ≥ 1 JAKi. Among evaluable patients, the median (IQR) time to achieve the first clinical response per daily pAMS was 4 (3.0-8.0) days (N = 373; Table). By the end of induction treatment (wk 8 or 16), 79.6% (258/324) of the evaluable UPA-treated patients achieved clinical response per pAMS (Table). Among UPA-treated patients, the occurrence rates of any treatment-emergent adverse events (TEAEs) and TEAEs possibly related to the study treatment were as follows: any adverse event (AE) (51.2%; 34.9%), serious AEs (5.5%; 2.2%), and severe AEs (5.1%; 2.2%) (Table).

Effectivenessa	Any UPA dose
Time to first achievementb of clinical response per Daily pAMSb Events analysed – n/N (%) Median (IQR), days Clinical response per pAMSc at week 8 or 16 of induction, n/N (%) [95% CI]	364/373 (97.6) 4.0 (3.0-8.0) 258/324 (79.6) [75.2, 84.0]
Overall TEAEs, Week 26 of Therapy,d n (%) Any AE AE with a reasonable possibility of being related to study treatmente Severe TEAE Serious TEAE AE leading to discontinuation of the study drug AE resulting in deathf	Any UPA dose (N = 490) 251 (51.2) 171 (34.9) 25 (5.1) 27 (5.5) 34 (6.9) 1 (0.2)
Overview of TEAEs With Reasonable Possibility of Being Related to Study Treatment Through Week 26,d n (%) Any AEe Severe TEAE Serious TEAE AE leading to discontinuation of the study drug AE resulting in death	Any UPA dose (N = 490) 171 (34.9) 11 (2.2) 11 (2.2) 24 (4.9) 0
Table. Summary of PROFUNDUS Interim Effectiveness and Safety Results. FAS, full analysis set; IQR, interquartile range; pAMS, partial Adapted Mayo Score; RBS, rectal bleeding score; SF, stool frequency; TEAE, treatment-emergent adverse event; UPA, upadacitinib. aEffectiveness population included evaluable patients who took at least 1 dose of UPA and had available diary scores to define the corresponding outcome among the first 500 patients who provided informed consent and satisfied eligibility criteria. Patients who discontinued due to lack of effectiveness or intolerability were categorised as nonresponders, while those who discontinued due to other reasons were treated as missing data for the responder outcome and censored for the time-to-event outcome. bDefined as a decrease in daily pAMS ≥ 1 point and ≥ 30% from baseline, in addition to a decrease in daily RBS ≥ 1 or a daily RBS ≤ 1. Time to first achievement was based on the difference in time between the date of first achievement and first dose of UPA. Only patients with baseline daily pAMS > 0 with at least one post-baseline score are included. If a patient never achieved this outcome within 183 days (week 26), then that patient's time to first achievement was censored at day 183 (week 26), UPA discontinuation, study discontinuation, or cut-off date, whichever comes earlier. Kaplan-Meier nonparametric estimates were reported. cDefined as a decrease from baseline in pAMS ≥ 1 point and ≥ 30%, in addition to a decrease from baseline in the RBS ≥ 1 or absolute RBS ≤ 1. Patients with baseline score ≥1 and available score at end of induction are included. dIncluded patients with at least 1 dose of UPA among the first 500 patients who provided informed consent and satisfied eligibility criteria. Included events within 26 weeks (183 days) of starting study treatment. eAs assessed by study investigator. fThere was 1 death due to drowning that was determined to have no reasonable possibility of being related to the study drug. Data cut-off date was 28 Feb 2025.

Conclusion

In this interim analysis of the PROFUNDUS study, UPA demonstrated rapid effectiveness in achieving clinical response in patients with moderate-to-severe UC in RW practice, in a wide variety of age ranges, consistent with the efficacy observed in the UPA UC clinical trials.¹ Overall, UPA was well-tolerated, with few serious AEs reported, and most of these were assessed as unrelated to UPA by the investigator.

References

1. AbbVie Inc. RINVOQ (Upadacitinib) [package insert] U.S. Food and Drug Administration website. https://www.rxabbvie.com/pdf/rinvoq_pi.pdf. Revised May 2023. Accessed 25 Feb 2025.
2. AbbVie DG& CoK. RINVOQ. Summary of Product Characteristics. European Medicine Agency website. https://www.ema.europa.eu/en/documents/product-information/rinvoq-epar-product-information_en.pdf. Revised Feb 2025. Accessed 25 Feb 2025.
3. Seidelin J, et al. J Crohn’s Colitis. 2025;19(1):i1260-i1262. [Abstract].
4. Louis E, et al. JAMA. 2024;332(11):881-897.

Disclosure

Funding: AbbVie funded this study (PROFUNDUS; NCT05494606) and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship.
Acknowledgments: AbbVie and the authors thank the participants, study sites, and investigators who participated in this clinical trial. Paulette A. Krishack, PhD, of AbbVie, provided medical writing support.
Disclosures: Remo Panaccione has received consulting fees, speaker fees, and research support from Abbott, AbbVie, Abbivax, Alimentiv Amgen, AnaptysBio, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring Pharmaceuticals, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, GlaxoSmithKline, JAMP Bio, Janssen Pharmaceuticals, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Sanofi, Satisfai Health, Sublimity Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Viatris, Ventyx, and UCB.
Gareth Parkesreports personal payments, honoraria, speaker fees, travel grants and/or fellowships from AbbVie, Allergan, Bristol Myers Squibb, Celltrion, Ferring, Galapagos, Janssen, Napp, Takeda, and Tillotts, and directorship and shareholding with Ampersand Health. TR reports personal grants from AbbVie; personal consulting fees from AbbVie, Arena, Aslan, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Ferring, Galapagos, Gilead, GSK, Heptares, LabGenius, Janssen, MonteRosa, Mylan, MSD, Novartis, Numab, Pfizer, Roche, Sandoz, Takeda, UCB and XAP; membership of the ECCO Scientific Committee, and membership in the UEG Scientific Committee; director of Endoread.
Mathurin Fumery has received lecture and consulting fees from AbbVie, Amgen, Biogen, BI, BMS, Celgene, Celltrion, CTMA, Ferring, Fresenius, Galapagos, Gilead, Janssen, Pfizer, Lilly, MSD, Sandoz, Takeda, Tillots, and Viatris.
Dominik Bettenworth is on the advisory board or consultant for Amgen, AbbVie, Dr. Falk Foundation, Ferring, MSD, Pfizer, Pharmacosmos, Roche, Takeda, Tillotts Pharma, and Vifor. Silvio Danese has served as a speaker, consultant, and advisory board member for Schering-Plough, AbbVie, Actelion, Alphawasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grünenthal, Johnson and Johnson, Millenium Takeda, MSD, Nikkiso Europe GmbH, Novo Nordisk, Nycomed, Pfizer, Pharmacosmos, UCB Pharma and Vifor.
Pierre A Morisset, Madhuja Mallick, Shirley H. Chen, and Smitha Suravaram are employees of AbbVie and may own stock options.