Introduction

Dose escalation (DE) of intravenous infliximab is an option for inflammatory bowel disease (IBD) patients who lose response after induction therapy^{1, 2}. DE of subcutaneous (SC) infliximab from 120 mg to 240 mg every 2 weeks (Q2W) showed restoring efficacy in the 54-week LIBERTY-UC and LIBERTY-CD studies, and safety profiles were generally comparable between patients with or without DE³. Both two studies included an extension phase through Week (W) 102, and we present post-hoc long-term efficacy and safety results of DE in patients who treated in extension phase in two studies.

Aims & Methods

Patients with moderately to severely active UC and CD were treated with 3 doses of infliximab IV 5mg/kg as induction therapy (Weeks 0, 2 and 6). Clinical responders at W10 were randomized (2:1) to receive either CT-P13 SC 120 mg or placebo Q2W as maintenance therapy up to W54. Patients who, in the opinion of the investigator, would benefit from continued treatment entered open-label extension study from W56 to W102 and received CT-P13 SC 120 mg regardless of previously assigned arm. From W22, the patients who met loss of response criteria were permitted to escalate the dose to CT-P13 SC 240 mg Q2W through W102 for both arms. The results from CT-P13 SC arm are analyzed.

Results

A total of 237 and 180 patients who were randomly assigned to CT-P13 SC 120 mg arm and treated in extension phase in UC and CD study, each. Among them, DE from CT-P13 SC 120 mg to CT-P13 SC 240 mg prior to W102 was more common in UC than CD (30.0% [71/237] vs 20.6% [37/180]). Patients showed improvement in terms of clinical remission at W102 (both CD and UC) or endoscopic response at W102 (CD) after DE. Also, patients showed improvement in other efficacy endpoints after DE (Table 1). Compared to the first DE visit, patients who escalated the dose had a statistically significant reduction of more than half in mean modified Mayo score in UC (5.9 vs 2.1, P<0.0001) and mean CDAI score in CD (270.58 vs 76.31, P<0.0001) at W102.
The incidence rate of treatment-emergent adverse events (TEAEs) in the maintenance and extension phase of both studies was comparable between patients with and without DE (In UC, 84.7% [61/72] vs 78.1% [132/169], In CD, 86.8% [33/38] vs 79.7% [118/148]). Among these, TEAEs of infection were as follows; In UC, 40.3% (29/72) vs 43.2% (73/169), In CD, 55.3% (21/38) vs 42.6% (63/148). The incidence rate of treatment-emergent serious adverse events in the maintenance and extension phase of both studies was also comparable between patients with and without DE (In UC, 12.5% [9/72] vs 10.1% [17/169], In CD, 13.2% [5/38] vs 10.8% [16/148]).

Table 1. Summary of efficacy outcome in CT-P13 SC treated patients at Week 102
CT-P13 SC in LIBERTY-CD			CT-P13 SC in LIBERTY-UC
	Proportion of patients achieving efficacy outcomes at W102 regardless of dose escalation, n/N* (%)	Proportion of patients with dose escalation achieving efficacy outcomes at W102, n’/N** (%)		Proportion of patients achieving efficacy outcomes at W102 regardless of dose escalation, n/N (%)	Proportion of patients with dose escalation achieving efficacy outcomes at W102, n’/N’ (%)
Clinical remission1	142/180 (78.9%)	26/37 (70.3%)	Clinical remission7	132/237 (55.7%)	25/71 (35.2%)
Endoscopic response2	102/180 (56.7%)	15/37 (40.5%)	Endoscopic-histologic mucosal improvement8	119/237 (50.2%)	21/71 (29.6%)
Clinical response3	148/180 (82.2%)	25/37 (67.6%)	Clinical response9	167/237 (70.5%)	43/71 (60.6%)
Corticosteroid-free remission4	44/74 (59.5%)	13/19 (68.4%)	Corticosteroid-free remission10	49/96 (51.0%)	14/41 (34.1%)
Clinical remission (alternative definition)5	131/180 (72.8%)	24/37 (64.9%)	-	-	-
Endoscopic remission6	71/180 (39.4%)	8/37 (21.6%)	-	-	-
n = Number of patients achieving efficacy endpoints at Week 102 regardless of dose escalation; N*= Number of patients who were randomly assigned to CT-P13 SC 120 mg arm and treated in extension phase and have a SES-CD score of at least 6 (or at least 4 if isolated ileal disease) at Screening; n’ = Number of patients achieving efficacy endpoints at Week 102 among dose-escalated patients; N**= Number of patients with dose escalation to CT-P13 SC 240 mg prior to Week 102 in CT-P13 SC 120 mg arm and treated in extension phase and have a SES-CD score of at least 6 (or at least 4 if isolated ileal disease) at Screening; N = Number of patients who were randomly assigned to CT-P13 SC 120 mg arm and treated in extension phase; N’= Number of patients with dose escalation to CT-P13 SC 240 mg prior to Week 102 in CT-P13 SC 120 mg arm and treated in extension phase. Clinical remission, defined as an absolute Crohn’s disease activity index (CDAI) score of <150 points Endoscopic response at Week 102, defined as > 50% decrease in Simplified endoscopic activity score for Crohn’s disease (SES-CD) score from the baseline value Clinical response, defined as a decrease in CDAI score of 100 points or more from the baseline value Corticosteroid-free remission, defined as being in clinical remission (by an absolute CDAI score of <150) in addition to not receiving any corticosteroids for at least 8 weeks prior to Week 102, among the patients who used oral corticosteroids at baseline Clinical remission, defined as an average worst daily abdominal pain (AP) score of ≤1 (using 4-point scale) and an average daily loose/watery stool frequency (SF) score of ≤3 (of Type 6 or Type 7 on BSFS) with no worsening in either average score compared with the baseline value. Endoscopic remission, defined as an absolute SES-CD score of ≤4 with no sub-score of >1 Clinical remission, defined as modified Mayo score with stool frequency subscore of 0 or 1 point, rectal bleeding subscore 0 point, and endoscopic subscore 0 or 1 point Endoscopic-histologic mucosal improvement, defined as absolute endoscopic subscore of 0 or 1 point from modified Mayo score and an absolute Robarts Histopathology Index (RHI) score of 3 points or less with an accompanying lamina propria neutrophils and neutrophils in epithelium subscore of 0 point Clinical response, defined as decrease in modified Mayo score from baseline of at least 2 points and at least 30%, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1 point Corticosteroid-free remission, defined as being in clinical remission (by modified Mayo score) in addition to not requiring any treatment with corticosteroid for at least 8 weeks at Week 102, among the patients who used oral corticosteroids at baseline

Conclusion

DE of CT-P13 SC from 120 mg to 240 mg Q2W following IV induction in patients who initially respond but subsequently lose response, shows clinical efficacy over an extended observation period of 102 weeks. Safety profiles were generally comparable between patients with or without DE, and no new safety concerns were found after DE as well in long term treatment.

References

1 Taxonera C et al. Infliximab dose escalation as an effective strategy for managing secondary loss of response in ulcerative colitis. Digestive Diseases and Sciences 2015; 60 (10): 3075-3084
2 Cesarini M et al. Dose optimization is effective in ulcerative colitis patients losing response to infliximab: A collaborative multicentre retrospective study. Dig Liver Dis.2014; 46(2): 135-139
3 S. Danese et al. MP362 Subcutaneous infliximab (CT-P13 SC) dose escalation as an option for managing the loss of response in inflammatory bowel disease: post hoc analysis of LIBERTY-UC study and LIBERTY-CD study. Gastroenterology. Volume 166, Issue 3, Supplement, 2024, Page S13

Disclosure

• S. Schreiber: Consultancy and personal fees from AbbVie, Arena, BMS, Biogen, Celltrion, Celgene, Falk, Ferring, Fresenius, Gilead, HIKMA, IMAB, Janssen, MSD, Morphic, Pfizer, Protagonist, Provention Bio, Sandoz, Takeda, and Theravance.
• J.F. Colombel: Receiving payment for lectures from AbbVie, Amgen, Allergan, Inc. Ferring Pharmaceuticals, Shire, and Takeda; Receiving consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, BMS, Celgene Corporation, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, Genentech, Glaxo Smith Kline, Janssen Pharmaceuticals, Kaleido Biosciences, Imedex, Immunic, Iterative Scopes, Merck, Microbia, Novartis, PBM Capital, Pfizer, Protagonist Therapeutics, Sanofi, Takeda, TiGenix, Vifor; Hold stock options in Intestinal Biotech Development.
• S.B. Hanauer: Consultancy from AbbVie, Allergan, Amgen, Arena, Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cosmos, Catalys Pacific, Covance, Genentech, GSK, Janssen, Lilly, Merck, Novartis, Pfizer, Progenity, Prometheus, Receptos, Salix, Samsung Bioepis, Seres Therapeutics, Sorriso, Takeda, TLL, UCB, Vhsquared; Clinical Research for AbbVie, Allergan, Amgen, Celgene, Genentech, GSK, Janssen, Lilly, Novartis, Pfizer, Prometheus, Receptos, Takeda, UCB; Speaker for AbbVie, Bristol Myers Squibb, Janssen, Pfizer, Takeda; Independent Data Monitoring Conference for Arena, Boehringer Ingelheim, Bristol Myers Squibb, Gossamer, Prometheus, Protagonist.
• W. Sandborn: Consulting fees from Alimentiv, Shoreline Biosciences; Stock or stock options from Prometheus Biosciences, Prometheus Laboratories, Ventyx Biosciences, Mirador Therapeutics; Employee at Ventyx Biosciences, Mirador Therapeutics; Board of Directors at Prometheus Laboratories.
• B.E. Sands: Consultant or received speaker’s fees from AbbVie, Abivax, Adiso Therapeutics, AgomAb, Alimentiv, Amgen, Arena Pharmaceuticals, Artizan Biosciences, Artugen Therapeutics, AstraZeneca, Bacainn Therapeutics, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Calibr, Celltrion, ClostraBio, Connect Biopharm, Cytoki Pharma, Eli Lilly and Company, Enthera, Evommune, Ferring, Fresenius Kabi, Galapagos, Gilead Sciences, Genentech, Glaxo SmithKline, Gossamer Bio, HMP Acquisition, Imhotex, Immunic, InDex Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Ironwood Pharmaceuticals, Janssen, Johnson & Johnson, Kaleido, Kalyope, Merck, MiroBio, Morphic Therapeutic, MRM Health, OSE Immunotherapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, RedHill Biopharma, Sun Pharma Global, Surrozen, Synlogic Operating Company, Takeda, Target RWE, Theravance Biopharma R&D, TLL Pharmaceutical, USWM Enterprises, Ventyx Biosciences, Viela Bio.
• S. Danese: Consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals Inc., Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB Inc., Vial, Vifor. Reports lecture fees from Abbvie, Amgen, Ferring Pharmaceuticals Inc., Gilead, Janssen, Mylan, Pfizer, Takeda.
• ​S.J. Lee, S.H. Kim, ​Y.J. Bae, S.H. Lee, S.G. Lee, J.H. Lee, J.M. Kim, G.H. Park, ​J.M. Lee, J.H. Lee are Employee of Celltrion, Inc.

Introduction

Guselkumab (GUS) is a dual-acting IL-23p19 subunit inhibitor that potently neutralizes IL-23 and binds to CD64, a receptor on cells that produce IL-23. In the QUASAR studies, GUS intravenous (IV) induction and subcutaneous (SC) maintenance demonstrated symptomatic, endoscopic, and histologic efficacy through 2 years.^1,2 Here, we describe maintenance of endoscopic and histologic efficacy in the long-term extension (LTE).

Aims & Methods

At maintenance week (W) 0, GUS IV induction responders were randomized 1:1:1 to GUS 100 mg SC every 8 weeks (q8w), GUS 200 mg SC q4w or placebo (GUS withdrawal). Participants (pts) completing the W44 visit could enter the LTE and continue the treatment regimen they were receiving at W44. Placebo pts discontinued after study unblinding. Efficacy data for randomized pts who continued to receive their GUS regimen assigned at W0 in the LTE were analyzed using 2 methods: 1) nonresponder imputation (NRI) accounting for pts with treatment failure or missing data, and 2) “as observed.”

Results

Overall, 303 randomized pts (155 for 100 mg q8w and 148 for 200 mg q4w) continued their GUS treatment assigned at W0 in the LTE. Of pts who achieved endoscopic improvement at W44, 87.2% of GUS 100 mg q8w pts and 80.2% GUS 200 mg q4w pts maintained endoscopic improvement through W92 (NRI analysis; Table). Of pts who achieved histologic improvement at W44, 77.9% and 75.2%, respectively, maintained histologic improvement at W92. Of pts who achieved histo-endoscopic mucosal improvement (HEMI) at W44, 73.5% and 75.5%, respectively, maintained HEMI through W92. Of pts who were in histologic remission at W44, 71.2% maintained histologic remission at W92 in both GUS groups. Results of the as-observed analysis were consistent with the NRI analysis; the dropout rate was low among GUS-treated pts in the LTE. Proportions of pts who maintained endoscopic and histologic outcomes from W0 to W92 are presented in the Table.

Table. Maintenance of endoscopic and histologic efficacy with GUS in the QUASAR LTE study
aPercentages represent proportions of pts achieving the endpoint at W92 among those who achieved the corresponding endpoint at W44. CIs in each treatment group are based on the normal approximation confidence limits. bPercentages represent proportions of pts achieving the endpoint at W92 among those who achieved the corresponding endpoint at W0 (baseline of the maintenance study). CIs in each treatment group are based on the normal approximation confidence limits. Includes pts with modified Mayo score of 5-9 at induction baseline who achieved clinical response to GUS IV induction and were randomized to receive GUS maintenance treatment and did not experience a dose adjustment from W8 through W32. Endoscopic improvement is defined as an endoscopic subscore of 0 or 1. Histologic improvement is defined as neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system. HEMI is defined as achieving a combination of histologic improvement and endoscopic improvement. Histologic remission is defined as the absence of neutrophils from the mucosa (both lamina propria and epithelium), no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system (equivalent to a Robarts Histopathology Index ≤2b, with subscores of 0 for lamina propria neutrophils and neutrophils in the epithelium and without ulcers or erosion). CI=Confidence interval; GUS=Guselkumab; HEMI=histologic-endoscopic mucosal improvement; IV=Intravenous; LTE=Long-term extension; m=Number of pts achieving endpoint at W0 or W44; n=Number of pts achieving endpoint at week 92; NRI=Nonresponder imputation; pts=Participants; q4w=Every 4 weeks; q8w=Every 8 weeks; SC=Subcutaneous; W=Week.
	Endpoint maintenance: W44 to W92a				Endpoint maintenance: W0 to W92b
	NRI analysis		As-observed analysis		NRI analysis		As-observed analysis
% [95% CI] (n/m)	GUS 100mg SC q8w	GUS 200mg SC q4w	GUS 100mg SC q8w	GUS 200mg SC q4w	GUS 100mg SC q8w	GUS 200mg SC q4w	GUS 100mg SC q8w	GUS 200mg SC q4w
Endoscopic improvement	87.2% [80.5, 94.0] (82/94)	80.2% [72.4, 88.0] (81/101)	92.1% [86.5, 97.7] (82/89)	90.0% [83.8, 96.2] (81/90)	80.3% [70.7, 89.9] (53/66)	85.9% [77.4, 94.5] (55/64)	85.5% [76.7, 94.3] (53/62)	94.8% [89.1, 100] (55/58)
Histologic improvement	77.9% [70.5, 85.2] (95/122)	75.2% [67.6, 82.8] (94/125)	83.3% [76.5, 90.2] (95/114)	83.2% [76.3, 90.1] (94/113)	74.3% [65.7, 82.8] (75/101)	72.0% [62.9, 81.2] (67/93)	80.6% [72.6, 88.7] (75/93)	80.7% [72.2, 89.2] (67/83)
HEMI	73.5% [64.0, 83.0] (61/83)	75.5% [66.8, 84.2] (71/94)	80.3% [71.3, 89.2] (61/76)	85.5% [78.0, 93.1] (71/83)	70.2% [58.3, 82.1] (40/57)	79.6% [68.9, 90.4] (43/54)	78.4% [67.1, 89.7] (40/51)	91.5% [83.5, 99.5] (43/47)
Histologic remission	71.2% [62.7, 79.6] (79/111)	71.2% [63.0, 79.4] (84/118)	76.7% [68.5, 84.9] (79/103)	77.8 % [69.9, 85.6] (84/108)	67.0% [57.4, 76.7] (61/91)	67.1% [56.9, 77.2] (55/82)	73.5% [64.0, 83.0] (61/83)	76.4% [66.6, 86.2] (55/72)

Conclusion

High rates of long-term sustained endoscopic and histologic endpoints were observed at W92 of the LTE with both GUS dose regimens.

References

1. Rubin DT, et al. Guselkumab in patients with moderately to severely active ulcerative colitis (QUASAR): phase 3 double-blind, randomised, placebo-controlled induction and maintenance studies. Lancet. 2025;405(10472):33-49.
2. Lichtenstein GR, et al. Efficacy and safety of guselkumab for ulcerative colitis through week 92 of the QUASAR long-term extension study. Presented at: Digestive Disease Week (DDW); May 4–6, 2025; San Diego, CA.

Disclosure

Study support: Johnson & Johnson.
TH: AbbVie, Bristol Myers Squibb, Daiichi-Sankyo, EA Pharma Co, Ltd., JIMRO, Eli Lilly, Gilead Sciences, Johnson & Johnson, Kissei Pharmaceutical Co, Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Inc, Takeda Pharmaceutical Co., Ltd.
JP: AbbVie, Alimentiv, Athos, Atomwise, Boehringer Ingelheim, Celsius, Ferring, Galapagos, Genentech/Roche, GlaxoSmithKline, Johnson & Johnson, Mirum, Nimbus, Pfizer, Progenity, Prometheus, Protagonist, Revolo, Sanofi, Sorriso, Surrozen, Takeda, Wasserman.
FM: AbbVie, Arena, Celltrion, Eli Lilly and Company, Ferring, Fresenius, Galapagos, GlaxoSmithKline, Johnson & Johnson, Merck, Pfizer, Prometheus Biosciences, Roche, Sandoz, Tillots, Takeda, Teva.
GRL: AbbVie, American College of Gastroenterology, CellCeutrix, Celgene, Clinical Advances in Gastroenterology, Ferring, Gastroenterology and Hepatology [Gastro-Hep Communications], Gilead, Johnson & Johnson, Orthobiotech, Eli Lilly, Luitpold / American Regent, Merck, McMahon Publishing, Pfizer, Prometheus, Romark, Salix/ Valeant, Shire, SLACK, Springer, Takeda, UCB, Up-To-Date, Vindico, Virgo.
JRA: Abbvie, Bristol Myer Squibb, Ferring, Finch, Iterative Scopes, Johnson & Johnson, Merck, Pfizer, Roivant, Seres Therapeutics, Roivant Adiso.
BB: AbbVie, Alimentiv, Allergan, Amgen, AMT, Bausch Health, Bristol Myers Squibb, Business Intelligence, Celgene, Celltrion, Eupraxia Fresenius Kabi, Ferring, Genentech/Roche, Gilead, Iterative Scopes, GlaxoSmithKline, Jamp, Johnson & Johnson, Merck, Microbiome Insights, Mylan, Novartis, Organon, Pendopharm, Pfizer, Protagonist, Qu Biologic, Sandoz, Takeda, Viatris.
WA: AbbVie, Amgen, BMS, Dynacare, Eli-Lilly, Johnson & Johnson, Merck, Novartis, Pfizer, Prometheus, Sandoz, Sanofi, Takeda, Theradiag.
MAS: AbbVie, Bristol-Myers Squibb, Falk, Galapagos, Janssen, Lilly, MSD, Pfizer, Samsung Bioepis, Sandoz, Sanofi, STADA, Takeda, Tillotts.
BDY: AbbVie Korea, BMS Pharmaceutical Korea Ltd., Celltrion, Chong Kun Dang Pharm, CJ Red BIO, Cornerstones Health, Curacle, Daewoong Pharm, Dong-A ST, Eisai Korea, Eli Lilly and Company Korea, Ferring Korea, Imscout, IQVIA, Johnson & Johnson, Johnson & Johnson Korea, JEIL PHARMACEUTICAL CO., Kangstem Biotech, Korea Otsuka Pharm, Korea United Pharm, Medtronic Korea, NanoEntek, ORGANOIDSCIENCES LTD, Pfizer Korea, Samsung Bioepis, Takeda, Takeda Korea, Yuhan.
SY, MG, NS, DP, YM, HZ: Johnson & Johnson.
AD: Abivax, AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, CED Service GmbH, Celltrion, Dr Falk Foundation, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Gilead, High5MD, Johnson & Johnson, Lilly, Materia Prima, MedToday, MSD, Pfizer, Pharmacosmos, Roche, Sandoz, Stada, Takeda, Thieme, Tillotts, UniMed Verlag, Vifor Pharma.
DTR: Abbvie, Altrubio, Apex, Avalo Therapeutics, Bristol-Myers Squibb, Buhlmann Diagnostics Corp, Celgene, Connect BioPharma, Intouch Group, Iterative Health, Johnson & Johnson, Lilly, Pfizer, Samsung Neurologica, Takeda.
BES: AbbVie, Abivax, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, AstraZeneca, Biolojic Design, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Celltrion, Equillium, Enthera, Enveda Biosciences, Evommune, Ferring, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Imhotex, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Johnson & Johnson, Kaleido, Kallyope, Lilly, Merck, Microba, Mirador Therapeutics, Mobius Care, Morphic Therapeutics, MRM Health, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Therapeutics, Reistone Biopharma, Sanofi, Sorriso Pharmaceuticals, Spyre Therapeutics, Sun Pharma, Surrozen, Takeda, Target RWE, Teva, TLL Pharmaceutical, Tr1X, Union Therapeutics, Ventyx Biosciences, and Vividion Therapeutics.

Introduction

Portal hypertension (PHT) most commonly due to cirrhosis, but non-cirrhotic portal hypertension (NCPH) related to metabolic dysfunction, specifically metabolic dysfunction-associated steatotic liver disease (MASLD), necessitates further clarification of its mechanisms and identification of therapeutic targets.

PHT may precede the development of hepatic fibrosis in MASLD, and even serve as a driving factor in the pathogenesis of MASLD. Consequently, metabolic dysfunction-associated PHT might not depend on structural alterations such as hepatic fibrosis or pseudolobule formation, but rather correlate with other factors such as endothelial dysfunction, which has been demonstrated to play a pivotal role in NCPH. Endothelial dysfunction encompasses endothelial injury and endothelial-to-mesenchymal transition (EndMT), the latter being a specific type of epithelial-to-mesenchymal transition (EMT). As reported, the JAK/STAT3 signaling pathway plays a pivotal role in the initiation and progression of EMT. Similarly, patients with NCPH induced by myeloproliferative neoplasms (MPN) often lack pathological features such as hepatic fibrosis or pseudolobule formation. The Janus kinase 2 (JAK2) V617F mutation is highly prevalent in MPN patients. Therefore, targeted inhibition of JAK2 serves as an effective therapeutic strategy for MPN.

Given the shared pathological features between MPN-associated portal hypertension and MASLD-associated portal hypertension, as well as the vital​ role of JAK2 in both disease, the application of JAK2 inhibitor holds significant therapeutic potential for metabolic dysfunction-associated portal hypertension.

Aims & Methods

This study aims to verify the therapeutic efficacy of JAK2 inhibition in attenuating MASLD-associated PHT, with particular focus on its modulation of EndMT. Mice were fed with a high-fat diet (HFD) diet for 12 weeks to induce MASLD-associated PHT and divided into two groups, the treatment group (Rux) and control (Ctr) group. Ruxolitinib (JAK2 inhibitor) was given as a suspension by gavage (60 mg/kg in 0.2 ml) every two days for 3 weeks, while controls received the same volume of saline, from week 10-12 of feeding. Portal pressure was measured, serological analysis and histopathological staining were performed. RT-PCR and Western Blot were conducted to measure EndMT-related genes expression.

Results

The treatment group (Rux) demonstrated a significant reduction in directly measured portal pressure, with concordant changes observed in the spleen-to-body weight ratio, which served as an indirect indicator of portal pressure. Concurrent improvement was noted in ALT, AST and TC. H&E, Masson and Sirius red staining showed decreased perisinusoidal and perivascular fibrosis in the Rux group. Electron microscopy revealed restoration of endothelial fenestration. Additionally, ruxolitinib treatment led to downregulation of endothelial damage markers, mesenchymal cell markers as well as EndMT-related regulatory factors, indicating an alleviation of EndMT and endothelial dysfunction.

Conclusion

The JAK2 inhibitor demonstrates therapeutic potential for MASLD-associated PHT through modulation of endothelial dysfunction and EndMT. These mechanistic insights position ruxolitinib as a promising candidate for clinical management of NCPH, particularly in the MASLD-associated PHT.

References

[1] European Association for the Study of the Liver; European Association for the Study of Diabetes; European Association for the Study of Obesity. EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD): Executive Summary. Diabetologia. 2024 Jun 13. [2] Song Z, Liu X, Zhang W, et al. Ruxolitinib suppresses liver fibrosis progression and accelerates fibrosis reversal via selectively targeting Janus kinase 1/2. Journal of Translational Medicine. 2022, 20(1): 157.
[3] Zhang XL, Zhang XY, Ge XQ, et al. Mangiferin prevents hepatocyte epithelial-mesenchymal transition in liver fibrosis via targeting HSP27-mediated JAK2/STAT3 and TGF-β1/Smad pathway. Phytotherapy Research. 2022, 36(11): 4167-4182.
[4] Jin W. Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial-Mesenchymal Transition. Cells. 2020;9(1):217.
[5] Hammoutene A, Rautou PE. Role of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease. Journal of Hepatology. 2019, 70(6): 1278–1291.

Introduction

Inhibition of interleukin (IL)-23 has been demonstrated as a safe and effective mechanism of action for treating various chronic inflammatory diseases, including Crohn's disease (CD). The phase 3b SEQUENCE study directly compared the efficacy and safety of risankizumab (RZB), a selective IL-23 p19 subunit inhibitor, and ustekinumab (UST), an IL-12/IL-23 p40 subunit inhibitor, in patients (pts) with moderate to severe CD.

Aims & Methods

SEQUENCE, an open-label, multicenter, randomized, efficacy assessment-blinded study, enrolled pts who previously failed ≥1 anti-TNF therapies and had a CD Activity Index score of 220-450, Simple Endoscopic Score for CD ≥6 for ileocolonic or colonic disease (≥4 for isolated ileal disease) excluding the presence of narrowing component, plus an average (avg) daily stool frequency ≥4 and/or avg daily abdominal pain score ≥2. In Part 1 of the trial, described herein, pts were randomized 1:1 to receive RZB (600 mg IV induction dosing at baseline [BL], weeks [wks] 4 and 8, followed by 360 mg SC maintenance dosing every 8 wks [Q8w] starting at wk12) or UST (a single weight-based IV induction dose, followed by 90 mg SC maintenance dosing Q8w starting at wk8) over a period of 48 wks.¹ Randomization was stratified by number of anti-TNF therapies failed (1, >1) and steroid use at BL (Y, N). A mandatory steroid taper started at wk2. Two primary endpoints were clinical remission at wk24 (non-inferiority of RZB vs UST in 50% of planned subjects) and endoscopic remission at wk48 (superiority of RZB vs UST). Ranked secondary endpoints included clinical remission at wk48, endoscopic response at wks 48 and 24, steroid-free (SF) endoscopic remission at wk48, and SF clinical remission at wk48 (all tested for superiority of RZB vs UST). Safety was assessed throughout the trial.

Results

Variable	RZB N=255 n/N (%)	UST N=265 n/N (%)	Treatment Difference RZB – UST % [95% CI]
Primarya 1. Clinical remission at wk 24 (ITT-1Hb) 2. Endoscopic remission at wk 48 (ITT-1d) Ranked Secondarya,d 1. Clinical remission at wk 48 2. Endoscopic response at wk 48 3. Endoscopic response at wk 24 4. Steroid-free endoscopic remission at wk 48 5. Steroid-free clinical remission at wk 48	75/128 (58.6%) 81/255 (31.8%) 155/255 (60.8%) 115/255 (45.1%) 115/255 (45.2%) 80/255 (31.4%) 155/255 (60.8%)	54/137 (39.5%) 43/265 (16.2%) 108/265 (40.8%) 58/265 (21.9%) 70/265 (26.4%) 41/265 (15.5%) 107/265 (40.4%)	Non-inferiorityc met; 18.4 [6.6, 30.3] 15.6 [8.4, 22.9], P<0.0001 19.7 [11.3, 28.1], P<0.0001 23.3 [15.4, 31.2], P<0.0001 18.9 [10.9, 26.9], P<0.0001 15.9 [8.8, 23.1], P<0.0001 20.1 [11.7, 28.4], P<0.0001
Treatment Emergent Adverse Events (AEs)e	RZB N=262 PYs = 257.6 Events (E/100PYs)f	UST N=265 PYs = 269.9 Events (E/100PYs)f	Treatment Difference RZB – UST % [95% CI]
All TEAEs Investigator-defined drug-related AEg,h Severe AE Serious AE AEs leading to study drug discontinuation Death Adverse Events of Special Interest Adjudicated MACE/Extended MACEi Serious infections Active tuberculosis Opportunistic infections excluding tuberculosis and herpes zosterj Herpes zoster Malignant tumoursk Non-melanoma skin cancer (NMSC) Malignancies excluding NMSC Hypersensitivity Serious hypersensitivity Adjudicated anaphylactic reaction Hepatic events Injection site reactions	879 (341.2) 167 (64.8) 60 (23.3) 36 (14.0) 10 (3.9) 0 0 10 (3.9) 0 1 (0.4) 1 (0.4) 1 (0.4) 1 (0.4) 0 37 (14.4) 0 0 26 (10.1) 5 (1.9)	763 (282.7) 111 (41.1) 82 (30.4) 64 (23.7) 14 (5.2) 0 1 (0.4) 14 (5.2) 0 0 1 (0.4) 1 (0.4) 0 1 (0.4) 32 (11.9) 0 0 23 (8.5)i 8 (3.0)	58.5 (28.3, 88.7) 23.7 (11.2, 36.2) -7.1 (-15.9, 1.7) -9.7 (-17.1, -2.4) -1.3 (-4.9, 2.3) 0 -0.4 (-1.1, 0.4) -1.3 (-4.9, 2.3) 0 0.4 (-0.4, 1.1) 0.0 (-1.0, 1.1) 0.0 (-1.0, 1.1) 0.4 (-0.4, 1.1) -0.4 (-1.1, 0.4) 2.5 (-3.7, 8.7) 0 0 1.6 (-3.6, 6.8) -1.0 (-3.7, 1.6)
AE – adverse event; BL - baseline; CD – Crohn’s disease; CDAI – CD activity index; ITT – intention to treat; RZB - risankizumab; PY, patient years; SES-CD, simple endoscopic score for CD; TEAE – treatment emergent AE; UST – ustekinumab; wk, week Clinical remission – CDAI < 150 Endoscopic remission - SES-CD ≤ 4 and at least a 2-point reduction versus BL and no sub score greater than 1 in any individual variable, as scored by a central reviewer blinded to treatment allocation Endoscopic response - decrease in SES-CD > 50% from BL (or for pts with isolated ileal disease and a BL SES-CD of 4, at least a 2-point reduction from BL), as scored by central reviewer Steroid-free endoscopic remission - endoscopic remission and not receiving steroids at the corresponding visit Steroid-free clinical remission - clinical remission and not receiving steroids at the corresponding visit *SEQUENCE Part 1 compared the efficacy and safety of RZB versus UST over 48 wks, while Part 2 is an ongoing open-label long-term extension to evaluate the long-term safety of RZB in pts who received RZB in Part 1 and completed wk48 visit. aCategorical variables were analyzed using Cochran-Mantel-Haenszel (CMH) test. For both the primary and secondary endpoints, the non-responder imputation while incorporating multiple imputation to handle missing data (due to COVID-19 or geopolitical conflict) was used. Primary and secondary endpoints were tested sequentially in the order specified using the CMH risk difference estimate test stratified by the number of failed anti-TNF therapies (1, > 1) and steroid use at baseline (yes, no). bITT1H population is a subset of ITT-1 population and includes approximately 50% of ITT1 subjects who have opportunity to reach wk24 by the time of the primary analysis of CDAI clinical remission at wk24; non-inferiority of RZB vs. UST cNon-inferiority test: If the lower limit of 95% confidence interval based on the CMH estimation for the risk difference between RZB and UST groups (RZB – UST) was greater than the negative of 10% noninferiority margin, then noninferiority was demonstrated for clinical remission at wk24. If non-inferiority was demonstrated for clinical remission (CDAI) at Week 24, the superiority for the endoscopic remission at Week 48 was subsequentially tested at two-sided significance level of 0.05 using the CMH test. dIntent-to-treat-1 (ITT-1) population included all randomized subjects who were randomized to RZB with the selected RZB dose (RZB 600 mg IV followed by RZB 360 mg SC) or UST and who received at least 1 dose of study drug during Part 1 of the study; superiority of RZB vs. UST eTEAEs are events that begin either on or after the first dose of UST or RZB in Part 1 and until the first dose of study drug (RZB) in Part 2 if the pt is enrolled into the Part 2 or within 140 days after the last dose administration of the study drugs (UST or RZB) in Part 1 if the pt does not participate in Part 2. Only safety data obtained before 12JUL2023 or Week 52 dosing date (the first dose date of Part 2), whichever occurred earlier, are reported here. fSA1 population includes all pts who received at least 1 dose of study drug during Part 1 of the study. gAs assessed by investigator hRZB related: 3 patients with SAEs related to RZB (anal fistula, anal abscess, campylobacter, cystitis, localized infection, genital fistula); 8 patients with SAEs related to UST (abdominal pain, anal fistula, CD, ileal stenosis, vomiting) iMACE: Major Adverse Cardiovascular Events, defined as cardiovascular death or death due to stroke, non-fatal myocardial infarction, and non-fatal stroke; extended MACE defined as MACE with hospitalization for unstable angina and coronary revascularization procedures jOpportunistic infection: RZB, oesophageal candidiasis kMalignant tumor: RZB, squamous cell carcinoma of skin; UST, anal squamous cell carcinoma iOne case of potential Hy’s Law in the UST treatment group

In total, 520 pts were randomized and assessed for efficacy: RZB (N=255) and UST (N=265). The proportion of pts who completed the study was numerically higher with RZB (89.4%) vs UST (74.0%). The two primary endpoints of the study were met. At wk24, in half of the patients enrolled, clinical remission rates were 58.6% (75/128) for RZB and 39.5% (54/137) for UST (Δ18.4 [6.6-30.3], non-inferiority met with the pre-defined margin of 10%) (Table). At wk48, endoscopic remission rates were 31.8% (81/255) for RZB and 16.2% (43/265) for UST (Δ15.6% [8.4-22.9], P<0.0001 for superiority). RZB was superior to UST for all secondary endpoints (all P<0.0001). Exposure adjusted adverse event (AE) rates (Events [E/100PYs]) were comparable between RZB (879 [341.2]) and UST (763 [282.7]). Rates of serious AEs and AEs leading to study drug discontinuation were numerically higher with UST than RZB (Table). Rates of serious infections and hepatic events were similar between treatment groups, with no serious hepatic events with RZB. Two cases of malignancy were reported (one in each treatment arm). There was one event of adjudicated MACE with UST. There were no deaths.

Conclusion

In pts with moderate to severe CD who failed anti-TNF therapy, RZB demonstrated non-inferiority to UST in achieving wk24 clinical remission, superiority in achieving wk48 endoscopic remission, and superiority for achieving all secondary endpoints. The safety profiles of RZB and UST were consistent with previously published results.

References

1. Stelara Label [Internet]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/125261s161lbl.pdf

Disclosure

Laurent Peyrin-Biroulet: Fees: Galapagos, AbbVie, Janssen, Genentech, Alimentiv, Ferring, Tillots, Celltrion, Takeda, Pfizer, Index, Sandoz, Celgene, Biogen, SamsungBioepis, Inotrem, Allergan, MSD, Roche, Arena, Gilead, Amgen, BMS, Vifor, Norgine, Mylan, Lilly, Fresenius Kabi, OSEImmunotherapeutics, Enthera, Theravance, Pandion, Gossamer, Viatris, ThermoFisher, ONOPharma, Mopac, Cytoki, Morphic, Prometheus, Applied MolecularTransport; J. Casey Chapman: Consultant: AbbVie, Medtronic; Advisory Board: AbbVie, Pfizer, Takeda; Speaker: AbbVie, BMS, Janssen, Pfizer, Takeda; Jean-Frederic Colombel: Grants: AbbVie, Janssen, Takeda, BMS; Speaking fees: AbbVie, Takeda; Consultant: AbbVie, Amgen, AnaptysBio, Allergan, Arena, BI, BMS, Celgene, Celltrion, Lilly, Ferring, Galmed, GSK, Genentech (Roche), Janssen, Kaleido, Immunic, IterativeScopes, Merck, Landos, Microba Life Science, Novartis, Otsuka, Pfizer, ProtagonistTherapeutics, Sanofi, Takeda, TiGenix, Vifor; Stock options: IntestinalBiotechDevelopment; Flavio Caprioli: Consultant: AbbVie, MSD, Takeda, Janssen, Roche, Celgene, BMS, Galapagos, Gllead, Pfizer, Mundipharma, Galapagos, Biogen; Speaker: AbbVie, Ferring, Takeda, AllergyTherapeutics, Janssen, Pfizer, Biogen; Research grants: Giuliani, Sofar, MSD, Takeda, AbbVie; Geert D’Haens: Advisor: AbbVie, Ablynx, ActiveBiotechAB, AgomabTherapeutics, Alimentiv, Allergan, Alphabiomics, Amakem, Amgen, AMPharma, AppliedMolecularTherapeutics, Arena, AstraZeneca, Biogen, BMS, BI, Celltrion, DSMPharma; Echo, Engene, Exeliom, Ferring, Dr Falk, Galapagos, Genentech/Roche, Gilead, GSK, Gossamerbio, Immunic, J&J, Kintai, Lilly, Lument, Lycera, Medtronic, MSD, MitsubishiTanabe, NovoNordisk, Otsuka, Pfizer, Photopill, ProciseDx, Prodigest, Progenity, Prometheus/Nestlé, Protagonist, RedHill, SamsungBioepis, Sandoz, Seres, Setpoint, Shire, Takeda, Teva, Tillotts, Topivert, Versant, Vifor. Marc Ferrante: Grants: AbbVie, Amgen, Biogen, EG, Janssen, Pfizer, Takeda, Viatris; Consultant: AbbVie, Agomab, BI, Celgene, Celltrion, Lilly, Janssen-Cilag, Medtronic, MSD, Pfizer, Regeneron, SamsungBioepis, Sandoz, Takeda, ThermoFisher; Speaker: AbbVie, Amgen, Biogen, BI, Falk, Ferring, Janssen-Cilag, Lamepro, MSD, Pfizer, Sandoz, Takeda, Truvion, Viatris; Stefan Schreiber: Consultant: AbbVie, Amgen, Arena, BMS, BI, Celltrion, Dr Falk, Ferring, Fresenius, Galapagos, Genentech, Gilead, GSK, IMAB-Biopharma, Janssen, Lilly, Merck, Novartis/Sandoz, Pfizer, Protagonist, Takeda, Theravance. Raja Atreya: Speaker, consultant, or grants: AbbVie, Amgen, Arena, Biogen, BI, BMS, Cellgene, Celltrion, DrFalk, Galapagos, Gilead, InDex, Janssen-Cilag, Lilly, MSD, Novartis, Pandion, Pfizer, Roche, SamsungBioepis, Takeda, Viatris; Silvio Danese: Consultant: AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, AthosTherapeutics, Biogen, BI, Celgene, Celltrion, Lilly, Enthera, Ferring, Gilead, Hospira, Inotrem, Janssen, J&J, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity, Takeda, TiGenix, UCB, and Vifor; Lecture fees: Abbvie, Amgen, Dr Falk, Ferring, Gilead, Janssen, Mylan, Pfizer, Takeda. James O. Lindsay: Consultant/advisory board: AbbVie, AtlanticHealthcare, BMS, Celgene, Celltrion, Lilly, Ferring, Galapagos, Gilead, GSK, Janssen, MSD, Napp, Pfizer, Shire, Takeda, Vifor; Speaker fees/sponsorship: AbbVie, Ferring, Janssen, MSD, Napp, Norgine, Pfizer, Shire, Tillotts, Takeda; Grants: AbbVie, Gilead, Pfizer, Shire, Takeda; Peter Bossuyt: Grants: AbbVie, Amgen, Janssen, Mundipharma, Mylan, Pfizer; Speaker: AbbVie, Celltrion, Janssen, Pfizer, Takeda; Advisory Board: AbbVie, Arena, BMS, Hospira, Janssen, Lilly, Merck, Mundipharma, PentaxMedical, Pfizer, PSI CRO, Roche, Sandoz, Takeda; Britta Siegmund: Consultant: AbbVie, Arena, BI, BMS, Celgene, Falk, Galapagos, Janssen, Lilly, Pfizer, Prometheus, Takeda; Speaker’s fees: AbbVie, CEDServiceGmbH, Falk, Ferring, Janssen, Novartis, Pfizer, Takeda; Peter Irving: Grants/ Fees: Janssen, MSD,Takeda; Personal fees: AbbVie, Arena, Dr. Falk, Lilly, Ferring, Genentech, Hospira, Pfizer, Pharmacosmos, SamsungBioepis, Sandoz, Shire, Tillotts, TopiVert, VHsquared, Vifor, WarnerChilcott. Remo Panaccione: Consultant: AbbVie, Abbott, Alimentiv, Amgen, Arena, AstraZeneca, BMS, BI, Celgene, Celltrion, Cosmos, Eisai, Elan, Ferring, Galapagos, Genentech, Gilead, GSK, Janssen, Lilly, Merck, Mylan, Oppilan, Pandion, Pfizer, Progenity, Protagonist, Roche, Sandoz, Satisfai, Schering-Plough, Shire, Sublimity, Theravance, UCB, Takeda; Speaker: AbbVie, Arena, Celgene, Ferring, Gilead, Janssen, Lilly, Merck, Pfizer, Roche, Sandoz, Shire, and Takeda; Grants: AbbVie, Ferring, Janssen, Pfizer, Takeda; Advisory board: AbbVie, Amgen, Arena, BMS, Celgene, Celltrion, Ferring, Galapagos, Genentech, Gilead, GSK, Janssen, Lilly, Merck, Mylan, Oppilan, Pandion, Pfizer, Sandoz, Shire, Sublimity, Takeda, Theravance. Marla Dubinsky: Consultant: AbbVie, Arena, BMS, Celgene, Lilly, Genentech, Gilead, Janssen, Pfizer, Prometheus, Takeda; Founder/shareholder Trellus Health.
Ezequiel Neimark, Kori Wallace, Toni Anschutz, Kristina Kligys, W Rachel Duan, Valerie Pivorunas, Xiu Huang, Sofie Berg, Lei Shu: AbbVie full-time employees; may own AbbVie stock or options.