Introduction

Up to 50% of patients (pts) with inflammatory bowel disease have one or more extraintestinal manifestations (EIMs), which are independent risk factors for poor quality of life and greater disability.¹ Here, we evaluated EIM resolution in patients (pts) with moderate to severe Crohn’s disease (CD) who received risankizumab (RZB), an anti-IL-23p19 monoclonal antibody, versus (vs) placebo (PBO) during the ADVANCE and MOTIVATE induction and FORTIFY maintenance studies.^2,3

Aims & Methods

In this post-hoc analysis of pooled data from ADVANCE and MOTIVATE, data collected from an EIM form, used by investigators to record the presence of 16 pre-specified EIMs (yes/no), were examined. EIM presence at induction baseline (BL), resolution (see Table footnote for definition) at wk 12 with intravenous (IV) RZB 600 mg vs PBO in ADVANCE+MOTIVATE, and maintained resolution at FORTIFY wk 52 among pts treated with subcutaneous (SC) RZB 180 mg or 360 mg vs PBO (withdrew RZB) were assessed.³ Statistical analysis methods are provided in Table footnotes. Nominal P-values for pairwise treatment comparisons are shown.

Results

Previously, EIM resolution at wk 12 in pts with EIMs at BL was evaluated as a ranked secondary endpoint in ADVANCE and MOTIVATE.² A greater proportion of pts achieved EIM resolution at wk 12 with IV RZB 600 mg vs PBO in ADVANCE (38.1% vs 20.5%, nominal P-value = 0.02), but not MOTIVATE (29.5% vs 23.7%, nominal P-value = 0.38). In this pooled analysis, at BL, 323 EIMs were reported for 240 pts in the IV RZB 600 mg arm, and 221 EIMs were reported for 161 pts in the PBO arm; approximately 45% of pts in each arm had ≥1 EIM at BL. The most frequently reported EIMs at BL were peripheral arthropathy (IV RZB 600 mg, 64% [103/161]; PBO, 70.4% [169/240]), anaemia (IV RZB 600 mg, 36% [58/161]; PBO, 28.8% [69/240]), and axial arthropathy (IV RZB 600 mg, 16.1% [26/161]; PBO, 19.2% [46/240]). Together, these EIMs accounted for most reported EIMs across the IV RZB 600 mg (87.9% [284/323]) and PBO (84.6% [187/221]) arms; the incidence of other EIMs were too low for clinically meaningful interpretation (see Table footnotes). A greater proportion of pts achieved resolution of any EIM at wk 12 vs PBO (P = 0.031) with IV RZB 600 mg (Table). A significantly greater proportion of pts with anaemia or axial arthropathy, but not peripheral arthropathy, at BL achieved resolution of the respective EIM at wk 12 with IV RZB 600 mg vs PBO (anaemia: RZB 600 mg, 26/69 [37.4%]; PBO, 13/58 [22.4%]; adjusted (adj) difference 14.4%, P = 0.049; axial arthropathy: RZB 600 mg, 23/46 [50%]; PBO, 8/26 [30.8%]; adj difference 22.6%, P = 0.042; peripheral arthropathy: RZB 600 mg, 67/169 [39.8%]; PBO, 32/103 [31.2%]; adj difference 6.8%, P = 0.236). With SC RZB 360 mg compared to PBO, a greater proportion of pts with EIMs at BL achieved resolution of EIMs at wk 52 (P = 0.005), and a greater proportion of pts who achieved resolution of any EIM at wk 12 maintained resolution at wk 52 (P=0.014) (Table).

Conclusion

References

1. Marinelli C, et al. Gastroenterology Research and Practice. 2019 Aug 21;2019:1–10.
2. D’Haens G, et al. The Lancet. 2022 May;399(10340):2015–30.
3. Ferrante M, et al. The Lancet. 2022 May;399(10340):2031–46.

Disclosure

Subrata Ghosh: SG has received consulting fees from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Gilead, Galapagos, Janssen, Pfizer, and Receptos; speaker fees from AbbVie, Falk Pharma, Pfizer, Ferring, Janssen, Shield, and Takeda
Marc Ferrante: Research grants from: AbbVie, Amgen, Biogen, EG, Janssen, Pfizer, Takeda and Viatris; Consultancy fees from: AbbVie, Agomab Therapeutics, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Janssen-Cilag, Medtronic, MSD, Pfizer, Regeneron, Samsung Bioepis, Sandoz, Takeda and ThermoFisher; Speakers’ fees from: AbbVie, Amgen, Biogen, Boehringer Ingelheim, Falk, Ferring, Janssen-Cilag, Lamepro, MSD, Pfizer, Sandoz, Takeda, Truvion Healthcare and Viatris
Britta Siegmund: Consultant for AbbVie, Arena, BI, BMS, Celgene, Falk, Galapagos, Janssen, Lilly, Pfizer, Prometheus, and Takeda; and received speaker’s fees from AbbVie, CED Service GmbH, Falk, Ferring, Janssen, Novartis, Pfizer, and Takeda
Takehiro Arai: Nothing to disclose
Walter Reinisch WR has served as a speaker for AbbVie, Celltrion, Falk Pharma GmbH, Ferring, Janssen, Galapagos Medice, MSD, Roche, Pfizer, Pharmacosmos, Shire, Takeda, Therakos, as a consultant for AbbVie, Amgen, AOP Orphan, Arena Pharmaceuticals, Astellas, Astra Zeneca, Bioclinica, Boehringer Ingelheim, Bristol Myers Squibb, Calyx, Celgene, Celltrion, Eli Lilly, Falk Pharma GmbH, Ferring, Galapagos, Gatehouse Bio Inc., Genentech, Gilead, Grünenthal, ICON, Index Pharma, Inova, Janssen, Landos Biopharma, Medahead, MedImmune, Microbiotica, Mitsubishi Tanabe Pharma Corporation, MSD, Novartis, OMass, Otsuka, Parexel, Periconsulting, Pharmacosmos, Pfizer, Protagonist, Provention, Quell Therapeutics, Sandoz, Seres Therapeutics, Setpointmedical, Sigmoid, Sublimity, Takeda, Teva Pharma, Therakos, Theravance, Zealand, as an advisory board member for AbbVie, Amgen, Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Galapagos, Janssen, Mitsubishi Tanabe Pharma Corporation, MSD, Pharmacosmos, Pfizer, Sandoz, Takeda, and has received research funding from AbbVie, Janssen, MSD, Sandoz, Sanofi, Takeda.
David Hudesman Consultant: AbbVie, BMS, Fresenius Kabi, Janssen, Pfizer, Prometheus, Takeda, UCB
Research Support: Janssen and Pfizer
Edouard Louis: Research grant: Janssen, Pfizer, Ferring, Falk, AbbVie and Takeda; educational grant: AbbVie, Janssen, Fresenius-Kabi and Takeda; speaker fees: AbbVie, Falk, Ferring, Janssen, Pfizer, Galapagos, BMS and Takeda; advisory board: Abbvie, Celgene, Ferring, Janssen, BMS, Pfizer, and Takeda, Galapagos, Gilead, Arena, Eli Lilly; consultant: Abbvie
Naomi Martin, Joanne Rizzo,Kristina Kligys, Yafei Zhang, Javier Zambrano, and Jasmina Kalabic are AbbVie employees and may own AbbVie stock and/or options.

Introduction

Upadacitinib (UPA) is an oral, reversible Janus kinase (JAK) inhibitor that recently demonstrated efficacy compared with placebo (PBO) in 2 double-blind, multicenter induction studies, U-EXCEED (NCT03345836) and U-EXCEL (NCT01205776), and in a pre-specified primary analysis of 502 patients in the phase 3 maintenance study U-ENDURE (NCT03345823).^1-3 UPA is approved for the treatment of moderately to severely active Crohn’s disease (CD).^4,5 The current analysis evaluated the efficacy and safety of UPA in the full intent-to-treat maintenance population of U-ENDURE.

Aims & Methods

After 12 weeks of induction therapy, clinical responders (patients who achieved ≥ 30% decrease in average daily very soft/liquid stool frequency [SF] and/or ≥ 30% decrease in average daily abdominal pain score [APS] and both not worse than baseline) to UPA 45 mg were re‑randomized to 52 weeks of maintenance therapy with UPA 30 mg (UPA30), UPA 15 mg (UPA15), or placebo (PBO) once daily. Efficacy outcomes, including clinical remission per SF/APS, clinical remission per CD Activity Index (CDAI), endoscopic response, maintenance of clinical remission, clinical response per CDAI (CR-100), endoscopic remission, steroid-free clinical remission, and deep remission (clinical remission combined with endoscopic remission) were assessed through 52 weeks. Safety during U-ENDURE was documented. The efficacy analysis included all patients who were randomized and received ≥ 1 dose of study drug in U‑ENDURE.

Results

Among 673 patients included in this analysis (UPA30, n = 229; UPA15, n = 221; PBO, n = 223), all efficacy endpoints were achieved by a greater proportion of patients receiving UPA at either dose vs PBO at week 52 (Table). More patients receiving UPA achieved the co‑primary endpoints of clinical remission (per SF/APS: UPA30, 49.3%; UPA15, 33.9%; PBO, 15.2%; per CDAI: UPA30, 51.5%; UPA15, 36.2%; PBO, 15.2%; P < .0001 for both UPA doses vs PBO) and endoscopic response (UPA30, 40.7%; UPA15, 27.3%; PBO, 7.2%; P < .0001 for both doses vs PBO) over 52 weeks. Rates of any adverse events (AEs), serious AEs, and severe AEs were numerically lower with UPA compared with PBO. The rates of most AEs of special interest were similar between UPA and PBO, with the exception of higher rates of herpes zoster, neutropenia, and creatine phosphokinase elevation in the UPA30 group. Hepatic disorders (mostly transaminase elevations) were reported more frequently with UPA than PBO. One gastrointestinal perforation was reported in each of the three treatment groups. No deaths, active tuberculosis, lymphoma, nonmelanoma skin cancer, major adjudicated cardiovascular events, or venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were reported for any treatment arm.

Conclusion

Both UPA maintenance doses were more efficacious than PBO for achieving clinical and endoscopic endpoints and had a tolerable safety profile with no new safety signals. Response and remission rates were numerically higher for patients receiving UPA30 compared with UPA15. These results are consistent with published data³ and further support the use of UPA as maintenance therapy in this patient population.

References

1. Loftus E, et al. United European Gastroenterol J. 2022;10:OP129.
2. Colombel JF, et al. Gastroenterology. 2022;162:867f.
3. Panés J, et al. Am J Gastroenterol. 2022;117:S10.
4. RINVOQ. Summary of Product Characteristics. AbbVie Deutschland GmbH & Co. KG; 2023. Accessed 24 April 2023. https://www.ema.europa.eu/en/documents/product-information/rinvoq-epar-product-information_en.pdf.
5. Electronic Medicines Compendium. Rinvoq (upadacitinib) 30 mg prolonged-release tablets: summary of product characteristics. Updated March 16, 2023. Accessed March 27, 2023. https://www.medicines.org.uk/emc/product/12830/smpc/

Disclosure

MR has received research support from AbbVie, Janssen, and Takeda and unrestricted educational grants from AbbVie, Janssen, Pfizer, Salix, Shire, Takeda, and UCB; and has served on advisory boards and as a consultant for AbbVie, Allergan, Amgen, Celgene, Janssen, Miraca Labs, Pfizer, Seres, Takeda, and UCB.
SDL has served as a consultant for Cornerstones, Janssen, Lilly, Pfizer, and UCB; and received grant and research support from AbbVie, Arena, Celgene, Janssen, Shield Therapeutics, Takeda, Tetherex, and UCB.
RA has served as a speaker or consultant, or received research grants from AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Celltrion, Dr Falk Pharma, Ferring, Galapagos, Gilead, InDex Pharmaceuticals, Janssen-Cilag, Kliniksa Pharmaceuticals, MSD, Novartis, Pfizer, Roche Pharma, Samsung Bioepsis, Takeda, and Tillotts Pharma.
EB has received speaking honoraria fees from AbbVie, Ferring, Janssen, and Takeda.
CR has received consultancy and/or speaking honoraria fees from AbbVie, Ferring, Galapagos, Janssen, Pfizer, and Takeda.
AAvB has served as a consultant or speaker for AbbVie, Arena, Ferring, Galapagos, Janssen, MSD, Pfizer, Takeda, Teva, Tramedico, Vifor, and Dutch Ministry of Health (ZonMW); received research grants from Ferring, Pfizer, and Teva; and has performed as principal investigator in studies sponsored by Abivax, Arena, Celltrion, Janssen, Pfizer, Roche, and Teva.
ED, APL, JL, TF, ZG, VPR, and SIA are employees of AbbVie and may own stock and/or options.
JP has received financial support for research from AbbVie and Pfizer; received lecture fee(s) from AbbVie, Ferring, Janssen, Takeda; and received consultancy fees from AbbVie, Arena Pharmaceuticals, Athos, Boehringer Ingelheim, Celltrion, Ferring, Galapagos, Genentech, GSK, Janssen, Mirum, Morphic, Origo, Pandion, Pfizer, Protagonist, Revolo, Robarts, Roche, Takeda, Theravance, and Wassermann.
Funding
AbbVie Inc. funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of this abstract. All authors had access to relevant data and participated in the drafting, review, and approval of this abstract. No honoraria or payments were made for authorship. AbbVie and the authors thank the patients who participated in the study and all study investigators for their contributions. AbbVie funded the research for this study and provided writing support for this abstract. Medical writing assistance, funded by AbbVie, was provided by Spencer Hughes, PhD, of JB Ashtin.