Introduction

Given the natural history of Crohn’s disease (CD), the beneficial effects of treatments may wane over time and result in loss of response. Treatment escalation may aid in re-capturing clinical benefit and improving markers of inflammation. Upadacitinib (UPA) is an oral reversible Janus kinase inhibitor that demonstrated efficacy compared with placebo in 2 phase 3 induction studies and 1 maintenance study, U‑ENDURE, in CD^1-3 and is approved for patients with moderately to severely active CD.⁴ In this post hoc analysis, we evaluated the effect of UPA 30 mg therapy among patients who experienced loss of response to UPA 15 mg maintenance treatment or upon treatment withdrawal.

Aims & Methods

Patients who achieved clinical response (≥ 30% decrease in average daily very soft/liquid stool frequency [SF] and/or abdominal pain score [APS], neither worse than baseline) to 12 weeks of UPA 45 mg once daily (QD) induction therapy were re-randomized to receive UPA 30 mg, UPA 15 mg, or placebo QD in U‑ENDURE (NCT03345823). Beginning at week 4, patients who experienced loss of response and required medical treatment could receive open‑label (OL) UPA 30 mg QD. Loss of response was defined as having clinical symptoms (average daily very soft/liquid SF ≥ 4.0 and/or average daily APS ≥ 2.0) plus an objective marker of inflammation (protocol-specified criteria for high‑sensitivity C-reactive protein [hsCRP], fecal calprotectin [FCP], or Simple Endoscopic Score for CD). Outcomes were assessed at 12 and 24 weeks after initiation of OL UPA 30 mg QD therapy and included clinical remission and clinical response (both per CD Activity Index [CDAI] and SF/APS), enhanced clinical response, and FCP and hsCRP levels. Safety was also assessed. Analyses were based on as observed data without imputation.

Results

Patients who received OL UPA 30 mg QD therapy had, at baseline, a mean CD duration of 10 years, mean CDAI of 304, median hsCRP of 14.3 mg/L, and median FCP of 1550 µg/g; 83.5% had prior biologic failure. At 12 weeks after initiation of OL UPA 30 mg QD, regardless of group during blinded maintenance, 84.4%–87.6% of patients achieved SF/APS clinical response, 77.2%–78.9% achieved enhanced clinical response, 63.3%–71.3% achieved CDAI clinical response, and 46.7%–53.8% achieved SF/APS or CDAI clinical remission (Table). Reponses were sustained through 24 weeks. Median hsCRP and FCP levels decreased after initiation of OL UPA 30 mg QD therapy. Adverse event rates in either group were consistent with those in the overall population. One major adjudicated cardiovascular event in the placebo group and 2 events of non-melanoma skin cancer in the UPA 15-mg group were reported after receiving UPA 30 mg.

Conclusion

Among patients with CD who responded to UPA 45 mg induction therapy and subsequently lost response during maintenance when randomized to placebo or UPA 15 mg QD, most regained clinical response and many achieved clinical remission 12 weeks after initiating UPA 30 mg QD therapy. These improvements were sustained through 24 weeks. No new safety signals were observed.

References

1. Colombel JF, et al. Gastroenterology. 2022;162:S1394.
2. Loftus EV Jr. United European Gastroenterol J. 2022;10;103–104.
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.

Disclosure

RP has received consultancy and/or speaking honoraria from Abbott, AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos, Eisai, Elan, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead, GSK, JAMP Bio, Janssen, Lilly, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion, Pendopharm, Pfizer, Progenity, Prometheus, Protagonist, Roche, Sandoz, Satisfai Health, Shire, Sublimity, Takeda, Theravance, Trellus, Viatris, and Ventyx, and has received research funding from Abbvie, Janssen, Pfizer, and Takeda.
JOL has received consulting and/or speaker fees from AbbVie, Bristol-Myers Squibb, Celgene, Celltrion, Ferring, Galapagos, Gilead, GSK, Janssen, Lilly, Napp, Pfizer, Shire, Takeda, and Vifor Pharma; and investigator-led research grants from AbbVie, Gilead, Pfizer, Shire, and Takeda.
JP has received financial support for research from AbbVie and Pfizer; consultancy fees/honorarium from AbbVie, Arena, Athos, Atomwise, Boehringer Ingelheim, Celgene, Celsius, Celltrion, Ferring, Galapagos, Genentech/Roche, GSK, Janssen, Mirum, Morphic, Nestlé, Origo, Pandion, Pfizer, Progenity, Prometheus, Protagonist, Revolo, Robarts, Sanofi, Takeda, Theravance, and Wasserman; reports payment for lectures, including service on speaker bureaus, from Abbott, Ferring, Janssen, Pfizer and Takeda; and reports payment for development of educational presentations from Abbott, Janssen, Pfizer, Roche and Takeda.
PS has received honoraria for consulting and/or speaking activities from AbbVie, Ferring, Janssen, Lilly, Roche, Pfizer, and Takeda. He has served as an investigator for clinical trials sponsored by Abbvie, Gilead, Janssen, Pfizer, and Takeda.
MNR has been a principal investigator for studies sponsored by AbbVie.
MDM-A has received consulting and/or speaker fees from AbbVie, Galapagos, Janssen, Pfizer, Takeda, and Tillotts, and has received research funding from AbbVie, Janssen, and Pfizer.
FB has served as an investigator for clinical trials sponsored by AbbVie and Janssen.
APL, ED, SF, SA, and TF are employees or contractors of AbbVie, and may own AbbVie stock and/or stock options.
GD'H has received honoraria for consulting and/or speaking activities from AbbVie, Alimentiv, Boehringer Ingelheim, Celltrion, Ferring, Galapagos, GSK, Gossamer Bio, Janssen, Lilly, Pfizer, Progenity, Takeda, and Tillotts.
Funding
AbbVie Inc. funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the 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 authors thank all the trial investigators and the patients who participated in this clinical trial. Medical writing support was provided by Lisa M Pitchford, PhD, of JB Ashtin, and funded by AbbVie.

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.