Introduction

The efficacy and safety of upadacitinib (UPA), an oral reversible Janus kinase inhibitor, were demonstrated for patients with Crohn’s disease (CD) in three phase 3 randomized, controlled, double-blind clinical trials: U-EXCEL (NCT03345849), U-EXCEED (NCT03345836), and U-ENDURE (NCT03345823).^1–3 UPA is approved for the treatment of moderately to severely active CD.^4,5 The STRIDE-II CD treat-to-target guidelines recommend using composite clinical and endoscopic treatment targets to improve patient outcomes.⁶ We assess the efficacy of UPA in patients with moderately to severely active CD using stringent, composite efficacy endpoints.

Aims & Methods

In two phase 3 induction studies, U‑EXCEL and U-EXCEED, patients were randomized 2:1 to receive once-daily UPA 45 mg or placebo (PBO) for 12 weeks. Those who achieved a clinical response (≥30% decrease in average daily very soft or liquid stool frequency [SF] and/or ≥30% decrease in average daily abdominal pain score [APS] and both not worse than baseline) to UPA were re-randomized 1:1:1 to receive UPA 15 mg, UPA 30 mg, or PBO in the 52-week U-ENDURE maintenance study. Five composite clinical and endoscopic endpoints were assessed at weeks 12 of induction and 52 of maintenance therapy: (1) enhanced clinical response (per very soft/liquid SF and APS) and endoscopic response; (2) clinical response (CR-100) and endoscopic response; (3) clinical remission per CD Activity Index (CDAI) and endoscopic response; (4) SF/APS clinical remission and endoscopic remission; and (5) CDAI clinical remission and endoscopic remission. Treatment group differences were compared using the Cochran-Mantel-Haenszel test, adjusted for stratification factors. Analyses used nonresponder imputation while incorporating multiple imputation to handle missing data due to COVID-19.

Results

A greater proportion of patients receiving UPA 45 mg vs PBO achieved stringent clinical and endoscopic endpoints at week 12: enhanced clinical response and endoscopic response (33.7 vs 6.1%); CR-100 and endoscopic response (27.8 vs 5.2%); CDAI clinical remission and endoscopic response (24.7 vs 5.2%); SF/APS clinical remission and endoscopic remission (15.7 vs 3.5%); and CDAI clinical remission and endoscopic remission (15.0 vs 3.7%; for all comparisons, nominal P values ≤ .001; Table). At week 52, a greater proportion of patients who received UPA 15 mg or UPA 30 mg achieved stringent clinical and endoscopic endpoints vs patients in the PBO group (Table). Composite endpoint achievement rates were numerically greater with UPA 30 mg than with UPA 15 mg (Table). The safety of UPA in CD was previously reported.^1–3
​

Conclusion

In both induction and maintenance studies, patients receiving UPA had greater achievement of stringent efficacy endpoints vs patients who received PBO. UPA 30 mg demonstrated numerically greater clinical and endoscopic efficacy vs UPA 15 mg. The largest differences between UPA and PBO treatment groups occurred for the enhanced clinical response and endoscopic response endpoint.

References

1. Colombel JF, et al. Gastroenterology. 2022;162(Suppl):1394.
2. Loftus EV Jr. United European Gastroenterol J. 2022;10(Suppl 8):103–104.
3. Panés J, et al. Am J Gastroenterol. 2022;117(Suppl):10.
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. RINVOQ. Summary of Product Characteristics. AbbVie Inc.; 2023. Accessed March 27, 2023. https://www.medicines.org.uk/emc/product/12830/smpc.
6. Turner D, et al. Gastroenterology. 2021;160(5):1570–1583.

Disclosure

SD has served as a speaker, consultant, and advisory board member for AbbVie, Actelion, Alfa Wasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grunenthal, Johnson & Johnson, Millennium Takeda, MSD, Nikkiso Europe GmbH, Novo Nordisk, Nycomed, Pfizer, Pharmacosmos, Schering-Plough, UCB Pharma, and Vifor.
BGF has consulted for AbbVie, AbolerIS, AgomAB Therapeutics, Allianthera, Amgen, AnaptysBio, Applied Molecular Transport Inc, Arena Pharma, Avoro Capital Advisors, Atomwise,, BioJamp, Biora Therapeutics, Boehringer-Ingelheim, Boxer, Celsius Therapeutics,Celgene/BMS, Connect BioPharma, Cytoki, Disc Medicine, Duality, EcoR1, Eli Lilly, Equillium, Ermium,, First Wave, First Word Group, Galapagos, Galen Atlantica, Genentech/Roche, Gilead, Gossamer Pharma, GSK, Hinge Bio, Hot Spot Therapeutics, Index Pharma, Imhotex, Immunic Therapeutics, JAKAcademy, Janssen, Japan Tobacco Inc., Kaleido Biosciences, Landos Biopharma, Leadiant, L.E.K. Consulting, Lenczner Slaght, LifeSci Capital, Lument AB, Millennium, MiroBio, Morgan Lewis, Morphic Therapeutics, Mylan, OM Pharma, Origo BioPharma, Orphagen, Pandion Therapeutics, Pendopharm, Pfizer, Prometheus Therapeutics and Diagnostics, Play to Know AG, Progenity, Protagonist, PTM Therapeutics, Q32 Bio, Rebiotix, REDX, Roche, Sandoz, Sanofi, Seres Therapeutics, Silverback Therapeutics, Surrozen Inc., Takeda, Teva, Thelium, Tigenix, Tillotts, Ventyx Biosciences, VHSquared Ltd., Viatris, Ysios, Ysopia, and Zealand Pharma; a speaker for AbbVie, Janssen, and Takeda; an advisor for AbbVie, Amgen, AMT, AnaptysBio, Axio Research, Boehringer-Ingelheim, Celgene/BMS, Ecor1Capital, Eli Lilly, Genentech/Roche, GSK, Index, Janssen, MiroBio, Morphic, Origo BioPharma, Pfizer, Progenity, Prometheus, REDX Pharma, Sanofi, Takeda, Teva, and Tillotts Pharma; a senior scientific director for Alimentiv Inc.; an employee of Western University; and holds stocks in Gossamer Pharma.
FM has served as a speaker and received honoraria from AbbVie, Biogen, Falk Pharma, Ferring, Hospira, Laboratorios Vitoria, Merck Sharp & Dohme, and Vifor.
PLL has been a speaker and/or advisory board member for AbbVie, Arena, Falk Pharma, Ferring, Genentech, Janssen, Kyowa Hakko Kirin Pharma, Mitsubishi Tanabe Pharma, MSD, Pfizer, Roche, Shire, Takeda, and Tillots; and has received unrestricted research grants from AbbVie, MSD, and Pfizer.
JOL has received grants for investigator led research from Takeda, Hospira / Pfizer, Abbvie, Gilead and has been a speaker and / or advisory board member for Allergan, Abbvie, Bristol Myers Squib, Celgene, Celltrion, Cornerstones US, Galapagos, Gilead, GSK, Lily, MSD UK, Shire, Ferring, Takeda, Pfizer, Janssen, Bristol Myers Squib,
TH has received research grants from AbbVie, Alfresa Pharma, Daiichi Sankyo, EA Pharma, JIMRO, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer, and Takeda. He has received lecture fees from AbbVie, EA Pharma, Janssen, Mitsubishi Tanabe Pharma, Pfizer, and Takeda.
BS has served as consultant for AbbVie, Boehringer, BMS, Celgene, Falk Pharma, Galapagos, Gilead, Janssen, Landos, Lilly, Pfizer, Prometheus, and Takeda, and received speaker’s fees from AbbVie, CED Service GmbH, BMS, Falk Pharma, Ferring, Galapagos, Janssen, Novartis, Pfizer, and Takeda.
ED, APL, AG, and CD, are employees of AbbVie, and may own AbbVie stock and/or stock options.
JDL has received personal fees, grants, and/or other support from AbbVie, Amgen, Arena Pharmaceuticals, Bridge Biotherapeutics, Bristol-Myers Squibb, Celgene, Galapagos, Gilead, Janssen Pharmaceuticals, Johnson & Johnson Consumer Inc., Lilly, Merck, Nestle Health Science, Pfizer, Protagonist Therapeutics, Samsung Bioepis, Sanofi, Takeda, and UCB.
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 Morgan A Gingerich, PhD, of JB Ashtin, and funded by AbbVie.