Introduction

Patients with moderately to severely active ulcerative colitis (UC) have debilitating symptoms that may incur substantial negative effects on health-related quality of life (HRQoL). According to the STRIDE-II consensus, restoration of HRQoL is a desirable long-term treatment goal for patients with active UC.¹ In this post-hoc analysis, we evaluated the extent to which patients treated with upadacitinib (UPA) achieved normalisation of HRQoL after induction and maintenance treatment.

Aims & Methods

Data from the multicentre, double-blind, Phase 3 trials, U-ACHIEVE (NCT02819635) and U-ACCOMPLISH (NCT03653026), were analysed. During induction, patients were randomised 1:2 to oral placebo (PBO) or UPA 45 mg once daily (QD) for 8 weeks. Patients achieving a clinical response to UPA per Adapted Mayo score at Week 8 were re-randomised 1:1:1 to PBO, UPA 15 mg, or UPA 30 mg QD for 52 weeks of maintenance. The proportion of patients achieving normalisation of each individual HRQoL outcome, per literature-base normative value thresholds, was assessed at Weeks 8 and 52: FACIT-Fatigue score; IBDQ score; WPAI-UC (overall work impairment, work time missed, impairment while working, activity impairment); SF-36 PCS; SF-36 MCS; EQ-5D-5L VAS; and EQ-5D-5L index. A stringent composite score including these outcomes was also calculated to determine the proportion of patients who achieved normalisation of all individual HRQoL-related scores. Point estimates were calculated for all outcomes and treatment differences between UPA and PBO were compared using the Cochran-Mantel-Haenszel test.

Results

During induction, 660 patients were randomised to UPA 45 mg and 328 patients to PBO. In patients receiving UPA 45 mg vs PBO, more patients achieved normalisation of each individual HRQoL outcome at Week 8 of induction (p<0.001; Table 1). Improvements were also observed at Week 52 of maintenance in patients receiving UPA 15 mg (n=148) and 30 mg (n=154), with more patients achieving normalisation of each HRQoL outcome with both doses of UPA vs PBO (p<=0.01). More patients achieved normalisation of composite HRQoL scores at Weeks 8 (UPA 45 mg: 18.9%; PBO: 5.5%) and 52 (UPA 30 mg: 24.0%; UPA 15 mg: 22.3%; PBO: 8.7%) with all doses of UPA compared to PBO (p<=0.001).
Table 1. Proportion of patients with UC achieving normalisation of HRQoL outcomes after treatment

Conclusion

UPA is more efficacious than PBO at achieving normalisation of patients’ HRQoL, at induction and through Week 52 of maintenance. These results suggest that UPA may help patients with moderately to severely active UC achieve the long-term treatment goal of normalisation of HRQoL.

References

1. Turner D, et al. Gastroenterology. 2021;160:1570–83.

Disclosure

Joana Torres has received grant funding/speaker fees from and/or has participated in advisory boards for AbbVie, Galapagos, Janssen, and Pfizer.
Gareth Parkes received personal payments/honoraria/speaker fees and/or accepted travel grants or fellowships from AbbVie, Allergan, BMS, Celltrion, Ferring, Galapagos, Janssen, Napp, Takeda, and Tillotts; and is a Director and Shareholder in Ampersand Health.
Corey Siegel has served as a consultant, advisor, speaker for CME activities, and/or received grant funding from AbbVie, BMS, Celltrion, Fresenius, Janssen, Lilly, Napo, Pfizer, Prometheus, Prometheus Labs, Roivant, and Takeda.
Julian Panés received consultancy fees/honorarium from AbbVie, Alimentiv, Athos, Atomwise, Boehringer Ingelheim, Celsius, Ferring, Galapagos, Genentech/Roche, GlaxoSmithKline, Janssen, Mirum, Nimbus, Pfizer, Progenity, Prometheus, Protagonist, Revolo, Sanofi, Sorriso, Surrozen, Takeda, and Wasserman; and has served on a data safety monitoring board for Alimentiv, Mirum, Sorriso, Sanofi, and Surrozen.
Edward V. Loftus Jr: served as a consultant for AbbVie, Alvotech, Amgen, Arena, Avalo, Boehringer Ingelheim, Bristol-Myers Squibb, Calibr, Celgene, Celltrion Healthcare, Eli Lilly, Fresenius Kabi, Genentech, Gilead, GlaxoSmithKline, Gossamer Bio, Iota, Iterative Scopes, Janssen, Morphic Therapeutics, Ono Pharma, Pfizer, Protagonist, Scipher Medicine, Surrozen, Sun Pharma, Takeda, and UCB; and received research grants from AbbVie, Bristol-Myers Squibb, Celgene, Genentech, Gilead, Gossamer Bio, Janssen, Pfizer, Receptos, Robarts Clinical Trials, Takeda, Theravance, and UCB.
Remo Panaccione served as a consultant for Abbott, AbbVie, Abbivax, Alimentiv (formerly Robarts), Amgen, AnaptysBio, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Spyre Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Union Biopharma, Viatris, Ventyx, UCB; and received speaker’s fees from AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Merck, Organon, Pfizer, Roche, Sandoz, Shire, and Takeda Pharmaceuticals; and was an advisory board member for AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, SandozShire, Sublimity Therapeutics, Takeda Pharmaceuticals, and Ventyx.
Yuri Sanchez Gonzalez, Si Xuan, Valencia Remple, Justin Klaff, Cecile Holweg, and Dolly Sharmaare full-time employees of AbbVie and may hold AbbVie stock and/or stock options.
Funding statement: Financial support for the study was provided by AbbVie. AbbVie participated in interpretation of data, review, and approval of the abstract. All authors contributed to development of the abstract and maintained control over final content. No honoraria or payments were made for authorship. Medical writing services provided by Kay Hallam, MSc, of Fishawack Facilitate, Ltd, part of Avalere Health and funded by AbbVie.

Introduction

OZA, an oral selective sphingosine 1-phosphate receptor modulator, is approved for the treatment of moderately to severely active ulcerative colitis and is under investigation for CD. Clinical, endoscopic, and histologic improvements were observed after 12 wk of treatment with OZA in pts with moderately to severely active CD in the phase 2 STEPSTONE study. Differential decreases in circulating lymphocytes were observed in STEPSTONE, with reductions in T and B cells; however, natural killer cells and monocytes were unaffected. Circulating MBCs have not been widely studied in CD.

Aims & Methods

This exploratory analysis of STEPSTONE assessed the association between levels of circulating lymphocyte subsets and OZA efficacy. Pts received OZA 0.92 mg for 12 wk. Lymphocyte subsets were evaluated using multicolor flow analysis on blood samples collected before treatment and at Week (W) 12; differences between Day 1 and W12 were analyzed by Wilcoxon signed-rank tests. Change in disease activity from baseline to W12 was determined for Simple Endoscopic Score for Crohn’s Disease, size of ulcers, extent of ulcerated surface, extent of affected surface, presence of narrowing, Crohn’s Disease Activity Index (CDAI), Robart’s Histopathology Index (RHI), Geboes Histology Activity Score (GHAS), and stool frequency. Efficacy outcomes (ie, clinical response, clinical remission, endoscopic response, endoscopic remission, global GHAS remission, RHI remission, and RHI mucosal healing) were evaluated at W12. Associations of lymphocyte subset levels with disease activity changes and efficacy outcomes were assessed using Spearman’s correlation and logistic regression, respectively.

Results

Of the 69 pts enrolled, 52 had disease activity, efficacy outcome, and flow cytometry data at baseline and W12 and were included in this analysis. Most lymphocyte subsets assessed were significantly associated with 1 or 2 efficacy outcomes, whereas nonswitched MBCs were significantly associated with most outcomes, including endoscopic response-25, endoscopic response-50, endoscopic remission, global GHAS remission, and RHI mucosal healing (Table). Baseline levels of nonswitched MBCs were significantly correlated with change from baseline to W12 in extent of affected surface (Spearman’s rho = –0.44, P<0.05), RHI (Spearman’s rho = –0.34, P<0.05), and GHAS (Spearman’s rho = –0.47, P<0.05). Changes in levels of nonswitched MBCs were significantly correlated with change from baseline to W12 in CDAI (Spearman’s rho = 0.38, P<0.05), RHI (Spearman’s rho = 0.37, P<0.05), GHAS (Spearman’s rho = 0.43, P<0.05), and stool frequency (Spearman’s rho = 0.43, P<0.05).

Conclusion

After 12 wk of OZA treatment, higher levels of nonswitched MBCs at baseline were associated with endoscopic and histologic improvement, and reductions in nonswitched MBCs were associated with decreases in clinical and histologic disease activity. These data implicate nonswitched MBCs, which are involved in T cell–dependent immune responses and some inflammatory diseases, as a marker associated with OZA response in CD.

Disclosure

The study was funded by Bristol Myers Squibb, Princeton, NJ, USA.
SHar, CW, YH, and RM: employees and/or shareholders of Bristol Myers Squibb.
BGF: consulted for AbbVie, ActoGeniX, Albireo, Amgen, AstraZeneca, Avaxia Biologics, Baxter, Biogen Idec, Boehringer Ingelheim, Bristol Myers Squibb, Calypso, Celgene, Elan, Eli Lilly, enGene, Ferring Pharmaceuticals, Roche/Genentech, gIcare Pharma, Gilead, Given Imaging, GlaxoSmithKline, Ironwood, Janssen, Johnson & Johnson, Lexicon, Merck, Millennium, Nektar, Novo Nordisk, Pfizer, Prometheus Laboratories, Protagonist, Sanofi, and UCB; director at Robarts Clinical Trials.
SHan: consulted for AbbVie, Actavis, Boehringer Ingelheim, Bristol Myers Squibb, Caremark, Celgene, Ferring Pharmaceuticals, Janssen, Merck, Pfizer, Salix, Sanofi-Aventis, Shire, and UCB.
SV: received research funding from AbbVie, Galapagos, Johnson & Johnson, Pfizer, and Takeda; received consulting and/or speaking fees from AbbVie, Abivax, AbolerIS, AgomAb, Alimentiv, Arena, AstraZeneca, Avaxia, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, CVasThera, Cytoki Pharma, Eli Lilly, Falk Pharma, Ferring, Galapagos, Genentech/Roche, Gilead, GlaxoSmithKline, Hospira, IMIDomics, Janssen, Johnson & Johnson, Materia Prima, MiroBio, Morphic Therapeutic, MRM Health, MSD, Mundipharma, Pfizer, ProDigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillotts Pharma AG, and Zealand.
SG: received research funding from AbbVie and GlaxoSmithKline; served as a lecturer for AbbVie, Celgene, Eli Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Pfizer, and Takeda; served as a consultant for AbbVie, Bristol Myers Squibb, Janssen, Novo Nordisk, Pfizer, Roche, and Takeda.
JY: employee and shareholder of Laboratory Corporation of America Holdings.
DCW: received honoraria as a speaker, consultant, and/or advisory board member from AbbVie, Arena, Celgene/Bristol Myers Squibb, Janssen, Pfizer, Prometheus, Takeda, and UCB.
GD: served as an advisor for AbbVie, Agomab Therapeutics, Alimentiv, Applied Molecular Therapeutics, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Cytoki, Eli Lilly, Exeliom, Ferring, Galapagos, GlaxoSmithKline, Gossamer Bio, Immunic, Johnson & Johnson, Pfizer, Polpharma, ProciseDx, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Seres, Takeda, Tillotts, and Versant; received speaker fees from AbbVie, Bristol Myers Squibb, Eli Lilly, Galapagos, Johnson & Johnson, Pfizer, Takeda, and Tillotts.