Introduction

Fistulating peri-anal Crohn’s disease can affect approximately 20% of patients and have a major impact on quality of life. Despite being an important area of unmet clinical need, there is a paucity of evidence for most medical treatments and a lack of dedicated clinical trials for perianal Crohn’s disease. Current studies also report a high level of heterogeneity for outcomes with both treatments and placebo - making interpretation of the available data challenging for both clinical practice and design of clinical trials. Use of Bayesian methodology offers an attractive solution to help address some of these challenges. We sought to conduct a Bayesian prior elicitation exercise to determine the efficacy of licensed medical therapies for fistulating perianal Crohn’s disease.

Aims & Methods

A formal Bayesian prior elicitation meeting was convened. This was composed of a group of 11 gastroenterologists and 5 statisticians. Consensus priors were developed leveraging both published data and expertise of the gastroenterologists, to determine one-year fistula remission rates for seven options of licensed medical treatments based on five different mechanisms of action (anti-TNF, anti-integrin, anti-IL12/23, anti-IL-23, and JAK inhibitor). Consensus priors on the efficacy of each of seven treatment options was determined relative to an elicited consensus prior for placebo control. The log-odds ratio for efficacy for each of the seven therapy options versus placebo control was also established.

Results

Consensus priors were obtained for seven medical treatments for likelihood of fistula remission at one year. The prior mean, together with a 90% prior credible interval, of the one-year fistula remission rate was 0.22 (0.05, 0.46) for placebo, 0.58 (0.09, 0.96) for intravenous infliximab, 0.39 (0.06, 0.82) for adalimumab, 0.53 (0.09, 0.93) for subcutaneous infliximab, 0.24 (0.03, 0.60) for intravenous vedolizumab, 0.44 (0.05, 0.90) for upadacitinib, 0.34 (0.04, 0.77) for ustekinumab, and 0.36 (0.04, 0.82) for risankizumab. When assessing treatment effect on the log-odds ratio scale, oral upadacitinib and subcutaneous infliximab had the strongest “priors”, with the highest probability for likely efficacy, alongside intravenous infliximab.

Conclusion

We have conducted, to the best of our knowledge, the first formal Bayesian prior elicitation exercise for efficacy of medical therapies in perianal Crohn’s disease. These priors developed for the efficacy of licensed medical therapies can be internationally validated and potentially taken forward for planning of dedicated clinical trials. Importantly, these results could be used to enhance the design and analysis of clinical trials for fistulating perianal Crohn’s disease. Notable potential benefits from these findings include: improved estimation of treatment efficacy, reduction in the required sample sizes, and with minimisation or even avoidance of placebo control arms for future dedicated fistulating perianal Crohn’s disease clinical trials.

Disclosure

NMN declares educational/travel grants and/or speaker fees from AbbVie, Bristol Myers Squibb, Celltrion, Dr Falk Pharma, Ferring, Galapagos, J&J, Lilly, Pfizer, Pharmacosmos, Takeda and Tillotts Pharma AG. RC reports personal fees from AbbVie, Galapagos, Lilly outside the submitted work, and grants from Celltrion, Ferring, Tillotts Pharma outside the submitted work; and fees from advisory board membership of AbbVie, Bristol Myers Squibb outside the submitted work. SD reports personal fees from AbbVie, Ferring, Janssen, Takeda outside the submitted work; and grants from AbbVie, Dr Falk, Janssen, outside the submitted work; and fees from advisory board membership of AbbVie outside the submitted work. HG has received speaker fees from: Janssen, Ferring, Takeda, and AbbVie, and consultancy fees from. AbbVie, Galapagos. KBK reports serving as a speaker, a consultant, and/or an advisory board member for Abbvie, Falk, Galapagos, Janssen, and Takeda. JOL reports personal fees from AbbVie, Atlantic Healthcare, Bristol Meyer Squibb, Celgene, Celltrion, Engytix, Eli Lilly, Ferring, Galapagos, Gilead, GSK, Janssen, MSD, Norgine, Pfizer, Shire, and Takeda outside the submitted work; and grants from AbbVie, Ferring, Gilead, Takeda, and Shire outside the submitted work. GWM declares consultancy fees/grant funding from AbbVie, AstraZeneca and Janssen; all outside the submitted work. KVP reports personal fees from AbbVie, DrFalk, Galapagos, Janssen, PredictImmune, Pfizer, Takeda outside the submitted work; and grants from AbbVie, Celltrion, Dr Falk, Ferring, Janssen, Takeda, Tillotts Pharma outside the submitted work; and fees from advisory board membership of AbbVie, Galapagos, Janssen, Pfizer outside the submitted work. SS reports consulting fees from Takeda, AbbVie, Merck, Ferring, Pharmacosmos, Warner Chilcott, J&J Innovative Medicine, Dr Falk Pharma, Biohit, TriGenix, Celgene, and Tillots Pharma outside the submitted work; payment or honoraria from AbbVie, Takeda, Celltrion, Pfizer, Biogen, AbbVie, J&J Innovative Medicine, Merck, Warner Chilcott, Dr Falk Pharma, outside the submitted work; and is co-director of research for the South Asian IBD Alliance. TR has received research/educational grants and/or speaker/consultation fees from Abbvie, Arena, Aslan, AstraZeneca, Boehringer-Ingelheim, BMS, Celgene, Eli Lilly, Ferring, Galapagos, Gilead, GSK, Heptares, LabGenius, Janssen, MonteRosa, Mylan, MSD, Novartis, Numab, Pfizer, Roche, Sandoz, Takeda, UCB, and XAP Therapeutics. SS reports person fees from Abbvie, Celltrion, Dr. Falk, Ipsen, Janssen, Takeda outside the submitted work. ALH has received consultancy fees from AbbVie, Bristol Myers Squibb, Celltrion, Galapagos, Johnson & Johnson, Takeda, Pfizer, and Lilly; has received honoraria from AbbVie, Bristol Myers Squibb, Celltrion, Galapogos, Johnson & Johnson, Takeda, Pfizer, Lilly; and has received support for attending meetings or travel from AbbVie, Bristol Myers Squibb, Celltrion, Galapagos, Johnson & Johnson, Takeda, Pfizer, and Lilly; all outside of the submitted work. MP reports personal fees from Janssen and Takeda outside the submitted work; and grants from AstraZeneca, Galapagos, Gilead, Pfizer outside the submitted work. All other authors declare no conflicts of interest.

Introduction

The Phase 3 QUASAR induction study (NCT04033445) was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study that evaluated efficacy and safety of guselkumab (GUS), an interleukin-23 p19 antagonist, as induction therapy in patients (pts) with moderately to severely active UC who had an inadequate response or intolerance to conventional (ie, thiopurines or corticosteroids) and/or advanced therapies (ie, TNF alpha antagonists, integrin receptor antagonists, or Janus kinase inhibitors).

Aims & Methods

The primary analysis population included randomized pts with a baseline modified Mayo score of 5 to 9, inclusive, a rectal bleeding subscore ≥1, and an endoscopy subscore ≥2 (centrally read). Pts were randomized 3:2 to receive IV GUS 200mg or placebo (PBO) at Weeks (Wks) 0, 4, and 8. The primary endpoint was clinical remission at Wk12. Symptomatic remission, clinical response, endoscopic improvement, histo-endoscopic mucosal improvement (HEMI), endoscopic normalization, and safety were also assessed.

Results

The primary analysis population included 701 pts (mean age, 40.5yrs; female, 43.1%; mean UC duration, 7.5yrs; mean modified Mayo score, 6.9; Mayo endoscopy subscore=3 (severe disease), 67.9%; median fecal calprotectin, 1641mg/kg; median CRP, 4.2mg/L; baseline oral corticosteroid use, 43.1%). Baseline characteristics were balanced across treatment groups. Approximately 50% had prior inadequate response/intolerance to advanced therapies (ADT-IR) for UC; nearly half of these (47.4%) had ≥2 ADT-IR classes. A significantly greater proportion of GUS- vs PBO-treated pts achieved clinical remission at Wk12 (22.6% vs 7.9%, adjusted ∆=14.9%, p<0.001; Table). Relative to PBO, GUS induction treatment resulted in significantly greater proportions of pts achieving symptomatic remission, clinical response, endoscopic improvement, and HEMI at Wk12 and symptomatic remission at Wk4. Adverse event (AE) frequencies through Wk12 in GUS group were similar to PBO (49.4% vs 49.3%, respectively). Most frequently reported AEs were anemia, COVID-19, worsening of UC, and headache. Infections and serious infections occurred at similar rates for GUS- vs PBO-treated pts (15.7% vs 15.4% and 0.7% vs 0.4%, respectively). GUS- vs PBO treated pts had numerically fewer serious AEs (2.9% vs 7.1%) and AEs leading to discontinuation (1.7% vs 3.9%). Through Wk12, 2 PBO-treated pts and 1 GUS-treated pt died (all cardiovascular in nature). No AEs within 1 hour of infusion were considered serious or resulted in treatment discontinuation. The incidence of anti-drug antibodies through Wk12 was low (1.5%, 6/409), and no neutralizing antibodies were detected.

Table. Primary and key secondary endpoints

	Placebo IV	GUS 200 mg IV	Adjusted treatment difference (95% CI)
Full Analysis set, N	280	421	-
Clinical remission at Wk12, n (%)a	22 (7.9%)	95 (22.6%)	14.9% (9.9%, 19.9%) p<0.001
Symptomatic remission at Wk4, n (%)b	36 (12.9%)	95 (22.6%)	9.9% (4.4%, 15.4%) p<0.001
Symptomatic remission at Wk12, n (%)b	58 (20.7%)	210 (49.9%)	29.4% (22.8%, 36.0%) p<0.001
Clinical response at Wk12, n (%)c	78 (27.9%)	259 (61.5%)	33.8% (26.9%, 40.7%) p<0.001
Endoscopic improvement at Wk12, n (%)d	31 (11.1%)	113 (26.8%)	16.0% (10.5%, 21.4%) p<0.001
Histo-endoscopic mucosal improvement at Wk12, n (%)e	21 (7.5%)	99 (23.5%)	16.2% (11.1%, 21.2%) p<0.001
Endoscopic normalization at Wk12, n (%)f	14 (5.0%)	63 (15.0%)	10.1% (5.9%, 14.3%)***
***Nominal p-value <0.001. a Clinical remission was defined as a Mayo stool frequency subscore of 0 or 1 and not increased from baseline, a Mayo rectal bleeding subscore of 0, and a Mayo endoscopy subscore of 0 or 1 with no friability present on the endoscopy. b Symptomatic remission was defined as a stool frequency subscore of 0 or 1 and not increased from baseline, and a rectal bleeding subscore of 0. c Clinical response was defined as a decrease from baseline in the modified Mayo score by ≥30% and ≥2 points, with either a ≥1-point decrease from baseline in the rectal bleeding subscore or a rectal bleeding subscore of 0 or 1. d Endoscopic improvement was defined as an endoscopy subscore of 0 or 1 with no friability present on the endoscopy. e Histo-endoscopic mucosal improvement was defined as achieving a combination of histologic improvement (neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations or granulation tissue according to the Geboes grading system, i.e., Geboes score ≤ 3.1) and endoscopic improvement. f Endoscopic normalization was defined as an endoscopy subscore of 0. Note: Patients who had a prohibited change in UC medication, an ostomy or colectomy, or discontinued study agent due to lack of therapeutic effect or due to an AE of worsening of UC prior to the designated analysis timepoint were considered not to have achieved the endpoint. Data after discontinuation of study agent due to COVID-19 related reasons (excluding COVID-19 infection) were considered to be missing. Patients who were missing one or more components pertaining to a specified endpoint at Week 12 were considered not to have achieved the endpoint. The p-values were based on the Cochran-Mantel-Haenszel (CMH) chi-square test.

Conclusion

In this Phase 3 study, GUS 200mg IV induction was safe and effective in the treatment of pts with moderately to severely active UC compared to PBO, with clinically meaningful improvements demonstrated across symptomatic and histo-endoscopic outcome measures. Overall, safety results through Wk12 were consistent with the known and favorable safety profile of GUS in approved indications.

Disclosure

Laurent Peyrin-Biroulet reports personal fees and Steering Committee member for Janssen.
Jessica R. Allegretti is a consultant and Steering Committee member for Janssen.
Brian G. Feagan received grant/research support from Janssen Research & Development LLC.; a consultant for JnJ/Janssen; a member of the speakers bureau for JnJ/Janssen; a member of the scientific advisory board for JnJ/Janssen.
Brian Bressler is an advisor/speaker/Steering Committee member for and has received research support from Janssen.
Gary R. Lichtenstein discloses relationships with Janssen/ Janssen Orthobiotech (Consultant, Research, Funding to University of PA [IBD Fellow Education]).
Kuan-Hsiang G. Huang is an employee of Johnson & Johnson and owns company stock/stock options.
Matthew Germinaro is an employee of Johnson & Johnson and owns company stock/stock options.
Nicole Shipitofsky is an employee of Johnson & Johnson and owns company stock/stock options
Lingjing Jiang is an employee of Johnson & Johnson and owns company stock/stock options.
Hongyan Zhang is an employee of Johnson & Johnson and owns company stock/stock options.
Tadakazu Hisamatsu is a Steering Committee member and has received consulting fees from Janssen Research & Development, LLC.
Julián Panés reports consulting fees/honorarium from Janssen; payment for lectures including service on speakers bureaus and Steering Committee for Janssen; payment for development of educational presentations from Janssen.
Axel Dignass reports fees for participation in clinical trials, review activities such as data monitoring boards, statistical analysis and end point committees from Janssen;Steering committee member for Janssen; consultancy fees from Janssen; payment from lectures including service on speakers bureaus from Janssen.
Bruce E Sands discloses research grants and consulting fees from Janssen and is a Steering Committee Member for Janssen.
David T Rubin has served as a consultant and a Steering Committee member to Janssen Pharmaceuticals.

Introduction

Interleukin (IL)-23 is a key driver in the pathogenesis of Crohn’s disease (CD). IL-23 is a heterodimer, consisting of p19 and p40 subunits encoded by IL-23A and -23R, respectively. Signaling through the IL-23 receptor complex leads to the transcription of effector cytokine genes, including IL-17A, -17F and -22. Risankizumab (RZB), a monoclonal antibody with specificity for IL-23p19 has demonstrated safety and efficacy for the treatment of CD.^1,2 Here we investigate if baseline (BL) IL-23 pathway gene expression (IL-17A, -17F, -22, -23R, and -23A) in CD patients (pts) is associated with clinical remission and endoscopic response at week (wk) 12 of induction in patients treated with RZB (see Table footnote for endpoint definitions).

Aims & Methods

RNA-sequencing was performed to examine IL-23 pathway gene expression at BL in intestinal biopsy samples (n=280) obtained from pts (n=160) in the 600 mg intravenous (IV) RZB arms of the ADVANCE and MOTIVATE induction studies.¹ Biopsies were taken from the site of active disease (colon [n=146] and/or ileum [n=134]). A linear model based differential expression was conducted between response and non-response using the co-primary endpoints of SF/APS clinical remission and endoscopic response at induction wk 12. Data were normalized using trimmed mean of M-values and log2 counts per million. P-values were adjusted using Benjamini-Hochberg method of multiple testing correction. Comparisons were performed between endoscopic responders or clinical remitters (R) and endoscopic non-responders or clinical non-remitters (NR) in all pts. Analyses were stratified by disease location and/or prior biologic response status.

Results

In the total cohort, IL-23A gene expression was higher at BL in clinical R versus (vs) NR (p=0.03) (see Table for results). However, this difference was only significant in patients with prior bio-failure (p=0.03). Additionally, no difference was observed in IL-23 pathway gene expression between endoscopic R vs NR. When stratifying by disease location, higher BL expression of IL-17A, -17F, -22 and -23A were observed in patients with colonic disease in clinical R vs NR with (p<0.05). This difference was observed in both bio-failure and non-bio-failure patients (p<0.05). No difference was observed between endoscopic R vs NR. In pts with ileal disease, no differences in IL-23 pathway gene expression were observed between clinical R versus NR. Higher BL expression of IL-17A and -17F, and lower BL expression of IL-23R, were demonstrated in endoscopic R vs NR at wk 12 (p<0.05). However this difference was only significant in bio-failure patients.

Conclusion

Endpoint	Patient Subgr​oups​​​​​	Baseline Gene Expression NR vs R Adjusted P-value (p<0.05 denoted in bold)
		IL-17A	IL-17F	IL-22	IL-23R	IL-23A
Clinical Remission at Week 12a	All Patients N=160 (62 R, 98 NR) Colonic Disease N=146 (56 R, 90 NR) Ileal Disease N=134 (47 R, 87 NR) Prior Bio-Failure N=113 (37 R, 76 NR) Without Prior Bio-Failure N=47 (25 R, 22 NR) Colonic Disease + Prior Bio-Failure N=101 (33 R, 68 NR) Colonic Disease + Without Prior Bio-Failure N=45 (23 R, 22 NR) Ileal Disease + Prior Bio-Failure N=94 (26 R, 68 NR) Ileal Disease + Without Prior Bio-Failure N=40 (21 R, 19 NR)	0.40 0.04 0.21 0.11 0.79 0.048 0.51 0.99 0.26	0.5 0.04 0.94 0.10 0.82 0.06 0.50 0.70 0.73	0.17 0.03 0.78 0.26 0.30 0.04 0.41 0.68 0.52	0.95 0.84 0.65 0.23 0.30 0.25 0.45 0.77 0.44	0.03 0.002 0.92 0.03 0.73 0.005 0.44 0.71 0.65
Endoscopic Response At Week 12b	All Patients N=160 (69 R, 91 NR) Colonic Disease N=146 (37 R, 109 NR) Ileal Disease N=134 (35 R, 99 NR) Prior Bio-Failure N=113 (23 R, 90 NR) Without Prior Bio-Failure N=47 (19 R, 28 NR) Colonic Disease + Prior Bio-Failure N=101 (20 R, 81 NR) Colonic Disease + Without Prior Bio-Failure N=45 (17 R, 28 NR) Ileal Disease + Prior Bio-Failure N=94 (18 R, 76 NR) Ileal Disease + Without Prior Bio-Failure, N=40 (17 R, 23 NR)	0.83 0.08 0.01 0.77 0.65 0.10 0.57 0.049 0.19	0.45 0.44 0.049 0.35 0.98 0.49 0.85 0.02 0.9	0.44 0.06 0.42 0.48 0.53 0.09 0.43 0.49 0.90	0.44 0.06 0.42 0.48 0.53 0.09 0.43 0.49 0.90	0.79 0.07 0.10 0.84 1.00 0.09 0.71 0.14 0.63
aAverage daily SF ≤ 2.8 and not worse than BL AND average daily AP score ≤ 1 and not worse than BL; bDecrease in SES-CD > 50% from BL (or for subjects with isolated ileal disease and a BL SES-CD of 4, at least a 2 point reduction from BL), as scored by central reviewer

Minimal differences in BL expression of IL-23 pathway genes were detected in the total cohort between clinical R vs NR and endoscopic R vs NR. Significant differences in BL expression of several IL-23 pathway genes were identified between clinical R and NR in pts with colonic disease. Shared and unique IL-23 pathway genes were significantly altered in pts with ileal disease between endoscopic R vs NR. However, these differences are unlikely to be clinically meaningful or predictive of response to RZB.

References

1. D’Haens G, Panaccione R, Baert F, Bossuyt P, Colombel JF, Danese S, et al. Risankizumab as induction therapy for Crohn’s disease: results from the phase 3 ADVANCE and MOTIVATE induction trials. The Lancet. 2022 May;399(10340):2015–30.
2. Ferrante M, Panaccione R, Baert F, Bossuyt P, Colombel JF, Danese S, et al. Risankizumab as maintenance therapy for moderately to severely active Crohn’s disease: results from the multicentre, randomised, double-blind, placebo-controlled, withdrawal phase 3 FORTIFY maintenance trial. The Lancet. 2022 May;399(10340):2031–46.

Disclosure

James Lindsay: Consultant and an advisory board participant for AbbVie, Atlantic Healthcare, Bristol-Myers Squibb, Celgene, Celltrion, Eli Lilly, Ferring Pharmaceuticals, Galapagos, Gilead, GSK, Janssen, MSD, Napp, Pfizer, Shire, Takeda, and Vifor Pharma; has received speaker fees and sponsorship for academic meetings from AbbVie, Ferring Pharmaceuticals, Janssen, MSD, Napp, Norgine, Pfizer, Shire, Tillotts Pharma, and Takeda; and has received investigator-led research grants from AbbVie, Gilead, Pfizer, Shire and Takeda.
Bram Verstockt: Research support from AbbVie, Biora Therapeutics, Landos, Pfizer, Sossei Heptares and Takeda. -Speaker’s fees from Abbvie, Biogen, Bristol Myers Squibb, Celltrion, Chiesi, Falk, Ferring, Galapagos, Janssen, MSD, Pfizer, R-Biopharm, Takeda, Truvion and Viatris. Consultancy fees from Abbvie, Alimentiv, Applied Strategic, Atheneum, Biora Therapeutics, Bristol Myers Squibb, Galapagos, Guidepont, Mylan, Inotrem, Ipsos, Janssen, Pfizer, Progenity, Sandoz, Sosei Heptares, Takeda, Tillots Pharma and Viatris.
Jean Frederic Colombel: Research grants from AbbVie, Janssen Pharmaceuticals and Takeda; receiving payment for lectures from AbbVie, Amgen, Allergan, Inc. Ferring Pharmaceuticals, Shire, and Takeda; 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; and hold stock options in Intestinal Biotech Development
Valerie Pivorunas, Naim Al Mahi, Nizar Smaoui, F. Stephen Laroux, Kristina Kligys Kori Wallace, and Heath Guay are AbbVie employees and may own AbbVie stock and/or options.

Introduction

Mirikizumab is a humanized immunoglobulin G4 monoclonal antibody against the p19 subunit of interleukin-23, a key inflammatory mediator in ulcerative colitis (UC). Here we report efficacy and safety in pediatric patients with moderate to severe UC from the Phase 2 SHINE-1 study (NCT04004611) following 52 weeks of mirikizumab treatment.

Aims & Methods

Patients aged 2 to <18 years with active UC who had an inadequate response, loss of response, or intolerance to corticosteroids, immunosuppressants, or biologic therapies, or had corticosteroid-dependent colitis, were included in the study. Patients weighing >40 kg received an induction dose of 300 mg via intravenous infusion; patients weighing ≤40 kg received 5 or 10 mg/kg via intravenous infusion at weeks 0, 4, and 8. At week 12, patients were assessed for clinical response using the Modified Mayo Score. Responders entered the maintenance period and received subcutaneous doses of mirikizumab at 200 mg (>40 kg), 100 mg (>20 kg to ≤40 kg), or 50 mg (≤20 kg) once every 4 weeks, with the last patient visit at week 52.

Results

All patients (N=26) completed induction through week 12, and 73.1% (N=19) completed through week 52. At week 12, 69.2% (18/26) were Modified Mayo Score responders; at week 52, 55.6% (10/18) of responders were in clinical and endoscopic remission. Clinical response, remission, and endoscopic remission rates were consistent with LUCENT Phase 3 UC adult studies.
The safety profile of mirikizumab was consistent with the safety profile in LUCENT adults. Three serious adverse events (11.5%) were reported: non-infective appendicitis, UC flare, and pseudarthrosis. The UC flare resulted in study discontinuation.

Conclusion

Mirikizumab demonstrated an acceptable safety profile, and similar clinical response, clinical remission, and endoscopic remission compared to LUCENT adults. These results are the foundation of the pivotal Phase 3 pediatric SHINE-2 study.

Disclosure

J. L. Kaplan has nothing to disclose; D. Turner received consulting fees from: AbbVie, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Ferring Pharmaceuticals, Janssen, Pfizer, Prometheus Biosciences, Takeda, Galapagos, and Sorriso Pharmaceuticals; and research funding from: AbbVie, Ferring Pharmaceuticals, Janssen, Pfizer, and Takeda; A. Bousvaros has received research support from: AbbVie, Arena Pharmaceuticals, Bristol Myers Squibb, BUHLMANN Diagnostics, Eli Lilly and Company, Janssen, Procise Diagnostics, and Takeda; was a consultant for: Best Doctors, Eli Lilly and Company, Fresenius Kabi, and Takeda; and has received honoraria and royalties from: Boston University and UptoDate; M. Dubinsky has received honoraria as a consultant for: AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, F. Hoffmann-La Roche, Genentech, Gilead Sciences, Janssen, Pfizer, Prometheus Therapeutics and Diagnostics, Takeda, and UCB Pharma; has been contracted for research by: AbbVie, Janssen, Pfizer, and Prometheus Biosciences; has stock interest in: Trellus Health; and has received licensing fees from: Takeda; W. J. Komocsar, A. Larkin, J. Johns, X. Zhang, W. Crandall, V. Arora, and K. Todd are employees and shareholders of: Eli Lilly and Company; J. S. Hyams is on an advisory board for: AbbVie, Eli Lilly and Company, Janssen, and Pfizer; and has been a consultant to: Boehringer Ingelheim, Bristol Myers Squibb, and Takeda.

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

HRQoL endpoints at Weeks 8 and 52, n (%)	Induction (Week 8) PBO N=328	Induction (Week 8) UPA 45 mg QD N=660	Between group diff. (UPA 45 mg vs PBO) % [95% CI]	Maintenance (Week 52) PBO N=149	Maintenance (Week 52) UPA 15 mg QD N=148	Maintenance (Week 52) UPA 30 mg QD N=154	Between group diff. (UPA 15 mg vs PBO) % [95% CI]	Between group diff. (UPA 30 mg vs PBO) % [95% CI]
FACIT-F score ≥40.1	109 (33.2)	357 (54.1)	20.8 *** [14.6, 27.1]	53 (35.7)	77 (52.0)	86 (55.7)	15.7 ** [5.1, 26.3]	19.1 *** [8.3, 29.8]
IBDQ score ≥170	85 (25.9)	407 (61.6)	35.6 *** [29.6, 41.5]	42 (28.5)	91 (61.5)	111 (72.3)	32.2 *** [22.1, 42.6]	42.8 *** [32.7, 52.8]
WPAI-UC 0% Overall work imp.a,b Work time misseda,b Imp. while workinga,b Daily activity imp.	24 (11.9) 92 (45.8) 27 (13.4) 37 (11.3)	112 (26.2) 261 (61.0) 126 (29.5) 199 (30.2)	13.7 *** [7.7, 19.7] 14.7 *** [6.5, 22.9] 15.3 *** [9.1, 21.6] 18.8 *** [14.0, 23.6]	14 (13.9) 41 (40.6) 14 (13.9) 28 (18.8)	37 (33.9) 72 (66.1) 39 (35.8) 55 (37.2)	33 (32.7) 62 (61.4) 35 (34.7) 62 (40.3)	21.1 *** [10.6, 31.6] 24.3 *** [11.4, 37.2] 23.1 *** [12.5, 33.7] 18.8 *** [9.2, 28.5]	19.0 *** [7.9, 30.1] 19.7 ** [6.5, 33.0] 21.0 *** [9.8, 32.2] 21.0 *** [11.2, 30.8]
SF-36 PCS ≥50	106 (32.3)	369 (55.9)	23.4 *** [17.2, 29.7]	44 (29.7)	89 (60.1)	102 (66.3)	29.5 ** [19.2, 39.8]	35.4 *** [25.1, 45.6]
SF-36 MCS ≥50	98 (29.9)	316 (48.0)	17.9 *** [11.7, 24.1]	38 (25.2)	70 (47.3)	82 (53.0)	22.1 *** [12.0, 32.2]	27.4 *** [17.2, 37.7]
EQ-5D-5L VAS ≥80	68 (20.7)	298 (45.1)	24.3 *** [18.6, 30.1]	40 (26.9)	65 (43.9)	88 (57.1)	15.6 ** [5.1, 26.0]	29.0 *** [18.5, 39.6]
EQ-5D-5L Index ≥0.825	89 (27.1)	339 (51.4)	24.3 *** [18.2, 30.4]	49 (33.0)	79 (53.4)	90 (58.5)	18.7 *** [8.3, 29.1]	24.1 *** [13.7, 34.6]
Composite HRQoL endpointc	18 (5.5)	125 (18.9)	13.2 *** [9.4, 17.1]	13 (8.7)	33 (22.3)	37 (24.0)	13.8 *** [6.0, 21.6]	14.8 *** [6.9, 22.7]
**p≤0.01. ***p≤0.001. aInduction: PBO, N=201; UPA 45 mg, N=428. bMaintenance: PBO, N=101; UPA 15 mg, N=109; UPA 30 mg, N=101. cProportion of patients achieving FACIT-F score ≥40.1, IBDQ score ≥170, 0% for WPAI-UC Daily Activity Impairment, SF-36 PCS ≥50 and MCS ≥50, EQ-5D-5L VAS ≥80.0 and EQ-5D-5L Index ≥0.825; employment-related scores were excluded. For induction data, the Cochran-Mantel-Haenszel test was used to calculate the 95% CI for differences between treatment groups and was adjusted for strata: baseline corticosteroid use (yes or no), baseline Adapted Mayo score (≤7 or >7) and bio-IR status (bio-IR or non–bio-IR). For maintenance data, the Cochran-Mantel-Haenszel test was used to calculate the 95% CI for differences between treatment groups and was adjusted for strata: bio-IR status (bio-IR or non-bio-IR) at the baseline of the induction study, clinical remission status at Week 0 (yes or no), and corticosteroid use at Week 0 (yes or no). Bio-IR, biologics inadequate response; CI, confidence interval; diff., difference; EQ-5D-5L, European Quality of Life 5 Dimensions 5 Levels; FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue; HRQoL, health-related quality of life; IBDQ, Inflammatory Bowel Disease Questionnaire; imp., impairment; MCS, Mental Component Summary; PBO, placebo; PCS, Physical Component Summary; QD, once daily; SF-36, Short Form 36; UC, ulcerative colitis; UPA, upadacitinib; VAS, visual analogue scale; WPAI, Work Productivity and Activity Impairment Questionnaire.

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.