Introduction

Fatigue is a debilitating multifactorial symptom experienced by many patients with Crohn's disease (CD).¹ Topline efficacy data of mirikizumab (MIRI), an anti-interleukin-23p19 antibody, vs. placebo (PBO) and ustekinumab (UST) in patients with moderately to severely active Crohn’s disease in the Phase 3 VIVID-1 study were previously reported.^2-4

Aims & Methods

This analysis assesses the impact of MIRI vs. PBO in improving fatigue and the correlation of patient variables with fatigue severity at baseline (BL) in the VIVID-1 study. Participants were randomized 6:3:2 to MIRI (900 mg intravenous at Week [W]0, W4, and W8, then 300 mg subcutaneous every 4W from W12-W52), UST or PBO. Fatigue was assessed via the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire (scale 0-52, higher scores indicating less fatigue,⁵ meaningful within-patient change identified as a 6–9 point [pt] increase). At W12 we report the proportion of PBO (N=199) and MIRI (N=579) patients achieving FACIT-F ≥6- or ≥9-pt increase from BL. Comparisons with PBO at W52 used composite (C) endpoints: clinical response by Patient-Reported Outcome at W12 (≥30% decrease in stool frequency [SF] or abdominal pain [AP], and neither worse than BL), and FACIT-F increase of either ≥6-pts (C≥6) or ≥9-pts (C≥9) by W52. p-Values were calculated via Cochran-Mantel-Haenszel test adjusted by biologic-failed status (yes/no); BL Simple Endoscopic Score for CD (SES-CD) total score (<12, ≥12); either BL SF ≥7 and/or AP ≥2.5 (yes or unknown/no). The pooled population of patients randomized to PBO or MIRI at BL, excluding those with missing data, with a range of patient variables was analyzed by the random forest method to assess the correlation with fatigue severity. Variables were ranked by importance by the random forest method and Pearson correlation coefficients (r) calculated for continuous variables.

Results

At W12, 31.2% (PBO) and 43.0% (MIRI) patients achieved FACIT-F ≥6-pt increase (p<0.005) and 22.1% (PBO) and 32.6% (MIRI) patients achieved FACIT-F ≥9-pt increase (p<0.01). At W52, 20.1% (PBO) and 34.9% (MIRI) patients met C≥6 (p<0.0005) and 15.6% (PBO) and 28.5% (MIRI) patients met C≥9 (p<0.0005). A strong association (r>0.5) was found between fatigue severity and Inflammatory Bowel Disease Questionnaire (IBDQ), and with the emotional functioning domain of IBDQ and Mental Component Summary (MCS) of Short Form (SF)-36 (Table). There was a weak association (r=0.1–0.3) with AP score, SF score, and Urgency Numeric Rating Scale, and insubstantial association (r<0.1) with objective markers of inflammation, including SES-CD, C-reactive protein, and fecal calprotectin.

Table: Correlation of highest ranked BL variables with FACIT-F

Conclusion

MIRI showed a nominally clinically significant improvement in fatigue vs. PBO at W12 and a nominally statistically higher improvement in composite endpoints vs. PBO at W52. At BL, fatigue was not associated with objective inflammatory markers of disease severity or with typical CD symptoms. The observed strong association between fatigue and MCS of SF-36 and the emotional functioning domain of IBDQ implies bidirectional effects of brain-gut interactions that are not well understood.

References

1. D’Silva A, et al. Clin Gastroenterol Hepatol. 2022;20:995-1009.
2. Ferrante M, et al. J Crohn's Colitis. 2024;18:i7–i9.
3. Jairath V, et al. J Crohn's Colitis. 2024;18:i62–i64.
4. Travis S, et al. J Crohn's Colitis.2024;18:i21-i23.
5. Tinsley A, et al. Aliment Pharmacol Ther. 2011;34:1328-1336.

Disclosure

P. Bossuyt has received financial support for research from: AbbVie, Amgen, Janssen, Pfizer, and Viatris; lecture fees from: AbbVie, Bristol Myers Squibb, CAG, Celltrion, Eli Lilly and Company, EPGS, Galapagos NV, Globalport, Janssen, Materia Prima, Pentax, Scope, and Takeda; and advisory board fees from: AbbVie, Bristol Myers Squibb, Celltrion, CIRC, Dr. Falk Pharma Benelux, Eli Lilly and Company, Galapagos NV, Janssen, Pentax, PSI-CRO, Roche, Takeda, and Tetrameros; M. Regueiro has served as an advisor and/or consultant for: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Genentech, Gilead Sciences, Janssen, Organon, Pfizer, Prometheus Therapeutics and Diagnostics, Salix Pharmaceuticals, Takeda, and UCB Pharma; M. Fischer has received consulting fees from: AbbVie, Bristol Myers Squibb, Eli Lilly and Company, Ferring Pharmaceuticals, Janssen, Pfizer, Rebiotix, Scioto Biosciences, and Seres Therapeutics; K. Traxler, G. Yu, M. N. Protic, K. Tsilkos, and A. Vadhariya are employees and shareholders of: Eli Lilly and Company; T. Hisamatsu has received lecture fees from: AbbVie, EA Pharma, Gilead Sciences, Janssen Pharmaceutical K.K., JIMRO, Kyorin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer, and Takeda; has received honoraria as an advisory board member or consultant for: AbbVie, Bristol Myers Squibb, EA Pharma, Eli Lilly and Company, Gilead Sciences, Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma, Pfizer, and Takeda; and has received pharmaceutical/research grants from: AbbVie, Boston Scientific, Daiichi Sankyo, EA Pharma, Kissei Pharmaceutical, JIMRO, Kyorin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nichi-lko Pharmaceutical, Nippon Kayaku, Pfizer, Takeda, and Zeria Pharmaceutical; P. Juillerat has received fees for lectures and consulting/advisory board from: AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly and Company, Ferring Pharmaceuticals, Gilead Sciences, Janssen, Merck Sharp & Dohme, Pfizer, Pierre Fabre, Sandoz, Takeda, Tillotts Pharma AG, and UCB Pharma.

Introduction

Fatigue is a common and debilitating symptom of Crohn’s disease (CD), associated with functional impairment and reduced quality of life.^1,2​

Aims & Methods

Here we qualitatively explore change in fatigue in participants with moderately to severely active CD who completed the phase 3, randomised, double-blind, placebo- and active-controlled, mirikizumab clinical trial (VIVID-1/NCT03926130). Qualitative, web-assisted, semi-structured, 90-minute exit interviews were conducted in 62 trial participants within 3 weeks of completing the final trial visit (May 2022–July 2023). Clinical trial arms were blinded for this study. A sub-set of participants from either mirikizumab, ustekinumab or placebo arms were asked open-ended questions to explore changes in fatigue (N=31). Interview audio recordings were transcribed verbatim and analysed using a directed content analysis approach in ATLAS.ti v9.

Results

Among the 31 participants who were asked about fatigue (61.3% male [n=19], 90.3% White [n=28]), median age was 42 (n=30; range: 24–75) years and median CD duration was 5.9 (n=30; range: 1.4–54.3) years. Overall, 31.0% (n=9/29) participants had a college degree or higher and 41.4% (n=12/29) participants were employed full-time. Participants were from the United States (n=15), Czech Republic (n=5), Germany (n=5), Poland (n=3), Australia (n=2) and Canada (n=1).
At the start of the trial, participants reported that they had difficulty in performing daily activities (n=7), walking or climbing stairs (n=3), completing outdoor tasks and activities (n=2), concentrating or focusing (n=2) and were unable to feel well-rested from sleep (n=3), lacked energy (n=2), felt exhausted (n=1), dozed off in evening (n=1) and took breaks during the day (n=1) due to fatigue. They also reported socialising less (n=1) and feeling worried (n=3), demotivated (n=2), grumpy (n=1), frustrated (n=1) and depressed (n=1).
Although it was unknown which treatment the participants had received, most participants reported experiencing an improvement in fatigue (74%, n=23/31) during the trial. Seven participants reported experiencing no change in fatigue (23%, n=7/31). Of these, four participants reported experiencing no or little fatigue at the start of the trial, which did not change until their last visit. One participant reported worsening of fatigue (3%, n=1/31) during the trial which impacted their daily activities as they needed to sleep more often during the day.
Among participants who experienced an improvement in fatigue, 11 reported an improved emotional well-being such as feeling more relaxed, confident, independent, and motivated. Overall, 9 participants reported that their physical function improved, and they were able to walk further, had more energy and felt stronger. Eight participants reported being able to function more day-to-day. Improvement in fatigue resulted in better friendships or relationships (n=4), being more successful in work or school (n=3), sleeping better (n=2), napping less (n=2), being able to exercise more (n=2), go out for longer duration (n=2), being able to work (n=1), and gaining more enjoyment in life (n=1). When participants were asked about meaningful improvement in fatigue, 10 out of 13 participants reported a meaningful improvement.

Conclusion

Exit interview results showed that irrespective of the treatment received, most interviewed participants with moderately to severely active CD experienced an improvement in fatigue by end of the trial, resulting in better energy levels, physical function, daily functioning, and emotional well-being.

References

1. Nocerino A, et al. (2020) Adv Ther. 37(1):97–112.
2. Regueiro M, et al. (2023) J Patient Rep Outcomes. 7(1):75.

Disclosure

Theresa Hunter Gibble: Employee and stockholder of Eli Lilly and Company
Jake Macey: Employee and stockholder of Clarivate
Harriet Makin: Employee and stockholder of Clarivate
Rodica Rosu: Employee and stockholder of Eli Lilly and Company
Katie Mellor: Employee of Clarivate
Helen Kitchen: Employee and stockholder of Clarivate
Emily Hon: Employee and stockholder of Eli Lilly and Company
Aisha Vadhariya: Employee and stockholder of Eli Lilly and Company
Sylvia Su: Employee and stockholder of Eli Lilly and Company
Miguel Regueiro: Advisory Boards and Consultant (both) for Abbvie, Janssen, UCB, Takeda, Pfizer, BMS, Organon, Amgen, Genentech, Gilead, Salix, Prometheus, Lilly, Celgene, Boehringer Ingelheim Pharmaceuticals Inc. (BIPI), Celltrion, Roche

Introduction

Mirikizumab (miri), an anti-IL-23p19 antibody, demonstrated robust efficacy in improving clinical, endoscopic, and inflammatory biomarker endpoints, and an acceptable safety profile for patients with moderately to severely active Crohn’s disease (CD) in the Phase 3 VIVID-1 study. Here, we investigate the onset of symptomatic improvement and the safety of miri as induction therapy through Week 12 (W12) for patients with moderately to severely active CD.

Aims & Methods

In VIVID-1 (NCT03926130), patients (N=1065) had moderately to severely active CD (unweighted daily average stool frequency (SF) ≥4 [loose and watery stools defined as Bristol Stool Scale Category 6 or 7] AND/OR unweighted daily average abdominal pain (AP) ≥2 at baseline) and had prior failure to biologic and/or conventional therapy. Patients were randomized in a 6:3:2 ratio to receive miri (a single 900mg intravenous (IV) dose at W0, W4, and W8 followed by a subcutaneous (SC) dose of 300mg at W12 and then every 4 weeks), ustekinumab (uste) (6mg/kg IV at W0 and SC dose of 90mg at W8 and then every 8 weeks), or placebo (PBO). Results for the co-primary endpoints and major secondary endpoints versus PBO, as well as for the 2 major secondary endpoints versus uste, have been reported previously ^1,2. This analysis focuses on comparisons of clinical response by Patient Reported Outcome (PRO) (defined as at least a 30% decrease in SF and/or AP with neither score worse than baseline), clinical remission by PRO (defined as SF≤3 and not worse than baseline [as per Bristol Stool Scale Category 6 or 7] and AP ≤1 and no worse than baseline), change from baseline (CFB) in SF, and CFB in AP up to W12 in patients who were randomized to miri or PBO.

Results

Baseline characteristics were balanced across the miri (N=579) and PBO (n=199) treatment groups¹. Compared to PBO, a greater proportion of patients on miri achieved clinical response by PRO at W4, 6, 8, and 12, and clinical remission by PRO at W6, 8, and 12. Treatment with miri resulted in significant improvements in SF at W6, 8, and 12, and in AP at W4, 6, 8, and 12 when compared to PBO (Table 1). The overall safety was consistent with the known safety profile of miri. The most common treatment-emergent adverse events (TEAEs) during induction period in miri-treated patients were COVID-19, anaemia and headache. There were lower frequencies of SAEs (miri: 5.9%, PBO: 9.0%) and discontinuations due to adverse events (miri: 2.4%, PBO:4.7%) in miri-treated patients versus PBO. There were no malignancies, no MACEs, no Hy’s law cases or deaths in the miri arm up to W12. One death was reported in the induction period in the PBO group.

Conclusion

In patients with moderately to severely active CD, miri induction was associated with higher rates of clinical response and greater improvement in AP as early as W4, and higher rates of clinical remission and greater improvement in SF as early as W6 versus PBO. Increasing treatment effect was observed through W12. The safety of miri induction therapy was consistent with its known favourable safety profile.

References

1. M Ferrante, S Danese, M Chen, G D'Haens, S Ghosh, T Hisamatsu, V Jairath, J Kierkus, L Peyrin-Biroulet, B Siegmund, S M Bragg, W Crandall, T Hunter Gibble, Z Lin, M Ugolini Lopes, N Morris, H Carlier, B Sands, VIVID Study Group, OP05 Primary efficacy and safety of mirikizumab in moderate to severe Crohn’s Disease: results of the treat-through VIVID 1 study, Journal of Crohn's and Colitis, Volume 18, Issue Supplement_1, January 2024, Pages i7–i9, https://doi.org/10.1093/ecco-jcc/jjad212.0005
2. V Jairath, B E Sands, P Bossuyt, F Farraye, M Ferrante, T Hisamatsu, A Kaser, J Kierkus, D Laharie, W Reinisch, B Siegmund, S M Bragg, E Hon, Z Lin, M Ugolini Lopes, N Morris, M Protic, S Danese, VIVID Study Group, OP35 Efficacy of mirikizumab in comparison to ustekinumab in patients with moderate to severe Crohn’s disease: Results from the phase 3 VIVID 1 study, Journal of Crohn's and Colitis, Volume 18, Issue Supplement_1, January 2024, Pages i62–i64, https://doi.org/10.1093/ecco-jcc/jjad212.0035

Disclosure

Bruce E Sands: reports consulting fees from Abbvie, Alimentiv , Amgen, Arena Pharmaceuticals, Artugen Therapeutics, Astra Zeneca, Boehringer Ingelheim, Boston Pharmaceuticals, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Evommune, Fresenius Kabi, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Kaleido, Kallyope, Merck, Morphic Therapeutics, MRM Health, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Sun Pharma, Surrozen, Target RWE,Teva, TLL Pharmaceutical, Ventyx Biosciences; consulting and speaking fees from Abivax; consulting and speaking fees and other support from Lilly; research grants, consulting and speaking fees and other support from Bristol Myers Squibb, Janssen, Pfizer, Takeda; research grants and consulting fees from Theravance Biopharma; and stock options from Ventyx Biopharma.
Minhu Chen: provided educational activities for AbbVie, China Medical System, IPSEN, Janssen, and Takeda; served on an advisory board for Boehringer Ingelheim and Janssen; and has support for clinical research from Janssen and Takeda.
Silvio Danese: has consulting fees from AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals Inc., Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB Inc., Vial, and Vifor; has lecture fees from Abbvie, Amgen, Ferring Pharmaceuticals Inc., Gilead, Janssen, Mylan, Pfizer, and Takeda.
Monika Fischer: has served as an Advisor, Review Panel Member, Speakers Bureau, or DSMB for AbbVie, BMS, Lilly, Ferring, Janssen, Pfizer, Rebiotix, Scioto, Seres
Tadakazu Hisamatsu: has joint research agreement from Kissei Pharmaceutical and EA Pharma; has received research grants from AbbVie, Daiichi Sankyo, EA Pharma, JIMRO, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Takeda, Boston Scientific, and Zeria Pharmaceutical; and has received consulting and lecture fees from AbbVie, EA Pharma, Gilead Sciences, Janssen Pharmaceuticals, JIMRO, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical, Pfizer, Kissei Pharmaceutical, and Takeda.
Sami Hoque: Reports advisory to Eli Lilly and Company and advisory and lecture fees to Tillots.
Laurent Peyrin-Biroulet: Reports the following: personal fees from Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillots, Pharmacosmos, Celltrion, Takeda, Boerhinger Ingelheim, Pfizer, Index Pharmaceuticals, Sandoz, Celgene, Biogen, Samsung Bioepis, Alma, Sterna, Nestle, Inotrem, Enterome, Allergan, MSD, Roche, Arena, Gilead, Hikma, Amgen, BMS, Vifor, Norgine, Mylan, Lilly, Fresenius Kabi, Oppilan Pharma, Sublimity Therapeutics, Applied Molecular Transport, OSE Immunotherapeutics, Enthera, and Theravance; grants from Abbvie, MSD, and Takeda; and stock options from CTMA
Frank Siebold: has consulting fees from Abbvie, Amgen, BMS, Dr. Falk, Eli Lilly, Geilead, Janssen, Pfizer, Takeda.
Geert D’Haens: has served as adviser and/or speaker for Abbvie, Alimentiv, Amgen, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Ferring, Eli Lilly, Engene, Galapagos, Glaxo Smith Kline, Immunic, Index Pharmaceuticals, Johnson and Johnson, Merck, Polpharm, Prometheus biosciences, Prometheus Laboratories, Procise diagnostics, Protagonist, Sandoz, Takeda, Tillotts, and Ventyx.
Frederick Durand, Emily Hon, Zhantao Lin, Nathan Morris, and Michelle Ugolini Lopes are all Eli Lilly and Company employees and stockholders.

Introduction

Mirikizumab (MIRI), a p19-directed antibody against interleukin-23, demonstrated improvements in fatigue, abdominal pain (AP) and stool frequency (SF) at Week (W) 12 and W52 in the VIVID-1 clinical trial.¹

Aims & Methods

The aim of this analysis is to show the effect of MIRI on fatigue, AP, SF and achievement of clinical remission by Patient-Reported Outcome (PRO; SF ≤3 and AP ≤1 and neither worse than baseline) in the VIVID-2 open-label extension study through W104. This analysis includes data from primary analysis set in patients with Crohn’s disease (CD) randomised to the MIRI treatment arm in VIVID-1 who achieved endoscopic response (≥50% reduction from baseline in Simple endoscopic score for CD) at W52 and continued the MIRI subcutaneous dosing (300 mg) in VIVID-2. Change from VIVID-1 baseline was measured for continuous endpoints. Endpoints included fatigue measured using FACIT-Fatigue (measured as change from baseline, and clinically-meaningful improvement of ≥6-points among patients with baseline ≤46), AP improvement (measured as change from baseline, and achievement of ≤1 among patients with baseline >1), SF improvement (measured as change from baseline, and achievement of ≤3 among patients with baseline >3) and clinical remission by PRO, assessed at W64 and 104. Missing data were handled using observed case (OC) and modified non-responder imputation (mNRI) for response rates, while using modified baseline observation carried forward (mBOCF) for change from baseline. Response rates were presented as unadjusted proportions with 2-sided 95% confidence intervals using the Rubin's Rules (mNRI). ANCOVA models were used for continuous variables, adjusting for baseline values and intervention group.

Results

Fatigue mean (standard error [SE]) change from baseline was 10.7 (0.56) at W64; 9.4 (0.59) at W104, (observed response, n [%]: 152 [67.6%] at W64; 136 [64.8%] at W104; Table). AP improved (mean [SE] change: −1.5 [0.04] at W64; −1.6 [0.05] at W104), with response rates increasing from 174 (77.3%) to 161 (84.7%). SF showed sustained improvement (mean [SE] change: −4.3 [0.14] at W64; −4.3 [0.16] at W104), with response rates reaching 155 (89.6%) at W104 (Table). Similar rates of achievement of clinical remission by PRO were observed (178 [73.6%] at W64; 165 [80.1%] at W104) (Table).

Table: Improvement in fatigue, abdominal pain, stool frequency and achievement of clinical remission by PRO up to Week 104

Conclusion

MIRI sustained improvement in fatigue, AP, SF and clinical remission by PRO through 104 weeks of continuous treatment. These consistent findings support the long-term treatment with MIRI to address key symptoms of CD.

References

1. Ferrante, MarcTron, Emiliano, et al. The Lancet. 404 (10470):2423-2436.

Disclosure

PB: Received financial support for research from AbbVie, EG; lecture fees from AbbVie, AMC ICP, Amgen, Bristol Myers Squibb, Celltrion, Dr Falk Benelux, EG, Galapagos, Globalport, Lilly, Medtalks, Materia Prima, Pentax, Springer Media; served on an advisory board for AbbVie, Bristol Meyers Squibb, CIRC, Galapagos, Janssen, Lilly, Pentax, PSI-CRO, Roche, Takeda, Tetrameros. AA: Consultant for Geneoscopy; received research support from Takeda. AV, GY and JW: Employee and shareholder of Eli Lilly and Company. NL: Consultant for Eli Lilly and Company. JRA: Consultant for Janssen, Pfizer, Abbvie, Vedanta, Geneteche, Seres Therapeutics, Ferring, GSK, Merck, Bristol Myer Squibb, Roivant, Celltrion, and TRXBio, Xencor, Shattuck Labs; Speaker for Abbvie, Janssen. MC: Provided educational activities for AbbVie, China Medical System, IPSEN, Janssen, and Takeda; served on an advisory board for Boehringer Ingelheim and Janssen; and has support for clinical research from Janssen and Takeda.

Introduction

Mirikizumab (miri) is an anti-IL23p19 antibody that has shown efficacy in Crohn’s disease (CD). We have previously shown that miri improves health-related quality of life (HRQoL) by 12 weeks as measured by the Inflammatory Bowel Disease Questionnaire (IBDQ) in a Phase 2, multicenter, randomized, double-blind, placebo (PBO)-controlled study (NCT02891226) conducted in patients (pts) with moderately-to-severely active CD. This analysis assesses IBDQ scores through Week 104 (W104).

Aims & Methods

At baseline, pts (N=191) were randomized 2:1:1:2 allocation amongst 4 treatment arms (PBO, and 200, 600, 1000mg miri, respectively, administered intravenously (IV) every 4 weeks (Q4W) at Weeks 0, 4, and 8). Pts who received miri and achieved ≥1 point improvement at W12 in Simple Endoscopic Score for Crohn’s Disease (SES-CD) were re-randomized 1:1 into double-blind maintenance to either continue IV treatment assignment Q4W (combined arms of 200, 600, and 1000mg miri IV treatment; IV-C; N=41) or to 300mg miri subcutaneous (SC; N=46) Q4W up to W52. Subjects who had clinical benefit from the maintenance period received 300mg SC Q4W from W52 to W104. For analysis purposes, all IV and all SC arms were pooled. IBDQ score change from baseline (BL), IBDQ response (improvement ≥16 points), and IBDQ remission (score ≥170 points) were assessed up to W104 in pts who achieved endoscopic improvement at W12. IBDQ scores, domain scores (bowel symptoms, systemic symptoms, emotional function, social function), response, and remission were analyzed by descriptive statistics. For IBDQ response and remission, missing data were imputed as nonresponse (NRI).

Results

Out of the 127 pts randomized to miri for induction, 68.5% (87/127) achieved endoscopic improvement at W12 and were rerandomized into maintenance. Among the W12 miri induction endoscopic improvers, IBDQ response rates at W52 were 75.6% (31/41) and 80.4% (37/46) and IBDQ remission rates were 65.9% (27/41) and 67.4% (31/46) in the IV-C and SC groups, respectively. Of the W12 endoscopic improvers, 74 finished W52 in the maintenance and entered period 3 (W52-W104) where 68 went on to complete treatment through W104. At W104, the IBDQ response rates were 81.8% (27/33) and 78.0% (32/41) and IBDQ remission rates were 69.7% (23/33) and 56.1% (23/41) in the IV-C and SC groups, respectively. W52 and W104 IBDQ outcomes and domain scores are reported in Table 1.

Table 1. Week 52 and Week 104 Safety and Efficacy Results in Week 12 endoscopic improvers.

Conclusion

Treatment with miri produced clinically meaningful improvement in HRQoL as measured by IBDQ at W52 and W104 in pts who achieved endoscopic improvement after miri induction with moderately-to-severely active CD.

Disclosure

Bruce E Sands: Received fees for consulting and speaking from Abivax, Bristol Myers Squibb, Janssen, Lilly Pfizer, and Takeda; for consulting from AbbVie; Adiso Therapeutics; Alimentiv; Amgen; Arena Pharmaceuticals; Artizan Biosciences; Artugen Therapeutics; AstraZeneca; Bacainn Therapeutics; Boehringer-Ingelheim; Boston Pharmaceuticals; Calibr; Celltrion Healthcare; ClostraBio; Cytoki Pharma; Connect Biopharma; Entera; Evommune; Fresenius Kabi; Galapagos; Genentech; Gilead Sciences; GlaxoSmithKline; Gossamer Bio; Imhotex; Immunic; Index Pharmaceuticals; Inotrem; Innovation Therapeutics; Ironwood Pharmaceuticals; Kaleido; Kallyope; MiroBio; Morphic Therapeutics; MRM Health; OSE Immunotherapeutics; Progenity; Prometheus Biosciences; Protagonist Therapeutics; Q32 Bio; Redhill Biopharma; Sun Pharma; Surrozen; Synlogic; Target RWE; Teva; Theravance Biopharma; TLL Pharmaceutical; USWM Enterprises; VielaBio: VTA Labs; and personal fees and stock options for consulting from Ventyx Biosciences.
Vipul Jairath: Consulting/advisory board fees: AbbVie, Alimentiv Inc, Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus, Reistone Biopharma, Roche, Sandoz, Second Genome, Sorriso pharmaceuticals, Takeda, Teva, Topivert, Ventyx, Vividion; speaker’s fees: Abbvie, Ferring, Bristol Myers Squibb, Galapagos, Janssen Pfizer Shire, Takeda, Fresenius Kabi
Brian G Feagan: Consultant 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, Zealand Pharma. Speakers bureau for AbbVie, Janssen, Takeda. Member, Scientific Advisory Board, DSMB: AbbVie, Amgen, AMT, AnaptysBio, Boehringer-Ingelheim, Celgene/BMS Eli Lilly, Genentech/Roche, Janssen, MiroBio, Origo BioPharma, Pfizer, Prometheus, REDX Pharma, Sanofi, Takeda,Tillotts Pharma, Teva, Progenity, Index, Ecor1Capital, Morphic, GSK, Axio Research. Stock Shareholder: Gossamer Pharma. Other: Employee, Western University, Senior Scientific Director, Alimentiv Inc.
Alessandro Armuzzi: Consulting/advisory board fees: AbbVie, Allergan, Amgen, Arena, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Eli-Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Mylan, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sandoz, Takeda; speaker’s fees: AbbVie, Amgen, Arena, Biogen, Bristol-Myers Squibb, Eli Lilly, Ferring, Galapagos, Gilead, Janssen, MSD, Novartis, Pfizer, Roche, Samsung Bioepis, Sandoz, Takeda, Tigenix; research grants: MSD, Takeda, Pfizer, Biogen
Peter Bossuyt: Received financial support for research from Abbvie, Amgen, Celltrion, Mylan, Pfizer and Takeda; lecture fees from AbbVie, Celltrion, Janssen, Lilly and Takeda; advisory board fees from Abbvie, Arena pharmaceuticals, BMS, Celltrion, Dr Falk, Galapagos, Janssen, Lilly, Pentax, PSI-CRO, Roche, Takeda and Tetrameros.
Theresa Hunter Gibble, Zhantao Lin, Kristina Traxler, Marijana Protic, and Rebecca Hozak: employees and shareholders of Eli Lilly and Company.

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
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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.