Introduction

Fatigue is a debilitating, multifactorial symptom experienced by many patients with Crohn’s disease (CD).¹ Mirikizumab (MIRI), an anti-interleukin-23p19 antibody, demonstrated significant improvement in fatigue in patients with moderately to severely active CD in the Phase 2 AMAG² and Phase 3 VIVID-1³ studies.

Aims & Methods

This analysis examines the association of changes in clinical, endoscopic (endo) and selected patient-reported outcomes with changes in fatigue in MIRI-treated patients in the VIVID-1 study. Co primary and gated secondary outcomes, including comparisons with ustekinumab, have been presented elsewhere^4,5Adult patients (N=1065) with moderately to severely active CD were randomized 6:3:2 to MIRI, ustekinumab or placebo. MIRI was given every 4 weeks (W) as 900 mg intravenous at W0, W4, and W8, then 300 mg subcutaneous from W12 to W52. Fatigue was assessed via the validated Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaire (scale from 0-52, higher scores indicating less fatigue⁶ andat least 6-point increase identified as a clinically meaningful within-patient change). Achievement of ≥6-point increase in FACIT-F at W52 was reported among those with and without clinical remission by Crohn’s Disease Activity Index (CDAI), endo response, endo remission, and Urgency Numeric Rating Scale (NRS) ≤2 at W52. For stool frequency (SF), abdominal pain (AP), fecal calprotectin (FCP), and C-reactive protein (CRP), the association of the change from baseline (CFB) at W52 vs. the CFB in FACIT-F at W52 was assessed by the Pearson correlation coefficient.

Results

At W52, 50.9% (268/527) of MIRI-treated patients achieved FACIT-F ≥6-point increase from baseline. Greater proportions of patients who achieved clinical and endo outcomes had ≥6-point increase in FACIT-F (p<0.05) vs. those who did not achieve the outcome (Table). There was weak/moderate correlation between CFB at W52 in AP, SF and log-transformed FCP and CRP, and the CFB in FACIT-F at W52 (Table).

Table: W52 FACIT-F, A: ≥6-pt Increase From BL by Outcomes at W52 and B: CFB Correlation With CFB at W52 in Outcomes

A. W52 FACIT-F ≥6-point Increase From BL by Outcome at W52a, NRI	Outcome Achieved n/N (%) (95% CI)b	Outcome NOT Achieved n/N (%) (95% CI)b	Risk Difference (95% CI)b	p-Valuec
Clinical remission by CDAId	185/280 (66.1) (60.5-71.6)	83/247 (33.6) (27.7-39.5)	32.5 (24.4-40.6)	<0.0001
Endo responsee	154/256 (60.2) (54.2-66.2)	114/271 (42.1) (36.2-47.9)	18.1 (9.7-26.5)	<0.0001
Endo remissionf	59/96 (61.5) (51.7-71.2)	209/431 (48.5) (43.8-53.2)	13.0 (2.1-23.8)	0.0216
Urgency NRS ≤2g	127/188 (67.6) (60.9-74.2)	127/311 (40.8) (35.4-46.3)	26.7 (18.1-35.4)	<0.0001
B. CFB in FACIT-F vs. CFB in Outcomes at W52	N	Pearson Correlation Coefficient	95% CIh	p-Value
CFB in AP score	574	-0.379	-0.447 to -0.306	<0.0001
CFB in SF score	572	-0.306	-0.378 to -0.230	<0.0001
CFB in log-transformed FCP	461	-0.112	-0.201 to -0.020	0.0166
CFB in log-transformed CRP	576	-0.208	-0.285 to -0.128	<0.0001

^aMIRI-treated patients with baseline (BL) FACIT-F score ≤46 points; ^bConfidence interval (CI) constructed using asymptotic method without continuity correction; ^cChi Square test; ^dCDAI <150; ^eSimple Endoscopic Score for CD (SES-CD) Total Score ≥50% improvement from BL; ^fSES-CD Total Score ≤4, ≥2-point reduction from BL and no subscore >1; ^gIn those with BL Urgency NRS ≥3; ^hPearson correlation with Fisher’s z-transformation. A negative correlation indicates an improvement in outcome is associated with an improvement in FACIT-F. Correlation strength defined as: >0.5=strong, 0.3 to ≤0.5=moderate, 0.1 to <0.3=weak, <0.1=insubstantial⁷
NRI=nonresponder imputation.

Conclusion

In patients with moderately to severely active CD treated with MIRI, improvements in clinical, endoscopic, and selected patient-reported outcomes were associated with clinically meaningful improvements in fatigue at W52.

References

1. D’Silva A, et al. Clin Gastroenterol Hepatol. 2022;20:995-1009.
2. Regueiro MD, et al. Am J Gastroenterol. 2023;118:S816.
3. Travis S, et al. J Crohn's Colitis.2024;18:i21–i23.
4. Ferrante M, et al. J Crohn's Colitis. 2024;18:S1 i7–i9.
5. Jairath V, et al. J Crohn's Colitis. 2024;18:i62–i64.
6. Tinsley A, et al. Aliment Pharmacol Ther. 2011;34:1328-36.
7. Cohen J. Statistical Power Analysis for the Behavioural Sciences, 1988, Routledge.

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. 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, Brystol 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

Microscopic colitis (MC) refers to two pathologies – Collagenous colitis (CC) and Lymphocytic colitis (LC) that cause chronic watery diarrhoea, urgency, incontinence leading to significantly decreased quality of life¹. It is thought that MC develops due to a pathological immune response to intestinal luminal antigens in genetically predisposed individuals, with microbiota playing an important role^{2, 3}. However, the pathogenesis of MC is still unclear.

Aims & Methods

The aim of this study was to identify and characterize changes in bacterial composition of MC patients in terminal ileum and different colonic segments and determine its relation to the clinical course of disease. Biopsies from terminal ileum and six segments of the colon were collected during diagnostic colonoscopies. DNA extraction was performed using AllPrep DNA/RNA Micro Kit (Qiagen) following the manufacturer’s instructions. To determine bacterial composition, sequencing of the 16S rRNA variable region V3-V4 was conducted using the 27F and 338R polymerase chain reaction primers and sequenced on a MiSeq (2×250 bp; Illumina, Hayward, CA). Bioinformatic analysis was performed using DADA2, and taxonomic classification was carried out with the RDP classifier.

Results

Biopsy samples from 20 active CC patients, 20 active LC patients, and 50 controls demonstrated distinct microbial profiles across different intestinal segments, as revealed by beta-diversity and differential compositional analyses. Compared with controls, CC patients had consistent alterations in three bacterial families throughout the entire colon, with Erysipelatoclostridiaceae and Coriobacteriaceae decreased and Pasteurellaceae increased. Additionally, 35 families had segment-specific changes, and 25 families displayed altered abundance in the terminal ileum.
LC patients exhibited a consistent increase in Erisypelotrichaceae across the entire colon, with 38 other families showing segmental changes, and 12 families displaying altered abundance in the terminal ileum. Comparing LC and CC revealed a significantly different bacterial profile. LC showed lower abundance across many families, particularly in the right colon and terminal ileum. After sample collection, 15 CC patients and 12 LC patients received budesonide, with 3 CC and 2 LC patients having incomplete response. Beta diversity analysis revealed significant differences in the ascending colon and left side of the colon of CC patients based on response to budesonide. Patients with incomplete response to budesonide had an increased abundance of the genus Paucibacter. Similar tendencies were not observed in LC.
1 CC patient exhibited a quiescent disease course, 6 reached a sustained remission after treatment, 7 had a relapsing and 6 had a chronic active disease. Significant differences in beta diversity were observed in transverse, descending colon and rectum. Beta diversity of the descending colon had a medium correlation with disease behaviour. In the LC group 6 patients had a quiescent disease, 8 had a sustained remission after treatment, 3 exhibited a relapsing and 4 had a chronic active disease. No significant correlation between microbiota and disease behaviour was observed in LC.

Conclusion

This study showed significant differences in bacterial composition between CC, LC and controls in the terminal ileum and colon. In both CC and LC, bacterial alterations were not consistent throughout the entire colon but varied between different colonic segments. Microbiome differences based on response to budesonide and disease behaviour were observed in CC, but not LC.

References

1. Verhaegh BPM, Münch A, Guagnozzi D, et al. Course of Disease in Patients with Microscopic Colitis: A European Prospective Incident Cohort Study. J Crohns Colitis. 2021;15(7):1174-1183.
2. Miehlke S, Guagnozzi D, Zabana Y, et al. European guidelines on microscopic colitis: United European Gastroenterology (UEG) and European Microscopic Colitis Group (EMCG) statements and recommendations. United European Gastroenterol J. Published online 2020.
3. Burke KE, D’Amato M, Ng SC, Pardi DS, Ludvigsson JF, Khalili H. Microscopic colitis. Nat Rev Dis Primers. 2021;7(1).

Introduction

Guselkumab (GUS), a dual-acting interleukin-23p19 subunit inhibitor, demonstrated efficacy in participants (pts) with ulcerative colitis (UC) treated with intravenous (IV) or subcutaneous (SC) induction. Here, we report the efficacy and safety of SC induction followed by SC maintenance through Week (W) 48 in ASTRO, a phase 3, randomized, double-blind, placebo (PBO)-controlled, treat-through study in pts with moderately to severely active UC.

Aims & Methods

Eligible pts had modified Mayo scores of 5 to 9, rectal bleeding subscore of ≥1, and Mayo endoscopic subscore (MES) ≥2. Pts also had documented inadequate response/intolerance to biologics, Janus kinase (JAK) inhibitors, and/or sphingosine-1-phosphate (S1P) inhibitors (BIO/JAKi/S1Pi-IR) or to corticosteroids, 6-mercaptopurine, or azathioprine. Randomization was stratified by baseline BIO/JAKi/S1Pi-IR status and MES with 418 pts allocated 1:1:1 to GUS 400 mg SC every 4 weeks (q4w) (×3)→GUS 200 mg SC q4w (N=140), GUS 400 mg SC q4w (×3)→GUS 100 mg SC every 8 weeks (q8w) (N=139), or PBO SC (N=139). PBO pts who met rescue criteria were switched to GUS at W16; GUS pts who met rescue criteria stayed on their assigned GUS dose regimen (sham rescue).

Results

At W48, greater proportions of pts in the GUS groups achieved clinical remission compared with PBO (36.7% for GUS 100 mg q8w [Δ 29.5%], 42.9% for GUS 200 mg q4w [Δ 35.6%], 7.2% for PBO) (Table). Endoscopic remission proportions were 25.9% for GUS 100 mg q8w (Δ 20.9%), 26.4% for GUS 200 mg q4w (Δ 21.4%), and 5.0% for PBO. Clinical response, symptomatic remission, endoscopic improvement, histologic improvement, and histologic remission proportions were also greater for GUS vs PBO. Consistent with the results of the overall population, efficacy was also observed for subpopulations of BIO/JAKi/S1Pi-naïve and BIO/JAKi/S1Pi-IR pts. Safety events per 100 pts-years were not greater in the GUS groups compared with the PBO group: adverse events (AE) (GUS 100 mg q8w and 200 mg q4w vs PBO: 308.3 and 310.7 vs 357.1), serious AEs (6.5 and 8.2 vs 38.4), serious infections (0.8 and 2.5 vs 3.7), and AEs leading to treatment discontinuation (4.9 and 4.1 vs 19.8).
Table. Efficacy endpoints at Week 48 in the overall population and by biologic, JAK inhibitor, and/or S1P inhibitor history

	Overall			BIO/JAKi/S1Pi-naïve			BIO/JAKi/S1Pi-IR
Outcomes at Week 48	Placebo SC (N=139)	GUS 400 mg SC→ GUS 100 mg SC q8w (N=139)	GUS 400 mg SC→ GUS 200 mg SC q4w (N=140)	Placebo SC (N=79)	GUS 400 mg SC→ GUS 100 mg SC q8w (N=81)	GUS 400mg SC→ GUS 200mg SC q4w (N=83)	Placebo SC (N=56)	GUS 400 mg SC→ GUS 100 mg SC q8w (N=57)	GUS 400 mg SC→ GUS 200 mg SC q4w (N=55)
Clinical remission	10 (7.2)	51 (36.7) Δ 29.5 P<0.001	60 (42.9) Δ 35.6 P<0.001	6 (7.6)	39 (48.1) Δ 40.3 P<0.001	42 (50.6) Δ 43.0 P<0.001	4 (7.1)	12 (21.1) Δ 13.7 P=0.034	18 (32.7) Δ 25.2 P<0.001
Clinical response	26 (18.7)	78 (56.1) Δ 37.4 P<0.001	83 (59.3) Δ 40.6 P<0.001	19 (24.1)	52 (64.2) Δ 39.5 P<0.001	54 (65.1) Δ 40.8 P<0.001	7 (12.5)	25 (43.9) Δ 30.9 P<0.001	29 (52.7) Δ 39.3 P<0.001
Endoscopic improvement	16 (11.5)	62 (44.6) Δ 33.1 P<0.001	66 (47.1) Δ 35.6 P<0.001	10 (12.7)	46 (56.8) Δ 44.0 P<0.001	45 (54.2) Δ 41.7 P<0.001	6 (10.7)	16 (28.1) Δ 16.0 P=0.024	21 (38.2) Δ 26.8 P<0.001
Endoscopic remission	7 (5.0)	36 (25.9) Δ 20.9 P<0.001	37 (26.4) Δ 21.4 P<0.001	5 (6.3)	27 (33.3) Δ 26.9 P<0.001	28 (33.7) Δ 27.5 P<0.001	2 (3.6)	9 (15.8) Δ 11.5 P=0.033	9 (16.4) Δ 12.6 P=0.025
Symptomatic remission	20 (14.4)	66 (47.5) Δ 33.1 P<0.001	75 (53.6) Δ 39.2 P<0.001	15 (19.0)	47 (58.0) Δ 38.6 P<0.001	51 (61.4) Δ 42.3 P<0.001	5 (8.9)	19 (33.3) Δ 24.3 P=0.001	24 (43.6) Δ 34.0 P<0.001
Histologic improvement	18 (12.9)	65 (46.8) Δ 33.8 P<0.001	73 (52.1) Δ 39.2 P<0.001	13 (16.5)	45 (55.6) Δ 38.6 P<0.001	50 (60.2) Δ 43.8 P<0.001	4 (7.1)	20 (35.1) Δ 26.8 P<0.001	23 (41.8) Δ 34.1 P<0.001
Histologic remission	15 (10.8)	52 (37.4) Δ 26.6 P<0.001	63 (45.0) Δ 34.2 P<0.001	11 (13.9)	35 (43.2) Δ 29.1 P<0.001	41 (49.4) Δ 35.5 P<0.001	4 (7.1)	17 (29.8) Δ 21.5 P=0.002	22 (40.0) Δ 32.4 P<0.001
Data are presented as n (%); ∆% (adjusted treatment difference) versus placebo; nominal p-value versus placebo. The adjusted treatment difference was based on the common risk difference by use of the Mantel-Haenszel stratum weights and the Sato variance estimator. In the overall population, the p-values were based on the Mantel-Haenszel test, stratified by BIO/JAKi/S1Pi-IR status (Yes/No) and Mayo endoscopic subscore at baseline (Moderate [2]/Severe [3]). For the BIO/JAKi/S1Pi-naive/-IR subgroups, the p-values were stratified only by the Mayo endoscopic subscore at baseline. Participants who, prior to Week 48, had an ostomy or colectomy, a prohibited change in UC medications, discontinued study agent due to lack of efficacy or an AE of worsening of UC, or met rescue criteria per IWRS were considered not to have achieved any of the key efficacy endpoints shown at Week 48. For participants who discontinued study agent due to COVID-19-related reasons (excluding COVID-19 infection) or regional crisis, their observed values were used, if available. Participants who discontinued study agent prior to Week 48 due to other reasons were considered not to have achieved any of the efficacy endpoints shown at Week 48. Participants who were missing one or more of the components pertaining to an endpoint at Week 48 were considered not to have achieved the endpoint. Endpoint definitions: clinical remission, Mayo SFS 0/1 and not increased from BL, Mayo RBS=0, and MES 0/1 with no friability; clinical response, ≥30% and ≥2-point decrease from BL in Modified Mayo score with ≥1-point decrease from BL in RBS or RBS 0/1; endoscopic improvement, MES 0/1 with no friability; endoscopic remission, MES of 0; symptomatic remission, SFS 0/1 and not increased from BL and RBS=0; histologic improvement, neutrophil infiltration in <5% of crypts; no crypt destruction; and no erosions, ulcerations, or granulation tissue per Geboes grading system; histologic remission, absence of neutrophils from the mucosa (both lamina propria and epithelium); no crypt destruction; and no erosions, ulcerations, or granulation tissue per Geboes grading system. AE=adverse event; BIO=biologic; BL=baseline; COVID-19=coronavirus disease 2019; GUS=guselkumab; IR=inadequate response; IWRS=Interactive Web Response System; JAK=Janus kinase; JAKi=JAK inhibitor; MES=Mayo endoscopic subscore; N=population size; n=sample size; [HZ1] q4w=every 4 weeks; q8w=every 8 weeks; RBS=rectal bleeding subscore; S1P=sphingosine-1-phosphate; S1Pi=S1P inhibitor; SC=subcutaneous; SFS=stool frequency subscore; UC=ulcerative colitis

Conclusion

GUS SC induction followed by SC maintenance was efficacious through 1 year in pts with moderately to severely active UC, and the safety profile is consistent with GUS in its approved indications including UC.

Disclosure

ML reports research support from Lilly, Pfizer, and Takeda; consulting for AbbVie, Bristol Myers Squibb, Intercept, Janssen (Johnson & Johnson), Lilly, Pfizer, Prometheus, Roivant, Takeda, and Target RWE.
JRA reports grant support from Janssen, Merck, and Pfizer; consultancy fees from AbbVie, Adiso, Bristol Myers Squibb, Ferring, Genentech, GlaxoSmithKline, Janssen, Merck, Pfizer, Roivant, Celltrion, TrexBio, Shattuck Labs and Seres Therapeutics; payments for speaking from AbbVie, Bristol Myers Squibb, and Janssen; and is a steering committee member and investigator for Janssen.
SD reports consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enthera, Ferring, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity, Takeda, TiGenix, UCB, and Vifor; and reports lecture fees from AbbVie, Amgen, Ferring, Gilead, Janssen, Mylan, Pfizer, and Takeda.
MG, TB, YA, KH, SJ, LJ, and HZ are employees of and may own stock in Johnson & Johnson.
TH reports research grants from AbbVie GK, Boston Scientific Corporation, EA Pharma Co. Ltd., JIMRO Co. Ltd., Kissei Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Pfizer Inc., Takeda Pharmaceutical Co. Ltd., and Zeria Pharmaceutical Co. Ltd.; consulting fees from AbbVie GK, Abivax, Bristol Myers Squibb, EA Pharma Co. Ltd., Gilead Sciences, Janssen Pharmaceutical K.K., Lilly, Mitsubishi Tanabe Pharma Corporation, and Pfizer Inc.; and lecture fees from AbbVie GK, EA Pharma Co. Ltd., Janssen Pharmaceutical K.K., JIMRO Co., Kissei Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Pfizer Inc., and Takeda Pharmaceutical Co. Ltd.
DTR reports consulting and/or speaker fees and/or advisory board participation for AbbVie, Altrubio, Apex, Avalo, Bristol Myers Squibb, Buhlmann Diagnostics, Celgene, Connect BioPharma, Intouch Group, Iterative Health, Janssen (Johnson & Johnson), Lilly, Pfizer, Samsung Neurologica, and Takeda; Altrubio, Datos Health, and Iterative Health stock options; grants from Takeda; and membership on the Board of Directors of Cornerstones Health, Inc. and on the Crohn’s & Colitis Foundation’s Board of Trustees.
LPB reports grants or contracts from Celltrion, Fresenius Kabi, Medac, MSD, and Takeda; consulting and/or payment or honoraria and/or data safety monitoring board or advisory board participation for AbbVie, Abivax, Adacyte, Alfasigma, Alimentiv, Amgen, Applied Molecular Transport, Arena, Banook, Biogen, Bristol Myers Squibb, Celltrion, Connect Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GlaxoSmithKline, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Kern Pharma, Lilly, Medac, Mopac, Morphic, MSD, Nordic Pharma, Novartis, Oncodesign Precision Medicine, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par' Immune, Pfizer, Prometheus, Protagonist, Roche, Samsung, Sandoz, Sanofi, Satisfay, Takeda, Telavant, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vectivbio, Ventyx, and Ysopia; and meeting attendance/travel support from AbbVie, Alfasigma, Amgen, Celltrion, Connect Biopharm, Ferring, Galapagos, Genentech, Gilead, Gossamer Bio, Janssen, Lilly, Medac, Morphic, MSD, Pfizer, Sandoz, Takeda, Thermo Fischer, and Tillots.

Introduction

The 52-week, phase 3 True North (TN) study (NCT02435992) demonstrated the efficacy and safety of ozanimod (OZA), a highly selective sphingosine 1-phosphate receptor 1 and 5 modulator, in patients (pts) with moderately to severely active ulcerative colitis (UC). A prior analysis reported the long-term safety of OZA up to ~4 y from TN baseline through Week (W) 142 of the ongoing TN open-label extension (OLE; NCT02531126).

Aims & Methods

This analysis assessed the cumulative long-term safety of OZA with an additional year of exposure (pt disposition available until OLE W190 [up to ~5 y of OZA]). All pts who entered the OLE from TN (ie, clinical nonresponders at W10 and those who lost response during maintenance or completed maintenance at W52) were included in this analysis. Treatment-emergent adverse events (TEAEs) were monitored from the first dose of OZA in TN or the OLE through data cutoff; exposure-adjusted incidence rates (EAIRs) per 100 patient-years (PY) are presented. Lab abnormalities, including absolute lymphocyte count (ALC) reductions, were assessed during the OLE through data cutoff.

Results

A total of 823 pts entered the TN OLE. At data cutoff, 43.0% of pts had completed OLE W190 and total OZA exposure was 2681 PY. Overall, the cumulative safety assessments did not meaningfully change with an additional year of OZA exposure (Table). EAIRs of TEAEs, serious TEAEs, and TEAEs leading to treatment discontinuation remained consistent, and there were no new cases of malignancy, bradycardia, third-degree atrioventricular (AV) block, myocardial ischemia, ischemic stroke, pulmonary embolism, deep vein thrombosis, or macular edema with an additional year of OZA exposure. Three pts newly developed infections; however, only 1 pt had a serious infection (keratouveitis), which was not related to treatment. Two additional pts experienced mild hypertension. Reductions in ALC <500 cells/µl were common in the OLE (57.2%), but few pts had ALC <200 cells/µl(6.6%). Occurrence of ALC <200 cells/µl was not temporally associated with serious or opportunistic infections. Most alanine aminotransferase and aspartate aminotransferase elevations were transient and resolved without treatment interruption, and no serious hepatic events occurred.

Table. Cumulative safety assessments during TN and the TN OLE in all pts who entered the OLE	Up to ~4 y of OZA exposurea (n=823) Total PYc = 2536 n (%) EAIRd		Up to ~5 y of OZA exposureb (n=823) Total PYc = 2681 n (%)e n (%)			Up to ~4 y of OZA exposurea (n=823) Total PYc = 2536 n (%) EAIRd		Up to ~5 y of OZA exposureb (n=823) Total PYc = 2681 n (%)e n (%)
TEAEs	685 (83.2)	85.5	687 (83.5)	85.1	Third-degree AV block	1 (0.1)	0.04	1 (0.1)	0.04
Serious TEAEs	158 (19.2)	7.0	163 (19.8)f	6.8	Hypertension	55 (6.7)	2.3	56 (6.8)	2.2
TEAEs leading to treatment discontinuation	64 (7.8)	2.5	66 (8.0)	2.5	Myocardial ischemia	3 (0.4)	0.12	3 (0.4)	0.11
Infection	378 (45.9)	22.7	381 (46.3)	22.1	Ischemic stroke	3 (0.4)	0.12	3 (0.4)	0.11
Herpes zoster	30 (3.6)	1.2	31 (3.8)	1.2	Pulmonary embolism	3 (0.4)	0.12	3 (0.4)	0.11
COVID-19	103 (12.5)	4.3	103 (12.5)	4.1	Deep vein thrombosis	3 (0.4)	0.12	3 (0.4)	0.11
Serious infection	44 (5.3)	1.8	45 (5.5)	1.7	Macular edema	3 (0.4)	0.12	3 (0.4)	0.11
Malignancy	18 (2.2)	0.71	17 (2.1)	0.63	Cystoid macular edema	3 (0.4)	0.12	3 (0.4)	0.11
Bradycardia	3 (0.4)	0.12	3 (0.4)	0.11

^aData cutoff of June 30, 2023. ^bData cutoff of January 10, 2024. ^cTotal PY was calculated as the sum of the number of years on study contributed by each pt from time of first dose to last date on study. ^dEAIRs were calculated as number of pts/PY × 100. ^eTN OLE is an ongoing study. Individual TEAE terms may not add up as harmonization of final data is pending. ^fFor the 5 pts who newly reported a serious TEAE, events included 1 pt each with UC exacerbation, colitis, pancreatitis, and umbilical hernia, and 1 pt with ulcerative keratitis and keratouveitis.

Conclusion

The ongoing safety profile of OZA is consistent with previous analyses, with no new safety concerns identified. Long-term OZA use representing 2681 PY of exposure continues to be well tolerated in pts with moderately to severely active UC.

Disclosure

Acknowledgment: This study was sponsored by Bristol Myers Squibb. Writing and editorial assistance was provided by Traci Stuve, MA, and Alexandra Stafford, PhD, of Peloton Advantage, LLC, an OPEN Health company, and was funded by Bristol Myers Squibb.

JT: received grants from AbbVie and Janssen; received advisory board or speaker fees from AbbVie, Bristol Myers Squibb, Janssen, Pfizer, and Sandoz.
RL: consulted for Bristol Myers Squibb and Pfizer.
KK: received lecture honoraria from Gore.
SL: consulted for AbbVie, Bristol Myers Squibb, Eli Lilly, and Janssen.
TK: served as an advisory board member, consultant, or speaker for AbbVie, Alfresa Pharma, Alimentiv, Astellas, Bristol Myers Squibb, Celltrion, Covidien, EA Pharma, Eli Lilly, Ferring, Galapagos, Gilead Sciences, Janssen, JIMRO, JMDC, Kissei Pharmaceutical, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Takeda, ThermoFisher Scientific, and Zeria Pharmaceutical; received research funding from AbbVie, Alfresa Pharma, EA Pharma, Gilead, Kyorin Pharmaceutical, Mochida Pharmaceutical, Nippon Kayaku, Otsuka Holdings, Pfizer, Sekisui Medical, Takeda, ThermoFisher Scientific, and Zeria Pharmaceutical.
DB: served as advisory board member or consultant for AbbVie, Amgen, Arena, Atheneum, BNG Service GmbH, Bristol Myers Squibb, CED Service GmbH, Celltrion, DGVS, Diaplan, Doctorflix, Eli Lilly, Else Kröner-Fresenius-Stiftung, Falk Foundation, Ferring, Galapagos, Gastroenterology Today, GlaxoSmithKline, Guidepoint, Impulze, Janssen-Cilag, Medical Tribune, MedTrix, MSD, Mylan, Onkowissen, Pfizer, Pharmacosmos, Roche, Sandoz, Streamed Up, Takeda, Tetrameros, Thieme, Tillotts, UCB, Viatris, and Vifor Pharma.
LK: reported no conflicts of interest.
DM, NRS, AP, MD, HW, DW, MTO, and AJ: employees and/or shareholders of Bristol Myers Squibb.
BPA: consulted for AbbVie, Bristol Myers Squibb, Celltrion, Eli Lilly, Janssen, Medtronic, Pfizer, Prometheus, Samsung Bioepis, and Takeda; lectured for AbbVie, Bristol Myers Squibb, Eli Lilly, Janssen, Pfizer, 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.

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.