Introduction

Conventional therapies, such as 5-aminosalicylate (5-ASA), corticosteroid (CS), and immunomodulators, are unable to maintain adequate disease control in many ulcerative colitis (UC) patients (pts), indicating a need for early use of advanced therapies. Ozanimod (OZA), an oral advanced therapy, is approved for the treatment of moderately to severely active UC. Previous studies have demonstrated superior OZA efficacy compared with placebo (PBO) in pts who were advanced therapy–naive and only exposed to conventional therapies.

Aims & Methods

The aim of the present post hoc analysis from the phase 3 True North study was to explore the efficacy of OZA maintenance therapy in advanced therapy–naive UC pts who had either moderate (Mayo endoscopic subscore [MES]=2) or severe (MES=3) baseline endoscopic disease activity. Pts continued on oral 5-ASA and/or CS during induction and CS were tapered during maintenance. In the induction period, pts in Cohort 1 were randomized to OZA 0.92 mg or PBO or received open-label OZA in Cohort 2. OZA clinical responders at Week (W) 10 in either cohort were rerandomized to OZA (OZA/OZA) or PBO (OZA/PBO) during maintenance through W52. Clinical and mucosal endpoints of clinical remission, clinical response, CS-free remission, endoscopic improvement, histologic remission, and mucosal healing were assessed at W52. Treatment differences for OZA/OZA vs OZA/PBO were based on the Cochran-Mantel-Haenszel test, stratified by remission status and CS use at W10.

Results

A higher proportion of advanced therapy–naive pts with baseline moderate disease (53% [157/297]) vs severe disease (47% [140/297]) were rerandomized to either OZA or PBO during maintenance. Baseline demographic and clinical characteristics were generally similar across groups. Overall, more pts who continued on OZA vs switched to PBO achieved clinical and mucosal efficacy at W52, with moderate pts having better outcomes than severe pts (Table). Almost all efficacy endpoints in pts who continued on OZA vs those who switched to PBO were statistically significantly higher in moderate pts but only numerically higher in severe pts. Consequently, treatment differences (OZA/OZA vs OZA/PBO) were slightly greater in moderate pts than severe pts for clinical remission (19.8% [95% CI, 5.2–34.4]; P=0.009 vs 16.0% [1.5–30.4]; P=0.04), clinical response (15.1% [–0.1 to 30.4]; P=0.06 vs 10.0% [–6.2 to 26.2]; P=0.23), CS-free remission (16.2% [1.7–30.6]; P=0.03 vs 14.6% [1.6–27.5]; P=0.03), histologic remission (18.4% [3.6–33.1]; P=0.02 vs 9.5% [–4.8 to 23.8]; P=0.21), and mucosal healing (16.7% [2.2–31.2]; P=0.02 vs 10.0% [–3.3 to 23.3]; P=0.15), but were similar in moderate vs severe pts for endoscopic improvement (17.8% [2.4–33.1]; P=0.03 vs 18.2% [3.0–33.4]; P=0.02).

OZA efficacy at W52 of TN maintenance period in advanced therapy–naive pts	Moderate disease (MES=2)		Severe disease (MES=3)
	OZA/PBO (n=85)	OZA/OZA (n=72)	OZA/PBO (n=67)	OZA/OZA (n=73)
Clinical remission,a n (%)	22 (25.9)	34 (47.2)	14 (20.9)	26 (35.6)
Clinical response,b n (%)	43 (50.6)	48 (66.7)	31 (46.3)	40 (54.8)
CS-free remission,c n (%)	21 (24.7)	31 (43.1)	11 (16.4)	21 (28.8)
Endoscopic improvement,d n (%)	30 (35.3)	39 (54.2)	19 (28.4)	33 (45.2)
Histologic remission,e n (%)	21 (24.7)	32 (44.4)	14 (20.9)	22 (30.1)
Mucosal healing,f n (%)	19 (22.4)	29 (40.3)	11 (16.4)	19 (26.0)
Pts with missing data were considered nonresponders. aClinical remission: RBS=0, SFS ≤1 point (and a decrease of ≥1 point from baseline SFS), and MES ≤1 point. bClinical response: decrease from baseline in the 3-component Mayo score (sum of RBS, SFS, and MES) of ≥2 points and ≥35% and a reduction of ≥1 point in RBS or absolute RBS of ≤1 point. cClinical remission at W52 while off CS for ≥12 wk. dEndoscopic improvement: MES ≤1 point. eHistologic remission: Geboes index score <2.0. fMucosal healing: MES ≤1 point and Geboes index score <2.0. RBS, rectal bleeding subscore; SFS, stool frequency subscore.

Conclusion

OZA, as an oral advanced therapy, was efficacious as a maintenance therapy in moderate and severe advanced therapy–naive UC pts whose disease was initially inadequately controlled on conventional therapies. Pts with moderate vs severe disease may benefit more from OZA, as they showed numerically greater clinical, endoscopic, and histologic benefit while on continuous OZA treatment.

Disclosure

This study was funded by Bristol Myers Squibb, Princeton, NJ, USA.
BS: served as a consultant for AbbVie, Arena, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Falk Pharma, Galapagos, Janssen, Pfizer, Prometheus, and Takeda; received speaker fees from AbbVie, CED Service GmbH, Falk Pharma, Ferring, Janssen, Novartis, Pfizer, and Takeda.
PI: received lecture fees from AbbVie, Bristol Myers Squibb, Celgene, Celltrion, Falk Pharma, Ferring, Galapagos, Gilead, MSD, Janssen, Pfizer, Sandoz, Sapphire Medical, Shire, Takeda, Tillotts, and Warner Chilcott; received financial support for research from Celltrion, MSD, Pfizer, and Takeda; received advisory fees from AbbVie, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly, Genentech, Gilead, Hospira, Janssen, MSD, Pfizer, Pharmacosmos, Prometheus Biosciences, Roche, Samsung Bioepis, Sandoz, Takeda, Topivert, VH2, Vifor, and Warner Chilcott.
GD: served as an advisor for AbbVie, Agomab, Alimentiv, Applied Molecular Therapeutics, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Cytoki, Eli Lilly, Exeliom Biosciences, Ferring, Galapagos, GlaxoSmithKline, Gossamer Bio, Immunic, Johnson & Johnson, Pfizer, Polpharma, ProciseDx, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Seres, Takeda, Tillotts, and Versant; received speaker fees from AbbVie, Bristol Myers Squibb, Eli Lilly, Galapagos, Johnson & Johnson, Pfizer, Takeda, and Tillotts.
CAS: consultant/advisory board member for AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Janssen, Pfizer, Prometheus, and Takeda; speaker for continuing medical education activities for AbbVie, Celgene, Janssen, Pfizer, and Takeda; grant support from AbbVie, Janssen, Pfizer, and Takeda.
EVL: served as a consultant for AbbVie, Alvotech, Amgen, Arena, Avalo Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Calibr, Celgene, Eli Lilly, Fresenius Kabi, Genentech, Gilead, GlaxoSmithKline, Gossamer Bio, Iota Biosciences, Iterative Scopes, Janssen, Ono Pharma, Pfizer, Scipher Medicine, Sun Pharma, Surrozen, Takeda, and UCB; received research grants from AbbVie, AstraZeneca, Bristol Myers Squibb, Celgene/Receptos, Genentech, Gilead, Gossamer Bio, Janssen, Pfizer, Takeda, Theravance, and UCB; shareholder of Exact Sciences.
AJ, HW, and MTO: employees and/or shareholders of Bristol Myers Squibb.
DTR: received grant support from Takeda; consulted for AbbVie, AltruBio, Aslan, Athos, Bellatrix, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Chronicles, ClostraBio, Connect BioPharma, EcoR1, Eli Lilly, Genentech/Roche, Gilead Sciences, Iterative Health, Janssen, Kaleido Biosciences, Pfizer, Prometheus Biosciences, Reistone, Seres, Syneos, Takeda, Target RWE, and Trellus Health.
MDL: received research funding from Pfizer and Takeda; consultant for AbbVie, Bristol Myers Squibb, Calibr, Eli Lilly, Genentech, Janssen, Pfizer, Prometheus, Roche, Salix, Takeda, Target RWE, and Theravance.

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

Tumor necrosis factor-like cytokine 1A (TL1A), a membrane costimulatory protein that also exists as a serum cytokine, drives multiple pro-inflammatory and fibrotic pathways relevant to the immunopathogenesis of inflammatory bowel disease (IBD). Intestinal inflammation and chronic mucosal injury are associated with submucosal fibrosis in ulcerative colitis (UC). In ARTEMIS-UC, a phase 2 placebo-controlled, multicenter, double-blind study, the anti-TL1A inhibitory monoclonal antibody PRA023 showed efficacy in adults with moderately to severely active UC. A significantly greater proportion of patients who received PRA023 achieved the primary endpoint of clinical remission at week 12. This study analyzed molecular biomarkers from ARTEMIS-UC patient samples obtained before and after treatment with PRA023 compared to placebo control.

Aims & Methods

Serum and RNAseq data from intestinal mucosal biopsies were analyzed for cytokines and gene expression, respectively, to evaluate the effects of TL1A blockade in 68 UC patients treated with PRA023 and 60 patients treated with placebo during the 12-week induction period. Serum cytokine levels were measured at baseline, weeks 2, 6, and 12, using mesoscale discovery (MSD) multiplexing. Intestinal mucosal biopsy RNAseq data were analyzed at baseline and week 12 using differential gene expression, pathway analysis (gene set variation analysis), and single-cell deconvolution approaches. Pathway signatures were curated from public datasets or derived from in vitro studies. Pharmacodynamic (PD) changes were correlated with modified Mayo score clinical remission, the primary clinical endpoint of the study, defined as an endoscopic score of 0 or 1, rectal bleeding of 0, and stool frequency of 0 or 1 and not greater than baseline.

Results

PRA023 reduced serum levels of T cell-derived cytokines (e.g., IL-5, IL-13, IL-17A, IL-22) and the monocyte/macrophage inflammatory cytokine IL-6 compared to placebo controls (p<0.05). In colonic tissue, 12 weeks of PRA023 treatment significantly reduced the expression of pro-inflammatory cytokine genes and pathways including Th1, Th17, Th2, and inflammatory monocyte gene sets, as well as TL1A-induced CD4+ T cell gene signatures (p<0.05); these changes were not observed in the placebo controls. These PD effects of PRA023 were only statistically significant in patients who achieved clinical remission. PRA023 also reduced the expression of fibrosis-associated genes and signatures in patients who achieved clinical remission (p<0.05). Cell-type deconvolution of bulk RNAseq using IBD single-cell reference datasets showed a reduction in the frequency of proliferating T cells and activated fibroblasts in PRA023-treated patients compared to placebo controls (p<0.01). The percent reduction in these cell types was greater in PRA023-treated patients who achieved clinical remission compared to non-remitters (p<0.0001).

Conclusion

Consistent with a role of TL1A in the immunopathogenesis of UC, biomarker analysis of PRA023-treated UC patients showed a reduction in Th1, Th17, Th2, and activated fibroblast gene signatures and peripheral inflammatory cytokines, providing insights into the mechanism of action of PRA023.

Disclosure

SD has received consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Dr. Falk Pharma, Eli Lilly and Company, Enthera, Ferring, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB Inc., Vial, and Vifor and lecture fees from AbbVie, Amgen, Ferring, Gilead, Janssen, Mylan, Pfizer, and Takeda.
MA has consulted and/or served on an advisory board for AbbVie Inc, Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Celsius Therapeutics, Eli Lilly and Company, Gilead Sciences, Janssen Pharmaceuticals, Microba Life Sciences, Pfizer Pharmaceutical, Prometheus Biosciences, UCB Biopharma SRL, and WebMD Global LLC; has taught, lectured and spoken for Alimentiv, Amgen, Janssen Pharmaceuticals, and Takeda Pharmaceuticals.
YW, HL, ED, FT, DDN, and EM are employees and shareholders of Prometheus Biosciences.
BGF has served as a consultant for AbbVie, AbolerIS Pharma, AgomAb, AllianThera, Amgen, AnaptysBio, Applied Molecular Transport, Arena, Avoro Capital Advisors, Atomwise, BIOJAMP, Biora Therapeutics, Boehringer Ingelheim, Boxer, Celsius Therapeutics, Bristol Myers Squibb/Celgene, Connect Biopharma, Cytoki, Disc Medicine, Duality, EcoR1 Capital, Eli Lilly and Company, Equillium, Ermium, First Wave, First Word Group, Galapagos, Galen Atlantica, Genentech/Roche, Gilead, Gossamer Bio, GSK, Hinge Bio, HotSpot Therapeutics, Index Pharma, Imhotex, Immunic Therapeutics, JAK Academy, Janssen, Japan Tobacco, Kaleido, 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 Pharma, Pendopharm, Pfizer, Prometheus Therapeutics, PlayToKnow AG, Progenity, Protagonist Therapeutics, PTM Therapeutics, Q32 Bio, Rebiotix, REDX, Roche, Sandoz, Sanofi, Seres Therapeutics, Silverback Therapeutics, Surrozen, Takeda, Teva, Thelium, TiGenix, Tillotts Pharma, Ventyx Biosciences, VHsquared, Viatris, Ysios, Ysopia, Zealand Pharma; on the speaker’s bureau for AbbVie, Janssen, and Takeda; and on advisory boards for AbbVie, Amgen, AMT, AnaptysBio, Boehringer Ingelheim, Bristol Myers Squibb/Celgene, Eli Lilly and Company, Genentech/Roche, Janssen, MiroBio, Origo BioPharma, Pfizer, Prometheus, REDX, Sanofi, Takeda, Tillotts Pharma, Teva, Progenity, Index, EcoR1 Capital, Morphic, GSK, and Axio Research.
BES has served as a consultant for or received speaker’s fees from AbbVie, Abivax, Adiso Therapeutics, Alimentiv, Amgen, Arena Pharmaceuticals, Artizan Biosciences, Artugen Therapeutics, AstraZeneca, Bacainn Therapeutics, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Calibr, Celltrion Healthcare, ClostraBio, Connect Biopharma, Cytoki Pharma, Eli Lilly and Company, Entera, Evommune, Ferring, Fresenius Kabi, Galapagos, Gilead, Genentech, GSK, Gossamer Bio, HMP Acquisition, Imhotex, Immunic, InDex Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Ironwood Pharmaceuticals, Janssen, Johnson & Johnson, Kaleido, Kallyope, Merck, MiroBio, Morphic Therapeutic, MRM Health, OSE Immunotherapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, RedHill Biopharma, Sun Pharma Global, Surrozen, Synlogic, Takeda, Target RWE, Theravance Biopharma R&D, TLL Pharmaceutical, USWM Enterprises, Ventyx Biosciences, and Viela Bio and has received stock options from Ventyx Biosciences.
FR is consultant to or on advisory board of Adiso, Adnovate, Agomab, Allergan, AbbVie, Arena, Astra Zeneca, Boehringer-Ingelheim, Celgene/BMS, CDISC, Celsius, Cowen, Ferring, Galapagos, Galmed, Genentech, Gilead, Gossamer, Granite, Guidepoint, Helmsley, Horizon Therapeutics, Image Analysis Limited, Index Pharma, Landos, Jannsen, Koutif, Mestag, Metacrine, Mopac, Morphic, Organovo, Origo, Palisade, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Sanofi, Surmodics, Surrozen, Takeda, Techlab, Teva, Theravance, Thetis, UCB, Ysios, and 89Bio.
ST has received consulting fees from Robarts Clinical Trials and Prometheus Biosciences and owns stock in Prometheus Biosciences; is a member of steering committees of Janssen, AbbVie, Boehringer Ingelheim, Gilead, Celgene, and Bristol Meyers Squibb; has received speaker honoraria from AbbVie, Takeda, Janssen, Ferring, Pfizer, and Celltrion; and has served on advisory committees of Janssen, Takeda, AbbVie, Eli Lilly, Pfizer, Gilead, Galapagos, and Roche.

Introduction

The Phase 2 GALAXI 1 study evaluated the efficacy and safety of guselkumab (GUS), a human selective IL-23p19 subunit antagonist, in patients (pts) with moderate to severe Crohn’s disease (CD). Pts were randomized to GUS, ustekinumab (UST), or placebo (PBO) through Week (Wk) 48 without rerandomization after IV induction. Previously, we reported that pts who were in clinical response after IV induction had higher rates of clinical and endoscopic outcomes at Wk48 than the overall study population.¹ In this post hoc analysis, we report outcomes for pts who did not achieve Wk12 clinical response based on CD activity index (CDAI) after IV induction.

Aims & Methods

Pts were randomized 1:1:1:1:1 to induction with GUS 200, 600, or 1200mg IV, UST ~6mg/kg IV, or PBO IV. At Wk12 (Wk8 for UST), pts were transitioned to maintenance dosing: GUS 200mg IV→100mg subcutaneous (SC) q8w, GUS 600mg IV→200mg SC q4w, GUS 1200mg IV→200mg SC q4w, UST ~6mg/kg IV→90mg SC q8w, PBO nonresponders→UST ~6mg/kg IV→90mg SC q8w, and PBO responders→PBO SC q4w. Clinical response (all time points) was defined as ≥100-point reduction from baseline in CDAI or CDAI <150. Other endpoints included clinical remission (CDAI <150), pt-reported outcome (PRO)-2 remission (unweighted CDAI components of average daily abdominal pain score ≤1 and average daily stool frequency ≤3, and no worsening from baseline), and endoscopic response (≥50% improvement from baseline in simple endoscopic score [SES]-CD or SES-CD ≤2). The study was not powered to evaluate between-group efficacy differences at Wk48; UST was used for reference.

Results

Table. Efficacy Outcomes Among Patients Not in Clinical Responsea at Week 12
Outcome, %b, c	Week	Combined Guselkumab (N=63)	Ustekinumab (N=21)
Clinical responsea	16 / 20 / 24	36.5 / 47.6 / 46.0	42.9 / 52.4 / 52.4
	28 / 32 / 36	47.6 / 54.0 / 50.8	42.9 / 47.6 / 57.1
	40 / 44	54.0 / 52.4	52.4 / 47.6
	48	58.7	47.6
Clinical remissiond	48	41.3	33.3
PRO-2 remissione	48	42.9	23.8
Endoscopic responsef	48	31.7	23.8
AP=abdominal pain; CD=Crohn’s disease; CDAI=Crohn’s disease activity index; PRO-2=Patient-reported CDAI components of abdominal pain and stool frequency; SES-CD=Simple Endoscopic Score for Crohn’s Disease; SF=stool frequency. a Clinical response was defined as ≥100-point reduction from baseline in CDAI or CDAI <150. b Patients who had a prohibited change in concomitant CD medication, a CD-related surgery, or discontinued study agent due to lack of efficacy, or an adverse event of worsening CD prior to the designated analysis timepoint, were considered not to have achieved the endpoint. c Patients who had insufficient data to calculate the outcome measure at the designated analysis timepoint were considered not to have achieved the endpoint. d Clinical remission was defined as a CDAI <150. e PRO-2 remission was defined as unweighted CDAI component of average daily AP pain score ≤1 and the unweighted CDAI component of average daily SF ≤3, and no worsening of AP or SF from baseline. f Endoscopic response was defined as ≥50% improvement from baseline in SES-CD or SES-CD ≤2.

At Wk12, 63/185 (34.1%) GUS pts and 21/63 (33.3%) UST did not achieve CDAI clinical response. Among GUS Wk12 nonresponders, 46.0% were in clinical response by Wk24 (Table). Percentages of Wk12 nonresponders who went on to achieve outcomes at Wk48 in the GUS and UST groups, respectively, were as follows: clinical response, 58.7% and 47.6%; clinical remission, 41.3% and 33.3%; PRO-2 remission, 42.9% and 23.8%; and endoscopic response, 31.7% and 23.8% (Table).

Conclusion

Pts not responding to IV induction with GUS may benefit from continued SC dosing. Among pts who did not achieve clinical response at Wk12, continued treatment with GUS SC resulted in nearly half achieving clinical response at Wk24. At Wk48, a majority achieved clinical response, >40% achieved either clinical remission or PRO-2 remission, and >30% achieved endoscopic response.

References

1. Panés J, et al. UEG Journal 2022; 10 (Suppl 8).

Disclosure

RP reports consulting fees, speaker fees, or research support from Abbott, AbbVie, Abbivax, Alimentiv (formerly Robarts), Amgen, 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, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Viatris, Ventyx, and UCB.
AA reports consulting fees from AbbVie, Takeda, Janssen, Bristol Myers Squibb/Celgene, Pfizer, Eli Lilly, Gilead, DiaSorin, and TLL Pharmaceuticals; reports speaker fees from Abbvie, Takeda, Janssen, Bristol Myers Squibb, and Pfizer; has served on advisory boards for Abbvie, Takeda, Janssen, Bristol Myers Squibb, Pfizer, Eli Lilly, and Gilead; has received research/education support from AbbVie, Janssen, Pfizer, Bristol Myers Squibb, and Takeda; and is the co-founder of IBD Horizons.
GRDH served as advisor for Abbvie, Ablynx, Amakem, Amgen, AM Pharma, Avaxia, Biogen, Bristol Myers Squibb, Boehringer Ingelheim, Celgene/Receptos, Celltrion, Cosmo, Covidien/Medtronics, Ferring, DrFALK Pharma, Eli Lilly, Engene, Galapagos, Genentech/Roche, Gilead, Glaxo-Smith Kline, Immunic, Johnson and Johnson, Lycera, Medimetrics, Millenium/Takeda, Mitsubishi Pharma, Merck Sharp Dome, Mundipharma, Nextbiotics, Novonordisk, Otsuka, Pfizer/Hospira, Prometheus laboratories/Nestle, Protagonist, Robarts Clinical Trials, Salix, Samsung Bioepis, Sandoz, Setpoint, Shire, Teva, Tigenix, Tillotts, Topivert, Versant, and Vifor; and has received speaker fees from Abbvie, Biogen, Ferring, Johnson and Johnson, Merck Sharp Dome, Mundipharma, Norgine, Pfizer, Samsung Bioepis, Shire, Millenium/Takeda, Tillotts, and Vifor.
LS, NAT, AS, MEF, and ZY are employees of Janssen Research & Development, LLC and own stock/stock options.
EZ reports receiving research support and consulting fees from Janssen, AbbVie, Takeda, Neopharm, Celgene, and Pfizer.
SD reports receiving consulting fees from Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion Healthcare, Ferring, Gilead Sciences, Hospira, Inc., Janssen Research & Development, LLC, Johnson & Johnson Health Care Systems, Inc., Pfizer, Sandoz, UCB, and Vifor International Inc.
TH has performed joint research with Alfresa Pharma Co. Ltd., and EA Pharma Co. Ltd.; has received grant support from Mitsubishi Tanabe Pharma Corporation, EA Pharma Co. Ltd., AbbVie GK, JIMRO Co. Ltd., Zeria Pharmaceutical Co. Ltd., Daiichi-Sankyo, Kyorin Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc., Mochida Pharmaceutical Co. Ltd., and JIMRO Co. Ltd; has received consulting fees from EA Pharma Co. Ltd., AbbVie GK, Celgene K.K., Janssen Pharmaceutical K.K., Pfizer Inc., and Nichi-Iko Pharmaceutical Co., Ltd; and has received lecture fees from Mitsubishi Tanabe Pharma Corporation, AbbVie GK, EA pharma Co. Ltd., Kyorin Pharmaceutical Co. Ltd., JIMRO Co., Janssen Pharmaceutical K.K., Mochida Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., and Pfizer Inc.