Introduction

GALAXI 2 & 3 are identically designed 48-week, randomized, double-blind, double-dummy, placebo (PBO)- and active-comparator, treat-through registrational trials assessing the efficacy and safety of IV induction and SC maintenance therapy with guselkumab (GUS), a dual-acting IL-23p19 subunit inhibitor, in participants (pts) with moderately to severely active Crohn’s disease (CD). Primary results of each study were previously reported; here we explore the impact of biologic therapy exposure on efficacy outcomes with GUS compared to PBO in the pooled GALAXI 2 & 3 dataset.

Aims & Methods

Pts with inadequate response or intolerance to conventional therapy or biologic therapy (BIO-ir), active CD (CDAI 220–450 + mean daily SF>3 or AP>1), and SES-CD≥6 (≥4 for isolated ileal disease) were randomly assigned 2:2:2:1 at week (Wk) 0 to GUS 200mg IV q4w (x3)→100mg SC q8w, GUS 200mg IV q4w (x3)→200mg SC q4w, UST IV→SC, or PBO. In each trial, the composite co-primary endpoints were 1) clinical response at Wk12 + clinical remission at Wk48, and 2) clinical response at Wk12 + endoscopic response at Wk48, comparing each GUS regimen to PBO. Major secondary endpoints included clinical remission at Wk12 and endoscopic response at Wk12. Analyses of BIO-ir and BIO-naïve subgroups in the individual trials were prespecified; pooled analyses were performed post hoc.

Results

​In the pooled dataset, 52% (378/730) of pts randomized to PBO or GUS had a prior history of BIO-ir and 42% (305/730) were BIO-naïve (6% [47/730] had prior exposure to biologics but no documented failure). At Wk12, GUS achieved higher rates of clinical remission and endoscopic response compared to PBO in the overall population and BIO-ir and BIO-naïve subgroups (Table). For the composite co-primary endpoints, both GUS regimens also achieved higher rates of 1) clinical response at Wk12 + clinical remission at Wk48 and 2) clinical response at Wk12 + endoscopic response at Wk48 compared to PBO in the overall population and BIO-ir and BIO-naïve subgroups.

Table. Efficacy of guselkumab (GUS) and placebo (PBO) for short- and long-term clinical and endoscopic endpoints in all participants and BIO-ir and BIO-naïve subgroups in the pooled GALAXI 2 & 3 dataset
	Overall population			Participants with a history of inadequate response or intolerance to at least 1 prior biologica (BIO-ir)			Participants with no history of exposure to biologicsa (BIO-naïve)
	PBO N=148	GUS 200mg IV combinedb N=582		PBO N=78	GUS 200mg IV combinedb N=300		PBO N=61	GUS 200mg IV combinedb N=244
Clinical remission at Wk12	28 (18.9%)	274 (47.1%) ∆ 28.0% P<.001*		15 (19.2%)	138 (46.0%) ∆ 26.9% P<.001*		10 (16.4%)	121 (49.6%) ∆ 32.1% P<.001*
Endoscopic response at Wk12	18 (12.2%)	215 (36.9%) ∆ 25.2% P<.001*		5 (6.4%)	87 (29.0%) ∆ 22.6% P<.001*		11 (18.0%)	113 (46.3%) ∆ 27.7% P<.001*
	PBO N=148	GUS 100mgc N=286	GUS 200mgd N=296	PBO N=78	GUS 100mgc N=153	GUS 200mgd N=147	PBO N=61	GUS 100mgc N=116	GUS 200mgd N=128
Clinical response at Wk12 + clinical remission at Wk48 (composite co-primary endpoint)	18 (12.2%)	137 (47.9%) ∆ 35.8% P<.001*	152 (51.4%) ∆ 39.0% P<.001*	10 (12.8%)	70 (45.8%) ∆ 33.2% P<.001*	73 (49.7%) ∆ 37.4% P<.001*	7 (11.5%)	60 (51.7%) ∆ 40.4% P<.001*	70 (54.7%) ∆ 41.8% P<.001*
Clinical response at Wk12 + endoscopic response at Wk48 (composite co-primary endpoint)	8 (5.4%)	104 (36.4%) ∆ 30.7% P<.001*	110 (37.2%) ∆ 31.8% P<.001*	4 (5.1%)	55 (35.9%) ∆ 30.9% P<.001*	46 (31.3%) ∆ 26.7% P<.001*	4 (6.6%)	47 (40.5%) ∆ 33.0% P<.001*	56 (43.8%) ∆ 36.5% P<.001*
Data are presented as n (%); ∆% (adjusted treatment difference) vs PBO; p-value vs PBO. Adjusted treatment differences and p-values were based on the common risk difference by use of Mantel-Haenszel stratum weights and the Sato variance estimator. The stratification variables used are baseline CDAI score (≤300 or >300), baseline SES-CD score (≤12 or >12), BIO-ir status (Yes or No; this variable used only in analyses of the overall population), and baseline corticosteroid use (Yes or No). Population N values reflect the primary analysis set, defined as all randomized participants who received at least 1 (partial or complete) dose of study intervention and had a screening SES-CD score ≥6 (or ≥4 for participants with isolated ileal disease). PBO pts not in clinical response at week (Wk) 12 switched to UST. Endpoint definitions: clinical remission, CDAI < 150; endoscopic response, ≥50% improvement from baseline in SES-CD or SES-CD ≤ 2; clinical response, ≥100-point reduction from baseline in CDAI or CDAI < 150. Participants with treatment failure or missing data were considered to not have met the endpoint. a. Anti-TNF agents or vedolizumab b. Participants assigned to either GUS 200mg IV every 4 weeks (q4w) (x3)→100mg SC q8w or GUS 200mg IV q4w (x3)→200mg SC q4w. At the Wk 12 assessment, GUS participants had only received GUS IV. c. Participants assigned to GUS 200mg IV q4w (x3)→100mg SC q8w d.Participants assigned to GUS 200mg IV q4w (x3)→200mg SC q4w * Nominal p-value

Conclusion

In pooled analyses of the double-blind GALAXI 2 & 3 trials, GUS was efficacious versus PBO in pts with CD regardless of prior biologic therapy exposure in both short-term (Wk12) endpoints and long-term (Wk12 + Wk48) composite endpoints.

Disclosure

Bruce E. Sands reports potential conflicts of interest with AbbVie, Abivax, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, Artugen Therapeutics, AstraZeneca, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Evommune, Ferring, Fresenius Kabi, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Janssen, Kaleido, Kallyope, Lilly, Merck, Microbiotica, Mobius Care, Morphic Therapeutics, MRM Health, Pfizer, Nexus Therapeutics, Nimbus Discovery, Odyssey, Therapeutics, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Therapeutics, Reistone Biotherapeutics, Sun Pharma, Surrozen, Target RWE, Takeda, Teva, Theravance Biopharma, TLL Pharmaceutical, TR1X, Union Therapeutics and Ventyx Biosciences.
Geert D’Haens reports potential conflicts of interest with AbbVie, Agomab, Alimentiv, AstraZeneca, AMT, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom, Galapagos, GlaxoSmithKline, Gossamerbio, Immunic, Index, Johnson & Johnson, Kaleido, Origo, Pfizer, Polpharma, Procise Diagnostics, Prometheus Laboratories, Prometheus Biosciences, Progenity, and Protagonist Therapeutics Inc., Seres Health, and Takeda.
Silvio Danese reports potential conflicts of interest with 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.
Tadakazu Hisamatsu reports potential conflicts of interest with AbbVie, Bristol Myers Squibb, Daiichi-Sankyo, EA Pharma Co, Ltd., Eli Lilly, Gilead Sciences, Janssen Research & Development, LLC., JIMRO, Kissei Pharmaceutical Co, Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Inc., and Takeda Pharmaceutical Co., Ltd.
Walter Reinisch reports potential conflicts of interest with AbbVie, Aesca, Agomab, Algernon, AltruBio, Amgen, AM, AMT, AOP Orphan, Aptalis, Arena, Astellas, AstraZeneca, Avaxia, Roland Berger, Bioclinica, Biogen, Boehringer-Ingelheim, Bristol Myers Squibb, Calyx, Cellerix, Chemocentryx, Celgene, Celltrion, Covance, Danone Austria, DSM, Elan, Eli Lilly, Ernest & Young, Falk, Ferring, Fresenius, Galapagos, Gatehouse, Genentech, Gilead, Grünenthal, ICON, Immundiagnostik, Index, Inova, Intrinsic Imaging, Janssen, Johnson & Johnson, Kyowa Hakko Kirin, Landos, Lipid, LivaNova, Mallinckrodt, Medahead, Medice, MedImmune, Millenium, Mitsubishi Tanabe, MSD, Nash, Nestle, Nippon Kayaku, Novartis, Ocera, OMass, Otsuka, Parexel, PDL, Periconsulting, Pfizer, Pharmacosmos, PLS Education, Procter & Gamble, Prometheus, Protagonist, Provention, Quell, Robarts Clinical Trial, Sandoz, Schering-Plough, Second Genome, Seres, Setpointmedical, Sigmoid, Sublimity, Takeda, Teva, Therakos, Theravance, Tigenix, UCB, Vifor, Yakult, Zealand, Zyngenia, and 4SC.
Natalie A. Terry, Leonardo Salese, Rian Van Rampelbergh, Zijiang Yang, and Jewel Johanns are employees of Janssen Research & Development (a Johnson & Johnson Company) and may own company stock/stock options.
George DuVall reports potential conflicts of interest with Janssen.
Niazy Abu Farsakh reports potential conflicts of interest with Abbott, Amgen, Antanea medical services, Ferring, Hikma, Janssen, and Pfizer.
Remo Panaccione reports potential conflicts of interest with Abbivax, Abbott, AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, 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.

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

As a small but important component of the intestinal microbiota, the fungal community (mycobiota) has received increasing attention for its involvement in the pathogenesis of Crohn's disease (CD)¹. In our previous study, we identified a significantly increased relative abundance of Exophiala dermatitidis (E. dermatitidis) in the gut of patients with CD, particularly those with active disease². Caspase recruitment domain family member 9 (CARD9), a key adaptor molecule in antifungal immune responses³, has also been strongly associated with CD susceptibility⁴. In this study, we aimed to explore the potential role and underlying mechanisms of E. dermatitidis in intestinal inflammation.

Aims & Methods

To evaluate the impact of E. dermatitidis on intestinal inflammation, we generated Card9-knockout (KO) (Card9^-/-) mice and constructed a dextran sulfate sodium (DSS)-induced colitis model colonized by E. dermatitidis. The underlying molecular mechanisms were investigated by a range of biochemical approaches. Flow cytometry was performed to analyze the proportions of myeloid cells, including CX3CR1⁺ macrophages, in the colonic lamina propria (LP).

Results

Compared to mice with DSS-induced colitis alone (WT-DSS group), the DSS-treated mice colonized by E. dermatitidis (WT-DSS + Ed group) showed a significant weight loss, a worsening of disease activity, a shorter length of the large intestine, and more severe intestinal inflammation characterized by increased inflammatory cell infiltration and crypt destruction in the histological examination of colon hematoxylin and eosin (H&E) staining. Card9^-/- mice were used to further investigate whether E. dermatitis-mediated inflammation was dependent on the CARD9 signaling pathway. We observed that CARD9 deficiency protected against E. dermatitidis-exacerbated colitis, as measured by a higher trend of body weight, longer colon lengths, and amelioration of disease activity in the KO-DSS + Ed group. In addition, flow cytometric analysis of the colonic lamina propria revealed a higher percentage proportion of CX3CR1+ macrophages in the WT-DSS + Ed group and a markedly reduced proportion in the KO-DSS + Ed group. Furthermore, we identified the Mincle-Syk-CARD9-nuclear factor kappa-B (NF-κB) signaling pathway as playing an important role in mediating the inflammatory immune responses to E. dermatitidis.

Conclusion

E. dermatitidis exacerbates the DSS-induced colitis in mice through the Mincle-Syk-CARD9-NF-κB pathway with the participation of CX3CR1+ macrophages, providing a novel therapeutic strategy for CD targeting specific intestinal fungi.

References

1. Sokol H, Leducq V, Aschard H, et al. Fungal microbiota dysbiosis in IBD. Gut 2017;66:1039-1048.
2. Zeng L, Feng Z, Zhuo M, et al. Fecal fungal microbiota alterations associated with clinical phenotypes in Crohn's disease in southwest China. PeerJ 2022;10:e14260.
3. Hu A, Hu Z, Zou H, et al. CARD9 in host immunity to fungal, bacterial, viral, and parasitic infections: An update. Frontiers In Microbiology 2022;13:1021837.
4. Franke A, McGovern DPB, Barrett JC, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nature Genetics 2010;42:1118-1125.

Introduction

Histologic inflammation persists in up to 1/4 of patients (pts) with Crohn’s Disease (CD) despite endoscopic mucosal healing. Responsiveness of histologic inflammation and of combined endoscopic-histologic endpoints to treatment are evolving measures of disease activity in CD. Mirikizumab (MIRI) increased histologic response (H-Res) and remission (H-Rem) relative to placebo (PBO) in the Phase 2 SERENITY trial.¹

Aims & Methods

To evaluate the impact of MIRI and ustekinumab (UST) on H-Res and H-Rem and combined endoscopic-histologic response (EH-Res) and remission (EH-Rem) in all pts, pts with prior biologic failure (BF), pts without prior BF in moderately to severely active CD, in the randomized, double-blind, double-dummy, treat-through Phase 3 VIVID-1 trial (NCT03926130). Two biopsy specimens from each of 5 intestinal segments (1 ileal and 4 colonic) were obtained from the edge of the ulcers, or the most inflamed mucosa from randomized pts at screening, and weeks (W)12, and 52. Criteria for H-Res were the absence of epithelial neutrophils and epithelial damage, erosions and ulceration or ≥50% decrease in either the active Robarts Histopathology Index or the active Global Histologic Disease Activity Score. H-Rem was defined as complete absence of mucosal neutrophils (in epithelium and lamina propria), and no epithelial damage, erosions and ulcers; these criteria had to be met in all biopsy specimens. Endoscopic response was defined as ≥50% improvement from baseline in Simple Endoscopic Score for CD (SES-CD). Endoscopic remission was defined as SES-CD total score ≤4 and ≥2-point reduction from baseline and no subscore >1 in any individual variable.

Results

At W52, nominally significant differences between MIRI and UST were observed in achieving H-Res in all pts (58.2% vs 48.8%; p=.007 and in BF pts (56.5% vs 41.3%; p=.006). For EH-Res, differences of MIRI vs UST were numerically greater but not statistically significant in all pts (41.1% vs 34.4%; p=.063) but were nominally significant among BF pts (39.6% vs 27.8%; p=.023). While numerical differences between MIRI and UST were observed in H-Rem and EH-Rem in all pts (H-Rem: 30.2% vs 28.9%; p=.685; EH-Rem: 17.2% vs 14.8%; p=.363) and in BF pts (H-Rem: 24.3% vs 19.8%; p=.365; EH-Rem: 13.3% vs 8.7%; p=.237), no significant differences were observed in these endpoints(Table).

		MIRI	USTE	P	Difference (95%CI)
Histologic Response (%)	All patients Without prior biologic failure With prior biologic failure	58.2 61.9 56.5	48.8 56.9 41.3	0.007 0.383 0.006	9.6 (2.6, 16.6) 5.0 (-5.3, 15.3) 15.2 (4.7, 25.7)
Endoscopic-Histologic Response (%)	All active patients Without prior biologic failure With prior biologic failure	41.1 42.5 39.6	34.4 40.8 27.8	0.063 0.829 0.023	6.8 (-0.3, 14.0) 1.7 (-8.6, 12.0) 11.8 (2.0, 21.7)
Histologic Remission (%)	All patients Without prior biologic failure With prior biologic failure	30.2 33.3 24.3	28.9 34.6 19.8	0.685 0.822 0.365	1.3 (-5.0, 7.7) -1.3 (-11.2, 8.6) 4.5 (-4.3, 13.2)
Endoscopic-Histologic Remission (%, 95%CI)	All active patients Without prior biologic failure With prior biologic failure	17.2 20.9 13.3	14.8 20.8 8.7	0.363 >0.999 0.237	2.6 (-2.8, 7.9) 0.1 (-8.4, 8.6) 4.6 (-1.9, 11.1)
All active patients are patients with active histologic disease at baseline. Histologic response and histologic remission in all patients were prespecified, non-multiplicity-controlled endpoints. All analyses in patients without prior biologic failure, patients with biologic failure and combined endoscopic-histologic response and remission were analyzed post hoc. For achieving histologic response, the sum of five segments active RHI or active GHAS needed to be reduced by ≥50% from baseline. CI=confidence interval; GHAS=Global Histologic Disease Activity Score; MIRI=mirikizumab; PBO=placebo; RHO=Robarts Histopathology Index; USTE=ustekinumab

Conclusion

Using strict definitions, all histology-based endpoints were achieved by MIRI versus PBO. For comparison versus UST, MIRI also showed nominal statistical difference for H-Res, which was prespecified and is considered the most sensitive to change, particularly driven by BF pts. The implication of these results on clinical endpoints and long-term outcomes, including hospitalization rates and surgeries, requires further evaluation.

References

1. Magro F, et al. Clin Gastroenterol Hepatol. 2023:S1542-3565(23)00948-5.

Disclosure

• V. Jairath received consulting/advisory board fees: AbbVie, Alimentiv, Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris Pharmaceuticals, AstraZeneca, Avoro Capital, Bristol Myers Squibb, Celltrion, Eli Lilly and Company, Endpoint Health, Enthera, Ferring Pharmaceuticals, Flagship Pioneering, Fresenius Kabi, Galapagos NV, Gilde Healthcare, GlaxoSmithKline, Genentech, Gilead Sciences, Innomar, JAMP, Janssen, Merck, Metacrine, Mylan, Pandion Therapeutics, Pendopharm, Pfizer, Prometheus Biosciences, Protagonist Therapeutics, Reistone Biopharma, Roche, Roivant Sciences, Sandoz, SCOPE, Second Genome, Sorriso Pharmaceuticals, Takeda, TD Securities, Teva, Topivert, Ventyx Biosciences, and Vividion Therapeutics; and speaker’s fees: AbbVie, Bristol Myers Squibb, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos NV, Janssen, Pfizer, Shire, and Takeda
• F. Magro speaker: AbbVie, Arena, Biogen, Bristol Myers Squibb, Eli Lilly and Company, Falk, Ferring Pharmaceuticals, Hospira, Janssen, Laboratórios Vitoria, Merck Sharp & Dohme, Pfizer, Sandoz, Takeda, UCB, and Vifor
• G. De Hertogh received fees for clinical trial activities with Centocor Inc; and received consultancy fees: Eli Lilly and Company and MRM Health
• B. Feagan was a consultant: AbbVie, AbolerIS Pharma, Agomab Therapeutics, Allianthera, Amgen, AnaptysBio, Applied Molecular Transport, Arena Pharmaceuticals, Avoro Capital Advisors, Atomwise, BioJamp, Biora Therapeutics, Boehringer Ingelheim, Boxer, Celgene/BMS, Celsius Therapeutics, Connect BioPharma, Cytoki Pharma, Disc Medicine, Duality, EcoR1, Eli Lilly and Company, Equillium, Ermium Therapeutics, First Wave BioPharma, First Word Group, Galapagos NV, Galen Atlantica, Genentech/Roche, Gilead Sciences, Gossamer Pharma, GlaxoSmithKline, Hinge Bio, Hot Spot Therapeutics, InDex Pharma, Imhotex, Immunic Therapeutics, JAKAcademy, Janssen, Japan Tobacco, Kaleido Biosciences, Landos Biopharma, Leadiant, L.E.K. Consulting, Lenczner Slaght, LifeSci Capital, Lument AB, Millennium Pharmaceuticals, 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 Therapeutics, PTM Therapeutics, Q32 Bio, Rebiotix, Redx Pharma, Roche, Sandoz, Sanofi, Seres Therapeutics, Silverback Therapeutics, Surrozen Inc., Takeda, Teva, Thelium, Tigenix, Tillotts, Ventyx Biosciences, VHsquared, Viatris, Ysios, YSOPIA Bioscience, and Zealand Pharma; was on the speaker’s bureau: AbbVie, Janssen, and Takeda; member of the Scientific Advisory Board, DSMB for: AbbVie, Amgen, AMT, AnaptysBio, Axio Research, Boehringer Ingelheim, Celgene/BMS, Ecor1Capital, Eli Lilly and Company, Genentech/Roche, GlaxoSmithKline, InDex Pharma, Janssen, MiroBio, Morphic, Origo BioPharma, Pfizer, Progenity, Prometheus, Redx Pharma, Sanofi, Takeda, Tillotts Pharma, and Teva; stock shareholder of: Gossamer Pharma; and employee as Senior Scientific Director of: Western University and Alimentiv
• N. Harpaz advisory board member and/or consultant: AbbVie, Bristol Meyers Squibb, Eli Lilly and Company, and PathAI Inc
• T. Hisamatsu received lecture fees: AbbVie, EA Pharma, Gilead Sciences, Janssen Pharmaceutical K.K., JIMRO, Kyorin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer, and Takeda; received honoraria as an advisory board member or consultant: AbbVie, EA Pharma, Eli Lilly and Company, Gilead Sciences, Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma, Pfizer, and Takeda; and received pharmaceutical/research grants from: AbbVie, Alfresa Pharma, Daiichi Sankyo, EA Pharma, JIMRO, Kyorin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nichi-lko Pharmaceutical, Nippon Kayaku, Pfizer, Takeda, and Zeria Pharmaceutical
• G. D’Haens advisor: AbbVie, Agomab Therapeutics, Alimentiv, AstraZeneca, Biora, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Eli Lilly and Company, Exeliom Biosciences, Galapagos NV, Genentech/Hoffmann-La Roche, GlaxoSmithKline, Immunic Therapeutics, Johnson & Johnson, Merck Sharp & Dohme, Pfizer, Protagonist Therapeutics, Samsung Bioepis, Sandoz, Seres Therapeutics/Nestec/Nestlé, Takeda, Tillotts Pharma AG, Ventyx; received speaker fees: AbbVie, Johnson & Johnson, Takeda, Pfizer, Tillotts Pharma AG
• R. Pai received consulting fees: Alimentiv Inc, Allergan, and BRACCO
• Z. Lin, N. Morris, M. Protic, E. Hon, C. Owen, R. Escobar are employees and shareholders: Eli Lilly and Company
• W. Reinisch received lecture and consulting fees from and/or served as an advisory board member: AbbVie, Actelion, Alpha Wasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring Pharmaceuticals, Genentech, Grunenthal, Johnson & Johnson, Millennium, Merck, Novo Nordisk, Nycomed, Pfizer, Pharmacosmos, Schering-Plough, Salix Pharmaceuticals, Takeda, UCB Pharma, and Vifor Pharma

Introduction

The efficacy and safety of mirikizumab (miri) for moderately to severely active ulcerative colitis (UC) was demonstrated in the Phase 3 LUCENT trials (LUCENT-1 and -2; NCT03518086, NCT03524092). 1,2 Some patients may improve more slowly and require a prolonged course of induction before achieving clinical response. Therefore, we evaluated clinical response in patients who had not responded by the end of the 12-week(W) induction period and who received extended induction treatment for an additional 12W.

Aims & Methods

^​Patients not responding to intravenous (IV) administration of 300 mg miri every 4 weeks (Q4W) (n=272) at W12 (LUCENT-1), received extended 12-W induction treatment of open label 300 mg miri IV Q4W for 3 additional doses (LUCENT-2). Patients responding at W24 (n=144) of continuous IV treatment, entered open label maintenance and received 200 mg miri Q4W subcutaneously (SC) until W52. Key outcomes through 52W are reported (Definitions in Table).

Results

Among the 272 patients who failed to achieve a clinical response after 12W of induction treatment, 72.4% had a Mayo endoscopic subscore of 3, indicating severe disease. Of these patients, 146 (53.7%) achieved a clinical response and 31 (11.4%) achieved clinical remission at W24. Of the 144 responders at 24W entering the open label maintenance study, 52 (36.1%) patients achieved clinical remission, 104 (72.2%) achieved clinical response, 62 (43.1%) achieved endoscopic remission and 60 (41.7%) patients achieved histologic improvement at W52. Furthermore, for these patients, there was a 3.8 (±2.7) point reduction from baseline in bowel urgency (BU) severity and 58.8% achieved clinically meaningful improvement in BU (defined as change from baseline in Urgency Numeric Rating Scale ≥3 in patients with Urgency Numeric Rating Scale ≥3 at induction baseline). Among these patients, 38.3% demonstrated treatment-emergent adverse events (TEAEs). Most TEAEs were mild (21.4%), while only 5.4% were serious. Overall, there was a 3.2% of discontinuation due to TEAEs. No new safety signals or deaths were reported.

Table: Clinical outcomes for the mirikizumab induction non-responder patient population at Weeks 12, 24 and 52 of extended induction

Outcomes for miri IV extended induction	W12 (end of induction) Miri induction non-respondersa N= 272	W24 (W12 extended induction) Miri induction non-respondersa 300 miri IV, Q4W N= 272	W52 (W40 extended induction) Miri induction non-respondersb 200 miri SC, Q4W N= 144
Symptomatic remissionc (NRI response) n, (%)	13 (4.8)	101 (37.1)	91 (63.2)
Clinical remissiond (NRI response) n, (%)	0	31 (11.4)	52 (36.1)
Clinical response (MMS)e (NRI response) n, (%)	0	146 (53.7)	104 (72.2)
Symptomatic responsef (NRI response) n, (%) HEMIg (NRI response) n, (%)	83 (30.5) 13 (4.8)	197 (72.4) 28 (10.3)	112 (77.8) 45 (31.3)
fCal change from baseline, [mBOCF; mean (SD)]	-1291.9 (5664.2)	-1638.8 (5558.9)	-2164.8 (4631.3)
CRP change from baseline, [mBOCF; mean (SD)]	-4.7 (11.5)	-4.5 (12.8)	-4.3 (10.4)
Endoscopic remissionh (NRI response) n, (%)	21 (7.7)	45 (16.5)	62 (43.1)
BU change from baselinei [mBOCF; mean (SD)]	-1.2 (2.2)	-2.5 (2.7)	-3.8 (2.7)
Abbreviations: BU=bowel urgency; CRP=C-reactive protein; fCal=faecal calprotectin; HEMI=histologic-endoscopic mucosal improvement; IV=intravenous; mBOCF=modified baseline observation carried forward; miri=mirikizumab; MMS= modified Mayo-Score; N=patient population; n=patient subpopulation; Nx=number of patients with Urgency Numeric Rating Scale ≥3 at induction baseline; NRI=non-response imputation; Q4W= every four weeks; SC=subcutaneous; W=weeks a The miri induction non-responder population only included patients who continued on to the maintenance trial (LUCENT-2) b Extended induction responders continued on 200 miri SC until W40 (52W of continuous treatment). Non-responders at extended induction W12 were discontinued. c Stool frequency =0 or stool frequency =1 with ≥1-point decrease in MMS from baseline; rectal bleeding=0 d stool frequency =0 or stool frequency =1 with ≥1-point decrease in MMS from baseline; rectal bleeding =0; and Endoscopic subscore =0 or 1 (excluding friability) e ≥2-point and ≥30% decrease in MMS from baseline; rectal bleeding =0 or 1 or, ≥1-point decrease from baseline f Symptomatic Response: defined as at least a 30% decrease from baseline in the composite clinical endpoint of the sum of stool frequency and rectal bleeding subscores g Endoscopic subscore=0 or 1 (excluding friability) + Geboes≤3.1 h Endoscopic subscore =0 or 1 (excluding friability); score ranges 0 to 4; a lower score indicates less mucosal damage i Change from baseline in Urgency Numeric Rating Scale score; range 0 to 10; a lower score indicates less severe bowel urgency

Conclusion

^​Among patients who did not initially respond to induction treatment with miri at 12W, 3 additional miri induction doses induced clinical response and remission in patients, highlighting the potential benefit of extended induction treatment with miri in those patients with more severe inflammation at baseline.

References

1. D’Haens et al., OP26: Efficacy and safety of mirikizumab as induction therapy in patients with moderately to severely active Ulcerative Colitis: Results from the Phase 3 LUCENT-1 study, Crohn's and Colitis, Vol. 16, Iss. Supplement_1, Jan. 2022, i028–i029
2. Dubinsky et al., 867e: Efficacy and safety of mirikizumab as maintenance therapy in patients with moderately to severely active Ulcerative Colitis: Results from the Phase 3 Lucent-2 study, Gastroenterology, Vol. 162, Iss. 7, S-1393-94

Disclosure

G. D’Haens has served as an advisor for: AbbVie, Ablynx, Active Biotech, Agomab Therapeutics, Allergan, AlphaBiomics, AM-Pharma, Amaken, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, AstraZeneca, Avaxia Biologics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb/Celgene, Celltrion, Cosmo Pharmaceuticals, Dr. Falk Pharma, DSM Pharma Solutions, Echo Pharmaceuticals, Eli Lilly and Company, enGene, Exeliom Biosciences, Ferring Pharmaceuticals, Galapagos NV, Genentech/Hoffmann-La Roche, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Immunic Therapeutics, Johnson & Johnson, Kintai Therapeutics, Lycera, Medimetrics, Medtronic, Merck Sharp & Dohme, Mitsubishi Tanabe Pharma, Mundipharma, Nextbiotics, Novo Nordisk, Otsuka, Pfizer, PhotoPills, ProciseDx, ProDigest, Progenity, Prometheus Laboratories/Nestlé, Protagonist Therapeutics, RedHill, Robarts Clinical Trials, Salix Pharmaceuticals, Samsung Bioepis, Sandoz, Seres Therapeutics/Nestec/Nestlé, Setpoint Medical, Shire, Takeda, Teva, TiGenix, Tillotts Pharma AG, Topivert, Versant and Vifor Pharma; and has received speaker fees from: AbbVie, Biogen, Ferring Pharmaceuticals, Galapagos NV/Gilead Sciences, Johnson & Johnson, Merck Sharp & Dohme, Millenium/Takeda, Mundipharma, Norgine, Pfizer, Samsung Bioepis, Shire, Tillotts Pharma AG and Vifor Pharma; P. Higgins has served as an advisor for: AbbVie, Arena Pharmaceuticals, Eli Lilly and Company, Genentech/Hoffmann-La Roche, Johnson & Johnson, Lycera and Pfizer; L. Peyrin-Biroulet has received consulting fees and/or grants and/or support for attending meetings and/or honoraria from and/or has participated on a data safety monitoring board or advisory board for: AbbVie, Alimentiv, Allergan, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly and Company, Enthera, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos NV, Genentech, Gilead Sciences, Gossamer Bio, InDex Pharmaceuticals, Inotrem, Janssen, Merck Sharp & Dohme, Mylan, Norgine, Ono Pharmaceutical, OSE Immunotherapeutic Pandion Therapeutics, Pfizer, Roche, Samsung Bioepis, Sandoz, Takeda, Theravance Biopharma, Thermo Fisher Scientific, Tillotts Pharma AG, Viatris and Vifor Pharma; and is a shareholder of: CTMA; B. E. Sands has served as a consultant 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 Scientific, Bristol Myers Squibb, Calibr/Scripps Research, Celltrion, ClostraBio, Connect Biopharma, Cytoki Pharma, Eli Lilly and Company, Enthera, Evommune, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos NV, Genentech, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Highlightll Pharma, HMP Acquisition, Imhotex, Immunic Therapeutics, InDex Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Ironwood Pharmaceuticals, Janssen, Johnson & Johnson, Kaleido Biosciences, Kallyope, Merck, MiroBio, Morphic Therapeutic, MRM Health, OSE Immunotherapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, RedHill, Sun Pharma, Surrozen, Synlogic Operating Company, Takeda, Target RWE, Theravance Biopharma, USWM Enterprises, Ventyx Biosciences and Viela Bio; and has stock options from: Ventyx Biosciences; S. Lee has received consulting fees and/or grants from: AbbVie, Applied Molecular Transport, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly and Company, Janssen and Protagonist Therapeutics; R. E. Moses, I. Redondo, R. Escobar and N. Morris are employees and shareholders of: Eli Lilly and Company; T. Kobayashi has received grants and/or contracts from: AbbVie, ActivAid, Alfresa Pharma, Bristol Myers Squibb, EA Pharma, Eli Lilly Japan K.K., Gilead Sciences, Google Asia Pacific, Janssen Pharmaceutical K.K., JIMRO, JMDC, Kyorin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Otsuka, Pfizer Japan K.K., Takeda and Zeria Pharmaceutical; has received lecture payments or honoraria from: AbbVie, ActivAid, Alfresa Pharma, Galapagos NV, Janssen Pharmaceutical K.K., JIMRO, Kyorin, Mitsubishi Tanabe Pharma, Nippon Kayaku, Pfizer Japan K.K., Takeda, Thermo Fisher Scientific and Zeria Pharmaceutical; has received payment for expert testimony from: AbbVie, ActivAid, Alfresa Pharma, EA Pharma, Janssen Pharmaceutical K.K., Kissei, Kyorin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Pfizer Japan K.K. and Takeda; and has participated on data safety monitoring boards or advisory boards for: Bristol Myers Squibb, EA Pharma, Eli Lilly and Company and Janssen.