Introduction

Bowel urgency (BU) is a bothersome symptom experienced by patients with ulcerative colitis (UC) and is associated with high clinical and quality-of-life burdens. Mirikizumab (MIRI), an anti-IL-23 antibody approved for the treatment of moderately-to-severely active UC, significantly reduced BU severity compared with placebo (PBO), and these improvements were associated with better clinical outcomes.¹ We evaluated the association between incremental improvement in BU severity at Week (W)12 and W52 with other patient-reported outcomes for MIRI-treated patients.

Aims & Methods

In LUCENT-1 (induction), patients were randomized 3:1 to intravenous MIRI 300 mg or PBO every 4 weeks (Q4W) for 12W. MIRI responders during induction were re-randomized 2:1 to subcutaneous MIRI 200 mg or PBO Q4W for 40W in LUCENT-2 (52W of continuous treatment). BU severity was measured using the Urgency Numeric Rating Scale ([UNRS] 0–10). Incremental improvement of BU severity was assessed as reduction of each single point of UNRS score from baseline (BL). The reduction of >7 points was pooled into one category due to sample size. The accumulative benefit of reducing 1 additional point of UNRS score was evaluated at W12 and W52 and was assessed for its association with mean percent improvement in inflammatory bowel disease questionnaire (IBDQ) total score, fatigue NRS, short-form (SF)-36 mental component score (MCS) and physical component score (PCS), and work productivity activity impairment (WPAI) productivity loss.

Results

Significantly greater proportions of patients receiving MIRI achieved UNRS score reduction at certain points versus PBO at W12 and W52. The reduction of each single point of UNRS score was associated with improvement in patient’s physical and mental health, fatigue, work productivity, and quality of life. At W12, fatigue and IBDQ showed greater percent improvements among all the PRO outcomes studied for each 1-point reduction of UNRS. Similar results were observed at W52 (Table 1).

Week 12 (N=868)	UNRS reduction	Fatigue NRS	IBDQ Total Score	MCS	PCS	WPAIa	Week 52 (N=365)	UNRS reduction	Fatigue NRS	IBDQ Total Score	MCS	PCS	WPAIb
	≤0	-11.9	16.0	6.6	9.4	4.9		≤0	8.9	35.9	18.5	21.2	23.9
	1	15.4	25.9	14.6	11.3	16.9		1	5.8	30.6	13.4	12.7	11.2
	2	28.7	31.1	13.7	14.0	20.1		2	32.4	37.5	18.8	18.6	30.1
	3	43.5	35.8	17.9	16.9	24.1		3	59.5	33.9	10.8	20.4	27.5
	4	49.8	49.1	19.7	23.5	24.2		4	62.4	55.6	17.9	33.7	42.1
	5	54.5	43.3	13.1	22.9	28.8		5	52.2	54.0	21.7	27.7	38.2
	6	59.3	55.2	22.1	24.0	36.4		6	68.9	63.0	26.0	26.5	41.9
	7	81.2	64.6	25.9	30.1	29.8		7	83.8	67.3	30.1	30.1	50.6
	>7	73.6	75.4	29.7	39.1	38.5		>7	88.1	87.6	35.0	45.4	54.8

^a Note: N=532, population was restricted to patients with baseline employment status = Yes.
^b Note: N=224, population was restricted to patients with baseline employment status = Yes.
Abbreviations: IBDQ = inflammatory bowel disease questionnaire; MCS = short-form-36 mental component score; N = number of patients in the analysis population; n = number of patients in the specified category; NRS= numeric rating scale; PBO = placebo; PCS = short-form-36 physical component score; UNRS = urgency numeric rating scale; WPAI= work productivity activity impairment productivity loss.
UNRS score was averaged from daily diary entries for a 7-day period. Data were considered as missing for that week if less than 4 days were available.

Conclusion

Incremental improvement in bowel urgency corresponded to improvements in outcomes important to patients, underscoring the importance of managing BU symptoms in improving the quality of life for patients with UC.

References

1. Dubinsky MC, et al. Crohns Colitis 360 2023;5(1):otac044.

Disclosure

MD reports consultancy fees from AbbVie, Arena Pharmaceuticals, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Gilead Sciences, Janssen, Pfizer, Takeda, and UCB.
ST reports grants and/or research support from AbbVie, Buhlmann Diagnostics, Celgene, Eli Lilly and Company, the International Organization for the Study of Inflammatory Bowel Disease, Janssen, the Norman Collisson Foundation, Takeda, UCB, and Vifor Pharma; consulting fees from Abacus Pharmaceuticals, AbbVie, Actial, ai4gi, Alcimed, Allergan, Amgen, Arena Pharmaceuticals, Asahi Kasei Pharma, Astellas Pharma, AstraZeneca, Atlantic Pharmaceuticals, Barco, Biocare Pharma, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Buhlmann Diagnostics, Calcico, Celgene, Cellerix, Celsius Healthcare, Cerimon Pharmaceuticals, ChemoCentryx, Cisbio, Coronado Biosciences, Cosmo Pharmaceuticals, Ducentis BioTherapeutics, Dynavax, Elan Corporation, Eli Lilly and Company, Enterome, Falk Foundation, Ferring Pharmaceuticals, FPRT Bio, Giuliani, Genentech, Genzyme, GlaxoSmithKline, Glenmark Pharmaceuticals, Grünenthal, GW Pharmaceuticals, Immunocore, Immunometabolism, Indigo Biosciences, Janssen, Lexicon Pharmaceuticals, Medarex, Merck, MSD, Neovacs, Netbiotix, Novartis, Novo Nordisk, NPS Pharma, Ocera Therapeutics, Otsuka, Palau Pharma, Pentax Medical, Pfizer, Philips, Procter & Gamble, Pronota, Proximagen, Ptima Pharma, Receptos, Resolute, Robarts Pharmaceutical, Roche, Sandoz, Santarus, Sensyne Health, Shire, Sigmoid Pharma, SynDermix, Synthon, Takeda, Theravance Biopharma, TiGenix, Tillotts Pharma, TopiVert, TxCell, UCB, Vertex, VHsquared, Vifor Pharma, Warner Chilcott, and Zeria Pharmaceutical; and speaker fees from AbbVie, Amgen, Biogen, Falk Foundation, Ferring Pharmaceuticals, GlaxoSmithKline, Janssen, Shire, Takeda, and Zeria Pharmaceutical.
TK has served as a speaker, a consultant or an advisory board member for AbbVie, Ajinomoto Pharma, Asahi Kasei Medical, Astellas, Alfresa Pharma, Celltrion, Covidien, EA Pharma, Eisai, Eli Lilly, Ferring Pharmaceuticals, Gilead Sciences, Janssen, JIMRO, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Takeda Pharmaceutical, Thermo Scientific, Zeria Pharmaceutical, and received research funding from AbbVie, Alfresa Pharma, Asahi Kasei Medical, EA Pharma, Kyorin Pharmaceutical, Mochida Pharmaceutical, Nippon Kayaku, Otsuka Holdings, Sekisui Medical, Thermo Fisher Scientific, Zeria Pharmaceutical.
BA-B has served on advisory board for Bristol Myers Squibb, Pfizer; and reports speaker fees from AbbVie, Takeda, Bristol Myers Squibb, Janssen Pharmaceuticals.
JW, BZ, HQ, CM, SF are employees and minor shareholders of Eli Lilly and Company.
DR reports grant support from Takeda and has served as a consultant for AbbVie, AltruBio, Arena Pharmaceuticals, Bristol Myers Squibb, Eli Lilly and Company, Genentech, Gilead Sciences, Iterative Scopes, Janssen, Pfizer, Prometheus Biosciences, Roche, Takeda, and Techlab.

Introduction

The therapeutic goal in inflammatory bowel disease (IBD), which includes Crohn´s disease (CD) and ulcerative colitis (UC), is the control of the inflammatory process frequently through biologic and JAK-inhibitor therapies, which are generally expensive and can cause adverse effects. Unfortunately, only about one-third of patients respond to these treatments, and there are no markers that accurately predict this response.

Aims & Methods

The aim of this study was to identify potential serum and urinary metabolic biomarkers predictive of IBD response to different drugs at baseline (before treatment), which could facilitate the selection of the most appropriate therapy for each patient. For this purpose, a prospective multicenter study was conducted including CD and UC patients who initiated biologic (anti-TNF, ustekinumab or vedolizumab) or JAK-inhibitor (tofacitinib) therapies. Patients were assessed at 14 weeks to determine if they had achieved an endoscopic response, based on the SES-CD and on the endoscopic subscore of the Partial Mayo Score. The analyses of the serum and urine metabolome, along with the deconvolution of the serum lipoprotein profile, were performed using nuclear magnetic resonance for a quantitative differential analysis comparing the baseline serum samples of responders and non-responders.

Results

A total of 150 patients were included (30 CD anti-TNF, 30 UC anti-TNF, 30 CD ustekinumab, 30 UC vedolizumab and 30 UC tofacitinib). Metabolomic analysis identified 55 potential predictive biomarkers of IBD treatment response with significantly altered levels (p<0.05) in the baseline urine and serum samples of subsequent responders compared to non-responders. Among them, 44 were drug-specific and none were shared between serum and urine. Moreover, based on ROC curve analysis, some of these biomarkers showed good sensitivity and specificity for distinguishing between responders and non-responders before treatment (Table 1). Finally, the integrated metabolite set enrichment analysis of urine and serum samples identified distinct biological pathways associated with the response to each treatment for IBD, with common pathways highlighted, including the metabolism of short-chain fatty acids, the citrate cycle and the metabolism of amino acids such as alanine, aspartate, glutamate, and arginine.

Conclusion

The present study represents a step towards personalized medicine in the selection of targeted therapies for IBD patients, addressing an important unmet need. Although further validation is needed, we have identified serum and urinary metabolic biomarkers with the potential to predict response to biologic and JAK-inhibitor therapies.

Table 1. Summary of potential metabolic biomarkers identified as predictive of endoscopic response before each IBD treatment.

*Biomarkers with significantly altered levels (p<0.05) in baseline serum or urine samples of responders vs non-responders. **AUC corresponding to the biomarkers with the best sensitivity and specificity for distinguishing between responder and non-responder patients before treatment. AUC: Area Under the Curve calculated using the Metabolanalyst software in univariate analysis; CD: Crohn's disease; IBD: Inflammatory bowel disease; UC: Ulcerative colitis.

Introduction

Short bowel syndrome with intestinal failure (SBS-IF) is a severe organ failure condition associated with long-term parenteral support (PS) dependence. In the first years after resection, spontaneous intestinal changes occur. Previous studies have examined the effects of SBS-IF on microbiota composition (mainly fecal) and report an enrichment of facultative anaerobes. Analogs of the glucagon-like peptide-2 (GLP-2) have been introduced as disease-modifying treatments for SBS-IF and are hypothesized to boost intestinal adaptation in the host resulting in increased absorption and reduced PS needs. Apraglutide (APRA) is a novel, long-acting GLP-2 analog in development for SBS-IF. Here, we investigated the effect of APRA on microbiota composition after 4, 24, and 48 weeks (W) of treatment along the GI tract.

Aims & Methods

STARS Nutrition was a 52-W multicenter, open-label, phase 2 study in adult patients with SBS-IF and a colon-in-continuity (CiC) (Leuven n=7, Paris n=2) receiving weekly subcutaneous APRA injections. Biopsies of the duodenum, distal small bowel (if preserved), and sigmoid colon biopsies were collected at screening, 24 and 48W. In addition, fecal samples were collected at baseline and at 4, 24, and 48W. For baseline comparison, duodenal and sigmoid colonic biopsies from 10 control patients were collected. Relative (mucosa-associated and fecal) and quantitative (fecal, incl. pH, microbial load, moisture, calprotectin) microbiome profiling was performed.

Results

At baseline, per-subject microbiota analysis revealed that distal small bowel, sigmoid colon and stool samples from patients with SBS-IF-CiC were enriched in Lactobacillus, while duodenum harbored a distinct and variable microbiota. Compared to controls, the sigmoid colonic microbiota in SBS-IF-CiC showed a significantly lower richness (Wilcoxon rank-sum Benjamini-Hochberg (BH) corrected, p<0.001) and Inverse Simpson (Wilcoxon rank-sum BH corrected, p=0.0024). No significant differences in duodenal microbial composition between these groups were observed, but common colonic genera were enriched in the sigmoid biopsies from controls while in SBS-IF-CIC genera such as Lactobacillus, Sutterella, and Bifidobacterium were more dominant. APRA did not lead to significant changes in alpha-diversity, fecal pH, moisture, and calprotectin, but a trend towards increased microbial load was observed at 24W (ANOVA, p=0.07). Moreover, higher intra-subject dissimilarity in stool was observed and inter-subject variation decreased over time in sigmoid colon and stool. In addition, the abundance of Bifidobacterium decreased significantly in the sigmoid colon and feces. More location-specific changes included a lower abundance of Parabacteroides, Parasutterella, Sutterella in sigmoid colon and Fusobacterium and Streptococcus in stool. In contrast, Prevotella was significantly enriched in stool during APRA, which correlated negatively with fecal pH. Overall, Lactobacillus was still the most dominant taxa enriched in these locations.

Conclusion

This study was the first to assess the mucosa-associated and fecal microbiome in patients with SBS-IF-CiC in relation to GLP-2 analog therapy. Our results show that patients with SBS-IF-CiC present an immature sigmoid colonic and fecal ecosystem characterized by lactate producers. APRA treatment induced converging effects in the more distal locations, with an early shift towards more mature microbiota in some subjects, while still being highly dominated by Lactobacillus. Treatments targeting both host and microbiota should be explored.

Disclosure

This research was supported by VectivBio, now part of Ironwood Pharmaceuticals.
Astrid Verbiest, Daniel Ekhlas, Mira Stas, Lise De Meyere, Muriel Derrien, Jeroen Raes: Nothing to disclose.
Palle Bekker Jeppesen : PBJ has received grants/research support/honoraria or consultation fees from Albumedix A/S, ArTara Therapeutics, Bainan Biotech, Baxter, Coloplast, Ferring, Fresenius Kabi, GLyPharma, Naia Pharma, NPS Pharmaceuticals, Shire, Takeda, The Novo Nordisk Foundation, Therachon, VectivBio and Zealand Pharma.
Francisca Joly : FJ has received grants/research support/honoraria or consultation fees from Baxter, Fresenius Kabi, Nestlé Health Sciences, BBraun, Theradial, Mayoli, Biocodex, mobile3e Consulting, Carembouche, NPS Pharmaceuticals, Shire, Takeda, Therachon, VectivBio and Zealand Pharma.
Tim Vanuytsel : TV has served on the speaker bureau for Fresenius Kabi, Remedus, Takeda, and VectivBio. TV has provided clinical advice to Baxter, Shire, Takeda, VectivBio, Zealand Pharma. TV has received research grants from Takeda and VectivBio.

Introduction

Mirikizumab (miri), a humanized IgG4-variant monoclonal antibody that specifically binds to subunit p19 of interleukin-23, showed efficacy in phase (Ph)3 induction (LUCENT-1) and maintenance (LUCENT-2) studies involving patients with ulcerative colitis.¹
Here we report the efficacy and safety of the Ph3 LUCENT-2 study, a double-blind, randomized withdrawal maintenance study, in Chinese subpopulation who responded to miri induction therapy from LUCENT-1.

Aims & Methods

Miri clinical responders after 12-week induction therapy (54.3%)were re-randomized in a 2:1 ratio to receive blinded miri 200 mg or placebo (PBO) subcutaneously (SC) every four weeks (Q4W) for 40 weeks (Chinese primary efficacy population N=80). Randomization was stratified by biologic agent/tofacitinib failed status, induction remission status and baseline corticosteroid (CS) use.
The primary objective was to test the hypothesis that Miri was superior to PBO in achieving clinical remission at Week 40. Key secondary endpoints included alternate clinical remission, CS-free remission, endoscopic remission, histologic-endoscopic mucosal remission (HEMR), improvement in bowel urgency, bowel urgency remission, and maintenance of clinical remission. Analyses in Chinese subpopulation were descriptive.

Results

Baseline demographic and disease characteristics were generally balanced across the two treatment groups, including the proportion of baseline CS/ immunomodulator use, biologic agent/tofacitinib failure status and pancolitis.
A greater proportion of patients treated with miri achieved clinical remission at Week 40 (miri 50.0%, PBO 12.5%; Δ=40.4 [95% confidence interval (CI) 22.5, 58.4]). Miri also improved key secondary endpoints at Week 40 including proportion of patients who achieved alternate clinical remission (miri 55.4%, PBO 12.5%; Δ=45.4 [95%CI 27.3, 63.4]), and who achieved CS-free remission, clinical remission, bowel urgency remission and HEMR compared to PBO.
The frequencies of treatment-emergent adverse events were similar between groups in Chinese patients. There were fewer serious adverse events and discontinuations due to adverse events in miri patients compared to PBO. No deaths were reported in Chinese subpopulation during this study.

Conclusion

In Chinese patients who responded to miri induction therapy, miri's maintenance treatment provided positive efficacy and safety profiles consistent with LUCENT-2 overall population, supporting benefits of miri treatment in the Chinese ulcerative colitis patients.

Table 1: Primary and key secondary endpoints of LUCENT-2 at Week 40 in Chinese population (Miri Induction Respondersa)	Placebo SC N=24	Miri 200 mg SC N=56
Clinical Remissionb, n (%) Common risk difference vs placebo	3 (12.5)	28 (50.0) 40.4
Alternate Clinical Remission c, n (%) Common risk difference vs placebo	3 (12.5)	31 (55.4) 45.4
Corticosteroid-free Clinical Remissiond, n (%) Common risk difference vs placebo	2 (8.3)	26 (46.4) 40.2
Endoscopic Remissione, n (%) Common risk difference vs placebo	4 (16.7)	33 (58.9) 45
HEMRf, n (%) Common risk difference vs placebo	2 (8.3)	24 (42.9) 35.6
Bowel Urgency Improvement from BLg, LSM (SE) LSM difference vs placebo (SE)	-2.23 (0.47)	-4.52 (0.33) -2.29 (0.53)
Bowel Urgency Remissionh, n/N (%) Common risk difference vs placebo	1/24 (4.2)	23/52 (44.2) 41.4
Maintenance of Clinical Remissioni, n/N (%) Common risk difference vs placebo	0/8 (0)	11/18 (61.1) 60.6
Modified Intent-to-Treat population. BL = baseline (Week 0 of LUCENT-1 induction study); LSM = least squares mean; miri = mirikizumab; SC = subcutaneous; SE = standard error. aMiri induction responders: Patients who had clinical response to miri at Week 12 of LUCENT-1 (decrease in the modified Mayo score of ≥2 points and ≥30% decrease from baseline (BL); and decrease of ≥1 point in the Rectal Bleeding (RB) subscore from BL or a RB score of 0 or 1) after receiving 300mg IV miri every 4 weeks for 12 weeks. bClinical Remission: Stool Frequency (SF) = 0, or SF = 1 with a ≥1-point decrease from BL; RB = 0; Endoscopic Subscore (ES) = 0 or 1 (excluding friability). cAlternate Clinical Remission: SF subscore = 0, or SF = 1, and RB subscore = 0, and ES = 0 or 1 (excluding friability). dCorticosteroid-free Clinical Remission: Clinical remission at Week 40; Symptomatic remission at Week 28; No corticosteroid use for ≥12 weeks prior to Week 40. eEndoscopic Remission: ES = 0 or 1 (excluding friability). fHEMR (Histologic-endoscopic mucosal remission): Histologic remission with absence of mucosal neutrophils, defined using the Geboes scoring system with subscores of 0 for grades: 2b (lamina propria neutrophils); 3 (neutrophils in epithelium); 4 (crypt destruction); 5 (erosion or ulceration), and Endoscopic Remission. gBowel Urgency Improvement: Change from induction baseline in the Urgency Numeric Rating Scale (NRS). The Urgency NRS is a patient-reported measure of the severity for the urgency (sudden or immediate need) to have a bowel movement in the past 24 hours using an 11-point NRS ranging from 0 (no urgency) to 10 (worst possible urgency). hBowel Urgency Remission: Urgency NRS = 0 or 1 among patients induced into clinical response with miri in LUCENT-1 and had Urgency NRS ≥3 at induction baseline. iMaintenance of Clinical Remission: Clinical remission at Week 40 among patients induced into clinical remission with miri in LUCENT-1.

References

1. Geert D'Haens, Marla Dubinsky, Taku Kobayashi, et al. Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J Med. 2023 Jun 29;388(26):2444-2455.

Disclosure

Zhihua Ran, Jie Zhong, Chengdang Wang, Xiang Gao, Xiaolan Zhang, Yijuan Ding and Qian Cao have been investigators of Eli Lilly and Company; Dan Tang, Chenxi Qian, Jiao Yu are employees and minor stockholders of Eli Lilly and Company.