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Shaping immunity: Innovation trials in IBD

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Shaping immunity: Innovation trials in IBD

Vipul Jairath 1

1 Alimentiv Inc., London, Canada

Event

UEG Week Copenhagen 2023

Topics

IBD Mechanisms & Personalised Medicine

Session

Prediction of response in IBD

Published

2023

UEG Presentation

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ASSOCIATION OF HISTOLOGIC-ENDOSCOPIC RESPONSE AND LONG-TERM CLINICAL OUTCOMES: RESULTS FROM PHASE 2 MIRIKIZUMAB TRIAL IN PATIENTS WITH MODERATELY-TO-SEVERELY ACTIVE CROHN’S DISEASE

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Introduction

Mirikizumab (miri), an anti-IL-23p19 antibody, has shown efficacy in patients with moderately-to-severely active Crohn’s disease (CD) to Week (W)52. We explored the potential relationship between early histologic and endoscopic responses on long term clinical outcomes after 2 years of miri treatment in a double-blind, placebo (PBO)-controlled Phase 2 trial (NCT02891226) in patients with CD.

Aims & Methods

Patients were randomized 2:1:1:2 to 4 treatment arms: miri 1000mg, 600mg, 200mg, and PBO administered intravenously (IV) at W0, W4, and W8. Patients who received miri and achieved ≥1 point improvement at W12 in Simple Endoscopic Score for Crohn’s disease score were re-randomized to either continue their induction IV dose or receive miri 300mg subcutaneously (SC) every 4 weeks up to W52. Subjects reported to experience clinical benefit received 300mg SC from W52 to W104. Biopsies were obtained during endoscopy at W0, W12 and W52 from the edges of any ulcers or from the most inflamed mucosa in the terminal ileum and 4 colonic segments and were scored by blinded central readers. Endpoints were defined post-hoc and prior to analyses (see Table 1). Among patients receiving miri with active histological disease at baseline, we determined the relationship between histologic and/or endoscopic response or remission at W12 and W52 and with clinical remission based on the Crohn’s Disease Activity Index (CDAI), patient-reported outcomes (PRO), and hospitalization rates at W104. Non-responder imputation for CDAI or PRO at W104 was used for patients who have observed histologic and endoscopic outcome value at W52 or W12. Hospitalizations were summarized by observed value. P-values for categorical values were determined with Fisher’s exact test.

Results

At W104, 56.9% patients (N=137) achieved CDAI remission compared to 41.5% of 176 patients at W52. We observed no association between early (W12) histologic, endoscopic, or combined (histo-endo) response and clinical remission (CDAI & PRO) at 2 years. After 2 years, the percentage of patients achieving remission based on CDAI varied according to their response at W52 by histology (60%), endoscopy (25.9%), both histo-endo (56.3%), or neither (10.5%, p=0.006; Table 1). Similarly, the proportion of patients who achieved 2-year clinical remission (by CDAI) varied according to W52 remission by histology (72.7%), endoscopy (40%), both histo-endo (40%) or neither (19.5%, p=0.007). Hospitalization rates during this period were low and varied according to W52 response by histology (16.7%), endoscopy (0%), both (0%) or neither (3.9%, p=0.021).

Table 1. Week 104 clinical remission and hospitalization rates by histologic and endoscopic response at Week 12 and Week 52, and by histologic and endoscopic remission at Week 52

Week 104	Without Histologic or Endoscopic Response	Histologic and Without Endoscopic Response	Endoscopic response Without Histologic	Histologic and Endoscopic Response	P‑value	Without Histologic or Endoscopic Remission	Histologic Without Endoscopic Remission	Endoscopic Without Histologic Remission	Histologic and Endoscopic Remission	P‑value
	Week 12^a					Week 12
CDAI remission	60 (12/20)	57.9 (11/19)	50 (2/4)	61.3 (19/31)	>0.999	Due to the low number of patients with endoscopic or histologic remission at Week 12, no data are shown in this quadrant
PRO remission	55 (11/20)	31.6 (6/19)	50 (2/4)	61.3 (19/31)	0.237
Hospitalizations due to CD^b	0 (0/42)	3.9 (1/26)	0 (0/8)	3.2 (1/31)	0.426
	Week 52^c					Week 52^c
CDAI remission	10.5 (2/19)	60 (6/10)	25.9 (7/27)	56.3 (9/16)	0.006	19.5 (8/41)	72.7 (8/11)	40 (6/15)	40 (2/5)	0.007
PRO remission	10.5 (2/19)	30 (3/10)	11.1 (3/27)	68.8 (11/16)	<0.001	12.2 (5/41)	63.6 (7/11)	33.3 (5/15)	40 (2/5)	0.003
Hospitalizations due to CD^b	3.9 (1/26)	16.7 (2/12)	0 (0/39)	0 (0/24)	0.021	3.9 (2/52)	5 (1/20)	0 (0/24)	0 (0/5)	0.809
Note: Data displayed as % (n/N). For categorical outcomes, p-values are based on Fisher’s exact test. Histologic response was defined as: a) absence of neutrophils in epithelium, and absence of epithelial damage, erosions and ulceration or b) decrease of either RHI or modified GHAS ≥50% from baseline. Endoscopic response is defined as a 50% reduction from baseline in SES-CD. Histologic remission was defined as absence of mucosal neutrophils, epithelial damage, erosions, and ulceration. Endoscopic remission is defined as SES-CD of <4 ileal-colonic or <2 for isolated ileal disease, and no subscore of >1. CDAI remission is defined as CDAI Total Score <150; PRO remission is defined as (7-day average of SF ≤2.5 and no worse than baseline) + (7-day average of AP≤1 and no worse than baseline). SF captures number of liquid or very soft stools; AP score is classified as 0=none, 1=mild, 2=moderate, 3=severe. Abbreviations: AP= abdominal pain; CDAI= Crohn’s Disease Activity Index; GHAS= Global Histologic Disease Activity Score; PRO= patient-reported outcomes; N=number of patients in the histologic/endoscopic response group; n = number of patients in the specified category; RHI= Robarts Histologic Index; SES-CD=Simple Endoscopic Score for Crohn’s Disease; SF= stool frequency. ^a Patients with Active histologic disease at Baseline and with both Endoscopic and Histologic measures at Week 12. ^b Defined as serious adverse event due to hospitalization. Week 12 columns depict hospitalizations from Weeks 12-52. Week 52 columns depict hospitalizations from Weeks 52-104. ^c Patients with Active histologic disease at Baseline and with both Endoscopic and Histologic measures at Week 52.

Conclusion

In CD patients treated with miri for 2 years, long term clinical remission (CDAI, PRO) was significantly correlated with histologic response alone as well as combined histologic-endoscopic response at Week 52, but not at Week 12. The small sample size was likely a limitation. This data will be further studied in Phase 3 trials.

Disclosure

VJ reports consulting/advisory board fees from AbbVie, Alimentiv Inc (formerly Robarts Clinical Trials), Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Reistone Biopharma, Roche, Sandoz, Second Genome, Takeda, Teva, Topivert, Vividion; speaker’s fees from, Abbvie, Ferring, Galapagos, Janssen, Pfizer, Shire, Takeda, Fresenius Kabi. 
WR reports lecture fees from AbbVie, Actelion, Alpha Wasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grunenthal, Johnson & Johnson, Millennium, Merck, NovoNordisk, Nycomed, Pfizer, Pharmacosmos, Schering-Plough, Salix, Takeda, UCB Pharma, and Vifor; consultant fees from AbbVie, Actelion, Alpha Wasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grunenthal, Johnson & Johnson, Millennium, Merck, NovoNordisk, Nycomed, Pfizer, Pharmacosmos, Schering-Plough, Salix, Takeda, UCB Pharma, and Vifor; and serves as an advisory board member for AbbVie, Actelion, Alpha Wasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuticals, Ferring, Genentech, Grunenthal, Johnson & Johnson, Millennium, Merck, NovoNordisk, Nycomed, Pfizer, Pharmacosmos, Schering-Plough, Salix, Takeda, UCB Pharma, and Vifor.
GDH reports that his institution has received fees for his clinical trial activities with Centocor J&J.
NH has served as an advisory board member or consultant for Eli Lilly and Company, Abbvie Inc., Bristol Meyer Squibb, Inc., and PathAI, Inc.
RP reports consulting fees from Seres Therapeutics, Eli Lilly, Protagonist, Genentech, and Robarts Clinical Trials.
MP, ZL, RH, HC are employees and minor shareholders of Eli Lilly and company. 
FM served as speaker for Abbvie, Arena, Biogen, Bristol-Myers Squibb, Falk, Ferring, Hospira, Janssen, Laboratórios Vitoria, Pfizer, Lilly, Merck Sharp & Dohme, Sandoz, Takeda, UCB, Vifor.

ASSOCIATION OF HISTOLOGIC-ENDOSCOPIC RESPONSE AND LONG-TERM CLINICAL OUTCOMES: RESULTS FROM PHASE 2 MIRIKIZUMAB TRIAL IN PATIENTS WITH MODERATELY-TO-SEVERELY ACTIVE CROHN’S DISEASE

Vipul Jairath 1, Marijana Protic 2, Walter Reinisch 3, Gert De Hertogh 4, Noam Harpaz 5, Rish Pai 6, Zhantao Lin 2, Rebecca Hozak 2, Hilde Carlier 2, Fernando Magro 7

1 Western University, London, Canada

2 Eli Lilly and Company, Indianapolis, United States

3 Medical University of Vienna, Wien, Austria

4 University Hospital Leuven, Leuven, Belgium

5 Icahn School of Medicine at Mount Sinai, New York, United States

6 Mayo Clinic, Scottsdale, United States

7 Centro Hospitalar São João, Porto, Portugal

Event

UEG Week Copenhagen 2023

Topics

Endoscopy Histopathology IBD

Submission format

Abstract

Session

IL-23-Blockers in IBD: Part 2

Citation

United European Gastroenterology Journal 2023; 11 (Supplement 8)

Published

2023

UEG Poster

Standard Poster

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Introduction

Patients with ulcerative colitis (UC) are at an increased risk of cytomegalovirus (CMV) infection. CMV infection in acute severe ulcerative colitis (ASUC) may worsen disease severity and clinical outcomes. Current guidelines recommend colonic biopsies for the exclusion of CMV in all patients with ASUC. One study found that CMV positivity in ASUC was associated with greater need for rescue therapy, longer hospital length of stay (LOS) and higher readmission rates but found no difference in rate of colectomy.¹ We aimed to investigate the impact of positive CMV result on clinical outcomes in patients presenting with ASUC.

Aims & Methods

A retrospective review included all ASUC presentations to a quaternary hospital over a 10-year period based on modified Truelove and Witts’ criteria. ASUC presentations were grouped based on CMV positivity as determined by colonic biopsy. Data on pre-admission medications was collected. Data was collected on rates of rescue therapy, referral to colorectal surgery, colectomy, total parenteral nutrition (TPN). Outcomes assessed included intensive care unit (ICU) admission, 30- and 90-day readmission rates, 30- and 90-day mortality rates and mean LOS.

Results

A total of 172 ASUC presentations were identified. Of these, 133 had available colonic biopsy CMV results. 11 patients (8%) had positive CMV. Positive CMV result was significantly associated with increased need for TPN (36% vs 11%, p=0.02), ICU admission (27% vs 5%, p=0.004) and referral to colorectal surgery (82% vs 43%, p=0.01). Patients with CMV had longer LOS (27.1±14.0 vs 11.0±7.4, p=0.003). There were no significant differences in rates of rescue therapy, inpatient colectomy, readmission or mortality rates. 9 of the patients (82%) were treated with ganciclovir or valganciclovir. Patients on maintenance advanced UC therapies, including biologics and small molecule inhibitors, had significantly higher rate of CMV (22% vs 5%, p=0.01). Biologic therapy alone was associated with higher rate of CMV (24% vs 7%, p=0.02), whereas small molecule inhibitor alone was not (p=0.6). Pre-admission use of 5-aminosalicylates, high dose steroids, thiopurines or combination therapies were not associated with CMV positivity.

Table 1: Comparison data of clinical outcomes in ASUC between patients with and without CMV positivity on colonic biopsy

	CMV on biopsy		p-value
	Positive	Negative
Rescue therapy (n)	7 (64%)	44 (36%)	p=0.07
TPN (n)	4 (36%)	14 (11%)	p=0.02*
Referral to colorectal surgery (n)	9 (82%)	52 (43%)	p=0.01*
Inpatient colectomy (n)	3 (27%)	14 (11%)	p=0.13
ICU admission (n)	3 (27%)	6 (5%)	p=0.004*
Readmission at 90 days (n)	4 (40%)	23 (19%)	p=0.11
Mortality at 90 days (n)	1 (9%)	2 (2%)	p=0.11
Length of stay (days)	27.1 ± 14.0	11.0 ± 7.4	p=0.003*

Conclusion

Patients with CMV positive colonic biopsies tend to require more inpatient interventions, including increased need for TPN, ICU admission, referral to colorectal surgery and longer hospital length of stay. Despite more complex admission course of ASUC patients with concurrent CMV infection, these patients were not observed to have worse outcomes than those without CMV diagnosis. Maintenance biologic and small molecule inhibitor use was associated with higher rates of CMV, reflecting the immunosuppressant effects of advanced UC therapies. CMV detection needs to be considered as a potential exacerbating factor in disease severity.

References

1. Huang D, Rennie M, Krasovec A, Nagubandi S, Liu S, Ge E, Khehra B, Au M, Sivagnanam S, Kwan V, Rogge C, Mitrev N, Kariyawasam V. Impact of cytomegalovirus on outcomes in acute severe ulcerative colitis: a retrospective observational study. Ther Adv Chronic Dis. 2024 Mar 28;15:20406223241233203. doi: 10.1177/20406223241233203. PMID: 38560721; PMCID: PMC10981253.