Introduction

The evolution of therapy in Inflammatory Bowel Disease (IBD) has included multiple biologics and small molecule options in recent years. Despite this, treatment failure remains high. Combination immune therapies targeting different targets may improve outcomes. Safety profile of combination biologic therapies require further evaluation with a paucity of real-world use currently available.

Aims & Methods

Aim: To review dual biologic efficacy, safety and long-term outcomes in patients with refractory IBD.
Method: All patients with IBD receiving combination immune therapies, mainly biologics in two IBD centres and academic teaching hospitals in South of Ireland were reviewed. Eligible patients had confirmed IBD on combination biologic therapies. Efficacy outcomes were clinical, biomarker, endoscopic and histological response. Long-term outcomes included IBD flare, steroid use, change in therapy for disease activity, hospitalisation and colectomy.

Results

61 patients were treated with dual biologic therapies. 64% were Crohn’s disease (n=39), the median age at initiation of combination was 33y (range 17-84), median time since diagnosis and initiation of combination therapy was 7y (range 0-26). Indications for combination therapy included refractory IBD (94%), Active Extra-intestinal manifestations (EIM) (4%) and Active IBD and EIM (3%). Previous biologic or oral synthetic drug exposure was as follows; anti-TNF (100%), Vedolizumab (28%), Ustekinumab (36%) and Tofacitinib (8%). Median duration of follow-up was 10 months (range;1-42).Full data available for 6 months, clinical response within 12 weeks was observed in 52%. We performed sub-group analysis as per combination groups; Vedolizumab-Ustekinumab, Vedolizumab-Other(Infliximab, Adaliumab, Tofacitinib, filgotinib), Ustekinumab-Other and Miscellaneous for 6 months follow up as detailed in Table 1.
The 3 groups were similar in FCP and CRP( Kruskall Wallis test).

	Vedo-UST	Vedo-Other	UST-Other	Misc(IFX-Tofa)
Number of pts	26	29	13	1 – colectomy
Clinical response at 12 wks	11	17	6	0
Clinical remission at 6mo	5 ( n=10)	6 (n=22)	6 (n=6)	NA
FCP baseline (median)	1800	899	476	1900
FCP 6mo (median)	608 (n=13)	725 (n=22)	317 (n=6)	NA
CRP baseline(median)	20.0	5.0	9.65	1
CRP 6mo (median)	6.95 (n=13)	3 (n=22)	9.2 (n=6)	NA

Of 24 patients who completed 1- year follow-up, 66% achieved clinical remission within 1 year. For 2 year follow-ups (n=11) clinical remission was achieved in 36%, with median FCP of 307 and 3-year data (n=6) demonstrated clinical and endoscopic remission in 33% and median FCP of 378.
Adverse events were documented in 10 cases (16%). 7 hospitalisations due to worsening disease or complications: 3 IBD flare, 2 perianal sepsis, 1 hyponatraemia, and 1 influenza, with a median length of stay of 4 days. The remaining adverse events were non-serious infections; URTI, LRTI and gastroenteritis. There were no reports of malignancy during study follow-up. Four patients underwent surgery; 1 colectomy,1 EUA perianal abscess and 2 ileocolic resections. 18 patients (26%) discontinued combination therapy during study follow-up; 11 switched to alternative combination biologic therapy, 5 de-escalated to monotherapy and 2 underwent surgery.

Conclusion

Our real-world study suggests efficacy in achieving clinical improvement in difficult-to-treat cohort of patients. Our study did not demonstrate new serious/opportunistic infections or new/recurrent malignancies on combination therapy. Dual therapy may be an option for refractory IBD patients with limited therapeutic options.

Introduction

Perianal fistulizing Crohn’s disease (pfCD) is a debilitating phenotype that severely impacts quality of life (QoL). pfCD frequently implies a stepwise, combined medical and surgical treatment approach. Treatment goals are ideally individual and include improvement of QoL, however precise outcomes are not determined yet. Currently, most commonly used outcomes are clinical response/remission, and radiological healing, the latter most relevant to long-term disease remission.

Aims & Methods

The aim of this study was to evaluate QoL in pfCD and compare it with clinical and radiological outcomes after 26 weeks of treatment.
In this prospective exploratory, observational cohort (AMFIBIO), we included patients with pfCD starting on anti-TNF-α therapy, mesenchymal stem cell injection (MST), or hyperbaric oxygen therapy (HBOT) combined with surgical closure. We collected patient-reported IBD-specific (IBDQ-32) and fistula-specific (CAF-QoL) QoL outcomes. MAGNIFI-CD (remission defined as MAGNIFI-CD ≤6), perianal disease activity index (PDAI; response defined as ≤4) and fistula drainage assessment (FDA) were evaluated at baseline and week 26. Paired T tests were used to analyze changes in QoL, clinical and radiological scores. Pearson’s correlation coefficients were used to correlate changes between the outcomes.

Results

Twenty-one patients were analyzed at week 26 (Table 1). Mean change between baseline and week 26 in CAF-QoL and IBDQ-32 was 13 (95%CI 3 – 23) and 9 (95%CI -5 – 24) respectively. FDA correlated moderately with improvement in CAF-QoL (ρ=0.59; 95%CI 0.19 – 0.82), and moderately with improvement in IBDQ-32 (ρ=0.49; 95%CI 0.04 – 0.77). Improvement in CAF-QoL (ρ=0.31; 95%CI -0.20 – 0.69) and IBDQ-32 (ρ=0.35; 95%CI -0.16 – 0.72) did not correlate with improvement in PDAI, nor with PDAI response (resp. ρ=0.38; 95%CI -0.009 – 0.71, and ρ=0.40; 95%CI -0.08 – 0.72). No correlation was seen between changes in CAF-QoL and MAGNIFI-CD (ρ=0.08; 95%CI -0.39 – 0.52), or MRI remission (ρ=0.22; 95%CI -0.26 – 0.61).

Table 1. Patient and fistula characteristics (n=21)

Age (years) at baseline, mean (95%CI)	34.7 (28.5 – 40.9)
Female, n (%)	16 (76)
Caucasian, n (%)	16 (76)
Crohn’s disease duration (years), mean (95%CI)	8.8 (3.3 – 14.3)
Perianal disease duration (years), mean (95%CI)	37.1 (3.3 – 10.8)
Perianal fistula classification (Geldof et al.), n (%)	2a: 11 (52) 2b: 8 (38) 2c-ii: 2 (10)
Therapy during study, n (%)	anti-TNF: 10 (48) MST: 6 (29) HBOT: 5 (24)
SES-CD at baseline, median [IQR]	2 [0 – 7.5]
CAF-QOL at baseline, mean (95%CI)	58.1 (51.0 – 65.2)
IBDQ-32 at baseline, mean (95%CI)	145.1 (130.7 – 159.4)

Conclusion

IBD- and fistula-specific Quality of Life scores improve after therapy at week 26 in patients with pfCD. This improvement correlates with fistula drainage assessment, however it does not correlate with PDAI and MRI outcomes.

Disclosure

LM, KB, JT and RvH have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this abstract. CB has received grants from Boehringer Ingelheim and Roche; speakers honoraria from AbbVie, Janssen, Galapagos, Takeda, and Tillotts. JS is President-elect of the European Society of Gastrointestinal and Abdominal Radiology. GD has served as consultant for AbbVie, Astrazeneca, Alimentiv, Bristol-Myers Squibb, Boehringer Ingelheim, Celltrion, Cosmo, Eli Lilly, Galapagos, GSK, Johnson and Johnson, Takeda, Pfizer Inc, Polpharma, Prometheus Biosciences, Tillotts and Ventyx; received speaker fees from AbbVie, Boehringer Ingelheim, Celltrion, Eli Lilly, Johnson and Johnson, Takeda, Pfizer Inc and Tillotts. KG has received grants from Pfizer Inc, Celltrion and Galapagos; consultancy fees from AbbVie, Arena Pharmaceuticals, Galapagos, Gilead, Immunic Therapeutics, Janssen Pharmaceuticals, Novartis, Pfizer Inc., Samsung Bioepis and Takeda and speaker’s honoraria from Celltrion, Ferring, Janssen Pharmaceuticals, Novartis, Pfizer Inc, Samsung Bioepis, Takeda and Tillotts.

Introduction

Despite new therapeutic strategies, substantial proportion of patients with ulcerative colitis (UC) undergo colectomy at some point. Restorative proctocolectomy with ileal pouch ano anastomosis (IPAA) is regarded as intervention of choice in these patients. However, the disease conversion to Crohn´s disease (CD) is reported in up to one third of these patients who necessitate immune suppressive treatment after IPAA. Considering the life-long need for immune suppressive therapy in these patients, ileo-rectal anastomosis (IRA) would represent a good alternative to IPAA in this specific group of patients. Todate, no data are available to predict the UC-CD conversion. One of the possibility to reduce the risk of performing IPAA in patients developing CD in pouch is to use the modified two-stage proctocolectomy approach and identify patients who develop CD endoscopically between colectomy and the restoration of continuity.

Aims & Methods

The aim of the present study was to assess the UC-CD conversion rate identified prior IPAA via ileoscopy.
All patients with UC operated in one tertiary IBD center between 2016 and 2021 were identified in medical records. The main outcome was CD detected at ileoscopy between the first stage operation, i.e. total colectomy with terminal ileostomy and the restoration of continuity either via IPAA or IRA. The ileoscopy was performed between three to six months after colectomy. The secondary outcome was the rate of conversion to CD after IPAA or IRA.

Results

Sixty patients underwent total colectomy (mean age 41 years, range 22-77; 62% were men); seven patients were lost to follow-up, finally the data from 53 patients were analysed. The majority of these patients (36 - 68%) underwent colectomy for therapy resistent chronically active UC, 9 (17%) patients for acute severe UC, 2 patients had benign colonic stenosis, 5 had high-grade dysplasia or colorectal cancer detected at surveillance colonoscopy and one patient had extensive pseudopolyposis.
All resection specimen were reviewed and no histopathological features of CD were found. Three out of the 53 (6%) ileoscopically assessed patients prior IPAA or IRA were diagnosed with CD in prestomal terminal ileum. During the further follow-up, additional 4 patients developped CD, two after IPAA, one with definitive ileostomy in prestomal ileum and one in neoterminal ileum after IRA.
In total 7 out of 53 patients in this cohort developped CD (13%). Using the two stage approach with ileoscopy between colectomy and restoration of continuity, three out of these seven patients with CD convertion in this cohort were detected prior the decision on the type of second-stage operation.

Conclusion

The conversion from ulcerative colitis to Crohn`s disease occurs in a significant proportion of IBD patients after colectomy. Ileoscopy performed between the two stages of restorative proctolectomy is helpfull in detecting these patients and guiding the decision on the type of surgical intervention to restore continuity.

Disclosure

Nothing to disclose.

Introduction

Perianal fistulas occur in up to 30% of patients with Crohn’s disease (pfCD) and frequently require a combined medical and surgical treatment approach. Hyperbaric Oxygen Therapy (HBOT) has previously shown benefit in treatment-refractory pfCD.

Aims & Methods

In this pilot study, we aim to assess the feasibility of surgical fistula closure 4 weeks after HBOT, and efficacy of combining surgical closure and 8 weeks HBOT.
Patients with complex pfCD refractory to at least 6 months of anti-TNF therapy were included in this study. All patients received a seton prior to starting treatment with 40 sessions (8 weeks) of HBOT (each lasting 110 minutes, with 5-minute air breaks) with 100% oxygen at 2.4 atmosphere. At week 4 the seton was removed, and surgical closure of the internal fistula opening was attempted. All patients continued stable dose of medical treatment during the study. Response was assessed by the fistula drainage assessment (FDA) and the perianal disease activity index (PDAI) at week 9, 26 and 52, and by pelvic MRI at week 9 and 26. MRI response was defined as a decrease of 2 points in MAGNIFI-CD score, MRI remission as a MAGNIFI-CD ≤6. (Serious) Adverse Events (AE) were reported for 52 weeks. Univariate logistical regression was used to explore potential variates associated with PDAI response (≤4) at week 26.

Results

Ten patients completed treatment and were analyzed (Table 1). All patients completed HBOT and underwent a technically successful surgical procedure at week 4. No proctitis was encountered at week 4 during examination under anesthesia. PDAI response was achieved by 30%, 60%, 58% at week 9, 26 and 52, respectively. FDA response/remission was achieved in 50%/20%, 80%/40% and 80%/50% of patients at week 9, 26 and 52, respectively. MRI response/remission was achieved in 60%/10% and 60%/20% of patients at week 9 and 26, respectively. No significant parameters were associated with PDAI response at week 26 in univariate logistical regression. (S)AEs included one patient with a potential oxygen toxicity seizure without long term effects, and one patient reported claustrophobia, no new AEs were reported.

Table 1 Patient and fistula characteristics (n=10)

Age (years), mean (95%CI)	30.5 (23.7 – 27.3)
Female, n (%)	9 (90)
Crohn’s disease duration (years), median [IQR]	9.0 [1.8 – 14,5]
Perianal disease duration (years), median [IQR]	3.5 [1.8 – 7.3]
Proctitis at baseline, n (%)	2 (20)
Internal fistula openings, n (%)	1: 7 (70) 2: 3 (30)
Primary fistula location, n (%)	anterior: 3 (30) lateral: 3 (30) posterior: 4 (40)
Fistula tracts, mean (95%CI)	3.5 (2.8 – 6.3)
Previous fistula surgeries, mean (95%CI)	4.1 (2.5 – 5.7)
Perianal fistula classification (Geldof et al.; class 1 – 4b), n (%)	2a: 3 (30) 2b: 1 (10) 2c-i: 1 (10) 2c-ii: 5 (50)

Conclusion

HBOT is feasible in combination with surgical therapy in patients with complex pfCD refractory to anti-TNF therapy. Patients had long-lasting benefit of the combined treatment approach. Further translational data are currently analyzed to clarify mechanisms of action and to explore potential biomarkers for therapy response.

Disclosure

LM, KB, JT and RvH have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this abstract. JS is President-elect of the European Society of Gastrointestinal and Abdominal Radiology. GD has served as consultant for AbbVie, Astrazeneca, Alimentiv, Bristol-Myers Squibb, Boehringer Ingelheim, Celltrion, Cosmo, Eli Lilly, Galapagos, GSK, Johnson and Johnson, Takeda, Pfizer Inc, Polpharma, Prometheus Biosciences, Tillotts and Ventyx; received speaker fees from AbbVie, Boehringer Ingelheim, Celltrion, Eli Lilly, Johnson and Johnson, Takeda, Pfizer Inc and Tillotts. CB has received grants from Boehringer Ingelheim and Roche; speakers honoraria from AbbVie, Janssen, Galapagos, Takeda, and Tillotts. KG has received grants from Pfizer Inc, Celltrion and Galapagos; consultancy fees from AbbVie, Arena Pharmaceuticals, Galapagos, Gilead, Immunic Therapeutics, Janssen Pharmaceuticals, Novartis, Pfizer Inc., Samsung Bioepis and Takeda and speaker’s honoraria from Celltrion, Ferring, Janssen Pharmaceuticals, Novartis, Pfizer Inc, Samsung Bioepis, Takeda and Tillotts.

Introduction

Targeting mitochondrial function and oxidative stress is successful in animal models of IBD. NLRX1 is a mitochondrial associated protein upregulating mitochondrial metabolism: It reduces oxidative stress and decreases pro-inflammatory cell differentiation and cytokine release. NX-13 is a first-in-class, orally active, once-daily, gut-selective NLRX1 agonist with low systemic exposure in development for Ulcerative Colitis (UC). In three mouse models of IBD, NX-13 effectively activated NLRX1 to reduce inflammatory responses and disease severity. In two phase 1 studies (56 healthy subjects; 38 UC patients) NX-13 was well tolerated. Low systemic drug exposure relative to stool levels suggested a gut-selective drug distribution. Phase 1B topline results were reported previously¹. We now present data demonstrating target engagement and downstream effects consistent with the preclinical mechanism of action (MOA).

Aims & Methods

In this double-blind phase 1B trial, 36 patients with active UC (Total Mayo Score 4-10; Mayo endoscopic subscore 2-3) were randomly assigned to NX-13 250mg Immediate Release (IR), 500mg IR, 500mg Delayed Release (DR) or Placebo to be taken QD for 4 weeks. We report pharmacodynamic results based on expression of NLRX1 and downstream immunometabolic markers in colonic tissue samples collected at screening and week 4 of treatment. NLRX1 protein levels were measured by immunohistochemistry scored by a blinded pathologist, and immunometabolic markers were measured by qRT-PCR.

Results

All NX-13 treated groups showed target engagement through mean positive increases in NLRX1 expression versus placebo at week 4, with more pronounced upregulation observed in responding patients (Table 1A). Gene expression profiles after 4 weeks of treatment showed upregulation of the mitochondrial metabolism gene MT-ND3, with downstream reductions in HIF1α and NLRP3 in the NX-13 IR groups but not in the placebo group (Table 1B). NX-13 250mg IR dosed patients also displayed downstream decreases in IL-17α and IL-1β gene expression, and the 500mg IR group showed reduction in IL-1β. Changes in NLRX1 expression and immunometabolic markers correlated with clinical response to NX-13 and were numerically greater in responding IR-dosed patients compared to non-responding patients (Table 1).

A. Immunohisto-chemistry	Definition	Subgroup	Placebo (n=2)		NX-13 250mg IR (n=8)		NX-13 500mg IR (n=8)		NX-13 500mg DR (n=8)
NLRX1 Composite Score Change from Baseline	Mean (Standard Error) of 4-point score accounting for NLRX1 intensity and number of positive cells in the epithelium and lamina propria	Responder	n/a	n/a	0.54	(0.36)	2.58	(0.46)	1.42	(0.68)
		Non-responder	-0.38	(0.38)	0.25	(0.25)	1.35	(0.84)	0.7	(0.76)
B. Gene Expression	Definition		Placebo (n=1)		NX-13 250mg IR (n=7)		NX-13 500mg IR (n=6)		NX-13 500mg DR (n=5)
MT-ND3	Median (Interquartile Range) fold change over baseline expression	Responder	(n/a)	(n/a)	1.37	(1.2-1.54)	1.52	(1.14-1.90)	n/a	n/a
		Non-responder	0.71	(n/a)	0.86	(0.45-1.28)	1.04	(0.96-1.14)	0.76	(0.34-1.68)
HIF1α		Responder	(n/a)	(n/a)	0.74	(0.53-0.81)	0.83	(0.80-0.86)	n/a	n/a
		Non-responder	1.06	(n/a)	2.18	(1.07-3.29)	0.95	(0.55-1.5)	1.11	(0.69-2.50)
NLRP3		Responder	(n/a)	(n/a)	0.65	(0.58-0.88)	0.59	(0.56-0.62)	n/a	n/a
		Non-responder	1.26	(n/a)	1.89	(1.28-2.50)	0.92	(0.30-2.04)	1.35	(0.64-2.34)

Conclusion

Treatment with NX-13 induced upregulation of its target, NLRX1, as well as downstream immunometabolic signaling consistent with preclinical MOA studies. Most importantly, target engagement parallels clinical benefit. This novel mechanism of action warrants further study and is currently being evaluated in a phase 2 proof of concept study (NCT05785715).

References

¹ L Peyrin-Biroulet, S Danese, J F Colombel, F Rieder, A Yarur, B Verstockt, S Lichtiger, R Mosig, F Cataldi, B Feagan, P577 A Phase 1b Study to Evaluate Safety, Tolerability, Pharmacokinetics and Clinical Efficacy of the Nucleotide-binding oligomerization domain, Leucine rich Repeat containing X1 (NLRX1) agonist NX-13 in Ulcerative Colitis, Journal of Crohn's and Colitis, Volume 17, Issue Supplement_1, February 2023, Pages i705–i706

Disclosure

BV - AbbVie, Alimentiv, Applied Strategic, Atheneum, Biora Therapeutics, Biogen, Bristol Myers Squibb, Celltrion, Chiesi, Falk, Ferring, Galapagos, Guidepont, Inotrem, Ipsos, Janssen, MSD, Mylan, Pfizer, Progenity, R-Biopharm, Sandoz, Sossei Heptares and Takeda, Tillots Pharma, Truvion and Viatris;
SV - grants from: AbbVie, J&J, Pfizer, Takeda and Galapagos, consulting / speaking fees from: AbbVie, Abivax, AbolerIS Pharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim, Celgene, CVasThera, Cytoki Pharma, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Lilly, Materia Prima, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillots Pharma AG, Zealand Pharma;
BS - consultant for AbbVie, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Falk, Janssen, Lilly, Pfizer, PredictImmune and Takeda; and received speaker’s fees from AbbVie, BMS, CED Service GmbH, Falk, Ferring, Janssen, Pfizer and Takeda (served as representative of the Charité);
FR - Adnovate, Agomab, Allergan, AbbVie, Arena, Boehringer-Ingelheim, Celgene/BMS, CDISC, Celsius, Cowen, Ferring, Galapagos, Galmed, Genentech, Gilead, Gossamer, Granite, Guidepoint, Helmsley, Horizon Therapeutics, Image Analysis Limited, Index Pharma, Jannsen, Koutif, Mestag, Metacrine, Mopac, Morphic, Organovo, Origo, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Sanofi, Surmodics, Surrozen, Takeda, Techlab, Teva, Theravance, Thetis, UCB, Ysios, 89Bio;
SL – owns Landos Stock;
RM – employee of Landos;
FC – employee of Landos;
SD - AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals Inc., Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB Inc., Vial, Vifor;

Introduction

Despite the increasing incidence of Crohn’s disease (CD), its early immune disturbances have not been described yet. The preclinical period provides an opportunity to gain insight into the initial processes involved in the pathogenesis of the disease.

Aims & Methods

The main aim of our study was to describe how the subclinical inflammatory process is modifying the individual’s immunologic environment while the patient is still on preclinical period. We analysed scRNASeq data from peripheral blood mononuclear cells (PBMC) of patients with incidentally-diagnosed CD according to ECCO criteria during the colorectal cancer screening programme, after histologic confirmation. Their gene expression profile was compared to healthy individuals acquired from publicly available datasets. The analytical pipeline included merging of the datasets followed by batch correction concerning integration from different studies, quality control and filtering, and finally cell-type annotation and differential gene expression analysis.

Results

Two patients with CD (mean age 53,5 years) and 2 healthy controls were included. We observed distinct transcriptomic profile in preclinical patients compared to controls, with small intragroup differences. The cell-type annotation identified B cells (B), CD4+ and CD8+ T-cells (CD4T, CD8T), dendritic cells (DC), monocytes (Mono) and natural killer cells (NK). The analytical pipeline included 17,021 cells (B:3,274, CD4T:5,798, CD8T:3,476, DC:315, 2, Mono:928, NK:3,230) and 3000 quantified genes. Considering each cell type individually, we identified 49 differentially expressed genes (DEG) between CD patients and controls (B:39, CD4T:37, CD8T:41, DC:42, Mono:37, NK:37), from which 30 were DEGs in all cell types.
Building on the list of 49 detected DEGs, we report three insights into the preclinical period of the disease.
First, pathway analysis revealed significant enrichment of the pathway that is related to immunoregulatory interactions between lymphoid and non-lymphoid cells, and functional annotation analysis identified gene products that are related to immunological defense. Second, we identified significant transcriptomic alterations in genes that have previously been related to the symptomatic phase of IBD, or reported as potential biomarkers. Third, after performing principal component analysis we observed greater separation between the patients groups in the CD8T cells compared to the other cell-types.

Conclusion

This study reveals the initial transcriptomic profiles and the main pathways that precede the onset of symptomatic inflammatory bowel disease. Our findings may help in identifying potential targets for early disease intervention.

Introduction

PRA023 is a humanized monoclonal antibody against tumor necrosis factor–like cytokine 1A (TL1A), a key pro-inflammatory cytokine and pro-fibrosis regulator, in development for inflammatory bowel diseases. In a phase 2 double-blind, placebo-controlled study (ARTEMIS-UC) assessing the efficacy and safety of PRA023 induction treatment in adults with moderately to severely active ulcerative colitis (UC), a significantly greater proportion of patients who received PRA023 achieved the primary endpoint of clinical remission after 12 weeks. This post hoc analysis assessed the impact of PRA023 on health-related quality of life using the Inflammatory Bowel Disease Questionnaire (IBDQ-32).

Aims & Methods

Adults with a modified Mayo score of 4 to 9, centrally read endoscopy subscore of ≥2, rectal bleeding subscore of ≥1, and history of insufficient response, loss of response, and/or intolerance to conventional and/or advanced therapies (≤4 advanced agents from ≤3 classes allowed) were stratified by prior biologic exposure and genetic-based diagnostic status and randomized 1:1 to placebo or intravenous PRA023 (1000 mg on day 1, and 500 mg at weeks 2, 6, and 10). IBDQ outcomes measures include: IBDQ response (score of ≥16-point from baseline), IBDQ remission (total score ≥170), and mean change from baseline in total and domain scores after 12 weeks of induction therapy. Score changes from baseline were compared among treatment groups, and the impact of prior advanced therapy exposure on IBDQ remission was assessed. Higher scores represent better quality of life.

Results

Of the 135 patients in the study, 60/67 (89.6%) in the placebo arm and 68/68 (100%) in the PRA023 arm completed the 12-week induction period. Baseline characteristics were similar between the treatment groups. Significantly greater proportions of patients in the PRA023 group achieved IBDQ response (82.4% PRA023 vs 49.3% placebo, ∆33.1%, p<0.0001) and IBDQ remission (51.5% PRA023 vs 19.4% placebo, ∆32.1%, p=0.0001) at week 12. Prior advanced therapy use did not affect the placebo-adjusted proportion of patients experiencing IBDQ remission in those who received PRA023 (Δ34.4% vs Δ30.0%, respectively, for prior and no prior advanced therapy). The total IBDQ score and all IBDQ domain subscores (bowel symptoms, systemic symptoms, emotional function, and social function) were significantly improved after 12 weeks of PRA023 induction treatment compared to placebo (Table 1).

Table 1. Inflammatory Bowel Disease Questionnaire (IBDQ) Outcomes with PRA023 Induction Therapy

IBDQ outcomes	Placebo	PRA023	% Difference vs placebo (95% CI)	P value
IBDQ response (%, n/N)†‡	49.3 (33/67)	82.4 (56/68)	33.1 (17.2–46.8)	<0.0001
IBDQ remission (%, n/N)‡	19.4 (13/67)	51.5 (35/68)	32.1 (16.0–45.9)	0.0001
-Prior advanced therapy	18.8 (6/32)	53.1 (17/32)	34.4 (10.9–53.1)	-
-No prior advanced therapy	20.0 (7/35)	50.0 (18/36)	30.0 (7.8–48.4)	-
Change in IBDQ scores from BL, mean±SD -Total score	20.8±37.59	48.6±34.85	26.8 (14.6–38.9)	<0.0001
-Bowel symptoms subscore	7.1±12.27	17.2±11.79	9.4 (5.3–13.4)	<0.0001
-Systemic symptoms subscore	3.0±5.97	7.0±6.56	4.0 (2.0–6.0)	0.0002
-Emotional function subscore	6.6±14.59	16.1±13.25	8.9 (4.3–13.5)	0.0002
-Social function subscore	4.1±7.74	8.2±7.38	4.4 (2.0–6.8)	0.0004

^†Prespecified secondary endpoint.
^‡Nonresponder imputation was applied to response and remission endpoints.
Abbreviations: BL, baseline; IBDQ, Inflammatory Bowel Disease Questionnaire.
P values are nominal except IBDQ response.

Conclusion

PRA023 significantly improved quality-of-life measures in patients with moderately to severely active UC, regardless of prior advanced therapy use. The greatest benefits were reported in the bowel symptoms and emotional function domains.

Disclosure

LPB has served as a consultant for or has received fees from AbbVie, Allergan, Alma, Amgen, Applied Molecular Transport, Arena, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Eli Lilly and Company, Enterome, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, Hikma, Index Pharmaceuticals, Inotrem, Janssen, MSD, Mylan, Oppilan Pharma, OSE Immunotherapeutics, Nestlé, Norgine, Roche, Pandion Therapeutics, Pfizer, Pharmacosmos, Samsung Bioepis, Sandoz, sterna biologicals, Sublimity Therapeutics, Takeda, Theravance Biopharma, Tillotts Pharma, and Vifor; has received grants from AbbVie, Fresenius Kabi, MSD, and Takeda; and has stock options from CTMA.
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.
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.
DTR has served as a consultant for AbbVie, AltruBio, Aslan Pharmaceuticals, Athos Therapeutics, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Chronicles, Corp/Syneos, ClostraBio, Connect Biopharma, Eco R1, Eli Lilly and Company, Genentech/Roche, Gilead Sciences, Iterative Health, Janssen Pharmaceuticals, Kaleido, Pfizer, Prometheus Biosciences, Reistone Biopharma, Seres Therapeutics, Takeda, Target RWE, and Trellus Health and has received grant support from Takeda, Helmsley Charitable Trust, and the Gastro-Intestinal Research Foundation.
DDN, QD, AM, and BD are employees and shareholders of Prometheus Biosciences.
CM has received consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma, BIOJAMP, Bristol Myers Squibb, Celltrion Healthcare, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Takeda, Pendopharm, Pfizer, Prometheus Biosciences, Roche, and Sanofi; speaker's fees from AbbVie, Amgen, AVIR Pharma, Alimentiv, Bristol Myers Squibb, Ferring, Fresenius Kabi, Janssen, Takeda, Pendopharm, and Pfizer; royalties from Springer Publishing; and research support from Ferring and Pfizer.
TER has been a speaker for Takeda Pharmaceuticals, Janssen, Pfizer, Bristol Myers Squibb, and Abbvie; has served on advisory boards for AbbVie, Ardelyx, Arena, Boehringer Ingelheim, Bristol Myers Squibb/Celgene, Eli Lilly and Company, Ferring, Genentech/Roche, Gilead, Intercept, Iterative Scopes, Janssen, Pfizer, Prometheus Biosciences, Sanofi, and Takeda; and has been a shareholder for Iterative Scopes.
RP has been a consultant for Abbott, AbbVie, Abivax, Alimentiv (formerly Robarts), Amgen, Arena, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly and Company, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, GSK, BIOJAMP, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda, Theravance Biopharma, Trellus, Viatris, Ventyx, and UCB; has received speakers fees from AbbVie, Amgen, Arena, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Merck, Organon, Pfizer, Roche, Sandoz, Shire, and Takeda; and has served on advisory boards for AbbVie, Alimentiv (formerly Robarts), Amgen, Arena, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, GSK, BIOJAMP, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Shire, Sublimity Therapeutics, Takeda, and Ventyx.