Introduction

Ustekinumab has pioneered IBD treatment by targeting the p40 subunit shared by IL- 12 and IL-23, crucial cytokines in gut inflammation. Despite its lower binding affinity compared to more recent anti-IL-23 antibodies targeting the p19 subunit, ustekinumab achieves comparable remission rates in IBD. This unexpected efficacy likely stems from its dual action; IL-12 neutralization suppresses the initiation of new inflammatory gut lesions, while IL-23 inhibition maintains disease control (Eftychi et al., 2019). However, ustekinumab's sub-optimal binding affinity and immunogenicity (3-12% neutralizing ADA per Stelara Prescribing Information), presents clear opportunities to develop MVP-523 as a next-generation, bio-better therapeutic. Discovered 25 years ago, ustekinumab predates our current understanding of IBD pathology and antibody optimization techniques. Its sub-optimal performance characteristics present opportunities for improvement. Moreover, ustekinumab's extensive patient years of data and favorable safety profile make it an ideal template for next-generation drug development.

Aims & Methods

Computational protein design enabled by CCG Molecular Operating Environment and Epimatrix software.
Variants were expressed, purified and tested experimentally biochemically, in vitro cell models and in vivo in mice.

Results

Our optimization efforts have yielded MVP-523, featuring increased binding affinity/potency and reduced immunogenicity, while having the potential to extend halflife and dosing intervals. CDR amino acid substitutions in both heavy and light chains reduced KD from ~300 pM to ~50 pM, significantly improving IC50 in cell-based assays and enhancing in vivo IL-12 neutralization. Concurrently, computational protein design combined with EpiVax's ISPRI (Interactive Screening and Protein Reengineering Interface) was employed for in-silico deimmunization. This process successfully reduced the anti-drug antibody (ADA) score from 10.4% (which correlates with 3-12% observed clinically) to a predicted score of 1.5%. Considering that the majority of ustekinumab-induced ADAs are neutralizing, this substantial improvement could potentially lead to significantly enhanced outcomes in clinical trials and increased treatment durability.

Conclusion

MVP-523 represents a novel, bio-better therapeutic, built on ustekinumab's reliability and offers a de-risked clinical development candidate for IBD and other diseases. Furthermore, it provides an intriguing platform for engineering trispecifics (IL-12, IL-23, other target) while maintaining the preferred bivalent structure of classical IgG.

Disclosure

JHS BLB AFH are shareholders in Multiverse Pharma

Introduction

The prevention of postoperative recurrence (POR) after ileocolonic resection is one of the most relevant issues in the management of Crohn's disease (CD). The role of ustekinumab (UST) and vedolizumab (VEDO) especially in the context of real-life studies is still not entirely clear, often due to small sample sizes, thus requiring further investigation and confirmation.

Aims & Methods

Our real life single-centre retrospective study aims to evaluate the effect of UST and VEDO therapy on prophylaxis of endoscopic recurrence after ileo-colonic resection in CD. In the whole cohort UST or VEDO were used as first-line therapy for prophylaxis of recurrence. All patients (pts) underwent the first endoscopic evaluation within 6-12 months to assess postoperative recurrence (POR), using the Rutgeerts score and were subsequently evaluated at 24 (+-3) months with a second endoscopy. Persistence on therapy two years after the surgery was also evaluated.

Results

64 pts with a mean age of 38 years were included, 25 pts received VEDO (Cohort 1) and 39 UST (Cohort 2).
In the two cohorts, 89% and 91% of pts had been previously resected; 58% and 55% were active smokers. Notably, 100% had already been exposed to one or more biological drugs and the most frequent reason for surgery was the presence of stenosing disease in both cohorts.
In cohort 1, the first post-operative colonoscopy at 6-12 months showed severe POR (RS score >i2) in 28% of pts, all of whom underwent a treatment change at this time point (71% and 29% drug change and VEDO optimisation, respectively). Among the pts who continued the drug (22 pts), the second endoscopy performed at 24 (+-3) months showed severe ROP in 10% of pts, who underwent treatment modification. At ~2 years persistence on therapy in the cohort was 72%.
In cohort 2, the first post-operative colonoscopy at 6-12 months showed severe POR in 25.6% of patients, who changed therapy at this time. Among patients who continued the drug (29 pts), the second endoscopy performed at 24 (+-3) months showed severe POR in 10.3% of pts, who underwent treatment change. At ~2 years persistence on therapy in the cohort was 66.6%. No patients discontinued the drug due to adverse effects in both cohorts.
Comparing the two cohorts regarding severe endoscopic recurrence at 6-12 months and perisistence on therapy at ~2 years, no significant differences emerged between the two groups (p = 1.000, OR: 0.89,IC 95%: 0.29–2.75 and p = 0.86, OR:1.29, IC 95%: 0.43–3.85, respectively).

Conclusion

In our real life cohort of patients with complex CD, ustekinumab and vedolizumab showed high levels of persistence on therapy at ~2 years after surgery. Limited to the small sample population, no significant differences were observed between the two drugs.

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

Crohn's disease (CD) is a chronic inflammatory bowel disease of unknown etiology with no cure. Reliable tools for the early identification of patients at risk, especially for long-term prediction, remain to be defined.

Aims & Methods

This study aimed to employ machine learning to develop proteomics-based models to predict future CD onset. We utilized data from 39,634 participants without baseline CD from the UK Biobank (UKB) as the training cohort. Feature selection involved Cox regression to identify proteins associated with incident CD, followed by automated machine learning-based importance ranking using five-fold cross-validation (10 repeats). Four machine learning algorithms were applied to construct predictive models. Independent validation was conducted in a geographically distinct UKB cohort (n = 13,262) and an external Southern China cohort (n =74).

Results

Among 2,736 proteins, Cox regression identified 44 proteins significantly associated with incident CD. CD274, CHI3L1, REG1B, ITGAV, PRSS8, ITGA11, GDF15, DEFA1_DEFA1B, and IL6 were ranked the top 9 in protein importance ordering. Machine learning models using four algorithms were constructed based on these proteins, with XGBoost demonstrating the best performance. In the geographically distinct UKB cohort, the protein model (area under the curve [AUC] 0.76) outperformed clinical risk models (highest AUC 0.67, P < 0.05) and was externally validated in the Southern China cohort (AUC 0.79). Combining these proteins with clinical data enabled desirable predictions up to 16 years pre-diagnosis (AUC 0.78). Our model performed better than existing PREDICTS model (AUC 0.68, P < 0.05) when applied to the UK Biobank population. Individuals in the high-risk group stratified by the protein model were 4.23 times more likely to develop CD.

Conclusion

Our findings suggest that proteomics-based models could be used to predict individuals who will develop CD up to 16 years in advance. The novel approach has important implications in identifying individuals at high-risk for evaluation of early intervention.

Introduction

The CACTUS-CD study (NCT06125678) prospectively evaluated 407 patients with small bowel Crohn’s disease (CD) and demonstrated that intestinal ultrasound (IUS), particularly smal intestinal contrsat ultrasound (SICUS), could approach the diagnostic accuracy of computed tomography enterography (CTE) and magnetic resonance enterography (MRE)[1]. The value of IUS/SICUS in monitoring of known CD in reference to device assisted enteroscopy (DAE) is not known [2].

Aims & Methods

This post hoc analysis aimed to compare these imaging modalities (IUS, SICUS, CTE/MRE) against DAE for lesion localization and stricture detection in a subset of patients.
Forty-eight patients with established small bowel CD underwent IUS, CTE or MRE, and DAE within one week. Segmental localization (proximal, mid, distal) was assessed across all modalities. Strictures on IUS were defined using wall thickness >3 mm, luminal narrowing <1 cm, and pre-stenotic dilatation[3]. Simplified Magnetic Resonance Index of Activity (MARIA) for MRE, International Bowel Ultrasound Segmental Activity Score (IBUS-SAS) for IUS, and modified Simple Endoscopic Score for Crohn’s Disease (SES-CD) score (0-12, based on ileal subscore) for DAE were compared [2,4,5].

Results

The median age was 42 years (range 18–73), with 43.8% female and a median BMI of 21 kg/m². Among MRE patients (n=22), the median simplified MARIA (Magnetic Resonance Index of Activity) score was 4.5 (range 1-5). IUS revealed a median bowel wall thickness of 5.55 mm (range 2.2-8.6), an median International Bowel Ultrasound Segmental Activity Score (IBUS-SAS) of 63.3 (8.8-87). For DAE, modified Simple Endoscopic Score for Crohn’s Disease (SES-CD) median score was 9 (0-11). Technical success of DAE was 46/48 (95.8%, technical failure: both post operative). The approach of DAE was antegrade (n=16), retrograde (n=26) and bidirectional (n=6). Median depth of maximal insertion was 120 cm (30-600 cm) with median time ​30 minutes (10-240).
All modalities had 100% agreement in distal bowel.In mid-bowel, CTE/MRE and DAE were fully concordant; IUS achieved 72.7%. Proximal agreement was 71.4% for CTE/MRE and 57.1% for IUS. For strictures, CTE/MRE yielded the highest sensitivity (81%), specificity (88%), and agreement (kappa 0.65). IUS had lower sensitivity (47%) but excellent specificity (94%). SICUS performed better than IUS with sensitivity of 75% (p=0.039) and kappa 0.62. Spearman’s correlation showed stronger association of MARIA with SES-CD (r = 0.659, p = 0.001) than IBUS-SAS (r = 0.486, p < 0.001).

Parameter	CTE/MRE	IUS	SICUS
Number of patients	48	48	48
Distal SB Localization Accuracy (%)	100	100	100
Mid SB Localization Accuracy (%)	100	72.7	72.7
Proximal SB Localization Accuracy (%)	71.4	57.1	57.1
Sensitivity for Stricture (%)	81	47	75 *
Specificity for Stricture (%)	88	94	94
Accuracy for Stricture (%)	83	62	81#
Kappa	0.65	0.32	0.62
SB: Small bowel, *statistically significant difference between IUS and SICUS (p=0.039), # Not statistically significant (p=0.

Conclusion

Intestinal ultrasound showed excellent concordance with enteroscopy for disease localization in the distal small bowel, supporting its use as a cost-effective, radiation-free, point-of-care modality. The addition of small intestinal contrast ultrasound (SICUS) significantly improved stricture detection. These findings support ultrasound-based strategies as first-line options for monitoring known Crohn’s disease, particularly in settings requiring repeated assessment or where access to cross-sectional imaging and device-assisted enteroscopy is limited.

References

1. Pal P, Mateen MA, Pooja K, et al. S1044 Correlation and Assessment of Small Bowel Lesions Using Cross-Sectional Imaging Techniques vs Small Intestinal Contrast UltraSonography in Known Crohn’s Disease (CACTUS-CD Trial): A Paired, Validating Study (NCT06125678). Official journal of the American College of Gastroenterology | ACG. 2024;119(10S):S731-S732. [10.14309/01.ajg.0001033544.90391.8a]
2. Na JE, Kim HS, Hong SN, et al. Comparison of an Endoscopic Scoring System and the Simplified Magnetic Resonance Index of Activity in Patients with Small Bowel Crohn’s Disease. Gut and Liver. 2024;18(1):97-105.
3. Lu C, Rosentreter R, Parker CE, et al. International expert guidance for defining and monitoring small bowel strictures in Crohn's disease on intestinal ultrasound: a consensus statement. Lancet Gastroenterol Hepatol. 2024;9(12):1101-1110.
4. Novak KL, Nylund K, Maaser C, et al. Expert Consensus on Optimal Acquisition and Development of the International Bowel Ultrasound Segmental Activity Score [IBUS-SAS]: A Reliability and Inter-rater Variability Study on Intestinal Ultrasonography in Crohn's Disease. J Crohns Colitis. 2021;15(4):609-616.
5. Roseira J, Ventosa AR, de Sousa HT, Brito J. The new simplified MARIA score applies beyond clinical trials: A suitable clinical practice tool for Crohn's disease that parallels a simple endoscopic index and fecal calprotectin. United European Gastroenterol J. 2020;8(10):1208-1216.