Introduction

Inflammatory bowel diseases (IBD) are systemic disorders that may be associated with extraintestinal manifestations in up to 40% of patients. Recognizing the recurrent emergence of these manifestations in IBD, with a particular emphasis on rheumatological aspect, becomes a pivotal focal point for a holistic therapeutic approach.

Aims & Methods

The aim of this study was to evaluate the impact of ankylosing spondylitis in IBD on disease course. We conducted a retrospective and comparative study, including patients followed for IBD over an 8-year period [2014 - 2022]. Clinico-biological data, disease severity, and long-term outcomes (surgery and disease course) were collected. IBD patients with ankylosing spondylitis (group1) and patients without (group2) were compared. Data were entered and analyzed via SPSS 26 software.

Results

One-hundred IBD patients were enrolled with a sex ratio of M/F=2.44 and a mean age of disease diagnose of 37.26 ± 13.46 years. Eighteen patients had ankylosing spondylitis (18%). The two groups were comparable in terms of age at disease onset, gender, smoking status and family history of IBD (p=0.65; p=0.9, p=1 and 0.1 respectively). In Crohn's disease, there was no difference between the two groups regarding the extent of the disease (p=0.71), the presence of upper gastro-intestinal tract involvement (p=0.11) and perineal manifestations (p=0.7). Inflammatory, structuring, and penetrating phenotypes were also comparable between the two groups (p=0.67; p=0.3; p=1 respectively). However, the occurrence of acute intestinal obstruction was significantly more common in ankylosing spondylitis patients (G1:54% vs. G2:10%; p=0.004). As for ulcerative colitis, extensive presentation (G1:28% vs. G2:41%; p=0.66) and the occurrence of disease extension during follow-up was comparable between the two groups (p=0.78). None of the patients with or without rheumatological involvement had any dermatological or ophthalmological involvement related to IBD, but there was a more significant prevalence of hepatic manifestations in ankylosing spondylitis group (G1:16% vs. G2:2%, p=0.01). The mean number of flare-ups was not significantly different between the two groups (G1:3.21±1.47 vs. G2:2.53±1.4; p=0.06). Regarding treatment, recourse to methotrexate (G1:16% vs. G2:2%; p=0.01) and the use of anti-TNF agents (G1:77% vs. G2:22%; p<0.001) was more frequent in group 1, with no difference in the occurrence of adverse events (p=1), the use of corticosteroids (p=0.22) or azathioprine (p=0.1). Surgical treatment was more frequently indicated in ankylosing spondylitis patients (G1:51% vs. G2:30%; p=0.06). Post-operative relapse of Crohn's disease was comparable between the two groups (p=1).

Conclusion

In our study, rheumatological involvement was not likely responsible of a more severe clinical phenotype of IBD.

Introduction

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disease characterized by intestinal inflammation, mainly including Crohn’s Disease (CD) and Ulcerative Colitis (UC), both of which will cause swelling and ulceration in the inner wall of gastrointestinal tract ^[1]. ISM5411 is an oral gut-restrictive small molecule inhibitor targeting PHD2 to stabilize hypoxia inducible factors (HIF-1α), thus promoting the expression of intestinal mucosal protective genes, maintaining the integrity and functions of intestinal barrier to finally achieve the purpose of protecting and repairing intestinal mucosal barrier together with anti-inflammation. Preclinical studies demonstrated that ISM5411 can significantly alleviate the symptoms of multiple animal models of colitis without significant increase in systemic erythropoietin (EPO) or vascular endothelial growth factor (VEGF) ^[2]. The first-in-human Phase I study in Australia was completed to evaluate safety, tolerability, pharmacokinetics and food effect in healthy subjects.

Aims & Methods

ISM5411-101 was a randomized, double-blinded, placebo-controlled, single and multiple-dosed and food effect first-in-human Phase I study conducted in healthy subjects at a single site in Australia. Seven dose levels from 50 mg to 1000 mg of single ascending doses and three dose levels from 200 mg to 800 mg once daily for 14 days of multiple doses of ISM5411 were administrated. Safety and tolerability, pharmacokinetics (PK) parameters (plasma, urine and feces) and biomarkers (EPO and VEGF levels) were evaluated.

Results

Seventy-six subjects were dosed with no serious adverse events (SAEs) or deaths recorded. One treatment emergent adverse event (TEAE) leading to discontinuation of ISM5411 occurred (Grade 1, rectal hemorrhage) in 200 mg once daily ISM5411 cohort was reported and judged as not related to ISM5411. The incidence of TEAEs was 25.0% and 55.0% in ISM5411 pooled cohort (n=56) and placebo cohort (n=20). All TEAEs reported in ISM5411 pooled cohorts were Grade 1. After single and multiple doses administration, ISM5411 was rapidly absorbed and metabolized to metabolite (ISM5411-M15). The plasma exposure of both analytes was very low without apparent dose-proportional manner. ISM5411 was excreted in the feces in its prototypic form by more than 30%. Systemic EPO level increased post-dose in most cohorts then decreased, and most changes were within normal range. No clear trend was observed in the change of mean systemic VEGF levels across cohorts.

Conclusion

ISM5411 tablets were safe and well-tolerated and demonstrated good gut-restrictive property, consistent with the intended PK profile. Another Phase I study in China was also completed. Phase 2a proof of concept study of ISM5411 is under planned in patients with ulcerative colitis to explore the safety, PK and clinical efficacy.

References

1. Chang JT. Pathophysiology of Inflammatory Bowel Diseases. N Engl J Med, 2020 Dec 31;383(27): 2652-2664
2. Fu, Y., Ding, X., Zhang, M. et al. Intestinal mucosal barrier repair and immune regulation with an AI-developed gut-restricted PHD inhibitor. Nat Biotechnol (2024).

Introduction

Existing treatments aim to induce and maintain remission in Ulcerative Colitis (UC); however, 30–55% of patients remain refractory during the induction phase, highlighting an unmet need for novel therapeutic options(1). Phosphodiesterase-4 (PDE4) is a cyclic adenosine monophosphate (cAMP)-specific enzyme expressed by immune and inflammatory cells. Abnormal expression of PDE4 and dysregulated signal transduction have been reported in colonic biopsies from patients with UC (2,3). Orismilast is an oral, B/D-selective PDE4 inhibitor with a modified-release formulation.

Aims & Methods

This study (the UCORIS study) was a phase 2a, open-label, single-arm exploratory clinical study assessing the efficacy and safety of orismilast in patients with moderate to severe UC. Patients with UC currently on stable 5-ASA treatment and experiencing moderate-severe disease activity (defined as a Mayo endoscopic sub score of 2 or 3) were eligible for inclusion. Orismilast was administered twice daily for 12 weeks, with investigators allowed to individualize the dose based on body weight, treatment response and side effects. Responding patients could extend treatment to a total duration of 52 weeks.
A last-observation-carried-forward (LOCF) approach was applied to early discontinuers when com-paring to those who completed treatment. No hypothesis testing was performed due to the small sample size. The primary endpoint was clinical remission at week 12, defined as a total Mayo score of 2 or lower, with no individual sub score exceeding 1.

Results

10 patients were included in the study. Six participants discontinued the study prematurely - three due to lack of efficacy and three due to adverse events. Clinical remission at week 12 was achieved by one patient, who continued orismilast for 50 weeks, maintaining endoscopic remission.
In the completed trial group, mean Total Mayo Score decreased from 9.75 to 5.25 (Δ– 4.50, [95% CI: -4.17;13.17], p=0.20), and Partial Mayo Score from 7.25 to 3.75 (Δ –3.5, [95% CI: -2.66;9.66], p=0.17). In the early determination group, Partial Mayo Score declined from 5.83 to 4.17 (Δ–1.66, [95% CI: -2.46;5.79], p=0.35); follow-up Total Mayo Scores were unavailable. Faecal calprotectin levels showed modest reductions in both groups.
A total of 75 adverse events (AEs) were recorded. Of these, 48 were mild (68%), consistent with previous findings(4). The most common ADRs were nausea (15% of AEs; 8 patients (80%)), abdominal pain (12%; 5 patients (50%)), dizziness (5%; 2 patients (20%)), and headache (4%; 2 patients (20%)). Three serious AEs occurred in one patient but did not result in discontinuation. None of the serious AEs were considered related to orismilast. The overall safety profile aligned with known effects of PDE4 inhibitors(4–6), although the frequency of nausea was higher, potentially reflecting overlap with underlying disease symptoms.

Conclusion

Orismilast demonstrated reductions in both Total and Partial Mayo scores among patients who completed the trial, and a reduction in Partial Mayo score among those who discontinued early. Although only one patient, who completed the full 12-week regimen, achieved both clinical and endoscopic response, three out of ten patients achieved remission based on Partial Mayo score, faecal calprotectin, and SCCAI. Adverse drug reactions were common; although none were severe, nausea had a notable impact on daily life. Effective management of this adverse event may be essential to improving tolerability and supporting the therapeutic potential of orismilast in the treatment of ulcerative colitis.

References

1. Zhao M, Sall Jensen M, et al. Trends in the use of biologicals and their treatment outcomes among patients with inflammatory bowel diseases – a Danish nationwide cohort study. Aliment Pharmacol Ther. 2022 Mar 1;55(5):541–57.
2. Spina D. PDE4 inhibitors: Current status. Vol. 155, British Journal of Pharmacology. 2008. p. 308–15.
3. Li H, Zhang Y, Liu M, et al. Targeting PDE4 as a promising therapeutic strategy in chronic ulcerative colitis through modulating mucosal homeostasis. Acta Pharm Sin B. 2022 Jan 1;12(1):228–45.
4. Silverberg JI, Eichenfield LF, et al. Orismilast, a PDE4B/D inhibitor, in moderate-to-severe atopic dermatitis: Efficacy and safety from a multicenter, randomized, placebo-controlled, phase 2b dose-ranging study (ADESOS). Br J Dermatol [Internet]. 2025 Jan 7;
5. Warren RB, French LE, et al. Orismilast in moderate-to-severe psoriasis: Efficacy and safety from a 16-week, randomized, double-blinded, placebo-controlled, dose-finding, and phase 2b trial (IASOS). J Am Acad Dermatol. 2024 Mar 1;90(3):494–503.
6. Frederiksen CG, Sedeh FB, et al. Orismilast for the treatment of mild to severe hidradenitis suppurativa: Week 16 data from OSIRIS, a Phase 2a, open-label, single-centre, single-arm, dose-finding clinical trial. Journal of the European Academy of Dermatology and Venereology. 2024 May 1;38(5):920–30.

Disclosure

TVH: No disclosures
JBS: Research grants from Takeda and Johnson and Johnson, national coordinator of studies from AbbVie, Arena Pharmaceuticals, Ely Lilly, and Boehringer Ingelheim.
JB: Dr. Burisch reports grants from AbbVie, Janssen-Cilag, MSD, Takeda, Tillots Pharma, Bristol Myers Squibb, and Novo Nordisk Foundation; personal fees from AbbVie, Janssen-Cilag, Celgene, MSD, Pfizer, Takeda, Tillots Pharma, Bristol Myers Squibb, Samsung Bioepis, Pharmacosmos, Ferring, Galapagos, Eli Lilly, Dr Falk Pharma, Celltrion and Orion Pharma.

Introduction

Despite recent advances in the treatment of IBD, patients still suffer from suboptimal efficacy and are eagering for more effective treatment options. Both human TL1A and IL-23 are clinically validated targets in treating IBD. Here we discovered and characterized SIM0709, a half-life extended bi-specific antibody simultaneously tarting both TL1A and IL-23p19, with the aim to further enhance clinical efficacy and improve patient’s compliance.

Aims & Methods

The binding activities to TL1A protein and IL-23 protein were determined by ELISA and BLI. Cell-based blocking functionalities of TL1A to DR3 and IL-23p19 to IL23R were evaluated by using FACS assays, meanwhile the competitive inhibition of TL1A binding to DcR3 and the inhibition of IL-23 binding to IL12R were also determined by ELISA. TL1A induced TF-1 cell apoptosis and interferon γ (IFNγ) secretion from CD4⁺ T cells stimulated by TL1A in combination with IL-12 and IL-18 were used to evaluate the outcomes of functional blockade of TL1A pathway. In addition, mouse IL-17 secretion from mouse splenocytes stimulated by human IL-23 was also assessed to evaluate the functional blockade of IL-23 pathway. The synergistic effect of dual pathway blockade was measured by Th17 differentiation co-stimulated with human IL-23 and TL1A. A cytokine-induced acute gut inflammation model was used to assess the in vivo efficacy of SIM0709 while the extended half-life was revealed in both human FcRn knock-in mice and non-human primate.

Results

SIM0709 simultaneously bound to both TL1A and IL-23 proteins with sub-nanomolar affinity and demonstrated superior functional activities under various functional assays on both TL1A and IL-23 axes compared to that of benchmark anti-TL1A mAb RG6631 and Guselkumab or its combination, respectively. SIM0709 also exhibited superior dual pathway blockade synergy in vitro in inhibiting Th17 differentiation and in vivo in the cytokine-induced acute gut inflammation model. Further analysis on ileum and colon tissues confirmed relived intestinal inflammation after SIM0709 treatment with significantly reduced inflammatory cytokines/chemokine levels and improved histological scores compared to either the anti-TL1A or anti-IL-23p19 monotherapies. SIM0709 also demonstrated an improved serum half-life in human FcRn knock-in mice compared to that of RG6631. Moreover, SIM0709 showed encouraging PK profile with over 15 days half-life, which together with its excellent developability profile, may support extended dosing interval in the clinic with a patient-friendly subcutaneous formulation.

Conclusion

Taken together, these data support the further development of SIM0709 as a potential FIC and BIC therapeutic agent for the treatment of IBD with expected first-in-human study in H1 2026.

Disclosure

The authors are employees of Jiangsu Simcere Pharmaceutical Co., Ltd and State Key Laboratory of Neurology and Oncology Drug Development.

Introduction

​Biologic therapies play a pivotal role in the management of ulcerative colitis (UC). Anti-TNFα agents are recommended as first-line biologics according to ECCO guidelines; however, JAK inhibitors have recently emerged as a viable alternative (1). Vedolizumab has also demonstrated effectiveness when introduced early in the disease course with a greater 52-week treatment persistence and reduced hospitalisation rates compared to anti-TNFα agents as second-line therapy (2). The AGA guidelines (3) now favour biologics such as anti-IL-23 and JAK inhibitors over Vedolizumab or S1P receptor modulators in patients previously exposed to anti-TNFα agents. Notably, Guselkumab is not yet approved for UC treatment in the UK. The latest ECCO guidelines (1) do not address the role of biologics in third-line or subsequent treatment settings, and there remains a lack of clear clinical guidance.

Aims & Methods

This study aimed to retrospectively evaluate the effectiveness of third-line biologic therapies in adult patients with UC over a 12-month period. Clinical response was assessed using the Simple Clinical Colitis Activity Index (SCCAI), Partial Mayo Score, and Physician Global Assessment, while biochemical and endoscopic responses were measured at 3, 6, and 12 months post-induction. Biochemical markers included faecal calprotectin and CRP levels. Endoscopic response was assessed using the Ulcerative Colitis Endoscopic Index of Severity (UCEIS). Colectomy rates were also recorded. Patients treated at a UK tertiary care centre were included up to March 2025. Statistical analyses were conducted using SPSS.

Results

A total of 24 patients were included in the analysis, with 13 receiving anti-IL-23 therapy and 11 treated with JAK inhibitors. Within the anti-IL-23 group, 5 patients received Mirikizumab and 8 Ustekinumab; Risankizumab was not used in this cohort. In the JAK group, 3 patients were treated with Upadacitinib, 4 with Filgotinib, and 4 with Tofacitinib. A statistically significant reduction in SCCAI scores at 6 months was observed in the JAK groups compared to anti-IL-23 (7.64 ± 3.61 vs 4.90 ± 1.97, p = 0.047). However, biochemical response, assessed by faecal calprotectin reduction, did not reach statistical significance at either 3 or 6 months (p = 1.000 and p = 0.314, respectively). Endoscopic response, measured by changes in UCEIS at 12 months, also showed no significant difference between groups (p = 0.668). Subgroup analysis within the anti-IL-23 cohort revealed no significant difference in SCCAI reduction between Ustekinumab and Mirikizumab at 3 months. Similarly, while Upadacitinib was associated with the greatest SCCAI reduction among the JAK inhibitors at 3 months, the difference among the three agents was not statistically significant (p = 0.106). Subtotal colectomy was performed in one patient in the Mirikizumab group following completion of induction therapy, and in two additional patients within three months of initiating the same agent (Table 1).

Conclusion

JAK inhibitors showed an improvement in SCCAI at 6 months compared to anti-IL-23 agents. No significant differences were found in biochemical or endoscopic response.

References

1. Raine T, Bonovas S, Burisch J, Kucharzik T, Adamina M, Annese V, et al. ECCO Guidelines on Therapeutics in Ulcerative Colitis: Medical Treatment. Journal of Crohn’s and Colitis. 2022 Jan 28;16(1):2–17.
2. Miller C, Kwok H, Harrow P, Vega R, Seward E, Mehta S, et al. Comparative effectiveness of a second-line biologic in patients with ulcerative colitis: vedolizumab followed by an anti-TNF versus anti-TNF followed by vedolizumab. Frontline Gastroenterol. 2022 Sep;13(5):392–401.
3. Singh S, Loftus EV, Limketkai BN, Haydek JP, Agrawal M, Scott FI, et al. AGA Living Clinical Practice Guideline on Pharmacological Management of Moderate-to-Severe Ulcerative Colitis. Gastroenterology. 2024 Dec;167(7):1307–43.