Introduction

GLPG3970, a potent and selective small molecule salt-inducible kinase (SIK) 2/3 inhibitor, exhibits a dual mechanism modulating both pro-inflammatory and immunoregulatory pathways that holds potential as a novel therapeutic option for inflammatory bowel disease.^1,2 Oral administration of GLPG3970 in colitis mouse models reduced disease activity scores, inhibited pro-inflammatory cytokine release and improved histological endpoints including protection of goblet cell health and MUC2 expression.^2,3 Mechanistic investigations demonstrated a broad immunomodulatory activity on colonic immune cell types. It remains unclear whether SIK2/SIK3 inhibition exerts a direct therapeutic activity on intestinal epithelial cell types or if these effects result indirectly from modulating pro-inflammatory and immunoregulatory mechanisms.³

Aims & Methods

We aimed to unravel the activity of SIK2/SIK3 inhibition using GLPG3970 in ulcerative colitis (UC) patient-derived epithelial cells focusing on SIK target engagement markers, inflammation and mucus production. Differentiated intestinal organoids from patients with UC were exposed to vehicle control, GLPG3970 (3 µM and 20 µM) or PGE2 (20 µM; positive control) for 24 hours (gene expression) or 48 hours (immunohistochemistry). Gene expression was evaluated in organoid cultures derived from five patients with UC, with or without 24 hours of pro-inflammatory stimulation (using a mix of 100 ng/mL TNFα, 20 ng/mL IL-1β and 1 µg/mL flagellin)⁴ prior to 24 hours of exposure in combination with the compound, and measured by RT-qPCR compared with vehicle control (Friedman, Dunn’s multiple comparison). Immunohistochemistry was performed for MUC2, DAPI, CK14 (n = 3 patients, minimum 10 images/condition, 3 replicates). Randomized images were analysed by Imaris Software by sectioning regions of interest (two-way ANOVA, Dunnett’s multiple comparison).

Results

Upon GLPG3970 exposure, UC patient-derived organoids showed transcriptional upregulation of SIK target engagement markers such as the CREB¹ activation genes NR4A1, NR4A2 and NR4A3. There was no effect with GLPG3970 on gene expression of inflammatory markers in colon epithelial cells, in the presence or absence of inflammatory stimulation, except for IL-1β and IL-8 upregulation after 24 hours of GLPG3970 exposure. Genes related to mucus production were upregulated in both noninflamed (MUC5AC, 20 µM, p < 0.01; AGR2, 20 µM, p < 0.05) and inflamed conditions (MUC2, 20 µM, p < 0.01; MUC5AC, 3 µM and 20 µM, p < 0.01) at the highest GLPG3970 concentration tested. Immunohistochemistry confirmed increased MUC2 secretion (secreted MUC2 surface × secreted MUC2 intensity) after 48 hours of GLPG3970 stimulation (3 µM, p < 0.05; 20 µM, p < 0.01); however, no significant increase was measured in absolute goblet cell number or goblet surface intensity compared with vehicle control.

Conclusion

SIK2/SIK3 inhibition by GLPG3970 showed a significant upregulation of target engagement markers as measured by the CREB activation genes NR4A1/2/3 in UC patient-derived colon epithelial cells, whereas no direct downregulation of inflammatory markers was observed. Exposure of UC patient-derived colonic organoids to GLPG3970 20 µM resulted in a signature of enhanced mucus secretion, both in the presence and absence of inflammation. Overall, these data indicate a direct impact of SIK2/SIK3 inhibition in intestinal epithelial cells with potential benefit in promoting barrier reinforcement via goblet cell mucus production in patients with active UC.

References

1. Peixoto C et al. J Med Chem 2024;67:5233–58.
2. Pereira-Fernandes A et al. [abstract] United European Gastroenterol J 2021;9:S8.
3. Lavazais S et al. [abstract] United European Gastroenterol J 2021;9:S8.
4. Arnauts K et al. Gastroenterology 2020;159:1564–67.

Disclosure

This study was funded by Galapagos NV (Mechelen, Belgium).
Editorial and publications management support was provided by PharmaGenesis London, London, UK, and was funded by Galapagos NV.
LG and KA are joint first authors.
LG and KA report no conflict of interest.
DM was an employee of Galapagos at the time of the work, and is now an employee of NovAliX.
BV reports research support from AbbVie, Biora Therapeutics (formerly Progenity), Landos Biopharma, Pfizer, Sosei Heptares and Takeda; speaker fees from Abbvie, Biogen, Bristol Myers Squibb, Celltrion, Chiesi, Falk, Ferring Pharmaceuticals, Galapagos, Janssen Pharmaceuticals, Lily, MSD, Pfizer, R-Biopharm, Sandoz, Takeda, Tillots Pharma, Truvion Healthcare and Viatris; consultancy fees from Abbvie, Alfasigma, Alimentiv, Applied Strategic, AstraZeneca, Atheneum, BenevolentAI, Biora Therapeutics (formerly Progenity), Boxer Capital, Bristol Myers Squibb, Galapagos, Guidepont, Landos, Lily, Mylan, Inotrem, Ipsos, Janssen Pharmaceuticals, Pfizer, Sandoz, Sanofi, Santa Ana Bio, Sapphire Therapeutics, Sosei Heptares, Takeda, Tillots Pharma and Viatris; and stock options from Vagustim.
SV reports speaker and/or consultancy fees from AbbVie, Abivax, AbolerIS Pharma, AgomAb Therapeutics, Alimentiv, Arena Pharmaceuticals, AstraZeneca, Biora Therapeutics (formerly Progenity), Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cytoki Pharma, Dr Falk Pharma, Ferring Pharmaceuticals, Galapagos, Genentech/Roche, Gilead Sciences, GSK, Hospira, IMIDomics, Janssen Pharmaceuticals, Johnson & Johnson, Lilly, Materia Prima, Mestag Therapeutics, MiroBio, Morphic Therapeutic, MRM Health, MSD, Mundipharma, Pfizer, ProDigest, Prometheus Biosciences, Robarts Clinical Trials, Surrozen, Takeda, Theravance Biopharma, Tillotts Pharma, VectivBio, Ventyx Biosciences and Zealand Pharma; grants from AbbVie, Galapagos, Johnson & Johnson, Pfizer and Takeda; and participation on a data safety monitoring board for Sanofi.
SDV is an employee of Galapagos.

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.

Introduction

STRIDE-II has underscored the importance of achieving timely, pre-defined therapeutic targets predictive of favorable long-term outcomes in patients with Inflammatory Bowel Disease. Early targets include post-induction clinical response (Clin-Resp), and clinical remission (Clin-Rem), whereas endoscopic healing is, currently proposed as the optimal long-term endpoint.

Aims & Methods

This study aims to record rates of Clin-Resp, Clin-Rem and endoscopical healing and evaluate their predictive value for long-term outcomes in patients with Ulcerative Colitis (UC), in a real-world setting. It is a retrospective cohort study of patients who have been followed up in the GI unit of “Sotiria” hospital, and commenced treatment with either infliximab, vedolizumab, or ustekinumab. We compared patients who achieved Clin-Resp (drop of UC-PRO2≥50%) without Clin-Rem at the end of induction to those with Clin-Rem (UC-PRO2=0) regarding rates of drug continuation, clinical remission, steroid-free clinical remission, and mucosal healing at one year on treatment. Additionally, we compared patients with endoscopic MAYO score (endo-MAYO) of 0 or 1 on treatment, regarding drug continuation rates 1, 2, 3 and 4 years post-endoscopy. SPSS 23 (IBM, Armonk, NY, USA) was used for the statistical analysis.

Results

In total, 145 patients were included [mean age=41.6 years (SD=16.6), men: 50.3% (n=73)]. Sixty-eight (46.9%) received infliximab, 41 (28.3%) vedolizumab and 36 (24.8%) ustekinumab. At the end of induction, 90 patients (62.1%) had Clin-Resp and 72 (49.7%) Clin-Rem. After one year of treatment, higher rates of drug continuation (94.4% vs 55.6%, P<0.001), clinical remission (87.5% vs 44.4%, P<0.001), steroid-free clinical remission (85.9% vs 33.3%, P<0.001) and mucosal healing (57.6% vs 23.5%, P=0.001) were reported for patients in Clin-Rem at the end of induction compared to those with sole Clin-Resp. Patients with endo-MAYO=0, at their first endoscopic evaluation after drug commencement, demonstrated higher rates of 1- (100% vs 70.6%, log-rank P=0.007) and 2-year (81.6% vs 41.7%, log-rank P=0.033) drug continuation, compared to those with endo-MAYO=1. No statistically significant difference was recorded regarding their 3- (61.5% vs 22.2%, log-rank P=0.088) and 4-year (33.3% vs 22.2%, log-rank P=0.254) drug continuation rates.

Conclusion

In ulcerative colitis, the achievement of clinical remission at the end of induction is a major predictive factor of long-term effectiveness of treatment. Simultaneously, our analysis shows the importance of optimal control of inflammation as a therapeutic target, since patients with complete endoscopic healing have a higher probability of prolonged drug continuation.

Disclosure

GB: Advisor/lecturer for Janssen, Pfizer, Takeda, Abbvie, MSD, Mylan, Genesis Pharma, Adacyte Therapeutics, Amgen, Ferring, Cooper; Funding (Grants/Honoraria): Pfizer, Takeda, Abbvie, Aenorasis; Research/Clinical Trials: Abbvie, Takeda.

Introduction

The STRIDE-2 consensus emphasizes achieving specific endoscopic targets in ulcerative colitis (UC), but robust evidence on the effectiveness of the Treat-to-Target (T2T) approach in UC is limited in the real-world setting.

Aims & Methods

TACTIC-UC is a monocentric, retrospective, observational study evaluating UC patients managed according to a T2T algorithm. Eligible patients: 1) were receiving anti-TNF (aTNF), vedolizumab (VDZ) or ustekinumab (UST) at standard doses, 2) had quiescent/mild clinical activity (stool frequency and rectal bleeding <1), 3) had moderate/severe endoscopic activity (endoscopic Mayo score, eMS≥2). All patients received dose optimization and had at least 1 follow-up endoscopy. Observation period lasted from optimization until 1 year /drug discontinuation/last available follow-up. The primary outcome was the probability of mucosal healing (MH, eMS≤1) within 1 year. Secondary outcomes included: 1) probability of endoscopic remission (ER, eMS=0) within 1 year, 2) adverse events (AEs) incidence. Inverse probability of treatment weighting was used to adjust cohorts’ imbalances. False discovery rate correction was applied for multiple comparisons.

Results

The cohort included 178 patients (main characteristics in Table 1); after IPTW, no significant differences were observed. The cumulative probabilities of achieving MH within the first year were 41%, 11% and 23% for aTNF, VDZ and UST, respectively. At pair-wise comparison, aTNF was superior to both VDZ and UST(p<.05), with UST trending towards superiority (p=.05) over VDZ. Cox-regression (bootstrapping, 1000 iterations) identified factors associated with a significantly reduced (p<.05) probability of achieving MH: difficult-to-treat UC (aHR 0.6, 95%CI 0.5-0.7), E3 (aHR 0.7, 95%CI 0.5-0.9), elevated CRP (aHR0.96, 95%CI 0.94-0.9), and elevated FCP (aHR 0.98, 95%CI 0.97-0.99); aTNF was associated with increased probability of MH compared to VDZ (aHR 1.4, 95%CI 1.1-1.7, p<.05) and UST (aHR 1.4, 95%CI 1.2-2.0, p<.05). For ER, the cumulative probabilities at 1 year were 13%, 3% and 9% for aTNF, VDZ and UST, respectively. Pairwise comparisons showed that aTNF was superior to VDZ (p<.05), and UST trended towards superiority over VDZ (p=.05). Cox regression (bootstrapping, 1000 iterations) found that difficult-to-treat UC (aHR 0.6, 95%CI 0.5-0-8), E3 (aHR 0.7, 95%CI 0.6-0.), higher CRP (aHR 0.97, 95% CI 0.95-0.99), higher FCP (aHR 0.99, 95%CI 0.98-1.0) were significantly (p<.05) associated with reduced probability of achieving ER; aTNF was associated with increased probability of achieving ER compared to VDZ (aHR 1.3, 95%CI 1.1-1.7, p<.05) and UST (aHR 1.4, 95%CI 1.1-2.0, p<.05), with no significant difference for VDZ vs UST. AEs were infrequent and mild across all groups (mostly infections and infusion reactions), with no significant differences in safety profiles. No serious AE was reported.
Table 1.

Conclusion

In this cohort of UC patients treated according to an endoscopy-driven T2T approach, aTNF outperformed VDZ and UST in inducing MH and ER. Disease severity markers were associated with reduced probabilities of achieving endoscopic targets. Safety profiles were comparable across therapies.