Introduction
The VERDICT study (NCT04259138) is a prospective comparison of ulcerative colitis (UC) treatments featuring algorithms based on early use of vedolizumab (VDZ). Treatment target groups include, Group 1: corticosteroid-free (CSF) symptomatic remission (SR); Group 2: CSF symptomatic+endoscopic remission (SER); and Group 3: CSF disease clearance1 (DC). We characterized serum protein signatures in bionaïve Group 3 patients (pts) by target achieved by week 16 (W16) and mapped their potential cellular source.
Aims & Methods
OLINK proteomics was performed at baseline and W16. Differential protein expression was analysed using limma.2 Biologic pathways were analysed using clusterProfiler and gene set enrichment analysis was done with Molecular Signatures Database Hallmark and Reactome pathways. Cell-type enrichment analysis mapped proteins to putative cellular sources using a human UC single-cell atlas.3
Results
As of 29 Feb 2024, baseline and W16 serum samples were available from 154 pts who achieved SR (n=25), SER (n=8), DC (n=82), and non-remitters (NR) for any W16 outcome (n=39). Baseline characteristics were similar (Table). Significant shifts in 426 differentially abundant proteins (p<0.01) were associated with DC, including downregulation of core inflammatory proteins and upregulation of metabolic proteins. Comparing DC vs SR and NR groups at baseline, we observed 33 and 44 differentially abundant proteins (p<0.01), increasing to 50 and 128 at W16. At baseline, DC differed from both SR and NR groups by enrichment of proteins involved in pleiotropic cytokine signalling and lymphocyte homeostasis, innate immune sensing and antimicrobial defence, and cytoskeletal organization. Conversely, proteins associated with immune exhaustion and T-cell signalling, complement activation and acute-phase response, myeloid signalling, and pro-fibrotic extracellular matrix (ECM) remodelling were consistently lower in DC, suggesting an immunologically active, regulated, yet less exhausted and less fibrotic, baseline state. After treatment, DC (vs NR) was characterized by upregulation of pathways involved in barrier restoration, ECM remodelling and tissue repair, growth factor and receptor tyrosine kinase signalling, glycoprotein biosynthesis, and tertiary lymphoid structure formation, alongside marked downregulation of inflammatory hallmarks spanning Th17 and neutrophilic inflammation, TNF superfamily signalling, complement cascade activation, and systemic acute-phase response. Protein mapping to UC single-cell data confirmed distinct cellular origins. Proteins elevated in DC were predominantly enriched in epithelium, fibroblasts and glia, pointing to a stromal remodelling and tissue/barrier repair program. Proteins reduced in DC were enriched in myeloid and T-cell compartments, consistent with resolution of innate inflammatory and lymphocyte exhaustion signals.
Conclusion
Distinct dynamic changes in proteomic signatures are associated with CSF DC in bionaïve UC pts in response to VDZ. These unique biological characteristics may uncover novel biomarkers to predict early DC or new therapeutic targets.
| Table. Demographics and clinical characteristics for Group 3, bionaïve, corticosteroid-free patients according to outcome achieved by week 16a,b,c |
|---|
Abbreviations: BMI, body mass index; n, number of patients; SD, standard deviation; TNF, tumour necrosis factor; UC, ulcerative colitis.
a: Data are based on in-stream data that have not been reconciled; data reconciliation will occur prior to final database lock.
b: Group 3: treatment target assessed as corticosteroid-free symptomatic remission (Mayo rectal bleeding subscore=0) + endoscopic improvement (Mayo endoscopic subscore <=1) + histologic remission (Geboes score <2.B.0).
c: Bionaïve is defined as no prior biologic (algorithm A) or >5 years since prior biologic use (algorithm B). |
|
| Non-remitter
(N=39)
| Symptomatic remission
(N=25)
| Symptomatic + endoscopic remission
(N=8) | Disease clearance (symptomatic + endoscopic +histologic remission)
(N=82)
| Total
(N=154)
|
| Age, mean (SD) |
| 40.4 (12.84)
| 42.6 (14.65)
| 40.5 (13.58)
| 41.2 (13.70)
| 41.2 (13.52)
|
| Sex, male |
| 23 (59.0%)
| 13 (52.0%)
| 3 (37.5%)
| 44 (53.7%)
| 83 (53.9%)
|
| BMI, mean (SD) |
| 25.37 (5.137)
| 25.76 (5.168)
| 24.71 (2.711) | 25.99 (4.950)
| 25.73 (4.917)
|
Corticosteroid use at screening
|
| 14 (35.9%)
| 13 (52.0%)
| 3 (37.5%)
| 39 (47.6%)
| 69 (44.8%)
|
Treatment Algorithm at Baseline
| A: Patients Not on UC Therapy
| 0 (0.0%)
| 0 (0.0%)
| 0 (0.0%)
| 1 (1.2%)
| 1 (0.6%)
|
| B: Patients on Nonbiologic UC Therapies
| 39 (100.0%)
| 25 (100.0%)
| 8 (100.0%)
| 81 (98.8%)
| 153 (99.4%)
|
| C: Patients on Anti-TNF, Tofacitinib or Ustekinumab Therapy
| 0 (0.0%)
| 0 (0.0%)
| 0 (0.0%)
| 0 (0.0%)
| 0 (0.0%)
|
References
1. Danese S, et al. JCC. 2021;15(Suppl1):S305.
2. Ritchie, ME et al. Nucleic Acids Res. 2015;43:e47
3. Smillie CS, et al. Cell. 2019;178:714.
Disclosure
Funding: This work was sponsored by Takeda Development Center Americas, Inc.
SM: Grants: Genentech, Brystol Myers Squib (BMS)Personal Fees: AbbVie, Adacyte, Alimentiv, Atticus, Brystol Myers Squib (BMS), Cabaletta, Georgia Immune, Merck, Novartis; NP: Grants: Takeda, BMS, Pfizer, Astra-Zeneca, Personal Fees: Abbvie, Abivax, Allergan, Astra-Zeneca, Bristol-Myers Squibb, Celgene, Celltrion, Dr Falk Pharma UK Ltd, Ferring, Galapagos, GSK, Janssen, MSD, Roche, Pfizer, Sobi, Takeda, Tillotts; MDP: Employee of Takeda and holds stock/options in Takeda; MSS: Consulting, speaker, advisory board fees: Takeda; CH-R: None; LPB: Personal fees: Alimentiv Inc., Takeda; JFC: Research grants, payment for lectures, consulting fees: Takeda; GRD: Consultant and/or speaker fees: Alimentiv Inc., Takeda; GWM: Consultant: Alimentiv Inc.; SS: Research grants: Takeda, personal fees for speaker role, advisory board meetings (outside the submitted work): Takeda; ST: Grants/research support, consulting fees, speaker fees: Takeda; MF, LM, JP, BS, MIS, WT: Employees of Alimentiv Inc.; VA, BS, CA, SF, PP: Employees of Takeda and holds stock/options in Takeda; SS: Consultancy and personal fees: AbbVie, Arena, BMS, Biogen, Celltrion, Celgene, Dr Falk, Ferring, Fresenius, Gilead, HIKMA, IMAB, Janssen, MSD, Mylan, Pfizer, Protagonist, Provention Bio, Sandoz, Takeda, and Ventyx; VP: Consulting/advisory board fees: Alimentiv Inc. (formerly Robarts Clinical Trials), Takeda; speaker fees: Takeda.