Introduction
The SELECTION trial (NCT02914522) demonstrated that filgotinib (FIL), a once-daily, oral, Janus kinase 1 preferential inhibitor, was effective at inducing and maintaining clinical remission in patients with moderately to severely active ulcerative colitis (UC).1 A post hoc analysis of FIL responders identified five unique patient groups with different trajectories of response modelled from partial Mayo Clinic Score (pMCS) data, ranging from sustained improvement to rebound of symptoms.2
Aims & Methods
We investigated the underlying biology associated with these pre-defined symptomatic trajectories using colon biopsies collected during SELECTION; the trial design has been reported previously.1 Using group-based trajectory modelling, FIL responders (defined as patients treated with FIL who were in clinical remission or with a Mayo Clinic Score response at week 10) were clustered into trajectories based on similar changes in pMCS from baseline to week 58.2 RNA was extracted from colonic mucosal biopsies collected at baseline and week 10, and RNA sequencing was performed as per standard protocols. Trajectory-specific transcriptional changes were assessed at baseline by differentially expressed gene (DEG) analysis. Key comparisons were: a) each trajectory at baseline versus the average of the other trajectories and b) the change from baseline to week 10, assessed separately for each trajectory group.
Results
Comparison of DEGs between each trajectory group demonstrated minimal transcriptional differences between the groups at baseline. However, the number of DEGs from baseline to week 10 differed between the trajectory groups (Table). Interestingly, trajectories associated with greater symptomatic improvement beyond week 10 had higher numbers of DEGs.
Conclusion
We identified transcriptional differences in the change from baseline to week 10 in DEGs between trajectory groups, aligning with symptomatic improvement beyond week 10 in patients receiving FIL. A qualitative analysis of DEGs is under investigation, for which preliminary results support the potential for personalized medicine in UC, by identifying differences in underlying pathophysiology associated with differential response to targeted therapy. These findings could further help to identify blood biomarkers that predict treatment outcomes in patients with UC on FIL.
Table. Change in number of significantly differentially expressed genes from baseline to week 10 for each trajectory
| Group A
| Group B | Group C | Group D | Group E |
n (%)
| 4683
(8.85%)
| 4356
(8.23%)
| 1306
(2.47%)
| 14 690
(27.76%)
| 14 677
(27.73%)
|
References
- Feagan BG et al. Lancet 2021;397:2372–84
- Schreiber S et al. [MP443] Poster presented at the United European Gastroenterology Week (UEGW), 8–11 October 2022, Vienna, Austria.
Disclosure
The SELECTION trial was sponsored by Gilead Sciences Inc (Foster City, CA, USA). Galapagos NV (Mechelen, Belgium) was a collaborator for the SELECTION trial and funded this analysis.
Medical writing support for the development of this abstract was provided by Annika Pecchia-Bekkum, PhD, of PharmaGenesis London, London, UK, and was funded by Alfasigma S.p.A.
SS and MR contributed equally.
MR and AO are employees of Alfasigma S.p.A at the time of abstract submission.
SS reports personal fees from AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos/Gilead Sciences, Hikma Pharmaceuticals, I-Mab, Janssen Pharmaceuticals, Morphic Therapeutic, MSD, Mylan, Pfizer, Protagonist Therapeutics, Provention Bio, Sandoz/Hexal, Takeda, Theravance Biopharma and Ventyx Biosciences.
MR and AO are former employees and shareholders of Galapagos NV, and are employees of Alfasigma S.p.A.
JH reports speaker and/or consulting fees from AbbVie, Aqilion, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma and the Falk Foundation, Eli Lilly, Ferring Pharmaceuticals, Galapagos, Gilead Sciences, Hospira, InDex Pharmaceuticals, Janssen Pharmaceuticals, MEDA Pharmaceuticals, Medivir, Medtronic, MSD, Novartis, Pfizer, Prometheus Laboratories Inc., Sandoz, Shire, Takeda, Thermo Fisher Scientific, Tillotts Pharma, Vifor Pharma and UCB; and grants from Janssen Pharmaceuticals, MSD and Takeda.
FR reports consulting fees from Adiso, Adnovate, Agomab, Allergan, AbbVie, Arena, Astra Zeneca, Bausch & Lomb, Boehringer-Ingelheim, Celgene/BMS, Celltrion, CDISC, Celsius, Cowen, Eugit, Ferring, Galapagos, Galmed, Genentech, Gilead, Gossamer, Granite, Guidepoint, Helmsley, Horizon Therapeutics, Image Analysis Limited, Index Pharma, Landos, Jannsen, Koutif, Mestag, Metacrine, Mirum, Mopac, Morphic, Myka Labs, Organovo, Origo, Palisade, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Sanofi, Surmodics, Surrozen, Takeda, Techlab, Teva, Theravance, Thetis, Trix Bio, UCB, Ysios and 89Bio.
PI reports lecture fees from AbbVie, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Ferring Pharmaceuticals, Galapagos, Gilead Sciences, Janssen Pharmaceuticals, MSD, Pfizer, Sandoz, Sapphire Medical, Shire, Takeda, Tillotts Pharma, and Warner Chilcott; grants from Celltrion, Galapagos, MSD, Pfizer and Takeda; and advisory fees from AbbVie, Apriso, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly, Genentech, Gilead Sciences, Hospira, Janssen Pharmaceuticals, MSD, Pfizer, Pharmacosmos, Prometheus, Roche, Sandoz, Samsung Bioepis, Takeda, Topivert, VH2, Vifor Pharma and Warner Chilcott.
BGF reports grants and personal fees from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Janssen Biotech/Centocor, Johnson & Johnson/Janssen, Pfizer, Receptos and Takeda; and personal fees from Ablynx, ActoGeniX, AdMIRx, Akebia Therapeutics, Allergan, Atlantic Pharmaceuticals, Avaxia Biologics, Avir Pharma, Baxter Healthcare Corporation, Biogen, BiomX Israel, Biora Therapeutics (formerly Progenity), Boehringer Ingelheim, Boston Pharmaceuticals, Calypso Biotech, Celgene, Elan/Biogen, Eli Lilly, enGene, Ferring Pharmaceuticals, Galapagos, Genentech/Roche, gIcare Pharma, Gilead Sciences, Given Imaging, Gossamer Bio, GSK, Inception IBD, Ironwood Pharmaceuticals, Japan Tobacco Company, Kyowa Hakko Kirin, Lexicon Pharmaceuticals, Lycera, Mesoblast, MSD, Nestlé, Nextbiotix, Novartis, Novo Nordisk, Par’Immune, Prometheus Therapeutics and Diagnostics, Protagonist Therapeutics, Qu Biologics, Salix Pharmaceuticals, Shire, Sienna Biopharmaceuticals, Sigmoid Pharma, Synergy Pharma, Takeda Oncology (formerly Millennium Pharmaceuticals), Teva Pharmaceuticals, TiGenix, Tillotts Pharma, UCB, Vertex Pharmaceuticals, VHsquared, Vivelix Pharmaceuticals, Wyeth, Zealand Pharma and Zyngenia.
LC is an employee of Open Analytics.
YB is an employee and shareholder of Galapagos NV.
WR reports speaker fees from AbbVie, Celltrion, Ferring Pharmaceuticals, Galapagos, Janssen Pharmaceuticals, Medice, MSD, Pfizer, Roche, Sobi and Takeda; consulting fees from AbbVie, Amgen, AOP Health (formerly AOP Orphan), Boehringer Ingelheim, Bristol Myers Squibb, Calyx, Celltrion, Eli Lilly, Galapagos, Gilead Sciences, InDex Pharmaceuticals, Janssen Pharmaceuticals, MedAhead, Microbiotica, Pfizer and Takeda; advisory board fees from AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Galapagos, Janssen Pharmaceuticals and Pfizer; and research funding from AbbVie, Janssen Pharmaceuticals, Sandoz, Sanofi and Takeda.