DOP066Pharmacokinetics and transcriptomic analysis reveal the molecular signature of mucosal healing in patients with Acute Severe Ulcerative Colitis treated with infliximab (PROTOS)

Abstract Background Infliximab (IFX), a monoclonal antibody targeting tumour necrosis factor-α, is utilised as a rescue therapy in acute severe ulcerative colitis (ASUC). The relationships between IFX concentrations in serum and colonic mucosa and the pharmacodynamic changes underlying mucosal healing are not well defined. Methods We conducted an open-label, prospective, observational study in hospitalised patients with ASUC requiring rescue IFX to characterise the pharmacokinetics (PK) of IFX in serum and colonic mucosa, and to assess the relationships between IFX exposure, molecular signatures, and treatment response. Patients were followed for up to 22 weeks (wks), with longitudinal collection of serum samples (wks 0-22) and biopsies (day 2 and between wk 1622). Serum and tissue IFX concentrations were compared between endoscopic remitters (ERs; Mayo endoscopic subscore of 0 or 1 at wk 22 without an interim UC-related hospitalisation or colectomy) and non-remitters (NRs). RNA sequencing was performed on colonic biopsies to analyse differential gene expression and pathways between ERs and NRs. Results 14 patients (7 ERs and 7 NRs) completed the study. PK analysis demonstrated that ERs maintained significantly higher median dose-normalised serum IFX area under the curve than NRs during early induction (wk 0-2: 0.943 vs 0.402 µg*day/mL/mg, p = 0.007), induction (wk 014: 2.053 vs 1.223, p = 0.007), and maintenance therapy (wk 15-22: 0.823 vs 0.188, p = 0.007) (Figure 1A). In contrast, tissue IFX concentrations were similar, regardless of inflammation status or response outcome (Figure 1B). Transcriptomic profiling showed similar gene expression on day 2 between ERs and NRs. However, at end of study, profound transcriptional changes were observed in ERs, with 382 genes upregulated and 2,536 genes downregulated (Figure 2A). NRs showed only 1 end-of-study differentially expressed gene (DEG) compared to day 2 (Figure 2B). Pathway analysis of the DEGs in ERs indicated a significant decrease in both innate and adaptive immune responses. This was accompanied by a concomitant upregulation of metabolic processes, reflecting the molecular hallmarks associated with mucosal healing. Conclusion Endoscopic remission in ASUC was strongly associated with high systemic IFX exposure across all treatment phases. Transcriptomic profiling showed a profound molecular differentiation, characterised by widespread suppression of inflammatory pathways and upregulation of metabolism in ERs, despite similar tissue IFX concentrations to NRs. Our study was the first to demonstrate the tissue transcriptional pharmacodynamics of IFX in ASUC while controlling for colonic drug exposure. Conflict of interest: Battat, Robert: Speaker/consulting/moderator: Bristol Myers Squibb, Johnson and Johnson Innovative Medicine, AbbVie, Takeda, Ferring, Celltrion, Pfizer, Merck, Eli Lilly Advisory boards: Celltrion, AbbVie, Pfizer, Janssen, Bristol Myers Squibb, Takeda, Merck, Eli Lilly Educational grants and educational sponsorships: Abbvie, Johnson and Johnson Innovative Medicine, Pfizer, Eli Lilly, Amgen, Pendopharm, Kye Pharma, Merck, Celltrion, Organon, Takeda Travel support: Pfizer, Celltrion, Johnson and Johnson Innovative Medicine, Abbvie. Massimino, Luca: Employee of Alimentiv Inc. Lefevre, Pavine: Employee of Alimentiv Inc. Ahmed, Waseem: No conflict of interest Charilaou, Paris: Advisory board fees from AbbVie and consulting fees from Prometheus Biosciences Boland, Brigid: consulting fees and participation on advisory board from Celltrion, Sanofi, Abbvie, Merck and has grant funding from Merck, Mirador, Prometheus, SRT Therapeutics and Gilead. Singh, Siddharth: No conflict of interest Dulai, Parambir: Grant: Takeda, Bristol Meyer Squibb, Merck, Genentech, Geneoscopy Personal Fees: Abbvie, Abivax, Alimentiv, Bristol Meyer Squibb, Boehringer Ingelheim, Celltrion, Cristcot, Genentech, Geneoscopy, Janssen, Lilly, Merck, Pfizer, Sanofi, Takeda Duijvestein, Marjolijn: Speaking fee from Bristol Meyers Squibb, Takeda, Galapagos, Janssen, Dr. Falk advisory board fees from Abbvie, Bristol Meyers Squibb, Celltrion, Galapagos/Alfasigma, Janssen, Takeda and grant/research support: Pfizer, Bristol Meyers Squibb, Galapagos Alfasigma, Janssen, MSD, Eli Lilly Eckmann, Lars: No conflict of interest Silverberg, Mark: Speaker for Abbvie, Janssen, Takeda, Pfizer, Ferring, Novartis, and Lilly. Advisor for Abbvie, Janssen, Takeda, Pfizer, Ferring, Gilead, Amgen, Merck, and Lilly. Research for Abbvie, Janssen, Takeda, Pfizer, and Gilead. Consults for Abbvie, Janssen, Takeda, Pfizer, and Lilly. Longman, Randy: Grant: Grant support from Boeringer Ingelheim. Personal Fees: Consultant for Pfizer, Sanofi, CJ Biosciences, Ancilia, Lukin, Dana: Consulting: Abbvie, Altrubio, Boehringer Ingelheim, Eli Lilly, Johnson & Johnson, Palatin, Pfizer, Prime, PSI, Takeda, Vedanta. Grants: Boehringer Ingelheim, Johnson & Johnson Speaking: Abbvie, Johnson & Johnson Scherl, Ellen: Grant/research support from Abbott (AbbVie), AstraZeneca, CCFA, Janssen Research &Development, Johns Hopkins University, National Institute of Diabetes and Digestive and Kidney (NIDDK), National Institute of Health (NIH), New York Crohn’s Foundation, Pfizer, UCB, UCSF–CCFA Clinical Research Alliance, Genentech, Seres Therapeutics, Celgene Corporation. Consulting fees are reported for AbbVie, Crohn’s and Colitis Foundation of America (CCFA), Entera Health, Evidera, GI Health Foundation, Janssen, Protagonist Therapeutics, Seres Health, Takeda Pharmaceuticals, Bristol Myers Squibb. Stock shareholder of Gilead, and honoraria of GIHealth Foundation for non-branded speaker’s bureau, Janssen for non-branded speaker’s bureau. Rueffer, Matthew: Employee of Alimentiv Inc. Smith, Michelle: Employee of Alimentiv Inc. Filice, Melissa: Employee of Alimentiv Inc. Teft, Wendy: Employee of Alimentiv Inc Feagan, Brian G.: Consulting Fees: AbbVie, Abivax, Adaxion, Adiso, AgomAB Therapeutics, Akros, Alira Health, Ally Bridge Group, Apini Therapeutics, Argenx, Attovia Tx, Avoro Capital Advisors, Belmore Law, Biora Therapeutics, Blackbird Laboratories, Boehringer-Ingelheim, BMS, Boxer Capital, Celgene/BMS, Clarivate, Connect Biopharm, EcoR1, Eli Lilly, Ensho Therapeutics, Equillium, Evida, Enveda, Evommune Inc. Faes Farma, First Wave, Forbion, Galapagos, Genentech/Roche, General Atlantic, Genesis Therapeutics, Gerson Lehrman Group, Gilead, Guidepoint, Imhotex, ImiDomics, Immunic Therapeutics, Janssen, Japan Tobacco Inc., LifeMine Therapeutics, Mage Biologics, Merck, Mirador Therapeutics, Mobius Care, Monte Rosa Tx, Morphic Therapeutics, Nimbus Therapeutics, Novartis, Nxera, OncoC3, Palisade Bio, Pendopharm, Pfizer,Q32 Bio, REDX, Roche, Sanofi, Sobi, Sorriso, Spyre Therapeutics, Sun Pharma, Surrozen Inc., Synedgen, Takeda, Tegus Inc., Teva, Tillotts, Trex Bio, TR1X Inc. TVM Lifesciences, Ventyx Biosciences, Versant Ventures, Vida Ventures, Ysios Capital, Zagbio Stock Shareholder: Connect Biopharm, EnGene, Evida, SRT, Imidomics, Enveda Sandborn, William: Grant: Abbvie, Abivax, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene, Genentech, Gilead Sciences, Glaxo Smith Kline, Janssen, Lilly, Pfizer, Prometheus Biosciences, Seres Therapeutics, Shire, Takeda, Theravance Biopharma Personal Fees: Abbvie, Abivax, Admirx, Alfasigma, Alimentiv (Robarts Clinical Trials, owned by Health Academic Research Trust HART), Alivio Therapeutics, Allakos, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, Bausch Health (Salix), Beigene, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Meyers Squibb, Celgene, Celltrion, Cellularity, Cosmo Pharmaceuticals, Escalier Biosciences, Equillium, Forbion, Genentech/Roche, Gilead Sciences, Glenmark Pharmaceuticals, Gossamer Bio, Immunic (Vital Therapies), Index Pharmaceuticals, Intact Therapeutics, Janssen, Kyverna Therapeutics, Landos Biopharma, Lilly, Oppilan Pharma, Otsuka, Pandion Therapeutics, Pfizer, Progenity, Prometheus Biosciences, Protagonists Therapeutics, Provention Bio, Reistone Biopharma, Seres Therapeutics, Shanghai Pharma Biotherapeutics, Shire, Shoreline Biosciences, Sublimity Therapeutics, Surrozen, Takeda, Theravance Biopharma, Thetis Pharmaceuticals, Tillotts Pharma, UCB, Vendata Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivelix Pharmaceuticals, Vivreon Biosciences, Zealand Pharma Other: Allakos, BeiGene, Gossamer Bio, Oppilan Pharma, Prometheus Biosciences, Progenity, Shoreline Bioscien