Introduction
No data exist on the relationship between serum and tissue infliximab (IFX) concentrations and outcomes in acute severe ulcerative colitis (ASUC).
Aims & Methods
In hospitalized patients (pts) with ASUC treated with IFX rescue therapy, we assessed relationships between longitudinal serum and tissue IFX concentrations and pt outcomes. In an open-label, prospective study, hospitalized ASUC pts treated with IFX rescue therapy were followed for 22 weeks (wks) at 2 centers. Inclusion criteria: (A) hospitalized ASUC (partial Mayo score [PMS] > 7, baseline Mayo endoscopic score [MES] ≥ 2 and met Truelove/Witts criteria) (B) receiving either standard or accelerated rescue IFX. From IFX initiation until wk 22, clinical scores (PMS) and serum sampling were performed at multiple induction and maintenance timepoints (hospital/outpatient). Colonoscopy scores (MES) and biopsies were collected on day 2-5 post first infusion (early inpatient) and wk 16-22 (maintenance). Outcomes: Median area under the curve (AUC) of serum IFX concentration during early induction (wk 0-2), induction (wk 0-14) and maintenance (wk 15-22) were compared between wk 22 endoscopic remitters (ERs) (MES 0 or 1 without UC-related hospitalization or colectomy) and non-remitters (NRs). Tissue IFX concentrations were compared between groups.
Results
110 serum samples over 22 wks (mean 7.9 samples/pt) with 54 samples between wk 0- 2 (mean= 3.9/pt) were collected. Biopsies at early inpatient (n=17) and maintenance colonoscopies (n=15) were collected from 14 pts. Mean age was 38 years, 50% were female, mean disease duration was 7.8 years and 69% had pancolitis. One NR needed colectomy and another was re-hospitalized. 50% achieved endoscopic remission at wk 22. ERs had numerically higher baseline CRP (49 [±28] vs. 31 [±24] mg/dL), immunomodulator use (71% vs. 43%) and clinical response (86% vs. 43%) to NRs, while albumin (3.3 [±0.9] vs. 2.9 [±0.6] g/dL) and total IFX dose between wk 0-2 (16 [±1] vs. 12 [±6] mg/kg) were more similar. Mean BMI was 23.8 kg/m2. Between wk 0-2, the mean number of IFX infusions per pt was 1.5 (±0.7), and median dose per infusion was 11.4 mg/kg (IQR 25-75: 11-19). Median serum IFX concentration AUC was higher in ERs than NRs in early induction (wk 0-2: 568 ug*day/mL [528-1627] vs. 293 [145- 423], p=0.004), all induction (wk 0-14: 3036 [2742-3199] vs. 1768 [1375-2468] p=0.004) and in maintenance (wk 15-22: 841 [309-3295] vs. 405 [295-718] p=0.002). Findings were similar for dose normalized AUC. Peak concentration 2 hrs post first infusion was numerically higher in ERs vs. NRs (median 365 ug/mL [200-484] vs. 187 [140-355] p=0.15) overall and dose-adjusted. Anti- IFX antibodies were detected in one NR maintenance sample. Baseline clearance inversely correlated with AUC (r=-0.7, p=0.03) or dose-normalized induction AUC (r=-0.8, p=0.01). Tissue IFX concentrations were similar in inflamed/non-inflamed tissue and were similar between ERs/NRs in early induction (median 104 ng/mg [89-114] vs. 107 [76-133], p=1.0), and maintenance (10 [4-69] vs. 26 [3-87], p=0.99). Percent of drug in tissue vs. serum was similar between ERs/NRs (induction: median 7% vs 8%; maintenance: 8% vs 6%).
Conclusion
Intense serum and tissue sampling of ASUC pts receiving IFX showed higher serum drug exposure at all timepoints in endoscopic remitters whereas tissue concentrations were similar regardless of outcome. Tissue IFX may be required but not sufficient for achievement of outcomes in ASUC.
Disclosure
PC, SS, and LE report no conflicts of interest.
PL, MR, MS, MF and WT are employees of Alimentiv Inc
RB Speaker/consulting/moderator: Bristol Myers Squibb, Janssen, 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, Merck, Celltrion, Organon. Travel support: Pfizer, Celltrion, Johnson and Johnson Innovative Medicine, Abbvie.
WA reports consulting fees and participation on advisory board from Johnson & Johnson and Takeda Pharmaceuticals, Inc.
BB reports consulting fees and participation on advisory board from Bristol Myers Squibb, Abbvie, Merck and has grant funding from Merck, Mirador, Prometheus, and Gilead.
PD reports consulting fees from Alimentiv.
MD M. Duijvestein reports speaking fee from Bristol Meyers Squibb, Takeda, Galapagos, Janssen, Dr. Falk, advisory board feest form Abbvie, Bristol Meyers Squibb, Celltrion, Galapagos/Alfasigma, Janssen, Takeda and grant/Research support: Pfizer, Bristol Meyers Squibb, Galapagos Alfasigma, Janssen
MSS 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.
RL Consultant for Xencor, Sanofi. SAB member for CJ Biosciences, Ancilia, and Montage Bio.
DL consulting: Abbvie, AltruBio, BMS, Boehringer Ingelheim, Eli Lilly, Johnson & Johnson, PSI, Palatin, Pfizer, Prime, Takeda, Vedanta. Speaking fees: Abbvie, Johnson & Johnson; Grants: Boehringer Ingelheim, Johnson & Johnson.
ES has obtained 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.
BGF reports consulting fees from AbbVie,Abivax,Adiso,AgomAB Therapeutics,Allianthera,Amgen,AnaptysBio,Arena Pharma,Avoro Capital Advisors,Atomwise,,BioJamp,Biora Therapeutics,Blackbird Laboratories,Boehringer-Ingelheim,Boxer Capital,Celsius Therapeutics,Celgene/BMS,Connect BioPharma,Cytoki,Disc Medicine,Duality,EcoR1,Eli Lilly,Equillium,Ermium,First Wave,Forbion,Galapagos,Galen Atlantica,Genentech/Roche,Gilead,Gossamer Pharma,GSK,Hinge Bio,Index Pharma,Imhotex,Immunic Therapeutics,Intercept,JAKAcademy,Janssen,Japan Tobacco Inc.,Kaleido Biosciences,Klick Health,Landos Biopharma,Lenczner Slaght,LifeSci Capital,Lument AB,Mage Biologics,Mestag,Millennium,MiroBio,Monte Rose Tx,Morgan Lewis,Morphic Therapeutics,Mylan,Nexys Therapeutics,Nimbus Therapeutics,OM Pharma,OrbiMed Origo BioPharma,Orphagen,Pandion Therapeutics,Pendopharm,Pfizer,Prometheus Therapeutics and Diagnostics (Merck),Progenity,Protagonist,PTM Therapeutics,Q32 Bio,Rebiotix,REDX,Roche,Roivant/Televant,Sandoz,Sanofi,Seres Therapeutics,Silverback Therapeutics,Sobi,Spyre Therapeutics,Surrozen Inc.,Synedgen,Takeda,Teva,Thelium,Tigenix,Tillotts,Triastek,Ventyx; lecture fees from Takeda,Janssen,and AbbVie; participation on advisory board for AbbVie,AnaptysBio,Boehringer-Ingelheim,Celgene/BMS,Eli Lilly,Genentech/Roche,Janssen,Merck,MiroBio,Origo BioPharma,Pfizer,REDX Pharma,Sanofi,Takeda,Teva,Ecor1Capital,Morphic,GSK; stock or stock options from Evida,EnGene,and Connect Biopharma.
WS reports consulting fees from Alimentiv, Eli Lilly, Forbion, Prometheus Biosciences, Prometheus Laboratories, Shoreline Biosciences, Ventyx Biosciences; stock or stock options from Eli Lilly, Prometheus Biosciences, Prometheus Laboratories, Shoreline Biosciences, Mirador Therapeutics, Ventyx Biosciences; and employee at Mirador Therapeutics and Ventyx Biosciences. Spouse: Eli Lilly – stock, Merck - employee; Prometheus Laboratories – stock, stock options; Ventyx Biosciences – stock, stock options
VJ reports consulting fees and participation on advisory board for AbbVie, Alimentiv, Altrubio, Amgen, AnaptysBio, Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, BiomeBank, Boehringer Ingelheim, Bristol Myers Squibb, Calluna Pharma, Celltrion, Eli Lilly, Endpoint Health, Ensho Therapeutics, Enthera, Exeliom Biosciences, Ferring, Flagship Pioneering, Fresenius Kabi, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, MRM Health, Nxera Therapeutics, Pandion, Pendopharm, Pfizer, Protagonist, Reistone Biopharma, Roche, Roivant, Sandoz, Sanofi, Second Genome, Sorriso, Spyre Therapeutics, Takeda, Teva, Tillotts, Ventyx, Vividion; speaker fees from AbbVie, Ferring, Bristol Myers Squibb, Galapagos, Janssen, Pfizer, Takeda, Tillotts, and Fresenius Kabi.
NVC reports research grants from R-Biopharm and consulting fees from AcelaBio, Alimentiv, Pfizer, ProciseDX, Prometheus Biosciences, and Spyre Therapeutics. NVC is a current employee of Mirador Therapeutics.