Introduction

Guselkumab (GUS), a dual-acting IL-23p19 subunit inhibitor, demonstrated efficacy in participants (pts) with moderately to severely active ulcerative colitis (UC) treated with GUS subcutaneous (SC) induction and maintenance in the Phase 3 ASTRO study. Here we present data for bowel urgency and abdominal pain symptoms as measured by the Ulcerative Colitis Patient-Reported Outcomes Signs and Symptoms (UC-PRO/SS) instrument at Week (W) 12 and W24.

Aims & Methods

Eligible pts had a modified Mayo score of 5 to 9, a rectal bleeding subscore of ≥1, and a Mayo endoscopic subscore (MES) ≥2. Pts had a documented inadequate response/intolerance to biologics, Janus kinase (JAK) inhibitors, and/or sphingosine-1-phosphate (S1P) inhibitors (BIO/JAKi/S1Pi-IR) or to corticosteroids, 6-mercaptopurine, or azathioprine. Randomization was stratified by baseline BIO/JAKi/S1Pi-IR status and MES with 418 pts allocated 1:1:1 to GUS 400 mg SC every 4 weeks (q4w) (x3)→GUS 200 mg SC q4w (N=140), GUS 400 mg SC q4w (x3)→GUS 100 mg SC every 8 weeks (q8w) (N=139), or placebo (PBO) (N=139). Pts who met rescue criteria at W16 were rescued: PBO pts switched to GUS; GUS pts stayed on their assigned GUS dose regimen (sham rescue). The prespecified analysis plan compared the combined GUS 400 mg SC group to PBO at W12 (both the GUS 100 mg q8w and 200 mg q4w groups received the same induction dosing regimen through W12) and each GUS group to PBO at W24. The UC-PRO/SS is a validated instrument to assess the severity of bowel-related symptoms.¹ Clinically meaningful improvements (CMI) in bowel signs and symptoms and abdominal symptoms scales were evaluated. Complete resolution of individual core symptoms (bowel urgency and abdominal pain) was assessed.

Results

Baseline mean UC-PRO/SS domain scores were similar across treatment groups (Table). The proportions of pts with bowel urgency at baseline were 81.3% in the GUS 100 mg group, 84.3% in the GUS 200 mg group, 82.8% in the GUS combined group, and 87.1% in the PBO group. Greater proportions of GUS-treated pts had resolution of bowel urgency at W12 (GUS combined vs PBO: 45.0% vs 23.1%, nominal P<0.001) and W24 (GUS 100 mg and GUS 200 mg vs PBO: 47.8% and 41.5% vs 22.3%; nominal P<0.001 for both). The proportions of pts with abdominal pain at baseline were 78.4% in the GUS 100 mg group, 74.3% in the GUS 200 mg group, 76.3% in the GUS combined and 78.4% in the PBO group. Greater proportions of GUS-treated pts had resolution of abdominal pain at W12 (GUS combined vs PBO: 48.8% vs 23.9%, nominal P<0.001) and W24 (GUS 100 mg and GUS 200 mg vs PBO: 45.9% and 45.2% vs 25.7%; nominal P<0.001 for both). The proportions of pts with no bowel urgency and no abdominal pain were greater for GUS vs PBO at W12 and W24 (Table). GUS-treated pts achieved greater improvement from baseline at W12 and W24 in domain and individual core symptoms compared with PBO-treated pts (Table). The proportions of pts achieving CMI in each domain score were greater for GUS vs PBO at both timepoints (Table).

Conclusion

Pts with moderately to severely active UC treated with GUS SC experienced CMI at W12 and W24 in UC signs and symptoms as measured by UC-PRO/SS compared with PBO.

References

Higgins PDR, et.al. J Patient Rep Outcomes. 2017;2:26.

Disclosure

SD reports consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enthera, Ferring, Gilead, Hospira, Inotrem, Janssen (Johnson & Johnson), Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity, Takeda, TiGenix, UCB, and Vifor and reports lecture fees from AbbVie, Amgen, Ferring, Gilead, Janssen (Johnson & Johnson), Mylan, Pfizer, and Takeda.

LPB reports grants or contracts from Celltrion, Fresenius Kabi, Medac, MSD, and Takeda; consulting and/or payment or honoraria and/or data safety monitoring board or advisory board participation for AbbVie, Abivax, Adacyte, Alfasigma, Alimentiv, Amgen, Applied Molecular Transport, Arena, Banook, Biogen, Bristol Myers Squibb, Celltrion, Connect Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GlaxoSmithKline, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen (Johnson & Johnson), Kern Pharma, Lilly, Medac, Mopac, Morphic, MSD, Nordic Pharma, Novartis, Oncodesign Precision Medicine, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par' Immune, Pfizer, Prometheus, Protagonist, Roche, Samsung, Sandoz, Sanofi, Satisfay, Takeda, Telavant, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vectivbio, Ventyx, and Ysopia; and meeting attendance/travel support from Abbvie, Alfasigma, Amgen, Celltrion, Connect Biopharm, Ferring, Galapagos, Genentech, Gilead, Gossamer Bio, Janssen (Johnson & Johnson), Lilly, Medac, Morphic, MSD, Pfizer, Sandoz, Takeda, Thermo Fischer, and Tillots.

ML reports research support from Lilly, Pfizer, and Takeda and consulting for AbbVie, Bristol Myers Squibb, Intercept, Janssen (Johnson & Johnson), Lilly, Pfizer, Prometheus, Roivant, Takeda, and Target RWE.

MG, TB, YA, MK, CH, SJ, LJ, and HZ are employees of and may own stock in Johnson & Johnson.

TH reports research grants from AbbVie GK, Boston Scientific Corporation, EA Pharma Co. Ltd., JIMRO Co. Ltd., Kissei Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Pfizer Inc., Takeda Pharmaceutical Co. Ltd., and Zeria Pharmaceutical Co. Ltd.; consulting fees from AbbVie GK, Abivax, Bristol Myers Squibb, EA Pharma Co. Ltd., Gilead Sciences, Janssen Pharmaceutical K.K., Lilly, Mitsubishi Tanabe Pharma Corporation, and Pfizer Inc.; and lecture fees from AbbVie GK, EA Pharma Co. Ltd., Janssen Pharmaceutical K.K., JIMRO Co., Kissei Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Pfizer Inc., and Takeda Pharmaceutical Co. Ltd.

DTR reports consulting and/or speaker fees and/or advisory board participation for AbbVie, Altrubio, Apex, Avalo, Bristol Myers Squibb, Buhlmann Diagnostics, Celgene, Connect BioPharma, Intouch Group, Iterative Health, Janssen (Johnson & Johnson), Lilly, Pfizer, Samsung Neurologica, and Takeda; Altrubio, Datos Health, and Iterative Health stock options; grants from Takeda; and membership on the Board of Directors of Cornerstones Health, Inc and on the Crohn’s & Colitis Foundation’s Board of Trustees.

JRA reports grant support from Janssen (Johnson & Johnson), Merck, and Pfizer; consultancy fees from AbbVie, Adiso, Bristol Myers Squibb, Ferring, Genentech, GlaxoSmithKline, Janssen (Johnson & Johnson), Merck, Pfizer, Roivant, and Seres Therapeutics; payments for speaking from AbbVie, Bristol Myers Squibb, and Janssen (Johnson & Johnson); and is a steering committee member and investigator for Janssen (Johnson & Johnson).

Introduction

In perianal fistulizing Crohn’s disease (PFCD), higher infliximab (IFX) serum trough concentrations are associated with improved outcomes. Most PFCD patients require dose intensification to achieve therapeutic target concentrations. IFX pharmacokinetics (PK) in PFCD have not been previously characterized. We hypothesized that IFX clearance (CL) is increased in PFCD compared to Crohn’s disease with luminal disease only (CD).

Aims & Methods

Patients with CD and PFCD starting standard-dose intravenous IFX (5 mg/kg at week 0, 2, 6, thereafter every 8 weeks) were enrolled. Pre-infusion samples were collected from week 2 to 26 to measure IFX trough levels (TL), and anti-drug antibodies if IFX TL was below 1.0 μg/mL. Target TL were 20 μg/mL (week 2), 15 μg/mL (week 6), and 10 μg/mL (week 14) for PFCD, and 5.0 μg/mL (week 14) for CD. A population PK model was constructed using nonlinear mixed-effects modeling and adjusted for clinically relevant covariates.

Results

A total of 148 patients were included (63 PFCD, 85 CD), contributing 761 serum samples. Baseline demographics were comparable, except for higher luminal disease activity and concomitant immunomodulator use in CD. During induction, target IFX TL were achieved in significantly fewer PFCD patients (43% vs. 57%, P = .038). At week 14, median IFX TLs were lower in PFCD (2.8 μg/mL [IQR 1.0-5.4] than in CD (4.8 μg/mL [IQR 2.0–6.6], P = .014), with target TL attainment in only 9% of PFCD versus 46% of CD patients (P < .001). In multivariate regression analysis, PFCD was independently associated with a sevenfold increased risk of underdosing at week 14 (adjusted risk ratio [aRR] = 7.14, P < .001). Anti-drug antibodies (ADA) against infliximab were detected in 10/19 (53%) of PFCD patients and 9/25 (36%) CD patients with IFX TL below 1 μg/mL (P = .36) after a median of 20 weeks, with 35% of cases being transient during follow-up. While more PFCD patients had very low infliximab levels at week 14 (<1 μg/mL; 22% vs. 10%, P = .07), ADA presence and median ADA levels at that time did not differ significantly between these groups (P = .99 and P = .25, respectively).
IFX PK was described by a two-compartment model with linear elimination. Population PK modeling of the first 14 weeks revealed an 18% increase in IFX CL among patients with active perianal fistulas adjusted for dose, weight, serum albumin and presence of anti-drug antibodies (P < 0.01).

Conclusion

Active perianal fistulas are independently associated with increased infliximab clearance in patients with Crohn’s disease, resulting in significantly lower and frequently subtherapeutic serum trough levels despite standard induction dosing. At week 14, patients with PFCD had a sevenfold higher risk of underexposure compared to those with luminal CD only. These findings highlight a critical need for intensified or personalized infliximab dosing strategies during induction in PFCD to optimize therapeutic exposure and improve clinical outcomes.