P0925Pharmacokinetics and exposure-response relationships of guselkumab intravenous or subcutaneous induction in participants with Ulcerative Colitis

Abstract Background Guselkumab (GUS), a dual-acting IL-23p19 subunit inhibitor, is highly efficacious in participants (pts) with ulcerative colitis (UC) after intravenous (IV) or subcutaneous (SC) induction, followed by SC maintenance therapy. Here, we evaluated the pharmacokinetics (PK) and exposure-response (E-R) of IV and SC GUS induction. Methods The GUS clinical development programme in pts with moderately to severely active UC consisted of the phase 2b/3 QUASAR studies of IV induction (200 mg every 4 weeks q4w x3) and SC maintenance (100 mg every 8 weeks q8w or 200 mg q4w) and the phase 3 ASTRO study of SC induction (400 mg q4w x3) and SC maintenance (same as QUASAR). All studies had randomised, double-blind, placebo-controlled, parallel group designs. To compare GUS PK exposure after 200 mg IV vs 400 mg SC induction through week 12 (W12), individual post-hoc PK parameter values (estimated with the established QUASAR 2-compartment linear population PK popPK model with first-order absorption and elimination) and pt dosing information from QUASAR and ASTRO were used to simulate concentration-time profiles and calculate individual induction exposure metrics. Comparative graphical E-R analysis (QUASAR vs ASTRO) was conducted for key W12 efficacy outcomes (clinical remission, clinical response, endoscopic improvement, and histologic-endoscopic mucosal improvement) using the overall exposure during induction (Cave, week 0–12) and associated exposure quartiles from the combined study populations. Results Consistent with model predictions, SC induction resulted in similar average concentrations (W0–W12), similar area under the concentration-time curves (W0–W12), lower peak concentrations (at W8), and higher trough concentrations (at W12) compared with the PK profile of IV induction (Table). GUS steady-state concentration was reached by W24, and popPK model-based simulations showed that serum GUS concentrations were comparable by W24 after the same maintenance dose regimen, regardless of induction administration route. Key efficacy outcomes at W12 were comparable within the same GUS concentration quartiles following IV vs SC induction (Figure). Similar positive E-R trends were observed after IV or SC induction. Conclusion Consistent average serum GUS concentrations and E-R patterns after IV and SC induction underscore the observed clinical efficacy and support the use of either induction administration route in UC patients. Conflict of interest: Peyrin-Biroulet, Laurent: reports consulting for AbbVie, Abivax, Adacyte, Alfasigma, Alimentiv, Amgen, Apini, Banook, Bristol Myers Squibb, Celltrion, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Iterative Health, Johnson & Johnson, LifeMine, Lilly, Medac, Morphic, MSD, Nordic Pharma, Novartis, Oncodesign, Precision Medicine, ONO Pharma, OSE Immunotherapeutics, Par’ Immune, Pfizer, Prometheus, Roche, Roivant, Samsung, Sandoz, Sanofi, Sorriso, Spyre, Takeda, Teva, ThirtyfiveBio, Tillots, Vectivbio, Vedanta, and Ventyx and lecture fees from AbbVie, Alfasigma, Amgen, Biogen, Celltrion, Ferring, Galapagos, Genentech, Gilead, Iterative Health, Johnson & Johnson, Lilly, Medac, MSD, Nordic Pharma, Pfizer, Sandoz, Takeda, and Tillots. Xu, Zhenhua: employee of and may own stock in Johnson & Johnson Shao, Jie: employee of and may own stock in Johnson & Johnson Hisamatsu, Tadakazu: Grant support: Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., AbbVie GK, JIMRO Co. Ltd., Zeria Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc., Mochida Pharmaceutical Co. Ltd., Boston Scientific Corporation, Kissei Pharmaceutical Co. Ltd. Consulting: Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., AbbVie GK, Janssen Pharmaceutical K.K., Pfizer Inc., Eli Lilly, Gilead Sciences, Bristol Myers Squibb, Abivax, MSD, Chugai. Lecture fee: Mitsubishi Tanabe Pharma Corporation, AbbVie GK, EA pharma Co. Ltd., Kyorin Pharmaceutical Co. Ltd., JIMRO Co., Janssen Pharmaceutical K.K., Mochida Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc., Kissei Pharmaceutical Co. Ltd. Long, Millie: reports research support from Lilly, Pfizer, Takeda, and Celltrion and consulting for AbbVie, Pfizer, Bristol Myers Squibb, Roivant, Johnson & Johnson, Merck, Takeda, Prometheus, Lilly, Intercept, Target RWE, Celltrion, Sanofi, and Spyre. Danese, Silvio: Personal Fees: AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals Inc., Gilead, Hospira, Inotrem, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB Inc., Vial, Vifor Lecture fees from Abbvie, Amgen, Ferring Pharmaceuticals Inc., Gilead, Janssen, Mylan, Pfizer, Takeda Germinaro, Matthew: employee of and may own stock in Johnson & Johnson Vetter, Marion: employee of and may own stock in Johnson & Johnson Yarandi, Shadi: employee of and may own stock in Johnson & Johnson Baker, Thomas: employee of and may own stock in Johnson & Johnson Allegretti, Jessica R: consultant for Abbvie, Bristol Myers Squibb, Celltrion, Ferring, Genentech, GSK, Johnson & Johnson, Merck, Pfizer, Roivant, Seres Therapeutics, Shattuck Labs, and Roivant Adiso speaker for Abbvie and Johnson & Johnson Rubin, David T.: Grant support: Takeda Pharmaceuticals Consultant: Abbvie, Abivax SA, Altrubio, Athos Therapeutics, Inc, Bristol-Myers Squibb, Celltrion, Connect BioPharma, Eli Lilly & Co., Genentech (Roche) Inc., Iterative Health, Johnson & Johnson, Merck & Co., Mirador, Odyssey Therapeutics, Pfizer, Sanofi, Spyre, Takeda Pharmaceuticals, Vedanta Biosciences, and Ventyx.