Introduction
Guselkumab (GUS), a dual-acting IL-23p19 subunit inhibitor, is highly efficacious in participants (pts) with Crohn’s disease (CD) after intravenous (IV) or subcutaneous (SC) induction followed by SC maintenance. This analysis characterized pharmacokinetics (PK) and exposure-response (E-R) for efficacy and safety of both administration routes and confirmed assumptions for the development of IV and SC induction formulations.
Aims & Methods
GUS efficacy and safety in pts with moderate to severely active CD were evaluated in the phase 2 GALAXI 1 (200, 600, or 1200 mg IV at week [W]0, W4, and W8),1 phase 3 GALAXI 2 and 3 (200 mg IV at W0, W4, and W8),2 and phase 3 GRAVITI studies (400 mg SC at W0, W4, and W8).3 All studies used treat-through designs and the same SC maintenance dose regimens (100 mg q8w or 200 mg q4w). With an estimated ~50% bioavailability of SC GUS, the 2-fold higher SC induction dose was predicted to provide similar overall exposure and noninferior trough concentrations compared with the IV dose.
To characterize GUS PK, a population PK model was used to simulate exposure metrics for IV and SC induction using individual post-hoc PK parameters and actual pt dosages. Relationships between GUS exposure and select efficacy endpoints (clinical response, clinical remission, and endoscopic response) at week 12 were assessed.
Results
SC induction resulted in higher trough serum concentrations (at W12), lower peak serum concentrations, similar average concentrations (W0–W12), and similar area under the concentration-time curves (W0–W12) vs IV induction (Table). Regardless of induction route (IV or SC) or maintenance regimen, GUS serum concentrations reached steady state by W24.
W12 efficacy outcomes were comparable within GUS concentration quartiles after SC vs IV induction. Although pts with higher serum GUS concentrations tended to achieve greater W12 efficacy outcomes, this trend was no longer evident after accounting for a pt’s drug clearance or the half-life of the drug. W48 outcomes were similar in pts who received the same maintenance regimen, regardless of induction dose route. No positive E-R trends were seen between peak concentration and W12 efficacy endpoints; thus, the higher peak concentration observed with IV induction did not seem to improve efficacy. Across concentration quartiles, the incidence of safety events was comparable between pts who received GUS IV or SC induction regimens. No positive associations between serum concentrations and adverse events (infections, serious infections, and serious adverse events) or abnormal liver function tests were observed.
| GUS 200 mg IV q4w
(N=622) | GUS 400 mg SC q4w
(N=229) |
Cmax (µg/mL)
Mean (SD) |
70.1 (25.1) |
27.7 (9.06) |
Cave, week 0-12 (µg/mL)
Mean (SD) |
21.4 (7.06) |
18.9 (6.47) |
Ctrough, week 12 (µg/mL)
Mean (SD) |
9.76 (5.38) |
14.7 (6.65) |
AUC week 0-12 (day*µg/mL)
Mean (SD) |
1,800 (593) |
1,590 (543) |
| AUCweek 0-12=area under the concentration-time curve from week 0 to week 12 (induction); Cave, week 0-12=average concentration from week 0 to week 12 (induction); Cmax=maximum concentration; Ctrough, week 12=trough concentration at week 12 (induction); IV=intravenous; PK=pharmacokinetic; q4w=every 4 weeks; SC=subcutaneous; SD=standard deviation; W=week. |
Conclusion
Average serum GUS concentrations and E-R relationships were similar after IV vs SC induction and had no impact on safety, supporting the use of either administration route and induction dose regimen in CD patients.
References
1. Sandborn WJ, et al. Guselkumab for the treatment of Crohn's disease: induction results from the phase 2 GALAXI-1 study. Gastroenterology. 2022; 162(6):1650-1664.e8.
2. Panaccione R, et al. Efficacy and safety of guselkumab therapy in patients with moderately to severely active Crohn’s disease: results of the GALAXI 2 & 3 phase 3 studies. Gastroenterology. 2024; 166 (5 Supplement):1057b.
3. Hart A, et al. Efficacy and safety of guselkumab subcutaneous induction and maintenance in participants with moderately to severely active Crohn's disease: results from the phase 3 GRAVITI study. Gastroenterology. 2025; S0016-5085(25)00522-0.
Disclosure
Geert D’Haens has served as advisor and/or speaker for Abbvie, Abivax, Agomab, Alimentiv, Anaptys Bio, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Galapagos, Glaxo Smith Kline, Index Pharmaceuticals, Johnson and Johnson, Merck, Polpharm, Prometheus biosciences, Sanofi, Takeda, Tillotts.
Omoniyi J. Adedokun, Tae Eun Yang, Nat A. Terry, Mobolaji Olurinde, Rian Van Rampelbergh, and Marion L. Vetter are employees of Janssen Research & Development (a Johnson & Johnson Company) and may own company stock/stock options.
Bruce E. Sands reports potential conflicts of interest with AbbVie, Abivax, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, Artugen Therapeutics, AstraZeneca, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Evommune, Ferring, Fresenius Kabi, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Janssen, Kaleido, Kallyope, Lilly, Merck, Microbiotica, Mobius Care, Morphic Therapeutics, MRM Health, Pfizer, Nexus Therapeutics, Nimbus Discovery, Odyssey, Therapeutics, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Therapeutics, Reistone Biotherapeutics, Sun Pharma, Surrozen, Target RWE, Takeda, Teva, Theravance Biopharma, TLL Pharmaceutical, TR1X, Union Therapeutics and Ventyx Biosciences.
Silvio Danese reports potential conflicts of interest with AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enthera, Ferring, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity, Takeda, TiGenix, UCB, and Vifor.
Tadakazu Hisamatsu reports potential conflicts of interest with AbbVie, Bristol Myers Squibb, Daiichi-Sankyo, EA Pharma Co, Ltd., Eli Lilly, Gilead Sciences, Janssen Research & Development, LLC., JIMRO, Kissei Pharmaceutical Co, Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Inc., and Takeda Pharmaceutical Co., Ltd.
Remo Panaccione reports potential conflicts of interest with Abbivax, Abbott, AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Viatris, Ventyx, and UCB.