Introduction
Anti-Tumor Necrosis Factor-α (anti-TNF) agents are widely used as first-line therapy for Crohn’s disease (CD), yet some patients experience loss of response over time. Guselkumab (GUS), a dual-acting IL-23p19 subunit inhibitor1, was efficacious vs placebo (PBO) and ustekinumab (UST) in biologic-inadequate response/intolerance (IR) participants (pts) with moderately to severely active CD in the Phase 3 GALAXI 2&3 studies.2 We evaluated the efficacy of GUS in anti-TNF-IR subgroups by history of prior anti-TNF therapy.
Aims & Methods
Post-hoc analyses pooled data from Phase 3 GALAXI 2&3 in adults with moderately to severely active CD and a history of IR to oral corticosteroids, azathioprine/6-mercaptopurine/methotrexate, or biologics randomized to GUS 200mg intravenously (IV) at Week (W) 0, W4, and W8, followed by 100mg subcutaneously (SC) every 8 weeks (Q8W) from W16-40; GUS 200mg IV at W0, W4, and W8, followed by 200mg SC Q4W from W12-44; UST ~6mg/kg IV at W0, followed by 90mg Q8W SC from W8-40; or PBO. Anti-TNF-IR subgroups were: 1 anti-TNF-IR (pts with only 1 prior anti-TNF-IR; may have failed other non‑anti‑TNF therapies), ≥2 anti-TNF-IR (pts with ≥2 prior anti-TNF-IR; may have failed other non‑anti‑TNF therapies), and anti-TNF-IR only (pts who had failed only anti-TNF agents prior). Clinical response (≥100-point decrease from W0 in CD Activity Index [CDAI] or CDAI<150), clinical remission (CDAI<150), and endoscopic response (≥50% improvement from W0 in Simple Endoscopic Score for CD [SES-CD] or SES-CD≤2) were assessed at W12 for GUS vs PBO. Clinical remission, endoscopic response, and endoscopic remission (SES-CD≤4, ≥2-point reduction from W0 in SES-CD, and no sub-score >1) were assessed at W48 for GUS vs UST. Pts with missing data after applying intercurrent event rules were considered as non-responders.
Results
Of 515 anti-TNF-IR pts in GALAXI 2&3, 149 received GUS 100mg SC, 143 GUS 200mg SC, 147 UST, and 76 PBO.
At W12, GUS induction showed higher rates vs PBO of clinical response (1 anti-TNF-IR: 62% vs 23%; ≥2 anti-TNF-IR: 58% vs 22%; anti-TNF-IR only: 61% vs 23%), clinical remission (47% vs 19%; 44% vs 17%; 47% vs 20%), and endoscopic response (30% vs 6%; 24% vs 9%; 30% vs 6%). W12 outcomes and treatment differences between GUS and PBO were consistent across anti-TNF-IR subgroups, suggesting similar induction responses irrespective of prior anti-TNF therapy history.
At W48, both SC GUS maintenance doses (100mg and 200mg) generally showed greater proportions of clinical remission, endoscopic response, and endoscopic remission at W48 vs UST across anti-TNF-IR subgroups (Table 1). In pts with ≥2 anti-TNF-IR, GUS SC 200mg achieved greater clinical and endoscopic outcomes than GUS SC 100mg and UST (Table 1).
Table 1. Clinical and endoscopic outcomes at W48 across treatment and anti-TNF-IR subgroups
| GUS 100mg SC Q8W | GUS 200mg SC Q4W | UST 90mg SC Q8W |
| 1 anti-TNF-IR (N=118) | ≥2 anti-TNF-IR (N=31) | Anti-TNF-IR only (N=128) | 1 anti-TNF-IR (N=112) | ≥2 anti-TNF-IR (N=31) | Anti-TNF-IR only (N=129) | 1 anti-TNF-IR (N=101) | ≥2 anti-TNF-IR (N=46) | Anti-TNF-IR only (N=125) |
| Clinical remission, % (95% CI) | 63%
(54, 71) | 48%
(31, 66) | 59%
(51, 68) | 64%
(55, 73) | 68%
(51, 84) | 67%
(59, 76) | 57%
(48, 67) | 35%
(21, 49) | 49%
(40, 58) |
| Endoscopic response, % (95% CI) | 49%
(40, 58) | 19%
(5, 33) | 45%
(37, 54) | 44%
(35, 53) | 58%
(41, 75) | 48%
(39, 57) | 36%
(26, 45) | 20%
(8, 31) | 30%
(22, 38) |
| Endoscopic remission, % (95% CI) | 31%
(23, 40) | 13%
(1, 25) | 29%
(21, 37) | 30%
(21, 38) | 23%
(8, 37) | 29%
(21, 37) | 21%
(13, 29) | 15%
(5, 26) | 18%
(11, 24) |
Conclusion
In pts with CD and anti-TNF-IR, GUS showed numerically greater clinical and endoscopic outcomes vs PBO at W12 and vs UST at W48. While both GUS SC maintenance doses had comparable efficacy for the 1 anti-TNF-IR and the anti-TNF-IR only subgroups, in more refractory pts (i.e., ≥2 anti-TNF-IR subgroup), GUS 200mg SC appeared more efficacious than GUS 100mg SC and UST.
References
- Sachen K. Frontiers in Immunology. 2025; doi:10.3389/fimmu.2025.1532852.
- Panaccione R. et al. Lancet. 2025; 406, 358-375.
Disclosure
WR speaker for AbbVie, Celltrion, Ferring, Johnson & Johnson, Galapagos Medice, MSD, Roche, Pfizer, Sobi, Takeda, consultant for AbbVie, Amgen, AOP Orphan, Boehringer Ingelheim, BMS, Calyx, Celltrion, Eli Lilly, Galapagos, Gilead, Index Pharma, J&J, Medahead, Microbiotica, Pfizer, Takeda; advisory board member for AbbVie, Amgen, Boehringer Ingelheim, BMS, Celltrion, Galapagos, J&J, Pfizer; and research funding from AbbVie, J&J, Sandoz, Sanofi, Takeda.
RP consulting fees from Abbivax, Abbott, AbbVie, Alimentiv, Amgen, Arena, AstraZeneca, Biogen, Boehringer Ingelheim, BMS, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring,Fresenius Kabi, Galapagos, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, J&J, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda, Theravance Biopharma, Trellus, Viatris, Ventyx, UCB; speaker’s fees from AbbVie, Amgen, Arena Pharmaceuticals, BMS, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Gilead Sciences, J&J, Merck, Organon, Pfizer, Roche, Sandoz, Shire, Takeda Pharmaceuticals; advisory boards for: AbbVie, Alimentiv, Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, BMS, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, GSK, JAMP Bio, Johnson & Johnson, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Shire, Sublimity Therapeutics, Takeda, Ventyx.
GD consultancy activities for AbbVie, Agomab, Alimentiv, AstraZeneca, AMT, Bristol Meyers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom, Galapagos, GlaxoSmithKline, Gossamerbio, Immunic, Index, J&J, Kaleido, Origo, Pfizer, Polpharma, Procise Diagnostics, Prometheus Laboratories, Prometheus Biosciences, Progenity, and Protagonist Therapeutics Inc.; speaker’s bureau for AbbVie, BMS, Galapagos, Pfizer, and Takeda; and data monitoring board activities for AbbVie, AstraZeneca, Galapagos, Seres Health.
TH grant support from AbbVie, Boston Scientific Corporation, EA pharma, JIMRO, Kissei, Kyorin, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Takeda, Zeria Pharmaceutical; consulting fees from AbbVie, BMS, EA pharma, Eli Lilly, Gilead Sciences, J&J, Mitsubishi Tanabe Pharma Corporation, Nichi-Iko Pharmaceutical, Pfizer; and lecture fee from AbbVie, EA pharma, JIMRO, J&J, Kissei, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical, Pfizer, Takeda.
BES honoraria consulting from Aclaris, Adaxion, Adiso, Agomab, Alfasigma, Alimentiv, Amgen, AnaptysBio, AstraZeneca, Attovia, Biolojic Design, BiomeBank, Biora, Boehringer-Ingelheim, Caldera Therapeutics, Cellarity, Cytoki Pharma, Disc Medicine, Eli Lilly, Ensho Therapeutics, Enthera, Enveda Biosciences, Equilium, Evommune, Ferring, Fzata, Galapagos, Genentech (Roche), Genesis Therapeutics, Gilead Sciences, GlaxoSmithKline, Globalport, Ignite Biomedical, Imedex, Imhotex, Immunitas Therapeutics, Immunyx Pharma, Kallyope, Kyowa Kirin, LifeMine Therapeutics, Merck, Merck Sharp & Dohme, Microba, Microbiotica, Mirador Therapeutics, Mitsubishi Tanabe Pharma, Mobius Care, Morphic Therapeutic, MRM Health, Nexus Therapeutics, Nimbus Discovery, Novartis, Numab Therapeutics, Odyssey Therapeutics, ONO Pharmaceutical, OSE Immunotherapeutics, Palisade Bio, Pioneering Medicines Explorations, Prometheus Biosciences, Protagonist Therapeutics, Q32 Bio, Quotient Therapeutics, Rasayana Therapeutics, Recludix Pharma, Reistone Biopharma, Sanofi, Slate Bio, Sorriso Pharmaceuticals, Spyre Therapeutics, Synlogic, Target RWE, Televant, Teva, Thetis Pharmaceuticals, SRT Therapeutics, TR1X, Trex Bio, Union Therapeutics, VectivBio, Vedanta Biosciences, Vividion Therapeutics, Xencor; for consulting and speaking and other support from AbbVie, Abivax, Bristol Myers Squibb, Celltrion, Eli Lilly, Genentech (Roche), Johnson & Johnson, Merck, Pfizer, Takeda, Teva; honoraria for consulting, stock options from Caldera Therapeutics, Mirador Therapeutics, and SRT Therapeutics; and stock from Doximity.
RVR, WvD, SA, and GS are employees of Johnson & Johnson and may own Johnson & Johnson stock/stock options.
SD consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enthera, Ferring, Gilead, Hospira, Inotrem, J&J, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity, Takeda, TiGenix, UCB, Vifor; and lecture fees from AbbVie, Amgen, Ferring, Gilead, Johnson & Johnson, Mylan, Pfizer, Takeda
AA potential conflicts of interest with AbbVie, BMS/Celgene, DiaSorin, Eli Lilly, Gilead, IBD Horizons, Janssen, Pfizer, Takeda, and TLL.
