Efficacy and safety of intravenous induction and subcutaneous maintenance therapy with guselkumab for patients with Crohn's disease (GALAXI-2 and GALAXI-3): 48-week results from two phase 3, randomised, placebo and active comparator-controlled, double-blind, triple-dummy trials
- PMID: 40684778
- DOI: 10.1016/S0140-6736(25)00681-6
Efficacy and safety of intravenous induction and subcutaneous maintenance therapy with guselkumab for patients with Crohn's disease (GALAXI-2 and GALAXI-3): 48-week results from two phase 3, randomised, placebo and active comparator-controlled, double-blind, triple-dummy trials
Abstract
Background: Despite the availability of biological therapies, suboptimal disease control remains a problem for patients with Crohn's disease. We report the results of the GALAXI-2 and GALAXI-3 studies, which aimed to assess the efficacy and safety of intravenous induction followed by subcutaneous maintenance therapy with guselkumab over 48 weeks in adults with moderately to severely active Crohn's disease.
Methods: GALAXI-2 and GALAXI-3 were identically designed, phase 3, randomised, double-blind, triple-dummy, treat-through trials with active and placebo comparators. Adult patients with moderately to severely active Crohn's disease (≥3 months duration) were enrolled at 257 sites across 40 countries. Eligible participants were randomly assigned (2:2:2:1) by use of a centralised computer-generated schedule to one of four treatment groups: (1) 200 mg intravenous guselkumab at weeks 0, 4, and 8, then 200 mg subcutaneous guselkumab every 4 weeks from week 12 to week 44 (guselkumab 200 mg group); (2) 200 mg intravenous guselkumab at weeks 0, 4, and 8, then 100 mg subcutaneous guselkumab every 8 weeks from week 16 to week 40 (guselkumab 100 mg group); (3) approximately 6 mg/kg intravenous ustekinumab at week 0, then 90 mg subcutaneous ustekinumab every 8 weeks from week 8 to week 40 (ustekinumab group); or (4) intravenous placebo every 4 weeks at weeks 0, 4, and 8 (placebo group). At week 12, participants without a clinical response to placebo received masked rescue therapy with ustekinumab; all other participants remained on their randomised regimen irrespective of response status at week 12. Participants, investigators, site personnel, and the funder were masked to study treatment until all participants had either completed the follow-up visit at week 48 or terminated study participation before week 48. Coprimary composite endpoints (comparing each guselkumab regimen with placebo) were (1) clinical response at week 12 and clinical remission at week 48 and (2) clinical response at week 12 and endoscopic response at week 48, measured in the primary analysis population of all randomly assigned participants who received at least one dose of the study agent and satisfied the Simple Endoscopic Score for Crohn's Disease (SES-CD) eligibility criteria introduced with the third protocol amendment as per health authority request. Safety was assessed in participants who received at least one dose of study treatment (all-treated analysis population). These trials are registered with ClinicalTrials.gov (NCT03466411).
Findings: From Jan 8, 2020, to Oct 20, 2023, 1048 participants were randomly assigned, treated, and followed up until week 48, of whom 1021 participants were included in the primary analysis population: 508 (49·8%) in GALAXI-2 and 513 (50·2%) in GALAXI-3. Both guselkumab regimens were superior to placebo for the endpoint of clinical response at week 12 and clinical remission at week 48 in GALAXI-2, which was observed in 80 (55%) of 146 participants in the guselkumab 200 mg group, 70 (49%) of 143 in the guselkumab 100 mg group, and nine (12%) of 76 in the placebo group (adjusted treatment difference 43% [95% CI 32-54] in the guselkumab 200 mg group and 38% [27-49] in the guselkumab 100 mg group; p<0·0001), and in GALAXI-3, observed in 72 (48%) of 150 participants in the guselkumab 200 mg group, 67 (47%) of 143 in the guselkumab 100 mg group, and nine (13%) of 72 in the placebo group (35% [24-46] and 34% [23-45]; p<0·0001). Similarly, both guselkumab regimens were superior to placebo for the endpoint of clinical response at week 12 and endoscopic response at week 48 in GALAXI-2, observed in 56 (38%) participants in the guselkumab 200 mg group, 56 (39%) in the guselkumab 100 mg group, and four (5%) in the placebo group (33% [24-42] in the guselkumab 200 mg group and 34% [24-43] in the guselkumab 100 mg group; p<0·0001), and in GALAXI-3, observed in 54 (36%) participants in the guselkumab 200 mg group, 48 (34%) in the guselkumab 100 mg group, and four (6%) in the placebo group (31% [21-40] and 28% [19-37]; p<0·0001). Serious adverse events occurred in 21 (7%) participants in the guselkumab 200 mg group (incidence rate 9·7 events per 100 participant-years), 32 (11%) in the guselkumab 100 mg group (14·9 events per 100 participant-years), 35 (12%) in the ustekinumab group (18·4 events per 100 participant-years), and 23 (15%) in the placebo group (23·8 events per 100 participant-years). No deaths were reported.
Interpretation: Intravenous induction followed by subcutaneous maintenance therapy with guselkumab was efficacious in participants with moderately to severely active Crohn's disease, showing superiority to placebo and ustekinumab at week 48 across multiple endpoints. Safety outcomes were favourable and consistent with the known profile of guselkumab in approved indications.
Funding: Johnson & Johnson.
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Conflict of interest statement
Declaration of interests RP reports consulting fees from Abbivax, Abbott, AbbVie, Alimentiv (formerly Robarts), Amgen, AnaptysBio, 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, BioJAMP, Johnson & Johnson, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Spyre Therapeutics, Sublimity Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Union Biopharma, Viatris, Ventyx Biosciences, and Union Chimique Belge (UCB); speaker's fees from AbbVie, Amgen, Arena Pharmaceuticals, Bristol Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Gilead Sciences, Johnson & Johnson, Merck, Organon, Pfizer, Roche, Sandoz, Shire, and Takeda Pharmaceuticals; and participation in advisory boards for AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, GlaxoSmithKline, BioJAMP, Johnson & Johnson, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Shire, Sublimity Therapeutics, Takeda Pharmaceuticals, and Ventyx Biosciences. BGF reports consulting fees from AbbVie, AbolerIS Pharma, Agomab Therapeutics, Allianthera, Amgen, AnaptysBio, Applied Molecular Transport, Arena, Avoro Capital Advisors, Atomwise, BioJAMP, Biora, Boehringer Ingelheim, Boxer, Celsius, Celgene (Bristol Myers Squibb), Connect BioPharma, Cytoki, Disc Medicine, Duality, EcoR1, Eli Lilly, Equillium, Ermium, First Wave, First Word Group, Galapagos, Galen Atlantica, Genentech (Roche), Gilead, Gossamer, GlaxoSmithKline, Hinge Bio, Hot Spot, Index, Imhotex, Immunic, JAK Academy, Japan Tobacco, Johnson & Johnson, Kaleido, Landos, Leadiant, LEK Consulting, LifeSci Capital, Lument AB, Millennium, MiroBio, Morphic, Mylan, OM Pharma, Origo, Orphagen, Pandion, Pendopharm, Pfizer, Prometheus, PlayToKnow AG, Progenity, Protagonist, PTM Therapeutics, Q32 Bio, Rebiotix, REDX, Roche, Sandoz, Sanofi, Seres, Silverback, Surrozen, Takeda, Teva, Thelium, Tigenix, Tillotts, Ventyx Biosciences, VHSquared, Viatris, Ysios, Ysopia, and Zealand Pharma; a member of the speakers bureau for AbbVie, Johnson & Johnson, Takeda, and Boehringer Ingelheim; payment for expert testimony from Morgan Lewis and Lenczner Slaght; support for attending meetings and/or travel from AbbVie, Johnson & Johnson, Pfizer, Takeda, and Boehringer Ingelheim; participation on a data safety monitoring board or advisory board from AbbVie, Amgen, AnaptysBio, Boehringer Ingelheim, Celgene (Bristol Myers Squibb), Eli Lilly, Genentech (Roche), Johnson & Johnson, MiroBio, Origo BioPharma, Pfizer, Prometheus, RedX, Sanofi, Takeda, Tillotts, Teva, Progenity, Index, Ecor1Capital, Morphic, GlaxoSmithKline, and Axio; and stock or stock options in Gossamer. AA reports serving as a speaker for AbbVie, Bristol Myers Squibb, Johnson & Johnson, Pfizer, and Takeda; a consultant for AbbVie, Bristol Myers Squibb, DiaSorin, Eli Lilly, Gilead, Johnson & Johnson, Pfizer, Takeda, and TLL Pharmaceuticals; an advisory board member for AbbVie, Bristol Myers Squibb, Eli Lilly, Gilead, Johnson & Johnson, Pfizer, and Takeda; and co-founder and board member of IBD Horizons and Scrubs & Heels Foundation. AA also reports receiving educational or research grants from AbbVie, Bristol Myers Squibb, Eli Lilly, Johnson & Johnson, Pfizer, and Takeda. DTR reports consulting fees, advisory board participation, and stock options from Altrubio and Iterative Health; consulting fees, advisory board participation, and grants from Takeda; and consulting fees and advisory board participation from AbbVie, Abivax, Athos Therapeutics, Bristol Myers Squibb, Celltrion, Connect BioPharma, Eli Lilly, Genentech (Roche), Johnson & Johnson, Merck, Odyssey Therapeutics, Pfizer, Sanofi, Spyre Therapeutics, Vedanta Biosciences, and Ventyx Biosciences. WR has served as a speaker for AbbVie, Celltrion, Ferring, Galapagos Medice, Johnson & Johnson, MSD, Roche, Pfizer, Sobi, and Takeda; a consultant for AbbVie, Amgen, AOP Orphan, Boehringer Ingelheim, Bristol Myers Squibb, Calyx, Celltrion, Eli Lilly, Galapagos, Gilead, Index Pharma, Johnson & Johnson, Medahead, Microbiotica, Pfizer, and Takeda; an advisory board member for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Galapagos, Johnson & Johnson, and Pfizer; and has received research funding from AbbVie, Johnson & Johnson, Sandoz, Sanofi, and Takeda. JP reports consultancy fees or honorarium from AbbVie, Alimentiv, Athos, Atomwise, Boehringer Ingelheim, Celsius, Ferring, Galapagos, Genentech (Roche), GlaxoSmithKline, Johnson & Johnson, Mirum, Nimbus, Pfizer, Progenity, Prometheus, Protagonist, Revolo, Sanofi, Sorriso, Surrozen, Takeda, and Wasserman; and has served on a data safety monitoring board for Alimentiv, Mirum, Sorriso, Sanofi, and Surrozen. SD reports consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enthera, Ferring, Gilead, Hospira, Inotrem, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity, Takeda, TiGenix, UCB, and Vifor; and lecture fees from AbbVie, Amgen, Ferring, Gilead, Johnson & Johnson, Mylan, Pfizer, and Takeda. TH reports grant support from Mitsubishi Tanabe Pharma Corporation, EA Pharma, AbbVie GK, JIMRO, Zeria Pharmaceutical, Kyorin Pharmaceutical, Nippon Kayaku, Takeda Pharmaceutical, Pfizer, Mochida Pharmaceutical, Boston Scientific Corporation, and Kissei Pharmaceutical; consulting fees from Mitsubishi Tanabe Pharma Corporation, EA Pharma, AbbVie GK, Johnson & Johnson, Pfizer, Eli Lilly, Gilead Sciences, Bristol Myers Squibb, and Abivax; and lecture fees from Mitsubishi Tanabe Pharma Corporation, AbbVie GK, EA Pharma, Kyorin Pharmaceutical, JIMRO, Johnson & Johnson, Mochida Pharmaceutical, Takeda Pharmaceutical, Pfizer, and Kissei Pharmaceutical. NAT, LS, RVR, MLV, JY, CH, MEF, KYYW, ZY, and JJ are employees of Johnson & Johnson and own stock or stock options from Johnson & Johnson. AS reports previous employment with Johnson & Johnson. JMA reports research support, speaker's fees, and/or honoraria to her institution or the Crohn's Colitis Cure for advisory board participation and coordination of educational events from AbbVie, Allergan, Anatara, Atmo Capsule, Bayer, Bristol Myers Squibb (2020), Celgene, Celltrion, Falk, Gilead, Hospira, Immuninc, ImmunsanT, Johnson & Johnson, MSD, Nestle, Novartis, Pfizer, Royal Adelaide Hospital Research Fund, Sandoz, Shire, Takeda, Vifor, The Hospital Research Fund (2020–22), and The Helmsley Trust (2020–23); and reports serving as board director for Gastroenterological Society of Australia, the board chair for Crohn's Colitis Cure, and an unpaid adviser to Crohn's and Colitis Australia. GRD'H reports consultancy activities for AbbVie, Abivax, Agomab, Alimentiv, AnaptysBio, AstraZeneca, Biora, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom, Johnson & Johnson, Merck, Mirador, Pfizer, Polpharma, Procise Diagnostics, Prometheus Laboratories, Prometheus Biosciences, Progenity, Protagonist Therapeutics, Sanofi, Sorriso, Spyre Therapeutics, and Takeda; speakers bureaus for AbbVie, Bristol Myers Squibb, Eli Lilly, Pfizer, and Takeda; and data monitoring board activities for AbbVie, AstraZeneca, Galapagos, and Seres Health. BES reports consulting fees from AbbVie, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, AstraZeneca, Biolojic Design, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Celltrion, Equillium, Enthera, Enveda Biosciences, Evommune, Ferring, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Imhotex, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Kaleido, Kallyope, Merck, Microba, Mirador Therapeutics, Mobius Care, Morphic Therapeutics, MRM Health, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Therapeutics, Reistone Biopharma, Sanofi, Sorriso Pharmaceuticals, Spyre Therapeutics, Sun Pharma, Surrozen, Target RWE, Teva, TLL Pharmaceutical, Tr1X, Union Therapeutics, Ventyx Biosciences, and Vividion Therapeutics; consulting and speaking fees from Abivax; consulting and speaking fees and other support from Lilly; research grants, consulting and speaking fees, and other support from Bristol Myers Squibb, Johnson & Johnson, Pfizer, and Takeda; and stock or stock options from Ventyx Biosciences.
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