Anti-TL1A antibody, afimkibart, in moderately-to-severely active ulcerative colitis (TUSCANY-2): a multicentre, double-blind, treat-through, multi-dose, randomised, placebo-controlled, phase 2b trial
- PMID: 40706613
- DOI: 10.1016/S2468-1253(25)00129-3
Anti-TL1A antibody, afimkibart, in moderately-to-severely active ulcerative colitis (TUSCANY-2): a multicentre, double-blind, treat-through, multi-dose, randomised, placebo-controlled, phase 2b trial
Abstract
Background: TNF-like ligand 1A (TL1A) is an emerging therapeutic target for inflammatory bowel disease. We evaluated the safety and efficacy of multiple doses of afimkibart, a TL1A-directed antibody, in patients with moderately-to-severely active ulcerative colitis.
Methods: The multicentre, double-blind, treat-through, multi-dose, randomised, placebo-controlled, phase 2b, TUSCANY-2 trial was conducted at 114 centres in 23 countries across North America, Europe, Asia, Africa, Australia, and South America. Adults (aged 18-75 years) with moderately-to-severely active ulcerative colitis (total Mayo score [tMS] 6-12, endoscopic subscore ≥2) were randomly assigned (2:2:2:2:2:3:1:1:1) to one of nine treatment sequences to receive subcutaneous afimkibart 50 mg, 150 mg, 450 mg, or matched placebo every 4 weeks during the 12-week induction period, and subcutaneous afimkibart 50 mg, 150 mg, or 450 mg during the treat-through 40-week maintenance period. Investigators and patients were masked to treatment. Study drugs were administered by masked site personnel following preparation by an unmasked pharmacist at the investigational site. Efficacy was assessed at weeks 14 and 56 in the intent-to-treat populations. The primary efficacy endpoint of clinical remission at week 14 by tMS (defined as tMS ≤2, with no individual subscore >1) was assessed in those who received at least one dose of drug or placebo during induction, excluding patients who had missing data due to complications resulting from COVID-19. Safety endpoints were also analysed in those who were randomly assigned and received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, NCT04090411.
Findings: Between Dec 19, 2019, and Oct 25, 2022, 246 patients were randomly assigned treatment, of whom 245 were treated, 228 completed induction, and 178 completed maintenance. Median age was 39 years (IQR 30·0-51·0), 99 (40%) patients were female and 146 (60%) were male; median disease duration was 4·7 years (IQR 2·5-10·2). At week 14, the primary endpoint of clinical remission by tMS was reported in 12 (26%) of 47 patients in the afimkibart 50 mg group (risk difference vs placebo [RD] 13·9% [90% CI -0·2 to 27·7]; p=0·0545), 14 (23%) of 60 patients in the afimkibart 150 mg group (RD 11·7% [-1·7 to 24·1]; p=0·0823), and 21 (24%) of 88 patients in the in the afimkibart 450 mg group (RD 12·2% [-0·6 to 22·9]; p=0·0642) versus five (12%) of 43 patients in the placebo group. In alignment with updated US Food and Drug Administration guidance, clinical remission using the modified Mayo score at week 14 was reported in 14 (30%) of 47 patients in the afimkibart 50 mg group (RD 18·2% [90% CI 3·3 to 32·2]), 21 (35%) of 60 patients in the in the afimkibart 150 mg group (RD 23·4% [6·2 to 36·3]), and 28 (32%) of 88 patients in the in the afimkibart 450 mg group (RD 20·2% [3·2 to 31·3]) versus five (12%) of 43 patients in the placebo group. Overall, 117 (48%) of 245 patients in the induction phase and 132 (59%) of 224 patients in the maintenance phase reported at least one treatment-emergent adverse event; incidences of treatment-emergent adverse events during induction were similar with placebo and afimkibart. The most common treatment-emergent adverse events (occurring in ≥5% of patients) during induction were nausea, urinary tract infection, ulcerative colitis, anaemia, fatigue, headache, and pyrexia. Six serious adverse events were reported during induction in the active treatment groups and four in the placebo group. Two patients who completed induction and did not receive the study drug during maintenance had serious adverse events during safety follow-up. During the maintenance period, 12 (5%) of 224 patients had 13 serious adverse events. No deaths occurred.
Interpretation: Differences in the primary endpoint of clinical remission by tMS were not significantly different for any dose of afimkibart compared with placebo. However, secondary endpoints suggest that afimkibart was associated with a favourable benefit-risk profile, with clinically meaningful improvements in clinical remission with the modified Mayo score for patients with moderately-to-severely active ulcerative colitis. These results support the continued development of afimkibart.
Funding: Pfizer, Roivant Sciences, and F Hoffmann-La Roche.
Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.
Conflict of interest statement
Declaration of interests SD has held a consultancy role or an advisory role for AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Enthera, Ferring Pharmaceutical, Gilead Sciences, Hospira, Inotrem, Janssen, Johnson & Johnson, Eli Lilly, Morphic, MSD, Mundipharma, Mylan, Pfizer, F Hoffmann-La Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB, Vial, and Vifor; and has received lecture fees from AbbVie, Amgen, Ferring, Gilead Sciences, Janssen, Mylan, Pfizer, and Takeda. JRA has held a consultancy role or an advisory role for Janssen, Pfizer, AbbVie, Finch Therapeutics, Seres Therapeutics, Ferring, GSK, Merck, Bristol Myers Squibb, Roivant, and Adiso; has been part of the speakers' bureau for Bristol Myers Squibb, AbbVie, and Janssen; and has received research funding from Pfizer, Janssen, and Merck. SS has held a consultancy role or an advisory role for AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos/Gilead Sciences, Hikma Pharmaceuticals, I-Mab, Janssen Pharmaceuticals, Morphic Therapeutic, MSD, Mylan, Pfizer, Protagonist Therapeutics, Provention Bio, Sandoz/Hexal, Takeda, Theravance Biopharma, and Ventyx Biosciences. L-PB has held a consultancy role or an advisory role for AbbVie, Abivax, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, Bristol Myers Squibb, Celltrion, Connect Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead Sciences, Gossamer Bio, GSK, Hac Pharma, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeuthics, Pandion Therapeuthics, Par' Immune, Pfizer, Prometheus, Protagonist, F Hoffmann-La Roche, Roivant, Samsung, Sandoz, Sanofi, Takeda, Theravance, Thermo Fischer, Tigenix, Tillotts, Viatris, Vifor, Vectivbio, Ventyx, and Ysopia; has been involved in the speakers' bureau for AbbVie, Amgen, Arena, Biogen, Celltrion, Ferring, Galapagos, Genentech, Gilead Sciences, Janssen, Lilly, Medac, MSD, Pfizer, Sandoz, Takeda, Tillotts, Viatris, and Vifor; and has received research funding from Celltrion, Fresenius Kabi, and Takeda, and travel support from AbbVie, Amgen, Celltrion, Connect Biopharm, Ferring, Galapagos, Genentech, Gilead Sciences, Gossamer Bio, Janssen, Lilly, Medac, Morphic, MSD, Pfizer, Sandoz, Takeda, Thermo Fischer, and Tillotts. VJ is employed by the Western University, London Health Sciences Centre, and Alimentiv; has held a consultancy role or an advisory role for AbbVie, Alimentiv, Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, AstraZeneca, Avoro Capital, Bristol Myers Squibb, Celltrion, Eli Lilly, Endpoint Health, Enthera, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GSK, Genentech, Gilead Sciences, Innomar, JAMP, Janssen, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus Biosciences, Reistone Biopharma, F Hoffmann-La Roche, Roivant, Sandoz, Second Genome, Sorriso, Synedgen, Takeda, TD Securities, Teva, Topivert, Ventyx, and Vividion; and has been involved in the speakers' bureau for AbbVie, Ferring, Bristol Myers Squibb, Galapagos, Janssen, Pfizer, Shire, Takeda, and Fresenius Kabi. GH has held a consultancy role or an advisory role for Alimentiv, AbbVie, Bristol Myers Squibb, Boehringer, Celltrion, Eli Lilly, GSK, Immunic, Index, Johnson & Johnson, Polpharm, Takeda, Tillotts, Ventyx, and Pfizer; has been involved in the speakers' bureau for Pfizer, Eli Lilly, and Takeda; and has received research funding from Pfizer, Takeda, Eli Lilly, and Celltrion. RWL has held a consultancy role or an advisory role for AbbVie, Aspen, Bristol Myers Squibb, Celgene, Celltrion, Chiesi, Ferring, Glutagen, Hospira, Janssen, Lilly, MSD, Novartis, Pfizer, Prometheus Biosciences, and Takeda; and has received research funding from Celltrion, Shire, Janssen, Takeda, Gastroenterological Society of Australia, National Health and Medical Research Council, Gutsy Group, Pfizer, Joanna Tiddy grant, and McCusker Charitable Foundation. AY has held a consultancy role or an advisory role for AbbVie, Takeda, Celltrion, Bristol Myers Squibb, Johnson & Johnson, and Abivax. MSV, AB, DEC, EP, SN, and KH are employed by Pfizer with stocks or other ownership interests in Pfizer. JMB, CS, and KL are employed by Genentech/F Hoffmann-La Roche with stocks or other ownership interests in Genentech/F Hoffmann-La Roche. DB is employed by F Hoffmann-La Roche. BF has held a consultancy role or an advisory role for AbbVie, Abivax, Adiso, AgomAB Therapeutics, Allianthera, Amgen, AnaptysBio, Arena Pharma, Avoro Capital Advisors, Atomwise, BioJamp, Biora Therapeutics, Blackbird Laboratories, Boehringer Ingelheim, Boxer Capital, Celsius Therapeutics, Celgene/Bristol Myers Squibb, Connect BioPharma, Cytoki, Disc Medicine, Duality, EcoR1, Eli Lilly, Equillium, Ermium, First Wave, Forbion, Galapagos, Galen Atlantica, Genentech/F Hoffmann-La Roche, Gilead Sciences, Gossamer Pharma, GSK, Hinge Bio, Index Pharma, Imhotex, Immunic Therapeutics, Intercept, JAK Academy, Janssen, Japan Tobacco, Kaleido Biosciences, Klick Health, Landos Biopharma, Lenczner Slaght, LifeSci Capital, Lument AB, Mage Biologics, Mestag, Millennium, MiroBio, Monte Rose Tx, Morgan Lewis, Morphic Therapeutics, Mylan, Nexys Therapeutics, Nimbus Therapeutics, OM Pharma, OrbiMed, Origo BioPharma, Orphagen, Pandion Therapeutics, Pendopharm, Pfizer, Prometheus Therapeutics and Diagnostics (Merck), Progenity, Protagonist, PTM Therapeutics, Q32 Bio, Rebiotix, REDX, F Hoffmann-La Roche, Roivant/Televant, Sandoz, Sanofi, Seres Therapeutics, Silverback Therapeutics, Sobi, Spyre Therapeutics, Surrozen, Synedgen, Takeda, Teva, Thelium, Tigenix, Tillotts, Triastek, Ventyx Biosciences, Zagbio, and Zealand Pharma; and has been involved in the speakers' bureau for Takeda, Janssen and AbbVie. JK has no competing interests.
Publication types
MeSH terms
Associated data
LinkOut - more resources
Full Text Sources
Medical
Research Materials
Miscellaneous
