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    Afimkibart

    Modality: TL1A monoclonal antibody

    Disease State: Inflammatory Bowel Disease (IBD)

    Summary

    Afimkibart targets both inflammatory and fibrotic pathways by inhibiting the tumor necrosis factor-like cytokine 1A (TL1A), a cytokine that amplifies inflammatory response and modulates fibrotic pathways in IBD.1

    Clinical Trials

    IBD
    Phase Enrollment Status Title
    Phase III Enrolling A Phase III, Multicenter, Double-Blind, Placebo-Controlled, Treat-Through Study to Assess the Efficacy and Safety of Induction and Maintenance Therapy With afimkibart (RO7790121) in Patients With Moderately to Severely Active Ulcerative Colitis (Ametrine-1) View Details
    Phase III Enrolling A Phase III, Multicenter, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Induction Therapy With afimkibart (RO7790121) in Patients With Moderately to Severely Active Ulcerative Colitis (Ametrine-2) View Details
    Phase III Enrolling A Phase III, Multicenter, Double-Blind, Placebo-Controlled, Treat-Through Study to Assess the Efficacy and Safety of Induction and Maintenance Therapy With afimkibart (RO7790121) in Patients With Moderately to Severely Active Crohn's Disease (Siberite-1) View Details
    Phase III Enrolling A Phase III, Multicenter, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Induction Therapy With afimkibart (RO7790121) in Patients With Moderately to Severely Active Crohn's Disease (Siberite-2) View Details

    Proposed Mechanism of Action

    Afimkibart is being investigated as an agent that targets both inflammatory and fibrotic pathways by inhibiting TL1A, a cytokine that is involved in the pathogenesis of IBD. TL1A binds its receptor, death domain receptor 3 (DR3), amplifies inflammatory response, and could modulate fibrotic pathways in patients with IBD. Early clinical studies with afimkibart demonstrated downregulated tissue T helper 1 (Th1) and T helper 17 (Th17) and showed first-in-human impact on fibrotic pathways.1

    TL1A in IBD

    TL1A, a member of the tumor necrosis factor (TNF) superfamily, is a cytokine that is involved in the pathogenesis of IBD and has been identified as a potential therapeutic target. It has been shown to amplify proinflammatory pathways and expression is upregulated in inflamed intestinal tissues.2-4

    • TL1A is expressed mainly on antigen-presenting cells (APCs) under inflammatory conditions and binds to its functional receptor DR3, which is primarily expressed on lymphocytes. The interaction between TL1A and DR3 modulates the immune response, particularly at the mucosal surfaces.5

    TL1A has been found to play an important role in the development of intestinal fibrosis, as demonstrated in animal studies. Sustained TL1A expression in colitis mouse models leads to small and large intestinal fibrostenosis and treatment with neutralizing TL1a antibody (Ab) reversed colonic fibrosis. Hence, the TL1A-DR3 antagonism may be a therapeutic opportunity for targeting inflammation and fibrosis in IBD and potentially other inflammatory/fibrotic conditions.4

    Figure 1.6

    DR3= death domain receptor 3; GM-CSF= granulocyte-macrophage colony-stimulating factor; IFN= interferon; IL= interleukin; ILC= innate lymphoid cell; TCR= T-cell receptor; TL1A= tumor necrosis factor-like cytokine 1A; TNF= tumor necrosis factor.

    1. Hassan-Zahraee M, Ye Z, Xi L, Baniecki ML, Li X, Hyde CL, Zhang J, Raha N, Karlsson F, Quan J, Ziemek D. Antitumor necrosis factor-like ligand 1A therapy targets tissue inflammation and fibrosis pathways and reduces gut pathobionts in ulcerative colitis. Inflammatory Bowel Diseases. 2022 Mar 1;28(3):434-46.
    2. Barrett R, Zhang X, Koon HW, Vu M, Chang JY, Yeager N, Nguyen MA, Michelsen KS, Berel D, Pothoulakis C, Targan SR. Constitutive TL1A expression under colitogenic conditions modulates the severity and location of gut mucosal inflammation and induces fibrostenosis. The American journal of pathology. 2012 Feb 1;180(2):636-49.
    3. Takedatsu H, Michelsen KS, Wei B, Landers CJ, Thomas LS, Dhall D, Braun J, Targan SR. TL1A (TNFSF15) regulates the development of chronic colitis by modulating both T-helper 1 and T-helper 17 activation. Gastroenterology. 2008 Aug 1;135(2):552-67.
    4. Shih DQ, Zheng L, Zhang X, Zhang H, Kanazawa Y, Ichikawa R, Wallace KL, Chen J, Pothoulakis C, Koon HW, Targan SR. Inhibition of a novel fibrogenic factor Tl1a reverses established colonic fibrosis. Mucosal immunology. 2014 Nov 1;7(6):1492-503.
    5. Valatas V, Kolios G, Bamias G. TL1A (TNFSF15) and DR3 (TNFRSF25): a co-stimulatory system of cytokines with diverse functions in gut mucosal immunity. Frontiers in immunology. 2019 Mar 27;10:421466.
    6. Figure developed with information from:
      • Nakase H, Sato N, Mizuno N, Ikawa Y. The influence of cytokines on the complex pathology of ulcerative colitis. Autoimmun Rev. 2022:21(3): 103017. do: 10.1016/​i.autrev.2021.103017
      • Bamias G, Kaltsa G, Siakavellas SI, et al. High intestinal and systemic levels of decoy receptor 3(DcR3) and its ligand TLIA in active ulcerative colitis. Clin Immunol. 2010;137(2): 242-249. doi:10.1016/​j.clim.2010.07.001
      • Xu W-D, Li R, Huang AF-. Role ofTL1A ni inflammatory autoimmune diseases: a comprehensive review. Front Immunol. 2022;13:891328. doi: 10.3389/​fimmu.2022.891328
      • Solitano V, Jairath V, Ungaro F, Peyrin-Biroulet L, Danese S. TL1A inhibition for inflammatory bowel disease treatment: from inflammation to fibrosis. Med. 2024;5(5):386-400. do:10.1016/​j.medj.2024.03.010
      • Hassan-Zahraee M, Ye Z, Xi L, et al. Antitumor necrosis factor-like ligand 1A therapy targets tissue inflammation and fibrosis pathways and reduces gut pathobionts in ulcerative colitis. Inflamm BowelDis. 2022;28(3):434-446. doi: 10.1093/​ibd/​izab193

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    TOP

    • Ab
      Antibody

    • APCs
      antigen-presenting cells

    • DR3
      death domain receptor 3

    • GM-CSF
      granulocyte-macrophage colony-stimulating factor

    • IBD
      Inflammatory Bowel Disease

    • IFN
      interferon

    • IL
      interleukin

    • ILC
      innate lymphoid cell

    • TCR
      T-cell receptor

    • Th1
      T helper 1

    • Th17
      T helper 17

    • TL1A
      tumor necrosis factor-like cytokine 1A

    • TNF
      tumor necrosis factor