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    Sefaxersen (RG6299, RO7434656)

    Modality: Antisense oligonucleotide that targets factor B

    Disease State: IgA nephropathy (IgAN)

    Summary

    Sefaxersen (ASO factor B) is an antisense oligonucleotide that inhibits complement factor B gene expression by binding with factor B mRNA.1

    Clinical Trials

    IgA nephropathy (IgAN)
    Phase Enrollment Status Title
    Phase III Recruiting A Study to Evaluate the Efficacy and Safety of Sefaxersen (RO7434656) in Participants With Primary Immunoglobulin A (IgA) Nephropathy at High Risk of Progression (IMAgINATION) View Details

    Proposed Mechanism of Action

    Complement Cascade

    • In IgAN, the alternative pathway is the main activator of the complement cascade2–4
      • Factors B and D drive complement cascade activation, resulting in C3 deposition2–4
      • Glomerular C3 deposition correlates with IgAN disease progression and is observed in 71–100% of patients with IgAN2
    • Inhibiting complement FB production suppresses alternative complement activation5,6

    ASO Factor B: Antisense Technology

    • Antisense technology interrupts the translation phase of protein production by preventing the mRNA instructions from reaching the ribosome1
    • The ASO drug binds to its target mRNA triggering the release of RNase H1 enzyme, which cleaves the target mRNA
    • Destruction of the target mRNA reduces production of the disease‑causing protein encoded by that mRNA

    Sefaxersen binds specifically to complement FB mRNA, triggering RNase H1-mediated mRNA degradation.7–10

    Figure adapted from Crooke ST, et al. Nucleic Acid Ther. 2019;29:16–32

    1. Barratt J, et al. Presented at the American Society of Nephrology (ASN) Kidney Week. November 2-5, 2023; Philadelphia, PA, USA. [SA-PO885]
    2. Caravaca-Fontán F, et al. Clin Kidney J. 2023;16:ii28-ii39;
    3. Dunkelberger JR, et al. Cell Res. 2010;20:34–50;
    4. Chiu YL, et al. Front Immunol 2021;12:638309;
    5. Reich HN, et al. J Am Soc Nephrol 2007;18:3177-83;
    6. Barbour S, Hladunewich M, Makris A, et al. Phase II results of an investigational RNA therapeutic to complement factor B, IONIS-FB-LRx, for treatment of IgA nephropathy. American Society of Nephrology (ASN) Kidney Week. October 23-27, 2024. San Diego, CA, USA. [TH-PO1205]
    7. Crooke ST, et al. Nucleic Acid Ther. 2019;1:16-32;
    8. Medjeral-Thomas NR, et al. Semin Immunopathol 2021;43:679-690;
    9. Debacker AJ, et al. Mol Ther. 2020; 28:1759-1771.
    10. Figure adapted from Crooke ST, et al. Nucleic Acid Ther. 2019;29:16–32

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    TOP

    • ASO
      Antisense Oligonucleotide

    • DNA
      deoxyribonucleic acid ribonucleic acid

    • eGFR
      estimated glomerular filtration rate

    • ESKD
      end-stage kidney disease

    • FB
      factor B

    • IgA
      immunoglobulin A

    • IgAN
      Immunoglobulin A nephropathy

    • LRx
      ligand prescription drug

    • mRNA
      messenger ribonucleic acid

    • RNA
      ribonucleic acid

    • RNAse
      ribonuclease