Skip To Main Content

Fenebrutinib (RG7845)

Modality: Bruton’s tyrosine kinase inhibitor (BTKi)

Disease State: Multiple Sclerosis (MS)

The information we provide may include references to a Genentech product or use of a Genentech product that the FDA has not approved; because the FDA has not approved such product(s) or use, no conclusions regarding safety or efficacy may be made.

Summary

Fenebrutinib is an investigational, potent, non-covalent, reversible Bruton’s tyrosine kinase inhibitor (BTKi) in Phase III studies for Relapsing Multiple Sclerosis (RMS) and Primary Progressive Multiple Sclerosis (PPMS)

Clinical Trials

Multiple Sclerosis
Phase Enrollment Status Title
Phase III ACTIVE, NOT ENROLLING A Phase III Multicenter, Randomized, Double-Blind, Double-Dummy, Parallel-Group Study to Evaluate the Efficacy and Safety of Fenebrutinib Compared With Ocrelizumab in Adult Patients With Primary Progressive Multiple Sclerosis (FENtrepid; NCT04544449) View Study Design
Phase III ACTIVE, NOT ENROLLING A Phase III Multicenter Randomized, Double-Blind, Double-Dummy, Parallel-Group Study to Evaluate the Efficacy and Safety of Fenebrutinib Compared With Teriflunomide in Adult Patients With Relapsing Multiple Sclerosis (FENhance 1; NCT04586010) View Study Design
Phase III ACTIVE, NOT ENROLLING A Phase III Multicenter Randomized, Double-Blind, Double-Dummy, Parallel-Group Study to Evaluate the Efficacy and Safety of Fenebrutinib Compared With Teriflunomide in Adult Patients With Relapsing Multiple Sclerosis (FENhance 2; NCT04586023)

Bruton's Tyrosine Kinase (BTK) and Multiple Sclerosis (MS)

Bruton’s Tyrosine Kinase (BTK) is an enzyme that plays a key role in the normal immune response but may contribute to both relapsing and progressive biologies underlying MS.

During the emergence of pathogenic B cells in the periphery, B-cell receptor stimulation triggers downstream BTK signaling, leading to activation and maturation of autoreactive B cells. Within the CNS, the stimulation of Fcγ receptors on microglia and macrophages triggers intracellular BTK signaling pathways that culminate in cellular activation. BTK inhibition therefore has the potential to impact both relapsing and progressive biologies underlying MS by suppressing activation of pathogenic B cells, macrophages and microglia.

Pathophysiology of MS Role of BTK Proposed MOA of Fenebrutinib

Pathophysiology of MS

Role of BTK

Proposed MOA of Fenebrutinib

  1. Absinta M, Sati P, Masuzzo F, et al. Association of chronic active multiple sclerosis lesions with disability in vivo. JAMA Neurol. 2019;76(12):1474–1483.
  2. Ahn JJ, Abu-Rub M, Miller RH. B cells in neuroinflammation: new perspectives and mechanistic insights. Cells. 2021;10(7):1605.
  3. Avasarala J. Redifining acute relapses in multiple sclerosis: implications for phase 3 clinical trials and treatment algorithms. Innov Clin Neurosci. 2017;14(3–4):38–40.
  4. Bar-Or A. The immunology of multiple sclerosis. Semin Neurol. 2008;28(1):29–45.
  5. Correale J, Marrodan M, Ysrraelit MC. Mechanisms of neurodegeneration and axonal dysfunction in progressive multiple sclerosis. Biomedicines. 2019;7(1):14.
  6. Crawford JJ, Johnson AR, Misner DL, et al. Discovery of GDC-0853: a potent, selective, and noncovalent bruton’s tyrosine kinase inhibitor in early clinical development. J Med Chem. 2018;61:2227–2245.
  7. Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol. 2015;15(9):545–558.
  8. De Stefano N, Giorgio A, Battaglini N, et al. Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes. Neurology. 2010;74(23):1868–1876.
  9. Garcia-Merino A. Bruton’s tyrosine kinase inhibitors: a new generation of promising agents for multiple sclerosis therapy. Cells. 2021;10(10):2560.
  10. Geladaris A, Hausler D, Weber MS. Microglia: the missing link to decipher and therapeutically control MS progression? Int J Mol Sci. 2021;22(7):3461.
  11. Graf J, Mares J, Barnett M, et al. Targeting B cells to modify MS, NMOSD, and MOGAD: Part 1. Neurol Neuroimmunol Neuroinflamm. 2020;8(1):e918.
  12. Hasse S, Linker RA. Inflammation in multiple sclerosis. Ther Adv Neurol Disord. 2021;14:17562864211007687.
  13. Hartkamp LM, Radstake T, Reedquist KA. Bruton’s tyrosine kinase in chronic inflammation: from pathophysiology to therapy. Int J Interferon Cytokine Mediator Res. 2015;7:27–34.
  14. Hauser SL, Bar-Or A, Francis G, et al. Evaluation of fenebrutinib, a highly selective BTKi, on disease progression in multiple sclerosis. Poster presented at: MSVirtual2020, the 8th Joint ACTRIMS-ECTRIMS Meeting. September 11–13, 2020. Online only.
  15. Johnson AR, Harp C, Yu J, et al. Fenebrutinib, a potent, highly selective, noncovalent BTK inhibitor for the treatment of multiple sclerosis. Poster presented at: MSVirtual2020, the 8th Joint ACTRIMS-ECTRIMS Meeting. September 11–13, 2020. Online only.
  16. Kil LP, de Bruijn MJW, van Nimwegen M, et al. BTK levels set the threshold for B-cell activation and negative selection of autoreactive B cells in mice. Blood. 2012;119(16):3744–3756.
  17. Lassman H. What drives disease in multiple sclerosis: inflammation or neurodegeneration? Clin Exp Neuroimmunol. 2010;1(1):2–11.
  18. Lassman H, van Horssen J, Mahad D. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol. 2012;8(11):647­–656.
  19. Lassman H. Pathogenic mechanisms associated with different clinical courses of multiple sclerosis. Front Immunol. 2019;9:3116.
  20. Maas A, Hendriks RW. Role of bruton’s tyrosine kinase in B cell development. Dev Immunol. 2001;8(3–4):171–181.
  21. Matthews PM. Chronic inflammation in multiple sclerosis—seeing what was always there. Nat Rev Neurol. 2019;15(10):582–593.
  22. Rip J, Van der Ploeg EK, Hendrix RW, et al. The role of bruton’s tyrosine kinase in immune cell signaling and systemic autoimmunity. Crit Rev Immunol. 2018;38(1):17–62.
  23. Rojas JI, Patrucco L, Miguez J, et al. Brain atrophy in radiologically isolated syndromes. J Neuroimaging. 2015;25(1):68–71.
  24. Rovira A, Auger C, Alonso J. Magnetic resonance monitoring of lesion evolution in multiple sclerosis. Ther Adv Neurol Disord. 2013;6(5):298–310.
  25. Trapp BD, Peterson J, Ransohoff RM, et al. Axonal transection in the lesions of multiple sclerosis. N Engl J Med. 1998;338(5):278–285.
  26. Whang JA, Chang BY. Bruton’s tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. Drug Discov Today. 2014;19(8):1200–1204.

Looking for more information?

Reach out to a Genentech Medical Science Liaison near you, or connect with the contact center.

Connect with an MSL
Submit a Request

Call Us: 1-800-821-8590 Hours: Monday-Friday, 5am-5pm PT