Chemistry:Fenebrutinib

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Fenebrutinib (also known as GDC-0853) is an experimental drug that acts as a selective, non-covalent inhibitor of Bruton's tyrosine kinase (BTK).[1] Developed by Roche, fenebrutinib is currently undergoing Phase III clinical trials for the treatment of multiple sclerosis and has shown promise in treating various autoimmune disorders.[2]

Mechanism of action

Fenebrutinib is characterized as a potent and highly selective BTK inhibitor with a measured inhibition constant (Ki) of 0.91 nM.[1] The drug demonstrates remarkable selectivity, being 130 times more selective for BTK compared to other kinases.[3] Unlike other BTK inhibitors, fenebrutinib is notable for being the only reversible inhibitor currently in Phase III trials for multiple sclerosis.[3]

The drug functions as a dual inhibitor, targeting both B-cell and microglia activation.[4] In the context of multiple sclerosis, this dual mechanism may be important for reducing both disease activity and neuroinflammation by modulating immune cell functions in both the central nervous system and peripheral tissues.[5]

Clinical development

Multiple sclerosis

Fenebrutinib has undergone extensive clinical testing for multiple sclerosis treatment. In Phase II trials, specifically the FENtopa study (NCT05119569), the drug demonstrated significant efficacy in patients with relapsing multiple sclerosis.[6] The trial met both primary and secondary endpoints, showing reduction in new gadolinium-enhancing T1 brain lesions.[7][8]

Long-term extension studies have shown that fenebrutinib can maintain near-complete suppression of disease activity and disability progression for up to two years in patients with relapsing multiple sclerosis.[9] The drug has demonstrated brain penetrance at clinically relevant concentrations and has shown the ability to suppress both acute and chronic MRI lesions.[2]

Currently, Roche is conducting three Phase III trials: FENhance 1 (NCT04586010) and FENhance 2 (NCT04586023) for relapsing multiple sclerosis, and FENtrepid (NCT04544449) for primary progressive multiple sclerosis.[10][11][12][13][14][15]

Other indications

Beyond multiple sclerosis, fenebrutinib has been investigated for other autoimmune conditions. Phase II studies have evaluated its efficacy in rheumatoid arthritis patients with active disease despite TNF inhibitor treatment.[16][17] The drug has also been investigated for potential applications in B-cell malignancies and other autoimmune disorders.[18]

Regulatory status

In March 2024, the U.S. Food and Drug Administration (FDA) placed a clinical hold on fenebrutinib's development in the USA due to concerns about liver injury.[6][4][19] Despite this temporary setback, clinical trials continue to progress, with results from Phase III studies expected to be available soon.[20]

The International Nonproprietary Names number for fenebrutinib is 10603.[21]

See also

References

  1. ↑ 1.0 1.1 "Fenebrutinib (GDC-0853)". https://www.targetmol.com/compound/Fenebrutinib. 
  2. ↑ 2.0 2.1 "Roche's fenebrutinib demonstrated near-complete suppression of disease activity and disability progression for up to 48 weeks in patients with relapsing multiple sclerosis". 2024-09-04. https://www.roche.com/media/releases/med-cor-2024-09-04. 
  3. ↑ 3.0 3.1 "Genentech's BTK inhibitor fenebrutinib significantly reduces disease activity in Phase II multiple sclerosis trial". 2023-05-16. https://www.gene.com/media/press-releases/14992/2023-05-16/genentechs-btk-inhibitor-fenebrutinib-si. 
  4. ↑ 4.0 4.1 "Fenebrutinib Multiple Sclerosis Clinical Trial Program Update". https://www.gene.com/media/statements/ps_113023. 
  5. ↑ "Fenebrutinib, a Bruton's tyrosine kinase inhibitor, blocks distinct human microglial signaling pathways". Journal of Neuroinflammation 21 (1): 276. 2024. doi:10.1186/s12974-024-03267-5. PMID 39465429. 
  6. ↑ 6.0 6.1 FDA Places Clinical Hold on Roche's BTK Inhibitor Fenebrutinib for Multiple Sclerosis. Spring 2024. 7. 2024-03-13. https://www.neurologylive.com/view/fda-places-clinical-hold-roche-btk-inhibitor-fenebrutinib-multiple-sclerosis. Retrieved 2025-07-17. 
  7. ↑ "Roche's BTK inhibitor succeeds in a Phase II MS trial". 2023-05-17. https://www.clinicaltrialsarena.com/news/roche-fenebrutinib-relapsing-multiple-sclerosis/. 
  8. ↑ Hoffmann-La Roche (2025-05-12). A Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy of Fenebrutinib in Relapsing Multiple Sclerosis (Report). clinicaltrials.gov. https://clinicaltrials.gov/study/NCT05119569. 
  9. ↑ "Roche's fenebrutinib maintains near-complete suppression of disease activity and disability progression for up to two years in people with relapsing multiple sclerosis". 2025-05-30. https://www.roche.com/media/releases/med-cor-2025-05-30. 
  10. ↑ "Roche's BTK inhibitor shines in multiple sclerosis trial". 2024-09-05. https://www.clinicaltrialsarena.com/news/roche-btk-inhibitor-success-trial-multiple-sclerosis/. 
  11. ↑ Hoffmann-La Roche (2025-05-28). 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 (Report). clinicaltrials.gov. https://clinicaltrials.gov/study/NCT04586010. 
  12. ↑ Hoffmann-La Roche (2025-05-28). 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 (Report). clinicaltrials.gov. https://clinicaltrials.gov/study/NCT04586023. 
  13. ↑ Hoffmann-La Roche (2025-05-28). 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. (Report). clinicaltrials.gov. https://clinicaltrials.gov/study/NCT04544449. 
  14. ↑ "1-year fenebrutinib inhibits nearly all MS signs in relapsing MS trial" (in en-US). 2024-09-05. https://multiplesclerosisnewstoday.com/news-posts/2024/09/06/r1-year-fenebrutinib-inhibits-nearly-all-signs-relapsing-ms-trial/. 
  15. ↑ "Roche Touts Phase II MS Data on Heels of Sanofi's Late-Stage Stumbles" (in en-US). 4 September 2024. https://www.biospace.com/drug-development/roche-touts-phase-ii-ms-data-on-heels-of-sanofis-late-stage-stumbles. 
  16. ↑ "Efficacy and Safety of Fenebrutinib, a BTK Inhibitor, Compared to Placebo in Rheumatoid Arthritis Patients". 2019-08-15. https://acrabstracts.org/abstract/efficacy-and-safety-of-fenebrutinib-a-btk-inhibitor-compared-to-placebo-in-rheumatoid-arthritis-patients-with-active-disease-despite-tnf-inhibitor-treatment-randomized-double-blind-phase-2-study/. 
  17. ↑ "Fenebrutinib versus Placebo or Adalimumab in Rheumatoid Arthritis: A Randomized, Double-Blind, Phase II Trial (ANDES Study)". Arthritis & Rheumatology (Hoboken, N.J.) 72 (9): 1435–1446. 2020-04-09. doi:10.1002/art.41275. ISSN 2326-5205. PMID 32270926. 
  18. ↑ "Investigation of Fenebrutinib Metabolism and Bioactivation Using MS3 Methodology in Ion Trap LC/MS". Molecules (Basel, Switzerland) 28 (10): 4225. 2023-05-22. doi:10.3390/molecules28104225. ISSN 1420-3049. PMID 37241965. 
  19. ↑ "Genentech MS drug on partial US hold on liver enzyme elevations" (in en). 2023-12-04. https://www.fiercebiotech.com/biotech/genentechs-ms-drug-partial-hold-us-after-liver-enzyme-elevations-2-patients. 
  20. ↑ "BTK Inhibitor Fenebrutinib Demonstrates Long-Term Suppression of MS Activity in Open-Label Extension". 2025-05-30. https://www.neurologylive.com/view/btk-inhibitor-fenebrutinib-demonstrates-long-term-suppression-ms-activity-open-label-extension. 
  21. ↑ "Fenebrutinib". Ligand page. IUPHAR/BPS Guide to PHARMACOLOGY. https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9299. 



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