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User:MaryGaulke/sandbox/Tolebrutinib mockup

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Tolebrutinib
Clinical data
Other namesPRN2246; SAR-442168
Legal status
Legal status
  • Investigational
Identifiers
  • 4-amino-3-(4-phenoxyphenyl)-1-[(3R)-1-prop-2-enoylpiperidin-3-yl]imidazo[4,5-c]pyridin-2-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC26H25N5O3
Molar mass455.518 g·mol−1
3D model (JSmol)
  • C=CC(=O)N1CCC[C@H](C1)N2C3=C(C(=NC=C3)N)N(C2=O)C4=CC=C(C=C4)OC5=CC=CC=C5
  • InChI=1S/C26H25N5O3/c1-2-23(32)29-16-6-7-19(17-29)30-22-14-15-28-25(27)24(22)31(26(30)33)18-10-12-21(13-11-18)34-20-8-4-3-5-9-20/h2-5,8-15,19H,1,6-7,16-17H2,(H2,27,28)/t19-/m1/s1
  • Key:KOEUOFPEZFUWRF-LJQANCHMSA-N

Tolebrutinib is an investigational new drug that is being evaluated to treat multiple sclerosis.[1] It is an orally administered Bruton's tyrosine kinase (BTK) inhibitor.[2] In December 2024, the U.S. Food and Drug Administration (FDA) gave the drug breakthrough therapy designation for the treatment of non-relapsing secondary progressive multiple sclerosis. Tolebrutinib is in Phase III clinical trials.

Pharmacology

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Tolebrutinib is a covalent BTK inhibitor[3] designed to penetrate the blood–brain barrier.[4] Research indicates that in this way, BTK inhibitors target the immunopathology mechanisms of multiple sclerosis (MS) in both the central nervous system and the periphery. BTK inhibitors modulate the functions of B cells (implicated in the relapse and progression of MS), microglia, and myeloid cells while preserving B cell viability,[3] avoiding the suppression of systemic immunity.[5] In studies in mice with B cell-dependent and T cell-dependent models of experimental autoimmune encephalomyelitis, tolebrutinib reduced severity of disease in a dose-dependent manner and demonstrated changes in B cell function.[3]

As an irreversible BTK inhibitor, tolebrutinib forms a covalent bond with cysteine residue in the ATP-binding site of BTK. Irreversible covalent BTK inhibitors generally offer higher binding affinities and have longer durations of action than reversible inhibitors; however, they can introduce risks related to potential immunogenicity of drug–receptor complexes that are covalently bound. Although tolebrutinib inactivates BTK irreversibly, normal protein turnover gradually replaces the inactivated enzyme, restoring signaling within five to seven days.[3]

History

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In November 2017, Sanofi entered into an agreement with Principia Biopharma to develop Principia's BTK inhibitor for the treatment of MS.[6] Principia also initiated a Phase I trial of the orally administered drug.[7]

Sanofi acquired tolebrutinib (then known by its compound code name SAR442168[8]) through its 2020 purchase of Principia Biopharma.[9] In December 2024, the drug received breakthrough therapy designation from the FDA for the treatment of adults with non-relapsing secondary progressive MS.[10] The FDA accepted Sanofi's regulatory submission for tolebrutinib in March 2025, giving the drug priority review.[11][12]

Research

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Results from a Phase IIb study of tolebrutinib demonstrated a dose-dependent reduction in gadolinium-enhancing lesions in people with relapsing MS after 12 weeks, showing how BTK inhibition can potentially modify inflammatory activity in the central nervous system.[13] The drug advanced to Phase III trials sponsored by Sanofi in October 2021.[14]

Results from the HERCULES Phase III study published in April 2025 showed that tolebrutinib reduced the risk of disability progression in non-relapsing secondary progressive MS.[15][5] At a dosage of 60mg daily, the drug outperformed a placebo in reducing new or enlarged T2 lesions.[16] Trial results showed a 31% relative reduction in the risk of disability progression confirmed after six months, making tolebrutinib the first therapy to show a significant effect in slowing progression in non-relapsing secondary progressive MS.[17][18] Ten percent of patients in the trial experienced a disability improvement confirmed after six months.[17]

The two GEMINI trials compared tolebrutinib and teriflunomide in patients with relapsing forms of MS.[4] Tolebrutinib did not outperform teriflunomide in reducing annualized relapse rate. However, fewer patients on tolebrutinib experienced confirmed worsening of disability after six months.[17] These findings indicate that tolebrutinib may target chronic smoldering neuroinflammation in the central nervous system.[4][17]

References

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  1. ↑ "Tolebrutinib - Sanofi". AdisInsight. Springer Nature Switzerland AG.
  2. ↑ Turner TJ, Brun P, Gruber RC, Ofengeim D (June 2024). "Comparative CNS Pharmacology of the Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib Versus Other BTK Inhibitor Candidates for Treating Multiple Sclerosis". Drugs in R&D. 24 (2): 263–274. doi:10.1007/s40268-024-00468-4. PMC 11315827. PMID 38965189.
  3. 1 2 3 4 Krämer J, Bar-Or A, Turner TJ, Wiendl H (2023). "Bruton tyrosine kinase inhibitors for multiple sclerosis". Nature Reviews Neurology. 19 (5): 289–304. doi:10.1038/s41582-023-00800-7. PMC 10100639. PMID 37055617.
  4. 1 2 3 Calabresi PA (2025). "Progress toward Mitigating Disability Progression in Multiple Sclerosis". New England Journal of Medicine. 392 (19): 1966–1968. doi:10.1056/NEJMe2503891. PMID 40367381.
  5. 1 2 d'Egidio F, Kacem H, Lombardozzi G, d'Angelo M, Cimini A, Castelli V (2025). "The Potential Therapeutic Role of Bruton Tyrosine Kinase Inhibition in Neurodegenerative Diseases". Applied Sciences. 15 (15): 8239. doi:10.3390/app15158239.
  6. ↑ Leuty R (13 November 2017). "How a new approach to MS landed Peninsula drug maker a potential $800M deal". San Francisco Business Times. Retrieved 9 September 2025.
  7. ↑ Keown A (9 November 2017). "Bay Area's Principia Biopharma Scores $765M MS Licensing Deal With Drug Giant Sanofi". BioSpace. Retrieved 9 September 2025.
  8. ↑ Owens TD, Smith PF, Redfern A, Xing Y, Shu J, Karr DE, et al. (2022). "Phase 1 clinical trial evaluating safety, exposure and pharmacodynamics of BTK inhibitor tolebrutinib (PRN2246, SAR442168)". Clinical and Translational Science. 15 (2): 442–450. doi:10.1111/cts.13162. PMC 8841436. PMID 34724345.
  9. ↑ Pagliarulo N (17 August 2020). "Sanofi, seeking control of key drug, to buy Principia for $3.7B". Biopharma Dive. Retrieved 9 September 2025.
  10. ↑ Halpern L (16 December 2024). "FDA Grants Breakthrough Therapy Designation to Tolebrutinib for Non-Relapsing Secondary Progressive Multiple Sclerosis". Pharmacy Times. Retrieved 9 September 2025.
  11. ↑ Meglio M (25 March 2025). "FDA Accepts Regulatory Submission for BTK Inhibitor Tolebrutinib for Non-Relapsing Secondary Progressive MS". NeurologyLive. Retrieved 17 September 2025.
  12. ↑ "Tolebrutinib regulatory submission accepted for priority review in the US for patients with multiple sclerosis". Sanofi (Press release). 25 March 2025. Retrieved 17 September 2025.
  13. ↑ Airas L, Bermel RA, Chitnis T, Hartung HP, Nakahara J, Stuve O, et al. (17 April 2024). "A review of Bruton's tyrosine kinase inhibitors in multiple sclerosis". Therapeutic Advances in Neurological Disorders. 17 17562864241233041. doi:10.1177/17562864241233041. PMC 11025433. PMID 38638671.
  14. ↑ Hurley D (7 October 2021). "Tolebrutinib Appears Promising Against Multiple Sclerosis in Phase 2 Trial". Neurology Today. 21 (19): 12–13. doi:10.1097/01.NT.0000797972.51189.e7. Retrieved 9 September 2025.
  15. ↑ Fox RJ, Bar-Or A, Traboulsee A, Oreja-Guevara C, Giovannoni G, Vermersch P, et al. (2025). "Tolebrutinib in Nonrelapsing Secondary Progressive Multiple Sclerosis". New England Journal of Medicine. 392 (19): 1883–1892. doi:10.1056/NEJMoa2415988. PMID 40202696.
  16. ↑ Abbas A, Sabet H, Abouelmagd ME, El-Moslemani M, Ewis DK, Soliman SM, et al. (2025). "Safety and efficacy of Bruton's tyrosine kinase inhibitors in multiple sclerosis: A systematic review and network meta-analysis of randomized controlled trials". Brain Network Disorders. doi:10.1016/j.bnd.2025.06.003.
  17. 1 2 3 4 Trojano M, Paolicelli D (2025). "Targeting smouldering neuroinflammation in multiple sclerosis: Insights from tolebrutinib clinical trials". The Lancet Regional Health - Europe. 54 101359. doi:10.1016/j.lanepe.2025.101359. PMC 12221558. PMID 40607163.
  18. ↑ Siffrin V (2025). "Pathways to Progressive Disability in Multiple Sclerosis: The Role of Glial Cells in Chronic CNS Inflammation". Glia. 73 (10): 1928–1950. doi:10.1002/glia.70044. PMC 12334871. PMID 40406903.
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