Table 1.
Bruton-tyrosine kinase inhibitors (BTKi) approved or in clinical trials. Mode of inhibition, targeted disease, bleeding side effects, and platelet-relevant off-target kinase activity.
| Generic Name | Brand Name | First Designation |
Mode of Inhibition |
Disease | Development Stage | Bleeding | Off-Target |
|---|---|---|---|---|---|---|---|
| Irreversible BTKi | |||||||
| Ibrutinib | Imbruvica® | PCI-32765 | Covalent (Cys-481) | CCL MCL WM MZL GVHD |
Approved (2013) Approved (2017) |
39% (any grade), 4% ≥ grade 3, 0.4% fatal Bleeding (>20%) |
Tec, Src-kinases (Src, Lyn, Fyn, Yes) Itk |
| GVHD | Approved (2017) | Bleeding (>20%) | Itk | ||||
| Acalabrutinib | Calquence® | ACP-160 | Covalent (Cys-481) | MCL CCL | Approved (2017) FDA | 22% * (any grade), 3% ≥ grade 3, 0.1% fatal |
Tec |
| Zanubrutinib | Brukinsa® | BGB-3111 | Covalent (Cys-481) | MCL | Approved (2019) FDA |
50% (any grade) 2% ≥ grade 3 |
Tec |
| Tirabrutinib | Velexbru® | ONO/GS-4059 | Covalent (Cys-481) | PCNSL LPL WM |
Approved (3/2020) Japan | Yes, see text | Tec |
| Branebrutinib | BMS-986195 | Covalent (Cys-481) | SLE, Sjögren syndrome | Phase 1 Phase 2 |
No Unknown |
Tec | |
| BI 705564 | Covalent (Cys-481) | SLE, RA | Phase 1 | 15% (grade 1,2) | Tec | ||
| Remibrutinib | LOU064 | Highly selective, Covalent (Cys-481) | CSU, Sjögren syndrome | Phase 2 | Not known | no | |
| Irreversible BTKi, brain-penetrant | |||||||
| Evobrutinib | M2951 | Covalent (Cys-481) | MS | Phase 1,2 Phase 3 ** |
no | Tec | |
| Tolebrutinib | SAR- 442168, PRN2246 |
Covalent (Cys-481) | MS | Preclinical, Phase 1 | no | Tec | |
| Reversible BTKi | |||||||
| BMS-986142 | reversible | RA | Phase 1,2 | no | Tec | ||
| Fenebrutinib | GDC-0853 | reversible | NHL,CLL RA SLE |
Phase 1 Phase 2 Phase 2 |
no no no |
no | |
| Rilzabrutinib | PRN1008 | reversible, transient covalent (Cys-481) |
ITP Pemphigus |
Phase 2 Phase 2 |
no no |
Tec |
* excluding petechiae and bruising, ** phase 3 started in 2020. CLL, chronic lymphocytic leukemia, identical with SLL, small lymphocytic lymphoma; CSU, chronic spontaneous urticaria; cGVHD, chronic graft versus host disease; Itk, interleukin-2 inducible kinase; ITP, diopathic thrombocytopenic purpura; LPL, lymphoplasmacytic lymphoma; MCL, mantle cell lymphoma; MS, multiple sclerosis; MZL, marginal zone lymphoma; NHL, non-Hodgkin lymphoma; PCNSL, primary central nervous system lymphoma; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; Tec, tyrosine kinase expressed in hepatocellular carcinoma; WM, Waldenström’s macroglobulinemia.