Table 2.
Characteristics of oral Bruton tyrosine kinase inhibitors in development for multiple sclerosis
| Characteristics | Evobrutinib | Tolebrutinib | Fenebrutinib | Remibrutinib | Orelabrutinib |
|---|---|---|---|---|---|
| Molecular weighta | 429.5 | 455.5 | 664.8 | 507.5 | 427.5 |
| Formula | C25H27N5O2 | C26H25N5O3 | C37H44N8O4 | C27H27F2N5O3 | C26H25N3O3 |
| Mechanism of action | Irreversible covalent binding | Irreversible covalent binding | Reversible non-covalent binding | Irreversible covalent binding | Irreversible covalent binding |
| Kinase selectivity | BMX (89–93%), BTK (90%), TEC (80–82%), BLK (36–42%), TXK (30–36%), ITK (−2 to 13%), ERBB2 (1%), EGFR (0–1%), JAK3 (0%) | >90% Inhibition for 7 of 250 kinases tested at 1 μM | BTK (99%), BMX (56%), TEC (23%), BLK (6%), JAK3 (5%), TXK (4%), ERBB4 (1%), ERBB2 (−1%), ITK (−1%), EGFR (−7%) | BTK (99%), TEC (76%), JAK3 (51%), BMX (47%), ERBB2 (20%), EGFR (18%), ITK (12%), TXK (10%), BLK (0%), ERBB4 (0%) | >90% Inhibition of BTK at 1 μM |
| BTK occupancy | Dose-dependent; ≥86% median occupancy for all dose groups at day 14 | >75% Mean occupancy for all dose groups at day 10 | ND | >95% Median occupancy for all dose groups at day 12 | >99% For doses ≤50 mg (sustained 24 h after dosing) |
| BTK IC50 |
8.9 nM (8.8 ng/ml) 37.9 nM (16.3 ng/ml) 58 nM (24.9 ng/ml) |
0.7 nM (0.3 ng/ml) | 2.3 nM (1.5 ng/ml) | 1.3 nM (0.7 ng/ml) | 1.6 nM (0.7 ng/ml) |
| Pharmacokinetics | |||||
| AUC (ng*h/ml) |
Single dose: AUC0–inf, geometric mean (CV%) 25 mg: 126 (46.4) 75 mg: 345 (44.6) 200 mg: 1,210 (34.0) |
Day 10: AUC0–24, mean (CV%) 7.5 mg: 3.07 (51) 15 mg: 5.85 (33) 30 mg: 14.9 (75) 60 mg: 18.2 (55) 90 mg: 56.6 (54) |
Day 14: AUC0–tau, geometric mean (CV%) 20 mg twice daily: 158 (32) 60 mg twice daily: 831 (28) 150 mg twice daily: 1,695 (50) 250 mg twice daily: 2,347 (42) 500 mg: 4,241 (79) |
Day 12: AUClast, mean (SD) 100 mg: 488 (172) 400 mg: 1,300 (602) 600 mg: 1,240 (3,341) 100 mg twice daily: 518 (334) 200 mg twice daily: 963 (439) |
ND |
| Peak serum concentration (ng/ml) |
Single dose: geometric mean (CV%) 25 mg: 80.4 (64.9) 75 mg: 252 (60.3) 200 mg: 782 (60.1) |
Day 10: mean (CV%) 7.5 mg: 1.32 (31) 15 mg: 2.51 (60) 30 mg: 7.46 (74) 60 mg: 6.69 (66) 90 mg: 21.7 (60) |
Day 14: mean (CV%) 20 mg twice daily: 28 (44) 60 mg twice daily: 217 (14) 150 mg twice daily: 379 (97) 250 mg twice daily: 463 (62) 500 mg: 653 (100) |
Day 12: mean (SD) 100 mg: 233 (84.1) 400 mg: 551 (263) 600 mg: 563 (229) 100 mg twice daily: 306 (202) 200 mg twice daily: 347 (112) |
ND |
| Time to reach maximum concentration (h) |
Single dose: median (range) 25 mg: 0.5 (0.3–1.0) 75 mg: 0.5 (0.3–1.0) 200 mg: 0.5 (0.5–1.0) |
Day 10: median (range) 7.5 mg: 1.0 (0.5–2.0) 15 mg: 1.0 (1.0–1.5) 30 mg: 1.0 (0.5–2.0) 60 mg: 1.5 (1.0–2.0) 90 mg: 1.5 (1.0–2.5) |
Day 14: median (range) 20 mg twice daily: 1.0 (1.0–2.0) 60 mg twice daily: 1.0 (1.0) 150 mg twice daily: 1.0 (1.0–2.0) 250 mg twice daily: 1.0 (1.0–4.0) 500 mg: 1.0 (1.0–3.0) |
Day 12: median (range) 100 mg: 0.867 (0.73–1.50) 400 mg: 0.758 (0.70–1.50) 600 mg: 0.883 (0.50–3.00) 100 mg twice daily: 0.775 (0.50–2.00) 200 mg twice daily: 0.992 (0.52–2.50) |
ND |
| Half-life (h) |
Single dose: geometric mean (CV%) 25 mg: 1.59 (18.2) 75 mg: 2.29 (18.9) 200 mg: 3.62 (70.5) |
Day 10: mean (CV%) 7.5 mg: 1.57 (50) 15 mg: 1.68 (21) 30 mg: 2.02 (34) 60 mg: 2.37 (44) 90 mg: 2.83 (30) |
Day 14: geometric mean (CV%) 20 mg twice daily: 6.1 (30.7) 60 mg twice daily: 4.9 (9.8) 150 mg twice daily: 6.0 (17.7) 250 mg twice daily: 4.9 (31.8) 500 mg: 10.3 (35.1) |
Day 12: median (range) 100 mg: 1.41 (1.41–11.9) 400 mg: 8.51 (1.22–22.3) 600 mg: 8.29 (4.69–17.3) 100 mg twice daily: 2.84 (2.15–18.9) 200 mg twice daily: 12.4 (2.26–26.3) |
~4 |
| Refs. | 66,152,176,179,203,204 | 151,180 | 66,176,205 | 66,206–208 | 209 |
aRelative molecular mass. All doses once daily and all studies in healthy volunteers, except where indicated. AUC, area under the receiver operating characteristic curve; BLK, B lymphocyte kinase; BMX, epithelial and endothelial tyrosine kinase; BTK, Bruton tyrosine kinase; CV, coefficient of variation; IC50, half maximal inhibitory concentration; ITK, IL-2-inducible T cell kinase; JAK, Janus kinase; ND, not done; TEC, tyrosine kinase expressed in hepatocellular carcinoma; TXK, resting lymphocyte kinase.