TABLE 3.
Overview of activated partial thromboplastin time (APTT) and thrombin peak in cynomolgus monkeys following exposure to Mim8
| Study | Dose (mg/kg/week) | Admininistration route | ADA status a |
APTT predose, s (n) |
APTT before final dose, s (n) |
Thrombin peak predose, nM (n) |
Thrombin peak before final dose, nM (n) |
|---|---|---|---|---|---|---|---|
| 4‐week | 1 | SC | ‐ | 20.9 (1) | 13.6 ± 0.2 (2) | N/A | 363 ± 111 (2) |
| 4 | SC | ‐ | 21.9 ± 0.5 (2) | 12.1 ± 0.2 (2) | 4.7 ± 1.1 (2) | 443 ± 23 (2) | |
| 20 | SC | ‐ | ‐ | 11.5 ± 0.1 (2) | 7.9 (1) | 331 (1) | |
| 60 | SC | ‐ | 26.6 ± 4.4 (2) | 13.1 ± 0.7 (2) | 15.7 ± 8.5 (2) | 331 ± 105 (2) | |
| 20 | IV | ‐ | 20.5 ± 0.8 (2) | 11.5 ± 0.2 (2) | 5.8 (1) | 379 ± 29 (2) | |
| 13‐week | 0 | SC | NA | 20.0 ± 0.5 (12) b | 20.0 ± 0.3 (6) | 4.9 ± 1.3 (12) b | 3.5 ± 1.4 (6) |
| 0.3 | SC | ‐ | 20.0 ± 0.3 (6) | 14.9 ± 0.2 (6) | 5.3 ± 1.8 (6) | 131 ± 8.0 (6) | |
| 6 | SC | ‐ | 19.8 ± 0.2 (12) b | 12.7 ± 0.9 (4)** | 6.5 ± 1.7 (12) b | 237 ± 17 (4)* | |
| + | ‐ | 20.6 ± 0.5 (2) | ‐ | 4.7±0.7 (2) | |||
| 12 | SC | ‐ | 20.2 ± 0.3 (16) c | 11.7 ± 0.2 (7)*** | 6.2 ± 2.2 (16) c | 292 ± 9.0 (7)*** | |
| + | ‐ | 19.0 ± 1.0 (2) | ‐ | 15.3 ± 3.5 (3) | |||
| 12 d | SC | ‐ | ‐ | 14.5 ± 1.5 (3) | ‐ | 125 ± 32 (3) | |
| + | ‐ | 18.7 (1) | ‐ | 4.4 (1) | |||
| 1 | IV | ‐ | 20.3 ± 0.3 (6) | 14 (1) | 9.7 ± 3.1 (6) | 234 (1) | |
| + | ‐ | 19.7 ± 1.1(5) | ‐ | 44.8 ± 38.8 (5) | |||
| 26‐week | 0 | SC | NA | 20.9 ± 0.7 (8) | 20.4 ± 0.4 (8) | 4.6 ± 1.1 (8) | 4.8 ± 1.0 (8) |
| 0.3 | SC | ‐ | 20.8 ± 0.5 (8) | 12.6 ± 0.6 (4)*** | 5.4 ± 0.7 (8) | 208 ± 19 (4) | |
| + | 20.5 ± 0.7 (4) | ‐ | 5.8 ± 1.4(4) | ||||
| 1 | SC | ‐ | 20.7 ± 0.5 (8) | 12.7 ± 0.6 (5)*** | 4.5 ± 0.7 (8) | 249 ± 20 (5)* | |
| + | ‐ | 21.4 ± 1.3 (3) | ‐ | 4.5 ± 0.6 (3) | |||
| 3 | SC | ‐ | 21.5 ± 0.7 (8) | 11.3 ± 0.1 (4)*** | 4.8 ± 0.9 (8) | 410 ± 57 (4)*** | |
| + | ‐ | 22.1 ± 1.2 (4) | ‐ | 6.4 ± 2.1(4) |
Abbreviations: IV, intravenous; N/A, not available; s, seconds; SC, subcutaneous.
*P < .05, **P < .01, ***P < .001. Data are mean ± standard error of the mean (SEM). Data are from three separate nonclinical studies. Thrombin peak was measured by thrombin generation assay. All thrombin peaks were measured are after adding a neutralizing FVIII antibody ex vivo to induce HA‐like conditions.
Status for neutralizing anti‐drug‐antibody development (ADA) at the end of the study: ‘+’: animals with ADA’s and affected exposure; ‘‐’: Animals with expected exposure; most of these animals were ADA negative, however some animals in the 4‐week and 13‐week study were ADA positive, without affected exposure.
Including data from interim animals (n = 6) taken down after 4 weeks;
Including data from interim animals sacrificed after 4 weeks (n = 6) and recovery animals (n = 4).
Animals dosed 13 weeks followed by a 13‐week recovery phase.