Assessment of clinical pathology and histopathology parameters following ISIS 416858 treatment
| Endpoint . | Control (PBS) . | ISIS 416858, mg/kg . | |||
|---|---|---|---|---|---|
| 4 . | 8 . | 12 . | 40 . | ||
| ALT, U/L | 60 ± 40 | 61 ± 15 | 74 ± 29 | 61 ± 22 | 94 ± 34 |
| BUN, mg/dL | 25 ± 4.8 | 27 ± 7.0 | 26 ± 4.3 | 24 ± 2.6 | 26 ± 6.4 |
| Total protein, g/dL | 7.3 ± 0.5 | 7.4 ± 0.3 | 7.0 ± 0.4 | 7.0 ± 0.9 | 7.8 ± 0.7 |
| Platelets, 10 × 3/μL | 506 ± 85 | 516 ± 141 | 452 ± 56 | 404 ± 93 | 357 ± 120 |
| RBCs, 10 × 6/μL | 5.1 ± 0.3 | 5.2 ± 0.1 | 5.2 ± 0.5 | 5.2 ± 0.3 | 5.1 ± 0.4 |
| Complement Bb* | − | − | − | 2 | 3 |
| Tissue weight* | |||||
| Liver | − | 1.0 | 1.1 | 1.1 | 1.3 |
| Spleen | − | 0.75 | 0.88 | 1.4 | 1.5 |
| Histopathology | |||||
| Liver-KC/hepatocytes | |||||
| Basophilic granules | − | + | + | ++ | ++ |
| Kidney-tubular epithelium | |||||
| Basophilic granules | − | − | − | + | ++ |
| Degeneration/regeneration | − | − | − | + | + |
| Lymph nodes | |||||
| Histiocyte hypertrophy | − | + | + − ++ | + − ++ | ++ |
| SC injection site | |||||
| Mononuclear cell infiltrates | + | + − ++ | + − ++ | + − +++ | + − +++ |
| Endpoint . | Control (PBS) . | ISIS 416858, mg/kg . | |||
|---|---|---|---|---|---|
| 4 . | 8 . | 12 . | 40 . | ||
| ALT, U/L | 60 ± 40 | 61 ± 15 | 74 ± 29 | 61 ± 22 | 94 ± 34 |
| BUN, mg/dL | 25 ± 4.8 | 27 ± 7.0 | 26 ± 4.3 | 24 ± 2.6 | 26 ± 6.4 |
| Total protein, g/dL | 7.3 ± 0.5 | 7.4 ± 0.3 | 7.0 ± 0.4 | 7.0 ± 0.9 | 7.8 ± 0.7 |
| Platelets, 10 × 3/μL | 506 ± 85 | 516 ± 141 | 452 ± 56 | 404 ± 93 | 357 ± 120 |
| RBCs, 10 × 6/μL | 5.1 ± 0.3 | 5.2 ± 0.1 | 5.2 ± 0.5 | 5.2 ± 0.3 | 5.1 ± 0.4 |
| Complement Bb* | − | − | − | 2 | 3 |
| Tissue weight* | |||||
| Liver | − | 1.0 | 1.1 | 1.1 | 1.3 |
| Spleen | − | 0.75 | 0.88 | 1.4 | 1.5 |
| Histopathology | |||||
| Liver-KC/hepatocytes | |||||
| Basophilic granules | − | + | + | ++ | ++ |
| Kidney-tubular epithelium | |||||
| Basophilic granules | − | − | − | + | ++ |
| Degeneration/regeneration | − | − | − | + | + |
| Lymph nodes | |||||
| Histiocyte hypertrophy | − | + | + − ++ | + − ++ | ++ |
| SC injection site | |||||
| Mononuclear cell infiltrates | + | + − ++ | + − ++ | + − +++ | + − +++ |
Cynomologus monkeys were administered ISIS 416858 (0, 4, 8, 12, 40 mg/kg/wk, SC) for up to 13 weeks. At the 13-week treatment time point, animals were subject to a complete necropsy. Blood was harvested for assessment of clinical chemistry and hematology parameters while tissue was preserved in formalin fixative and processed for microscopic evaluation. Data represents mean ± SD.
KC indicates Kupffer cell; ALI, alanine aminotransferase; BUN, blood urea nitrogen; and SC, subcutaneous.
Denotes fold above the control group. Histopathology severity score: −, not present; +, minimal/mild; ++, moderate; and +++, severe.