Cablivi
caplacizumab
Sources:EMA assessment report ↗
Species
MonkeyPigOther
Longest study
26 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Guinea pig and cynomolgus monkey
“The toxicology of caplacizumab was evaluated in single and repeat-dose toxicity studies in both rodent (guinea pig) and non-rodent species (Cynomolgus monkey).”
Why that species
Cross-reactive with cynomolgus monkey and guinea pig vWF; no pharmacological activity in rats, mice or dogs
“Caplacizumab is cross-reactive to vWF in Cynomolgus monkey and guinea pig, but displays no pharmacological activity in rats, mice and dog.”
Surrogate molecule
No surrogate; the clinical Nanobody was tested in guinea pig and cynomolgus monkey
“This shows that caplacizumab is pharmacologically active in both species used for toxicity testing and that the animals were sufficiently exposed”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“In the pivotal 26-week repeat-dose toxicity study in Cynomolgus monkey Cmax- and AUC-levels were 1.5-1.7 times higher in males.”
Pivotal GLP studies
GLP repeat-dose studies in guinea pigs and cynomolgus monkeys (IV or SC) designed for continuous target saturation
“Repeat-dose toxicity studies were conducted with caplacizumab in guinea-pigs and Cynomolgus monkeys by i.v. or s.c. routes and designed to achieve continuous maximal target occupancy (target saturation)”
Route in tox
Intravenous and subcutaneous
“Toxicokinetic investigations were performed in the repeat-dose toxicity studies in guinea pig and Cynomolgus monkey after both intravenous (i.v.) and subcutaneous (s.c.) administration.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“In line with ICH S6(R1), genotoxicity studies are not considered relevant for proteins and were not performed with caplacizumab.”
Carcinogenicity
Not conducted (ICH S6(R1)); no carcinogenic risk identified from mode of action and 26-week monkey data
“In line with ICH S6(R1), no carcinogenicity studies have been performed. No carcinogenic risk was identified based on the pharmacological mode of action, results from chronic dosing toxicity studies in Cynomolgus monkey (up to 26 weeks)”
Reproductive & developmental
Guinea pig placental transfer study: fetal exposure shown, no effects on fetal development
“The placental transfer study with caplacizumab in pregnant guinea pigs qualitatively demonstrated foetal exposure to caplacizumab but exact concentrations could not be measured in the foetuses. Exposure of the dams had no effects on foetal development.”
Safety pharmacology
Incorporated into repeat-dose monkey and guinea pig studies; no adverse cardiovascular effects besides bleeding
“Overall, the safety pharmacology studies in vivo indicate that, besides bleeding, there are no adverse cardiovascular effects (ECG, blood pressure and heart rate)”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Cablivi don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for monoclonal antibodies outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: 26-week monkey NOAEL 4 mg/kg/day, based on high-dose (40 mg/kg/day) male sacrificed with persistent anaemia (EMA assessment report, p. 28)
NOAEL / key findings
26-week monkey NOAEL 4 mg/kg/day, based on high-dose (40 mg/kg/day) male sacrificed with persistent anaemia
“In this study, the NOAEL was set to 4 mg/kg/day based on a premature sacrifice of one male in the high dose-group administered 13.5 mg/kg 3 times/day (40 mg/kg/day) on day 85 due to persistent signs of anaemia”
Risksopen answer page →
Immune & cytokine safety
Anti-drug antibodies observed but did not affect exposure except in one 26-week monkey
“Anti-drug antibodies were observed but did not affect drug exposure, with the exception of one animal in the 26-week Cynomolgus monkey study, which consequently was excluded from the study interpretation.”
Biodistribution & persistence
Mouse radiolabel study: free drug eliminated via kidneys, vWF-complexed drug targets and is likely catabolized in liver
“data from the biodistribution study in mice using 125I-radiolabeled caplacizumab suggest that free caplacizumab is eliminated via the kidneys, while vWF-complexed caplacizumab appears to target and possibly be catabolized in the liver.”
Modality-specific risk
Bleeding from exaggerated pharmacology (vWF neutralization)
“Excessive pharmacology in the form of increased bleeding was identified as the only relevant safety risk.”