Cablivi
caplacizumab
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”
Species: general tox
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).”
Species: DART
Guinea pig (embryo-fetal development by i.m. dosing, plus placental-transfer TK study)
“To support clinical development in women of child bearing potential a formal segment II study on embryo-foetal development was conducted in guinea pigs by i.m. administration and a follow-up TK study to assess placental transfer as well as maternal and foetal plasma levels of caplacizumab.”
Species: carcinogenicity
Not conducted (ICH S6(R1))
“In line with ICH S6(R1), no carcinogenicity studies have been performed.”
Surrogate used in
No surrogate used; clinical Nanobody pharmacologically active in both toxicity species
“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)”
Genotox: Ames
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.”
Genotox: in vitro mammalian
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.”
Genotox: in vivo
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 model
Not conducted; no carcinogenic risk identified from mode of action and monkey studies up to 26 weeks
“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) or other specific characteristics of caplacizumab.”
Carcinogenicity timing
Not required (ICH S6(R1))
“In line with ICH S6(R1), no carcinogenicity studies have been performed.”
hERG / QT
No hERG assay; no adverse ECG, blood pressure or heart rate effects in vivo 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
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
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.”
Anti-drug antibodies: animals
ADA observed but did not affect exposure, except one 26-week monkey excluded from interpretation
“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.”
Anti-drug antibodies: patients
Treatment-emergent ADA in 3% of HERCULES patients, with neutralizing potential
“Treatment-emergent anti-drug antibodies (TE ADA) against caplacizumab-yhdp were detected in 3% of patients treated with CABLIVI in the HERCULES study. In the HERCULES study, TE ADA were further characterized as having neutralizing potential.”
Label warnings
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
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
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week cynomolgus monkey study (pivotal); recovery phase not stated
“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)”
DART package
Species: DART
Guinea pig (embryo-fetal development by i.m. dosing, plus placental-transfer TK study)
“To support clinical development in women of child bearing potential a formal segment II study on embryo-foetal development was conducted in guinea pigs by i.m. administration and a follow-up TK study to assess placental transfer as well as maternal and foetal plasma levels of caplacizumab.”
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.”
PPND / ePPND: when
PPND not conducted: no concern from guinea pig embryo-fetal study and clinical experience in vWF-deficient pregnancies
“the lack of effects in the conducted embryo-foetal development study in guinea pigs, which did not cause concern on caplacizumab treatment during embryo- and organogenesis and later development, no pre- and postnatal development study were performed.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S6(R1))
“In line with ICH S6(R1), no carcinogenicity studies have been performed.”
Carcinogenicity model
Not conducted; no carcinogenic risk identified from mode of action and monkey studies up to 26 weeks
“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) or other specific characteristics of caplacizumab.”
Carcinogenicity timing
Not required (ICH S6(R1))
“In line with ICH S6(R1), no carcinogenicity studies have been performed.”
Safety marginopen answer page →
Safety margin at NOAEL
Not definable per EMA: dose-dependent bleeding at all doses precludes a NOAEL and clinical exposure margin
“Increased bleeding (dose dependent and reversible) was observed at all doses tested and a NOAEL and exposure margin to the clinic is therefore not possible to define.”
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”
Efficacy evidenceopen answer page →
Efficacy evidence
Baboon model of acquired TTP induced by an inhibitory anti-ADAMTS13 antibody (preventive and therapeutic dosing)
“The in vivo efficacy of caplacizumab was evaluated in a baboon model of TTP after preventive and therapeutic treatment. In this model mimicking the early onset of acquired TTP, the disease is induced by functional inhibition of ADAMTS13 through administration of an inhibitory monoclonal antibody (3H9).”
Why that model
Baboons and guinea pigs are cross-reactive species; mice are not
“The non-clinical pharmacokinetic properties of caplacizumab were analysed in guinea pigs and baboons as cross-reactive species, as well as in mice (not cross-reactive).”
Reviewer's view of the efficacy data
EMA: acute baboon model has limitations (no long-term/relapse data), superseded by clinical efficacy data
“This acute disease model has limitations as no information is available regarding the long-term effect and /or relapses of the disease. However, the lack of such preclinical information is considered superseded by clinical efficacy data in patients.”
Flexibilityopen answer page →
Flexibility accepted
DARTAcceptedBeyond the letter
No pre- and postnatal development study; only guinea pig embryo-fetal development and placental transfer studies
Why: No concern from the guinea pig embryo-fetal development study · Weight of evidence
“the lack of effects in the conducted embryo-foetal development study in guinea pigs, which did not cause concern on caplacizumab treatment during embryo- and organogenesis and later development, no pre- and postnatal development study were performed.”
GLPAcceptedBeyond the letter
Functional fertility assessments in the 13-week monkey study (spermiogram, testicular ultrasound, oestrus cycles) conducted non-GLP
Why: Well performed by qualified experts and therefore reliable · Other reason
“The functional assessments on male and female fertility parameters, although conducted non-GLP, are considered well performed by qualified experts and therefore considered reliable.”
Safety marginVerdict not stated
No NOAEL or exposure margin definable: dose-dependent bleeding at all doses tested
“Increased bleeding (dose dependent and reversible) was observed at all doses tested and a NOAEL and exposure margin to the clinic is therefore not possible to define.”
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