Adakveo
crizanlizumab
Species
Monkey
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
Cynomolgus monkey only
“The toxicity of crizanlizumab was evaluated in GLP-compliant 4- and 26-week toxicology studies in cynomolgus monkeys.”
Why that species
Binds human and cynomolgus platelet P-selectin; no binding to dog or rat P-selectin
“Crizanlizumab bound to human and cynomolgus monkey platelets expressing P-selectin, but did not bind to platelets expressing P-selectin from dog or rat. Thus, monkey is an appropriate toxicological animal model to study crizanlizumab.”
Surrogate molecule
No surrogate; the clinical antibody (earlier SelG1 material and commercial SEG101) was tested in cynomolgus monkeys
“The preclinical safety profile of crizanlizumab was mostly characterised using the previous CHO-K1-derived material (SelG1) in Cynomolgus monkeys. The current crizanlizumab SEG101 was tested in the enhanced pre- and postnatal developmental toxicity study.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“26-Week Intravenous Injection Toxicity and Toxicokinetic Study (Seven Doses) with SelG1 in Cynomolgus Monkeys with a 4-Week Recovery Phase/8259995”
Pivotal GLP studies
GLP cynomolgus studies: 4-week IV every 2 weeks up to 25.2 mg/kg; 26-week IV every 4 weeks up to 50 mg/kg
“Monkeys received crizanlizumab intravenously, once every 2-weeks up to 25.2 mg/kg in the 4-week study and once every 4-weeks up to 50 mg/kg in the 26-week study.”
Route in tox
Intravenous (bolus)
“Route of administration: Intravenous (bolus) injection”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“Genotoxicity studies are not considered relevant for a biological product in accordance with ICH S6.”
Carcinogenicity
Not conducted; weight-of-evidence risk assessment concluded low carcinogenic risk
“Instead, a comprehensive risk assessment including feasibility assessment of available animal models for carcinogenicity testing was performed. Based on the weight of evidence the risk of carcinogenicity can be considered low.”
Reproductive & developmental
Monkey ePPND (IV, organogenesis to delivery): non-dose-related increased fetal loss (abortions/stillbirths) at ~2.8x clinical exposure
“In an animal reproduction study, intravenous administration of crizanlizumab-tmca to pregnant cynomolgus monkeys from the onset of organogenesis through delivery resulted in a non-dose related increased fetal loss (abortions/stillbirths) at doses approximately 2.8 times the exposure at the recommended clinical dose at 5 mg/kg/dose once every 4 weeks”
Safety pharmacology
Incorporated into 4- and 26-week monkey studies; no cardiovascular, CNS or respiratory effects
“No effects on cardiovascular, CNS or respiratory function were observed in Cynomolgus monkeys in the 26-week repeat-dose toxicity study.”
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 Adakveo 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: Well tolerated up to 25 mg/kg for 26 weeks; vascular inflammation in several tissues in two animals at 50 mg/kg (EMA assessment report, p. 42)
NOAEL / key findings
Well tolerated up to 25 mg/kg for 26 weeks; vascular inflammation in several tissues in two animals at 50 mg/kg
“Toxicity data suggests that crizanlizumab is well tolerated up to 25 mg/kg once per week intravenous administration up to 26 weeks. An inflammatory reaction in the blood vessels of several tissues was observed in two animals of the high dose of 50 mg/kg group.”
Risksopen answer page →
Immune & cytokine safety
ADA in 40% of treated monkeys in the 26-week study, with hypersensitivity reactions in some animals
“Primate anti-human antibodies (ADAs) were detected in toxicological studies in Cynomolgus monkeys, accompanied by hypersensitivity reactions in some animals. Anti-human antibodies against SelG1 were detected in 40% of all treated animals at least once throughout the observation period in a 26-week repeat-dose toxicity study.”
Biodistribution & persistence
TCR: binding to platelets (blood, spleen) and blood vessels in most human and cynomolgus tissues
“Crizanlizumab binding was seen in platelets in the blood and spleen, and in blood vessels in the majority of tissues examined of both human and cynomolgus monkey.”
Modality-specific risk
Fetal loss with placental infarcts (pharmacology or immunogenicity); vascular inflammation in monkeys
“The cause for the fetal losses in monkeys is unknown but may be related in part due to the development of anti-drug antibodies against crizanlizumab-tmca.”
Similar precedents
Alhemoconcizumab · TFPIMonkey only · 52 wkArzerraofatumumab · CD20Monkey only · 30 wkCablivicaplacizumab · von Willebrand factor (A1 domain)Monkey only · 26 wkEnjaymosutimlimab · Complement C1sMonkey only · 26 wkGamifantemapalumab · IFN-γMonkey only · 13 wkGazyvaobinutuzumab · CD20Monkey only · 26 wk