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.”
Species: general tox
Cynomolgus monkey only (GLP 4- and 26-week studies)
“The toxicity of crizanlizumab was evaluated in GLP-compliant 4- and 26-week toxicology studies in cynomolgus monkeys.”
Species: DART
Cynomolgus monkey enhanced PPND only; fertility assessed in 26-week monkey study, no separate fertility/early embryonic study
“The reproductive and developmental toxicology program includes one study, an enhanced pre- and postnatal developmental toxicity study. No separate studies for fertility or early embryonic development were conducted.”
Species: carcinogenicity
Not conducted (ICH S6); weight-of-evidence risk assessment instead
“In line with the ICH S6 (R1) guideline for the preclinical safety evaluation of biotechnology-derived pharmaceuticals, carcinogenicity studies with crizanlizumab have not been conducted.”
Surrogate used in
No surrogate used; earlier SelG1 material for general toxicity and current SEG101 for ePPND
“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.”
Genotox: Ames
Not conducted (ICH S6)
“Genotoxicity studies are not considered relevant for a biological product in accordance with ICH S6.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Genotoxicity studies are not considered relevant for a biological product in accordance with ICH S6.”
Genotox: in vivo
Not conducted (ICH S6)
“Genotoxicity studies are not considered relevant for a biological product in accordance with ICH S6.”
Carcinogenicity model
Not conducted; carcinogenicity waiver requested from FDA in 2017
“The Applicant submitted a waiver request to conduct carcinogenicity studies for crizanlizumab to the FDA in 2017.”
Carcinogenicity timing
Not required: FDA carcinogenicity committee concurred with waiver (no binding/activity in rodents)
“4. The executive carcinogenicity assessment committee at the FDA concurred with the Applicant’s plan based on lack of binding/pharmacologic activity in rodents.”
hERG / QT
No hERG; safety pharmacology in monkey repeat-dose 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
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: 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.”
Anti-drug antibodies: animals
26-week monkey study: 9/22 treated animals ADA-positive, not dose- or sex-dependent
“Serum samples revealed that 9/22 animals that received crizanlizumab were positive for ADA. There were no dose-dependent increases or gender dependent increases in ADA response.”
Anti-drug antibodies: patients
0% (0 of 84) treatment-induced ADA in Phase 3 SCD study at 5 mg/kg
“No treatment induced anti-crizanlizumab-tmca antibodies were detected (0 of 84 patients) in a Phase 3 study at 5 mg/kg over the 52 week time period (samples collected at baseline, Weeks 3, 15, 19, 27, and 51).”
Label warnings
- Infusion-Related Reactions
- Laboratory Test Interference
Hypersensitivity & infusion reactions
US prescribing information, Warnings and PrecautionsDailyMed ↗
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 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
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: 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week cynomolgus monkey IV study (seven doses) with 4-week recovery
“26-Week Intravenous Injection Toxicity and Toxicokinetic Study (Seven Doses) with SelG1 in Cynomolgus Monkeys with a 4-Week Recovery Phase”
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.”
DART package
Species: DART
Cynomolgus monkey enhanced PPND only; fertility assessed in 26-week monkey study, no separate fertility/early embryonic study
“The reproductive and developmental toxicology program includes one study, an enhanced pre- and postnatal developmental toxicity study. No separate studies for fertility or early embryonic development were conducted.”
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”
PPND / ePPND: when
ePPND in cynomolgus monkey (IV every 2 weeks): completed and reviewed before the marketing application
“In an enhanced pre- and post-natal development study in cynomolgus monkeys, crizanlizumab was administered to pregnant dams once every 2-weeks, at dose levels of 10 or 50 mg/kg.”
Carcinogenicity
Species: carcinogenicity
Not conducted (ICH S6); weight-of-evidence risk assessment instead
“In line with the ICH S6 (R1) guideline for the preclinical safety evaluation of biotechnology-derived pharmaceuticals, carcinogenicity studies with crizanlizumab have not been conducted.”
Carcinogenicity model
Not conducted; carcinogenicity waiver requested from FDA in 2017
“The Applicant submitted a waiver request to conduct carcinogenicity studies for crizanlizumab to the FDA in 2017.”
Carcinogenicity timing
Not required: FDA carcinogenicity committee concurred with waiver (no binding/activity in rodents)
“4. The executive carcinogenicity assessment committee at the FDA concurred with the Applicant’s plan based on lack of binding/pharmacologic activity in rodents.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey 50 mg/kg (dose with vascular inflammation) ~13.5x human AUC at 5 mg/kg
“Crizanlizumab exposure levels at 50 mg/kg was AUC0-504h 274500 μg*h/mL, resulting in approximately 13.5-fold higher exposure than in humans receiving the 5 mg/kg dose of crizanlizumab (AUCtau 20400 μg*h/mL).”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human cells in vitro: blockade of neutrophil rolling/adhesion and sickled red cell binding to human endothelium
“The published in vitro data demonstrate that crizanlizumab blocks binding of human P-selectin to its ligand PSG-1, blocks neutrophil binding to P-selectin, blocks leukocyte rolling and adhesion to human vascular endothelium under shear stress, inhibits interaction of neutrophils with stimulated platelets, and blocks binding of human sickled red cells to human endothelium under flow.”
Why that model
Immunological reactions and species differences in P-selectin recognition hampered animal PD studies; no in vivo SCD model used
“Primary pharmacodynamics was only studied ex vivo with SelG1 and SEG101 because of occurrence of immunological reactions and species differences in target recognition of P-selectin, which hamper animal PD studies.”
Reviewer's view of the efficacy data
EMA: pharmacology lacks firm in vitro documentation, but parental-antibody functional data sufficiently support the rationale
“Taken together, the primary pharmacology evaluation of SEG101 (crizanlizumab) lacks firm in vitro documentation, leaving some uncertainty on specificity and off-target activity. However, the supportive functional data generated with the parental antibody SelG1 provide sufficient support for the rationale for crizanlizumab´s biological activity in the prevention of vaso-occlusive crises.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity studies for a chronic non-oncology indication; comprehensive carcinogenic risk assessment instead
Why: No binding or pharmacologic activity in rodents; weight-of-evidence risk assessment · Weight of evidence · No relevant species
“Carcinogenicity studies with crizanlizumab have not been conducted. Instead, a comprehensive risk assessment including feasibility assessment of available animal models for carcinogenicity testing was performed.”
“4. The executive carcinogenicity assessment committee at the FDA concurred with the Applicant’s plan based on lack of binding/pharmacologic activity in rodents.”
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