Praxbind
idarucizumab
Species
MonkeyRat
Longest study
4 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
Rat and rhesus monkey
“Toxicity studies with idarucizumab were performed in rats and rhesus monkeys. All studies in monkeys were conducted in the absence and presence of DE.”
Why that species
Target is dabigatran: rhesus chosen as dabigatran half-life is similar to humans and rhesus form its active glucuronides; rats do not
“Dabigatran half-life of dabigatran is similar in rhesus and humans, while it is much shorter in rats. Furthermore, rhesus monkeys generate the active glucuronide metabolites of dabigatran, whereas in rats this is negligible.”
Surrogate molecule
No surrogate; the clinical Fab was tested in rats and rhesus monkeys, with and without dabigatran etexilate
“Toxicity studies with idarucizumab were performed in rats and rhesus monkeys. All studies in monkeys were conducted in the absence and presence of DE.”
Species: general tox
Rat and rhesus monkey (monkey studies with and without dabigatran etexilate)
“Toxicity studies with idarucizumab were performed in rats and rhesus monkeys. All studies in monkeys were conducted in the absence and presence of DE.”
Species: DART
Not conducted (single-day emergency use); reproductive tissues assessed in repeat-dose studies
“It was also agreed that reproductive and developmental toxicity studies are not warranted taking into consideration the proposed used of idarucizumab on single days in emergency situations.”
Species: carcinogenicity
Not conducted
“No genotoxicity, carcinogenicity, or reproductive toxicity studies have been conducted.”
Surrogate used in
No surrogate used; clinical Fab tested in rats and rhesus monkeys
“Toxicity studies with idarucizumab were performed in rats and rhesus monkeys. All studies in monkeys were conducted in the absence and presence of DE.”
Study lengthopen answer page →
Longest pivotal study
4 weeks
“The nonclinical toxicology studies were designed to evaluate the potential toxicity of idarucizumab in rats and monkeys in GLP studies of up to 4- and 2-weeks of daily treatment, respectively.”
Pivotal GLP studies
GLP daily IV studies: rat up to 4 weeks; rhesus monkey up to 2 weeks, with or without dabigatran etexilate
“The nonclinical toxicology studies were designed to evaluate the potential toxicity of idarucizumab in rats and monkeys in GLP studies of up to 4- and 2-weeks of daily treatment, respectively.”
Route in tox
Intravenous (dabigatran etexilate given orally as background)
“In addition, a GLP 2-week study was performed, with repeated daily IV administration of idarucizumab (up to 500 mg/kg) on a background of daily oral vehicle or dabigatran etexilate, followed by a 28-day recovery period and a 3-day re-administration of oral vehicle or dabigatran etexilate.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted
“No carcinogenicity or genotoxicity studies have been conducted with idarucizumab.”
Carcinogenicity
Not conducted; based on mechanism of action and protein nature, no carcinogenic or genotoxic effects anticipated
“Studies to evaluate the mutagenic and carcinogenic potential of idarucizumab have not been performed as based on its mechanism of action and the characteristics of proteins no carcinogenic or genotoxic effects were anticipated.”
Reproductive & developmental
No dedicated studies; no treatment-related effects on reproductive tissues in 4-week rat and 2-week monkey studies
“No treatment-related effects have been identified in reproductive tissues of either sex during repeat dose intravenous toxicity studies of up to four weeks in the rat and two weeks in monkeys.”
Safety pharmacology
Incorporated into repeat-dose studies: no cardiovascular effects in rhesus monkeys, no respiratory or CNS effects in rats
“In line with ICH S6(R1) inclusion of cardiovascular and CNS safety pharmacology assessment was included into GLP repeated-dose toxicity studies. There were no test-article-related effects on cardiovascular functions, as evaluated in rhesus monkeys, and respiratory or CNS functions as evaluated in rats.”
Genotox: Ames
Not conducted (protein; mechanism of action)
“Studies to evaluate the mutagenic and carcinogenic potential of idarucizumab have not been performed as based on its mechanism of action and the characteristics of proteins no carcinogenic or genotoxic effects were anticipated.”
Genotox: in vitro mammalian
Not conducted (protein; mechanism of action)
“Studies to evaluate the mutagenic and carcinogenic potential of idarucizumab have not been performed as based on its mechanism of action and the characteristics of proteins no carcinogenic or genotoxic effects were anticipated.”
Genotox: in vivo
Not conducted (protein; mechanism of action)
“Studies to evaluate the mutagenic and carcinogenic potential of idarucizumab have not been performed as based on its mechanism of action and the characteristics of proteins no carcinogenic or genotoxic effects were anticipated.”
Carcinogenicity model
Not conducted; no carcinogenic effects anticipated from mechanism of action and protein nature
“Studies to evaluate the mutagenic and carcinogenic potential of idarucizumab have not been performed as based on its mechanism of action and the characteristics of proteins no carcinogenic or genotoxic effects were anticipated.”
Carcinogenicity timing
Not required: omission accepted based on product nature and mechanism of action
“Based on the nature of the product and its mechanism of action, omission of genotoxicity studies and carcinogenicity studies was accepted.”
hERG / QT
No hERG assay; no cardiovascular effects (HR, ECG) in rhesus monkeys
“In line with ICH S6(R1) inclusion of cardiovascular and CNS safety pharmacology assessment was included into GLP repeated-dose toxicity studies. There were no test-article-related effects on cardiovascular functions, as evaluated in rhesus monkeys, and respiratory or CNS functions as evaluated in rats.”
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 Praxbind 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: Rhesus NOAEL 500 mg/kg/day with or without dabigatran (2 days or 2 weeks); margins 5-7x Cmax, 3-6x AUC (EMA assessment report, p. 24)
NOAEL / key findings
Rhesus NOAEL 500 mg/kg/day with or without dabigatran (2 days or 2 weeks); margins 5-7x Cmax, 3-6x AUC
“In summary, the NOAEL in rhesus monkeys treated with idarucizumab in the absence or presence of dabigatran for 2 days or 2 weeks was 500 mg/kg/day. The resulting exposure multiples, taking into account different human populations (healthy, elderly, with renal impairment) were approx. 5-7x based on Cmax and 3-6x based on AUC0-24.”
Risksopen answer page →
Immune & cytokine safety
No anti-dabigatran antibodies; circulating immune complexes normal; no renal immune complex deposition in monkeys
“However, there was no evidence for the development of anti-dabigatran antibodies. Circulating immune complexes were within normal limits in all animals and there was no evidence for immune complex deposition in the kidneys as evaluated by immunohistochemistry.”
Biodistribution & persistence
Half-life about 6 h in rats and 4-5 h in rhesus monkeys; low clearance and small volume of distribution
“The plasma concentration-time profile was biphasic with a rapid initial decline phase and a slow terminal phase, with a half-life of approx. 6 hrs in rats and 4-5 hrs in rhesus monkeys. The clearance of idarucizumab was low and the volume of distribution was small.”
Modality-specific risk
Potential prothrombotic activity investigated (D-dimer, F1+2); no prothrombotic effect found
“Apart from general toxicity, the 2-week study in rhesus monkeys also investigated the potential for pro-thrombotic activity of idarucizumab. Based on D-dimer and F1+2 evaluation, there was no evidence for a pro-thrombotic effect of idarucizumab.”
Anti-drug antibodies: animals
Anti-idarucizumab antibodies in some monkeys (end of treatment and recovery); no anti-dabigatran antibodies; circulating immune complexes normal
“In this study anti-idarucizumab antibodies were detected in some of the animals at the end of treatment and also at the end of the recovery period. However, there was no evidence for the development of anti-dabigatran antibodies. Circulating immune complexes were within normal limits in all animals”
Anti-drug antibodies: patients
Treatment-emergent low-titre ADA in 4% (10/224) of subjects and 2% (8/501) of patients
“Treatment-emergent possibly persisting anti-idarucizumab antibodies with low titers were observed in 4% (10/224) of the subjects and 2% (8/501) of patients treated with idarucizumab.”
Label warnings
- Thromboembolic Risk
- Re-elevation of Coagulation Parameters
- Hypersensitivity Reactions
- Risks of Serious Adverse Reactions in Patients with Hereditary Fructose Intolerance due to Sorbitol Excipient
Thrombosis & embolismHypersensitivity & 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 Praxbind 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: Rhesus NOAEL 500 mg/kg/day with or without dabigatran (2 days or 2 weeks); margins 5-7x Cmax, 3-6x AUC (EMA assessment report, p. 24)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
4-week GLP rat study (daily IV) with 4-week recovery
“4-week with 4-week recovery (GLP) Rat 0/0, 0/150 & 0/500 NOAEL = 0/500 mg/kg/day”
Pivotal GLP studies
GLP daily IV studies: rat up to 4 weeks; rhesus monkey up to 2 weeks, with or without dabigatran etexilate
“The nonclinical toxicology studies were designed to evaluate the potential toxicity of idarucizumab in rats and monkeys in GLP studies of up to 4- and 2-weeks of daily treatment, respectively.”
DART package
Species: DART
Not conducted (single-day emergency use); reproductive tissues assessed in repeat-dose studies
“It was also agreed that reproductive and developmental toxicity studies are not warranted taking into consideration the proposed used of idarucizumab on single days in emergency situations.”
Reproductive & developmental
No dedicated studies; no treatment-related effects on reproductive tissues in 4-week rat and 2-week monkey studies
“No treatment-related effects have been identified in reproductive tissues of either sex during repeat dose intravenous toxicity studies of up to four weeks in the rat and two weeks in monkeys.”
PPND / ePPND: when
Not conducted: reproductive and developmental studies not warranted for single-day emergency use
“It was also agreed that reproductive and developmental toxicity studies are not warranted taking into consideration the proposed used of idarucizumab on single days in emergency situations.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No genotoxicity, carcinogenicity, or reproductive toxicity studies have been conducted.”
Carcinogenicity model
Not conducted; no carcinogenic effects anticipated from mechanism of action and protein nature
“Studies to evaluate the mutagenic and carcinogenic potential of idarucizumab have not been performed as based on its mechanism of action and the characteristics of proteins no carcinogenic or genotoxic effects were anticipated.”
Carcinogenicity timing
Not required: omission accepted based on product nature and mechanism of action
“Based on the nature of the product and its mechanism of action, omission of genotoxicity studies and carcinogenicity studies was accepted.”
Safety marginopen answer page →
Safety margin at NOAEL
Rhesus NOAEL 500 mg/kg/day: approx. 3-6x human AUC and 5-7x Cmax across human populations
“In summary, the NOAEL in rhesus monkeys treated with idarucizumab in the absence or presence of dabigatran for 2 days or 2 weeks was 500 mg/kg/day. The resulting exposure multiples, taking into account different human populations (healthy, elderly, with renal impairment) were approx. 5-7x based on Cmax and 3-6x based on AUC0-24.”
NOAEL / key findings
Rhesus NOAEL 500 mg/kg/day with or without dabigatran (2 days or 2 weeks); margins 5-7x Cmax, 3-6x AUC
“In summary, the NOAEL in rhesus monkeys treated with idarucizumab in the absence or presence of dabigatran for 2 days or 2 weeks was 500 mg/kg/day. The resulting exposure multiples, taking into account different human populations (healthy, elderly, with renal impairment) were approx. 5-7x based on Cmax and 3-6x based on AUC0-24.”
Efficacy evidenceopen answer page →
Efficacy evidence
Dabigatran-anticoagulated bleeding models: rat tail bleeding, mouse intracranial haemorrhage, pig liver trauma
“The rat tail bleeding model represents a situation with limited blood loss. Also the intracranial haemorrhage in mice is associated with limited bleeding. In contrast, the pig liver trauma model is associated with severe blood loss, haemorrhagic shock and ultimately mortality.”
Why that model
Controlled data cannot be obtained from patients treated in emergencies, so animal bleeding models were used
“As it is difficult to obtain controlled information from humans treated in emergency situations, these non-clinical PD studies were considered justified and the results were adequately reflected in section 5.1 of the SmPC.”
Reviewer's view of the efficacy data
Pharmacology adequately demonstrated in vitro; specificity and lack of pro-thrombotic activity sufficiently shown
“The pharmacology of idarucizumab was adequately demonstrated in vitro. Idarucizumab binds with high affinity to dabigatran and thereby blocks the anti-coagulant activity of dabigatran in human plasma. Absence of idarucizumab binding to other thrombin substrates and lack of pro-thrombotic activity was sufficiently demonstrated as considered by the CHMP.”
Flexibilityopen answer page →
Flexibility accepted
DARTAcceptedBeyond the letter
No reproductive and developmental toxicity studies
Why: Use on single days in emergency situations · Other reason
“It was also agreed that reproductive and developmental toxicity studies are not warranted taking into consideration the proposed used of idarucizumab on single days in emergency situations.”
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