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.”
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.”
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 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: 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.”