Unituxin
dinutuximab
Species
MonkeyRat
Longest study
4 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat (repeat-dose) and cynomolgus monkey (single-dose safety pharmacology)
“Animal studies exploring the safety of dinutuximab were conducted in Sprague Dawley rats and cynomolgus monkeys.”
Why that species
Antibody binds GD2 in rats and lowers mechanical pain thresholds; TCR staining consistent with GD2 expression in rat and rabbit
“Though there were no histopathological indications of an effect of dinutuximab on peripheral nerves in this study, ch14.18 has been shown to bind to GD2 in rats.”
Surrogate molecule
No surrogate; the clinical antibody was tested in rats and cynomolgus monkeys
“Animal studies exploring the safety of dinutuximab were conducted in Sprague Dawley rats and cynomolgus monkeys.”
Study lengthopen answer page →
Longest pivotal study
4 weeks
“The safety of dinutuximab was evaluated in a 28-day repeat-dose toxicology study in rats.”
Pivotal GLP studies
GLP 4-week IV rat study (4 days on, 3 days off weekly) with 6-week recovery
“Rats were administered dinutuximab at doses significantly higher than the clinically recommended dose for 4 weeks (4 days on, 3 days off/week) with a 6-week”
Route in tox
IV
“Sprague-Dawley rat SBL354-003 Yes PIVOTAL STUDY IV”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“Consistent with the ICH S6 guidance, genetic toxicology studies were not conducted or required for dinutuximab.”
Carcinogenicity
Not conducted (advanced cancer); carcinogenic potential considered low
“Carcinogenicity studies were not required to support the licensing application for a product intended to treat advanced human cancer”
Reproductive & developmental
Not conducted (pediatric population); no reproductive organ effects in rat repeat-dose study at high exposures
“In the repeat-dose toxicity studies, administration of dinutuximab in male and female rats resulted in no adverse effects on reproductive organs at exposures that were at least 60 fold higher than those observed clinically.”
Safety pharmacology
Single-dose CV/respiratory study in cynomolgus monkeys: increased heart rate and blood pressure, shortened PR/QT, QTc unaffected
“Increases in blood pressure and heart rate along with corresponding findings of shortened PR and QT intervals in ECG evaluations were noted, though QTc intervals were unaffected.”
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 Unituxin 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 oncology monoclonal antibodies (ICH S9)
In cancer patients the start dose should be pharmacologically active yet reasonably safe. A common small-molecule approach is one-tenth of the dose severely toxic to 10% of rodents, or one-sixth of the highest non-severely toxic dose in non-rodents.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Rat NOAEL below 5 mg/kg/day; liver changes, decreased erythrocyte parameters, increased hematopoiesis (EMA assessment report, p. 33)
NOAEL / key findings
Rat NOAEL below 5 mg/kg/day; liver changes, decreased erythrocyte parameters, increased hematopoiesis
“(NOAEL) for males and females was lower than 5 mg/kg/day based on the liver-related changes, the slight decrease in erythrocyte parameters, and changes related to hematopoiesis”
Risksopen answer page →
Immune & cytokine safety
Rats: increased lymphocytes, neutrophils and NK cells; anti-drug antibodies affected exposure
“Increases in lymphocytes, neutrophils, and NK cells were also noted in rats. The rats did appear to develop an anti-drug antibody response which affected the pharmacokinetics of dinutuximab, particularly at the lowest dose level.”
Biodistribution & persistence
Human TCR: membrane binding in kidney, GI, spleen, GALT, ovary, neurons and brain
“Conclusion: Membrane/membrane granules of kidney, GI, spleen, GALT, ovary, neurons, cerebrum, and brain were identified as ch14.18-target tissues in humans.”
Modality-specific risk
Neuropathic pain and neuropathy from GD2 binding on peripheral nerves with complement- and ADCC-mediated damage
“Together these data suggest that the clinically reported pain response following administration of dinutuximab is a pharmacologic consequence of dinutuximab binding to peripheral nerves and causing damage through CDC and ADCC.”