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.”
Species: general tox
Sprague-Dawley rat (repeat-dose); cynomolgus monkey single-dose only
“Animal studies exploring the safety of dinutuximab were conducted in Sprague Dawley rats and cynomolgus monkeys.”
Species: DART
Not conducted: not required for paediatric population (90% under 5 years)
“Based on the median age of the proposed patient population (90% of patients less than 5 years of age), the Agency agreed that reproductive and developmental toxicology studies would not be required to support the BLA for Unituxin for the treatment of high risk neuroblastoma.”
Species: carcinogenicity
Not conducted
“No carcinogenicity studies have been conducted.”
Surrogate used in
Pharmacology literature also used surrogate antibodies with murine constant regions; toxicology used dinutuximab
“The pharmacologic characterization of dinutuximab is based on published literature detailing experiments using ch14.18 and surrogate antibodies with the same variable domain but with alternative murine constant regions.”
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.”
Genotox: Ames
Not conducted (ICH S6)
“Consistent with the ICH S6 guidance, genetic toxicology studies were not conducted or required for dinutuximab.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Consistent with the ICH S6 guidance, genetic toxicology studies were not conducted or required for dinutuximab.”
Genotox: in vivo
Not conducted (ICH S6)
“Consistent with the ICH S6 guidance, genetic toxicology studies were not conducted or required for dinutuximab.”
Carcinogenicity model
Not conducted (advanced cancer indication)
“Carcinogenicity studies were not required to support the licensing application for a product intended to treat advanced human cancer and are neither planned nor expected as post-marketing requirements at this time.”
Carcinogenicity timing
Not required for advanced cancer; not planned as a postmarketing requirement
“Carcinogenicity studies were not required to support the licensing application for a product intended to treat advanced human cancer and are neither planned nor expected as post-marketing requirements at this time.”
hERG / QT
No hERG (antibody); single-dose monkey CV study: increased heart rate, no clear QTc change
“In this study increases in heart rate were observed, consistent with tachycardia noted clinically, however, no clear changes in QTc, respiratory rate, or blood gas parameters were noted.”
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)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“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.”
Anti-drug antibodies: animals
Rat: probable ADA response at 5 mg/kg/day with rapid clearance of ch14.18
“In the rat, rapid elimination of ch14.18 after the final dose indicates a potential anti-drug antibody response which was observed only at 5 mg/kg/day.”
Anti-drug antibodies: patients
ADA in 86/418 (20.6%) patients with GM-CSF, IL-2 and RA; 45 (52.3%) of these neutralizing
“Among the 418 patients who were treated with Unituxin in combination with GM-CSF, IL-2, and RA in Study 2, Study 3 and Study DIV-NB-201, 86 patients (20.6%) tested positive for anti-dinutuximab antibodies (ADA). Of the 86 ADA positive patients, 45 (52.3%) tested positive for neutralizing antibodies.”
Label warnings
Boxed warning: Serious infusion reactions and neurotoxicity
- Serious Infusion Reactions
- Neurotoxicity
- Capillary Leak Syndrome
- Hypotension
- Infection
- Bone Marrow Suppression
- Electrolyte Abnormalities
- Atypical Hemolytic Uremic Syndrome
- Embryo-Fetal Toxicity
Hypersensitivity & infusion reactionsNeurotoxicityCardiovascularInfectionsCytopeniasMetabolic & endocrineEmbryo-fetal toxicity
US prescribing information, Boxed Warning and 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 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)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
4-week rat (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 recovery period.”
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”
DART package
Species: DART
Not conducted: not required for paediatric population (90% under 5 years)
“Based on the median age of the proposed patient population (90% of patients less than 5 years of age), the Agency agreed that reproductive and developmental toxicology studies would not be required to support the BLA for Unituxin for the treatment of high risk neuroblastoma.”
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.”
PPND / ePPND: when
Not conducted: reproductive toxicology not required because 90% of patients are under 5 years (median age 18 months)
“Because the median age of the proposed patient population is 18 months and 90% of the cases occur in children under the age of 5, reproductive toxicology studies of dinutuximab were not required to support the submission of the Unituxin BLA.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No carcinogenicity studies have been conducted.”
Carcinogenicity model
Not conducted (advanced cancer indication)
“Carcinogenicity studies were not required to support the licensing application for a product intended to treat advanced human cancer and are neither planned nor expected as post-marketing requirements at this time.”
Carcinogenicity timing
Not required for advanced cancer; not planned as a postmarketing requirement
“Carcinogenicity studies were not required to support the licensing application for a product intended to treat advanced human cancer and are neither planned nor expected as post-marketing requirements at this time.”
Safety marginopen answer page →
Safety margin at NOAEL
No NOAEL identified in the 28-day rat study; no margin stated
“The CHMP notes that a NOAEL has not been identified for the 28-day study in the rat.”
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”
Efficacy evidenceopen answer page →
Efficacy evidence
Published SCID mouse xenografts: ch14.18 with human PBMCs and IL-2 prevented GD2+ melanoma growth
“In a separate study, administration of ch14.18 with PBMCs and IL-2 prevented the establishment and growth of GD2+ melanoma tumours, whereas treatment with ch14.18 alone or PBMCs and IL-2 alone had no effect on tumour growth.”
Why that model
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.
Reviewer's view of the efficacy data
EMA: literature shows ADCC/CDC killing; IL-2/GM-CSF enhancement supports the combination regimen
“The augmentation of cell lysis and ADCC in the presence of IL-2 and GM-CSF, respectively, therefore aims to optimise cytotoxicity in vivo and is therefore supportive of the proposed treatment regimen.”
Flexibilityopen answer page →
Flexibility accepted
Study lengthAccepted with a conditionBeyond the letter
Only a 28-day rat repeat-dose study; chronic toxicity and peripheral neuropathy to be investigated after approval
Why: Chronic toxicity concern addressed as a postmarketing requirement; further peripheral nerve investigations post-authorisation
“However, to date, only a study of 28 days duration has been conducted. Given that this is the first molecule of its class, the CHMP was of the view that the incidence and extent of this peripheral neuropathy following repeated administration, the underlying pathophysiology, and the potential for reversibility would benefit from further investigation.”
“Thus, this concern can be addressed as a post-marketing requirement, and there are no outstanding issues from a pharmacology/toxicology perspective that would prevent the approval of dinutuximab for the treatment of the proposed patient population.”
Safety marginVerdict not stated
No NOAEL identified in the 28-day rat study
“The CHMP notes that a NOAEL has not been identified for the 28-day study in the rat.”
DARTAcceptedBeyond the letter
No reproductive and developmental toxicity studies
Why: Paediatric patient population (high-risk neuroblastoma) · Other reason
“Based on the age of the proposed patient population, FDA agreed that traditional reproductive toxicology studies were not warranted to support the use of this product in the treatment of patients with maintenance phase of high risk neuroblastoma.”
OtherVerdict not stated
No formal pharmacokinetic, distribution or single-dose toxicity studies; published data on ch14.18 and murine predecessors used instead
“Formal pharmacokinetic studies with ch14.18 have not been conducted, and instead data has been obtained and summarized from the public literature.”
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