Danyelza
naxitamab
Species
Rat
Longest study
13 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Partial / alternative Partly stated
Speciesopen answer page →
Species
Nude rat (athymic) only
“Y-mAbs conducted a GLP-compliant 13-week toxicology study in nude rats.”
Why that species
Immunodeficient nude rats (with NK cells and PMN) chosen to avoid anti-drug antibodies during long-term dosing; FDA judged the model inadequate
“Investigators reasoned that the use of nude rats rather than fully immune competent animals would allow for avoidance of the formation of anti-drug antibodies that would prevent long-term assessment of a human antibody in a rodent model.”
Surrogate molecule
No surrogate in toxicology studies; the clinical antibody was tested in nude rats (literature anti-GD2 14.G2a used for rat pain pharmacology)
“Intravenous or intrathecal administration of a murine IgG2a isotype anti-GD2 monoclonal antibody (14.G2a) to adult immunocompetent Sprague Dawley rats led to mechanical allodynia, confirming the enhanced pain effect of anti-GD2 administration in animals.”
Species: general tox
Athymic nude rat (Hsd:RH-Foxn1rnu) for 6- and 13-week repeat-dose studies; mouse single-dose study
“The safety profile of naxitamab is based on a single-dose toxicity study in mice and repeat-dose toxicology studies (6- and 13-week) in Hsd: RH-Foxn1rnu nude rats.”
Species: DART
Not conducted; FDA did not request an EFD study because patients are primarily ≤5 years old
“In addition, because the age of the proposed patient population is primarily ≤5 years old, FDA did not request an embryo-fetal development study to support the use of naxitamab.”
Species: carcinogenicity
Not conducted
“Y-mAbs has not conducted carcinogenicity studies with naxitamab.”
Surrogate used in
Literature surrogate only: murine anti-GD2 antibody 14.G2a in immunocompetent rats caused mechanical allodynia
“Intravenous or intrathecal administration of a murine IgG2a isotype anti-GD2 monoclonal antibody (14.G2a) to adult immunocompetent Sprague Dawley rats led to mechanical allodynia, confirming the enhanced pain effect of anti-GD2 administration in animals.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“Y-mAbs conducted a GLP-compliant 13-week toxicology study in nude rats.”
Pivotal GLP studies
GLP 13-week IV nude rat study: 4 cycles of 3 doses (Days 1, 3, 5) at 10 or 50 mg/kg
“Rats received intravenous naxitamab for 4 cycles of 3 treatment days per cycle (every other day on Days 1, 3, and 5) at doses of 0, 10, or 50 mg/kg.”
Route in tox
IV infusion
“A 13-Week Toxicity Study by Intravenous Infusion Administration to Hsd:RH-Foxn1rnu Nude Rats Followed by a 4-Week Recovery Period (YN70HM)”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6/S9, advanced cancer)
“Y-mAbs has not conducted genetic toxicology studies with naxitamab. In accordance with ICH S6 and ICH S9, these studies are not considered necessary to support a marketing application for a biotechnology-derived pharmaceutical intended to treat advanced cancer.”
Carcinogenicity
Not conducted (ICH S6/S9, advanced cancer)
“Y-mAbs has not conducted carcinogenicity studies with naxitamab. In accordance with ICH S6 and ICH S9, these studies are not considered necessary to support a marketing application for a biotechnology-derived pharmaceutical intended to treat advanced cancer.”
Reproductive & developmental
Not conducted: no fertility studies (advanced cancer); EFD not requested as patients are mainly ≤5 years old
“Y-mAbs did not conduct dedicated studies to assess fertility or carcinogenicity and these studies are not warranted to support the development of a drug intended to treat patients with advanced cancer. In addition, because the age of the proposed patient population is primarily ≤5 years old, FDA did not request an embryo-fetal development study to support the use of naxitamab.”
Safety pharmacology
No stand-alone studies (advanced cancer); CV, CNS and respiratory endpoints included in general toxicity studies
“FDA agrees that stand-alone safety pharmacology studies are not expected for an antibody intended for the treatment of patients with advanced cancer. In general cardiovascular, CNS, and respiratory safety endpoints are included in general toxicity studies.”
Genotox: Ames
Not conducted (ICH S6/S9, advanced cancer)
“Y-mAbs has not conducted genetic toxicology studies with naxitamab. In accordance with ICH S6 and ICH S9, these studies are not considered necessary to support a marketing application for a biotechnology-derived pharmaceutical intended to treat advanced cancer.”
Genotox: in vitro mammalian
Not conducted (ICH S6/S9, advanced cancer)
“Y-mAbs has not conducted genetic toxicology studies with naxitamab. In accordance with ICH S6 and ICH S9, these studies are not considered necessary to support a marketing application for a biotechnology-derived pharmaceutical intended to treat advanced cancer.”
Genotox: in vivo
Not conducted (ICH S6/S9, advanced cancer)
“Y-mAbs has not conducted genetic toxicology studies with naxitamab. In accordance with ICH S6 and ICH S9, these studies are not considered necessary to support a marketing application for a biotechnology-derived pharmaceutical intended to treat advanced cancer.”
Carcinogenicity model
Not conducted (ICH S6/S9, advanced cancer)
“Y-mAbs has not conducted carcinogenicity studies with naxitamab. In accordance with ICH S6 and ICH S9, these studies are not considered necessary to support a marketing application for a biotechnology-derived pharmaceutical intended to treat advanced cancer.”
Carcinogenicity timing
Not required for an advanced-cancer biologic (ICH S6/S9); FDA agreed
“Y-mAbs has not conducted carcinogenicity studies with naxitamab. In accordance with ICH S6 and ICH S9, these studies are not considered necessary to support a marketing application for a biotechnology-derived pharmaceutical intended to treat advanced cancer. The FDA’s Assessment: FDA agrees.”
hERG / QT
Not conducted: no hERG or stand-alone safety pharmacology studies (ICH S9)
“In accordance with ICH S9 guidance, Nonclinical Evaluation for Anticancer Pharmaceuticals (October 2009), Y-mAbs has not conducted any standalone safety pharmacology studies with naxitamab.”
First doseopen answer page →
First-in-human starting dose
Initial trials based on prior clinical data with the murine parent antibody, not on toxicology data with naxitamab
“The initial clinical trials investigating the activity and dosing of naxitamab were conducted on the basis of previous clinical data with the murine parent antibody rather than supported by toxicology data with the clinical candidate.”
NOAEL / key findings
13-week NOAEL 10 mg/kg/day (30 mg/kg per cycle) in male nude rats; adverse glandular stomach findings
“In the 13-week study, adverse findings in histopathology evaluations of the stomach resulted in the NOAEL to be established at 10 mg/kg/day (30 mg/kg per cycle) in male rats only”
Risksopen answer page →
Immune & cytokine safety
In vitro ADCC with nude rat effector cells ~22% vs 55% with human NK cells, underpredicting human activity
“Naxitamab induced approximately 22% ADCC in human LAN-1/rat splenocyte co-cultures whereas there was 55% ADCC against the same cell line in the presence of human NK cells, indicating that the rat/rat and rat/human systems underpredicted the activity of the human/human system.”
Biodistribution & persistence
TCR: on-target binding to peripheral nerve, cerebellum, spinal cord, frontal lobe and pons
“FDA agrees that tissue cross reactivity studies showed binding to peripheral nerve, cerebellum, spinal cord, frontal lobe, and pons.”
Modality-specific risk
Neuropathic pain from binding GD2 on peripheral nerve fibers and myelin with immune-mediated cytotoxicity
“Non-clinical studies suggest that naxitamab-gqgk-induced neuropathic pain is mediated by binding of the antibody to the GD2 antigen located on the surface of peripheral nerve fibers and myelin and subsequent induction of immune-mediated cytotoxic activity.”
Anti-drug antibodies: animals
Immunodeficient nude rats chosen to avoid anti-drug antibodies limiting long-term exposure
“Investigators reasoned that the use of nude rats rather than fully immune competent animals would allow for avoidance of the formation of anti-drug antibodies that would prevent long-term assessment of a human antibody in a rodent model.”
Anti-drug antibodies: patients
8% (2/24) in Study 201; 23% (27/117) in Study 12-230 with a not fully validated assay
“In Study 201, 2 of 24 (8%) patients tested positive for anti-drug antibodies (ADA) after treatment with DANYELZA. In Study 12-230, 27 of 117 patients (23%) tested positive for ADA after treatment with DANYELZA by an assay that was not fully validated”
Label warnings
Boxed warning: SERIOUS INFUSION-RELATED REACTIONS and NEUROTOXICITY
- Serious Infusion-Related Reactions
- Neurotoxicity
- Myocarditis
- Hypertension
- Orthostatic Hypotension
- Embryo-Fetal Toxicity
Hypersensitivity & infusion reactionsNeurotoxicityCardiovascularEmbryo-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
None with naxitamab: initial clinical trials relied on prior clinical data with the murine parent antibody
“The initial clinical trials investigating the activity and dosing of naxitamab were conducted on the basis of previous clinical data with the murine parent antibody rather than supported by toxicology data with the clinical candidate.”
First-in-human starting dose
Initial trials based on prior clinical data with the murine parent antibody, not on toxicology data with naxitamab
“The initial clinical trials investigating the activity and dosing of naxitamab were conducted on the basis of previous clinical data with the murine parent antibody rather than supported by toxicology data with the clinical candidate.”
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week IV nude rat study with 4-week recovery
“A 13-Week Toxicity Study by Intravenous Infusion Administration to Hsd:RH-Foxn1rnu Nude Rats Followed by a 4-Week Recovery Period (YN70HM)”
Pivotal GLP studies
GLP 13-week IV nude rat study: 4 cycles of 3 doses (Days 1, 3, 5) at 10 or 50 mg/kg
“Rats received intravenous naxitamab for 4 cycles of 3 treatment days per cycle (every other day on Days 1, 3, and 5) at doses of 0, 10, or 50 mg/kg.”
DART package
Species: DART
Not conducted; FDA did not request an EFD study because patients are primarily ≤5 years old
“In addition, because the age of the proposed patient population is primarily ≤5 years old, FDA did not request an embryo-fetal development study to support the use of naxitamab.”
Reproductive & developmental
Not conducted: no fertility studies (advanced cancer); EFD not requested as patients are mainly ≤5 years old
“Y-mAbs did not conduct dedicated studies to assess fertility or carcinogenicity and these studies are not warranted to support the development of a drug intended to treat patients with advanced cancer. In addition, because the age of the proposed patient population is primarily ≤5 years old, FDA did not request an embryo-fetal development study to support the use of naxitamab.”
PPND / ePPND: when
Not conducted: no reproductive studies; embryo-fetal study not requested as patients are mainly ≤5 years old
“In addition, because the age of the proposed patient population is primarily ≤5 years old, FDA did not request an embryo-fetal development study to support the use of naxitamab.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Y-mAbs has not conducted carcinogenicity studies with naxitamab.”
Carcinogenicity model
Not conducted (ICH S6/S9, advanced cancer)
“Y-mAbs has not conducted carcinogenicity studies with naxitamab. In accordance with ICH S6 and ICH S9, these studies are not considered necessary to support a marketing application for a biotechnology-derived pharmaceutical intended to treat advanced cancer.”
Carcinogenicity timing
Not required for an advanced-cancer biologic (ICH S6/S9); FDA agreed
“Y-mAbs has not conducted carcinogenicity studies with naxitamab. In accordance with ICH S6 and ICH S9, these studies are not considered necessary to support a marketing application for a biotechnology-derived pharmaceutical intended to treat advanced cancer. The FDA’s Assessment: FDA agrees.”
Safety marginopen answer page →
Safety margin at NOAEL
Nude rat 50 mg/kg exposure 32x (males) and 25x (females) human AUC at 9 mg/kg
“Exposures achieved in rats at the 50 mg/kg dose level were 32 (males) and 25 (females) times higher than the AUC in patients (2386 µg*h/mL) at the once every 3 days per cycle clinical dose of 9 mg/kg.”
NOAEL / key findings
13-week NOAEL 10 mg/kg/day (30 mg/kg per cycle) in male nude rats; adverse glandular stomach findings
“In the 13-week study, adverse findings in histopathology evaluations of the stomach resulted in the NOAEL to be established at 10 mg/kg/day (30 mg/kg per cycle) in male rats only”
Efficacy evidenceopen answer page →
Efficacy evidence
Athymic nude mice bearing subcutaneous human neuroblastoma xenografts treated with naxitamab
“The mouse model used in the biodistribution study, athymic nude mice harboring subcutaneous human neuroblastoma xenografts, was the same model used for in vivo primary pharmacodynamics studies evaluating the efficacy of naxitamab in an animal model of disease.”
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
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.
Flexibilityopen answer page →
Flexibility accepted
SpeciesAccepted with a conditionBeyond the letter
Repeat-dose toxicity only in immunodeficient nude rats, judged an inadequate toxicology model; juvenile study in a relevant species required postmarketing
Why: Additional juvenile toxicology study in a relevant species needed to characterize nerve risk in the pediatric population
“Literature cited by the Applicant using other antibodies targeting GD2 in fully immunocompetent rat or mouse models demonstrates the ability of these rodents to model the allodynia observed clinically, further suggesting that though some immune-competent rodent models may adequately predict the toxicity of the antibody the nude rat is does not, making it an inadequate toxicology model for this product.”
“Due to the lack of changes in nociception in the nonclinical toxicology studies provided in the BLA and the age of the animals used, an additional toxicology study in juvenile animals of a relevant species is needed to adequately characterize the risk of the use of naxitamab on the central and peripheral nerves as related to the indicated pediatric population.”
First doseVerdict not stated
Initial clinical trials supported by prior clinical data with the murine parent antibody, not by toxicology data with naxitamab
Why: Prior clinical data with the murine parent antibody
“The initial clinical trials investigating the activity and dosing of naxitamab were conducted on the basis of previous clinical data with the murine parent antibody rather than supported by toxicology data with the clinical candidate.”
DARTAccepted
No fertility or embryo-fetal development studies
Why: Patient population primarily 5 years old or younger; fertility studies not warranted for advanced cancer · Within the guideline · Other reason
“In addition, because the age of the proposed patient population is primarily ≤5 years old, FDA did not request an embryo-fetal development study to support the use of naxitamab.”
“Y-mAbs did not conduct dedicated studies to assess fertility or carcinogenicity and these studies are not warranted to support the development of a drug intended to treat patients with advanced cancer.”
Similar precedents
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