Danyelza

“Y-mAbs conducted a GLP-compliant 13-week toxicology study in nude rats.”

“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.”

“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.”

“Y-mAbs conducted a GLP-compliant 13-week toxicology study in nude rats.”

“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.”

“A 13-Week Toxicity Study by Intravenous Infusion Administration to Hsd:RH-Foxn1rnu Nude Rats Followed by a 4-Week Recovery Period (YN70HM)”

“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.”

“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.”

“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.”

“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.”

“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.”

“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”

“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.”

“FDA agrees that tissue cross reactivity studies showed binding to peripheral nerve, cerebellum, spinal cord, frontal lobe, and pons.”

“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.”