Vyloy
zolbetuximab
Species
MonkeyMouse
Longest study
13 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
Mouse and cynomolgus monkey
“Pivotal toxicology studies with zolbetuximab included a 13-week GLP repeat-dose study in mice and a 4-week GLP repeat-dose study in cynomolgus monkey with once weekly intravenous administration.”
Why that species
Binds mouse (KD 2.6 nM) and cynomolgus monkey (KD 2.22 nM) CLDN18.2 orthologs
“Flow cytometry binding was observed for a mouse CLDN18.2 ortholog (KD=2.6 nM) and cynomolgus monkey (KD=2.22 nM).”
Surrogate molecule
Yes: murine variant of zolbetuximab with comparable Fc effector function, given to a group of mice in the mouse toxicity study
“A group of mice received the murine variant of zolbetuximab which exerts comparable Fc effector function to human IgG1.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“Pivotal toxicology studies with zolbetuximab included a 13-week GLP repeat-dose study in mice and a 4-week GLP repeat-dose study in cynomolgus monkey with once weekly intravenous administration.”
Pivotal GLP studies
GLP 13-week mouse and 4-week cynomolgus monkey studies, once weekly IV
“Pivotal toxicology studies with zolbetuximab included a 13-week GLP repeat-dose study in mice and a 4-week GLP repeat-dose study in cynomolgus monkey with once weekly intravenous administration.”
Route in tox
Intravenous
“Pivotal toxicology studies with zolbetuximab included a 13-week GLP repeat-dose study in mice and a 4-week GLP repeat-dose study in cynomolgus monkey with once weekly intravenous administration.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6 and S9)
“No genotoxicity studies have been conducted per ICH S6 and ICH S9 guidelines.”
Carcinogenicity
Not conducted (advanced cancer, ICH S9)
“No carcinogenicity studies have been conducted. Zolbetuximab. is intended for the treatment of patients with advanced cancer in the scope of the ICH S9.”
Reproductive & developmental
Mouse EFD (IV during organogenesis): no embryo-fetal toxicity up to 300 mg/kg (about 1.9 times clinical AUC)
“In an embryo-fetal development toxicity study, zolbetuximab was intravenously administered to pregnant mice during the period of organogenesis and did not result in embryo-fetal toxicity at doses up to 300 mg/kg (approximately 1.9 times the recommended clinical dose based on AUC).”
Safety pharmacology
No CNS effects in mouse Irwin test at 100 mg/kg; no cardiovascular or respiratory effects in the 4-week monkey study up to 100 mg/kg
“In safety pharmacology studies with 100 mg/kg zolbetuximab, there were no CNS effects noted by Irwin’s test in mice. No cardiovascular or respiratory effects were observed in monkeys (Study 22337) at the highest dose of zolbetuximab (100 mg/kg) after once weekly IV administration for 4 weeks (5 doses in total).”
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 Vyloy 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: No adverse findings in mice; isolated vomiting in one male each at 10 and 30 mg/kg on Day 8 in the 4-week monkey study (FDA multi-discipline review, p. 52)
NOAEL / key findings
No adverse findings in mice; isolated vomiting in one male each at 10 and 30 mg/kg on Day 8 in the 4-week monkey study
“No adverse findings were observed in mice. In the 4-week monkey study, vomiting was observed in one male each from the 10 mg/kg and 30 mg/kg dose groups on Day 8 (second administration).”
Risksopen answer page →
Immune & cytokine safety
ADA in 13/18 monkeys after a single dose; none detected in the 4-week monkey toxicity study
“In this study, ADAs were detected in 13/18 animals but not in the 4-week toxicity study.”
Biodistribution & persistence
Crosses the placenta in mice: fetal serum levels on GD18 higher than maternal levels on GD16
“Zolbetuximab crossed the placental barrier resulting in higher fetal serum concentrations on Day 18 of gestation than maternal serum concentrations on Day 16 of gestation.”
Modality-specific risk
On-target gastric mucosal injury causing retching and vomiting
“However, the hypothesis was confirmed that zolbetuximab causes cellular damage to the gastric mucosa, resulting in retching and vomiting.”