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.”
Species: general tox
Mouse (13-week) and cynomolgus monkey (4-week)
“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.”
Species: DART
Mouse (EFD only); fertility and pre/postnatal studies omitted per ICH S9
“Reproductive and developmental toxicity studies were performed in mice. In line with ICH S9, only embryofoetal development was assessed; omission of studies on fertility and early embryonic development and on pre-/post-natal development is acceptable.”
Species: 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.”
Surrogate used in
Yes: murine IgG2a variant of zolbetuximab given to one group 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).”
Genotox: Ames
Not conducted (ICH S6)
“In line with ICH S6(R1), genotoxicity studies are not warranted for mAbs.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“In line with ICH S6(R1), genotoxicity studies are not warranted for mAbs.”
Genotox: in vivo
Not conducted (ICH S6)
“In line with ICH S6(R1), genotoxicity studies are not warranted for mAbs.”
Carcinogenicity model
Not conducted (monoclonal antibody, advanced cancer population)
“No genotoxicity or carcinogenicity studies are warranted given the structure of zolbetuximab (monoclonal antibody) and the patient population (advanced cancer).”
Carcinogenicity timing
Not required (ICH S9, advanced cancer)
“No genotoxicity or carcinogenicity studies are warranted given the structure of zolbetuximab (monoclonal antibody) and the patient population (advanced cancer).”
hERG / QT
No cardiovascular effects in 4-week monkey study up to 100 mg/kg
“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)
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: 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.”
Anti-drug antibodies: animals
ADA in 13/18 monkeys in a single-dose study; not detected in the 4-week toxicity study
“In this study, ADAs were detected in 13/18 animals but not in the 4-week toxicity study.”
Anti-drug antibodies: patients
9.5% (46 of 485 ADA-evaluable patients)
“the incidence of anti-zolbetuximab-clzb antibody formation was 9.5% (46 of 485 ADA-evaluable patients)”
Label warnings
- Hypersensitivity reactions, including anaphylaxis reactions, and infusion related reactions
- Severe Nausea and Vomiting
Hypersensitivity & infusion reactionsGastrointestinal
US prescribing information, 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 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)
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: 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week mouse (IV) with 4-week treatment-free recovery
“To investigate reversibility after a 4-week treatment-free period, an additional 5 males and 5 females were assigned to the control and 300 mg/kg groups”
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.”
DART package
Species: DART
Mouse (EFD only); fertility and pre/postnatal studies omitted per ICH S9
“Reproductive and developmental toxicity studies were performed in mice. In line with ICH S9, only embryofoetal development was assessed; omission of studies on fertility and early embryonic development and on pre-/post-natal development is acceptable.”
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).”
PPND / ePPND: when
PPND not conducted: omission acceptable under ICH S9; only embryo-fetal development assessed (mouse)
“In line with ICH S9, only embryofoetal development was assessed; omission of studies on fertility and early embryonic development and on pre-/post-natal development is acceptable.”
Carcinogenicity
Species: 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.”
Carcinogenicity model
Not conducted (monoclonal antibody, advanced cancer population)
“No genotoxicity or carcinogenicity studies are warranted given the structure of zolbetuximab (monoclonal antibody) and the patient population (advanced cancer).”
Carcinogenicity timing
Not required (ICH S9, advanced cancer)
“No genotoxicity or carcinogenicity studies are warranted given the structure of zolbetuximab (monoclonal antibody) and the patient population (advanced cancer).”
Safety marginopen answer page →
Safety margin at NOAEL
NOAEL serum AUC 11-12x human exposure (clinical PK) or 6-7x (Pop-PK model)
“Serum AUC at the NOAEL was at 11-12-fold based on clinical data, and 6–7-fold based on the new Pop-PK model.”
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).”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse xenograft models of human gastric cancer
“In vivo anti-tumour activity of zolbetuximab was evaluated in mouse xenograft models of human gastric cancer.”
Why that model
Epitope lies in a CLDN18.2 region highly conserved across species, allowing mouse models
“the epitope recognised was identified in the 1st extracellular loop of CLDN18.2, a region that is highly conserved across species.”
Reviewer's view of the efficacy data
EMA: in vivo data sufficiently support combination with fluoropyrimidine- or platinum-containing chemotherapy
“These data sufficiently support the combination of zolbetuximab with fluoropyrimidine- or platinum-containing chemotherapeutics in the clinic.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted
Embryo-fetal development studied in one species only (mouse)
Why: ICH S9 allows one species for biopharmaceuticals · Within the guideline
“EFD studies were conducted in one species only. According to ICH S9, this is acceptable for biopharmaceuticals.”
GLPVerdict not stated
Toxicokinetics of pivotal 4-week monkey study analysed non-GLP; complementary GLP single-dose TK study conducted
“Since toxicokinetic analysis in the 4-week repeat dose toxicity study in cynomolgus monkeys [Study 22337] was conducted under non-GLP conditions, a complementary single dose toxicokinetic study in cynomolgus monkeys [Study 8951-TX-0001] was conducted in compliance with GLP.”
Similar precedents
CampathAntibodies · alemtuzumab · CD52Monkey + rodent · 4 wkErbituxAntibodies · cetuximab · EGFRMonkey + rodent · 39 wkTecentriqAntibodies · atezolizumab · PD-L1Monkey + rodent · 26 wkUnituxinAntibodies · dinutuximab · GD2Monkey + rodent · 4 wkBavencioAntibodies · avelumab · PD-L1Monkey only · 13 wkCyramzaAntibodies · ramucirumab · VEGFR2Monkey only · 39 wk