Zynyz
retifanlimab
Species
Monkey
Longest study
13 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
Cynomolgus monkey only
“In vitro studies showed retifanlimab bound to human and cynomolgus monkey PD-1 with nanomolar affinity (0.6 and 3.6 nM, respectively) and did not cross react with rodent or canine PD-1, supporting the use of cynomolgus monkeys as the single pharmacologically relevant species for toxicity assessment.”
Why that species
Binds human and cynomolgus PD-1 with nanomolar affinity (0.6 and 3.6 nM); no rodent or canine PD-1 cross-reactivity
“In vitro studies showed retifanlimab bound to human and cynomolgus monkey PD-1 with nanomolar affinity (0.6 and 3.6 nM, respectively) and did not cross react with rodent or canine PD-1, supporting the use of cynomolgus monkeys as the single pharmacologically relevant species for toxicity assessment.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkeys
“The Applicant evaluated the toxicity of retifanlimab in a 13-week GLP-compliant repeat-dose toxicology study in cynomolgus monkeys.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“The Applicant evaluated the toxicity of retifanlimab in a 13-week GLP-compliant repeat-dose toxicology study in cynomolgus monkeys.”
Pivotal GLP studies
GLP cynomolgus monkey 4-week (0-150 mg/kg, 10-week recovery) and 13-week (0-100 mg/kg) studies, weekly IV infusion
“Pivotal repeat-dose toxicity studies with retifanlimab in cynomolgus monkeys include a 4-week study (doses: 0, 10, 40, or 150 mg/kg) with a 10-week recovery period (T19-01-03) and a 13 week study (doses: 0, 5, 20, 100 mg/kg; T18 02-10).”
Route in tox
IV infusion
“In both studies, retifanlimab was administered once weekly by IV infusion (1 hour infusion in 4-week study, 30 minute infusion in 13-week study).”
Skipped studiesopen answer page →
Genotoxicity
Not conducted; not warranted
“Genetic toxicology studies were not warranted.”
Carcinogenicity
Not conducted; not warranted
“Carcinogenicity studies were not warranted.”
Reproductive & developmental
Not conducted; weight-of-evidence reproductive risk assessment submitted instead
“Reproductive and developmental toxicology studies were not conducted with retifanlimab. Instead, the Applicant submitted a weight-of-evidence reproductive risk assessment for retifanlimab.”
Safety pharmacology
Incorporated into 4-week GLP monkey study (CNS, cardiovascular, respiratory); no adverse effects up to 150 mg/kg
“No retifanlimab-related findings suggestive of adverse effects on the CNS, cardiovascular, or respiratory systems were noted at any dose level evaluated (10-150 mg/kg).”
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 Zynyz 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 monoclonal antibodies
ADCs with cytotoxic payloads follow the S9 rules (1/10 STD10 or 1/6 HNSTD of the ADC, scaled by body surface area). For immune agonists, a MABEL-based start dose should be considered instead.
“For example, for cytotoxic payloads, the starting clinical dose can be determined using either 1/10th the Severely Toxic Dose (STD) in 10% of animals (STD10) in rodents or 1/6th the Highest Non- Severely Toxic Dose (HNSTD) in non-rodents, for the ADC based on body surface area, depending on which is the most appropriate and/or sensitive species.”
This product's starting point
NOAEL / key findings: 13-week monkey NOAEL 100 mg/kg per dose, the highest dose evaluated (EMA assessment report, p. 47)
NOAEL / key findings
13-week monkey NOAEL 100 mg/kg per dose, the highest dose evaluated
“Following administration for 13 weeks, the NOAEL was considered to be 100 mg/kg per dose, the highest dose evaluated (sex combined mean Cmax of 4.88 mg/mL and AUC of 237 h•mg/mL).”
Risksopen answer page →
Immune & cytokine safety
No cytokine production by human PBMCs with soluble or immobilized antibody at 10-100 µg/mL
“Upon exposure of PBMCs to retifanlimab concentrations of 10 µg/mL and 100 µg/mL (ie, 10-200 times higher than the positive control antibody OKT3), no cytokine production was observed with all three conditions of retifanlimab presentation.”
Biodistribution & persistence
Human TCR staining limited to lymphocytes in expected tissues
“Staining was observed in expected tissues and was limited to lymphocytes.”
Modality-specific risk
Potential for severely enhanced immune responses to infection with PD-1 blockade
“Based on data from the literature and its mechanism of action, there may be a potential for severely enhanced immune responses to infection following treatment with retifanlimab.”