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.”
Species: general tox
Cynomolgus monkey
“The Applicant evaluated the toxicity of retifanlimab in a 13-week GLP-compliant repeat-dose toxicology study in cynomolgus monkeys.”
Species: DART
Not conducted; not required for advanced cancer therapeutics (ICH S9)
“Standard fertility and early embryonic development, embryofetal development and pre- and postnatal development studies have not been conducted with retifanlimab as not required for advanced cancer therapeutics (ICH S9 2009).”
Species: carcinogenicity
Not conducted; not warranted
“Carcinogenicity studies were not warranted.”
Surrogate used in
No surrogate used; in vivo studies limited to cynomolgus monkeys with retifanlimab
“Retifanlimab cross reacts with PD-1 from cynomolgus and rhesus monkeys, but not with PD-1 from nonprimate species. Thus, in vivo studies were limited to cynomolgus monkeys with retifanlimab delivered by IV infusion.”
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).”
Genotox: Ames
Not conducted (ICH S6)
“No genotoxicity or carcinogenicity studies with retifanlimab have not been conducted, according to ICH S6(R1) (2011) and ICH S9 (2009) guidelines.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“No genotoxicity or carcinogenicity studies with retifanlimab have not been conducted, according to ICH S6(R1) (2011) and ICH S9 (2009) guidelines.”
Genotox: in vivo
Not conducted (ICH S6)
“No genotoxicity or carcinogenicity studies with retifanlimab have not been conducted, according to ICH S6(R1) (2011) and ICH S9 (2009) guidelines.”
Carcinogenicity model
Not conducted; not warranted
“Carcinogenicity studies were not warranted.”
Carcinogenicity timing
Not required
“Carcinogenicity studies were not warranted.”
hERG / QT
No hERG assay; no CNS, cardiovascular or respiratory effects in monkeys at 10-150 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.”
Anti-drug antibodies: animals
13-week monkey study: ADA in 10/30 animals; reduced exposure in 8/10, 3/10, 1/10 at 5, 20, 100 mg/kg
“Anti-drug antibodies (ADA) were detected in 10/30 animals. After repeat administration, changes in INCMGA00012 exposure (serum) were measured in 8/10, 3/10, and 1/10 animals in 5, 20, and 100 mg/kg dosing groups, respectively.”
Anti-drug antibodies: patients
MCC: treatment-emergent ADA 2.8% (3/106); neutralizing in 2 of 3
“The incidence of retifanlimab treatment-emergent ADAs was 2.8% (3/106) using a bridging enzyme‑linked immunosorbent assay following a median exposure time of 312 days. Neutralizing antibodies were detected in 2 of 3 patients with treatment-emergent ADAs.”
Label warnings
- Severe and Fatal Immune-Mediated Adverse Reactions
- Infusion-Related Reactions
- Complications of Allogeneic HSCT
- Embryo-Fetal Toxicity
Immune-mediated reactionsHypersensitivity & infusion reactionsEmbryo-fetal toxicity
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week GLP cynomolgus monkey (IV, once weekly); no recovery phase
“T18-02-10 (GLP) Cynomolgus monkeys/ 5M 5F 0, 5, 20, 100 mg/kg IV 30 min. infusion 13 weeks, no recovery”
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).”
DART package
Species: DART
Not conducted; not required for advanced cancer therapeutics (ICH S9)
“Standard fertility and early embryonic development, embryofetal development and pre- and postnatal development studies have not been conducted with retifanlimab as not required for advanced cancer therapeutics (ICH S9 2009).”
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.”
PPND / ePPND: when
Not conducted: not required for advanced cancer therapeutics (ICH S9)
“Standard fertility and early embryonic development, embryofetal development and pre- and postnatal development studies have not been conducted with retifanlimab as not required for advanced cancer therapeutics (ICH S9 2009).”
Carcinogenicity
Species: carcinogenicity
Not conducted; not warranted
“Carcinogenicity studies were not warranted.”
Carcinogenicity model
Not conducted; not warranted
“Carcinogenicity studies were not warranted.”
Carcinogenicity timing
Not required
“Carcinogenicity studies were not warranted.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey top dose 150 mg/kg corresponds to 26-fold the proposed MRHD exposure
“Across the studies, animals were given weekly doses ranging between 1 and 150 mg/kg (150 mg/kg corresponds to 26-fold the proposed MRHD exposure) administered via IV infusion.”
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).”
Efficacy evidenceopen answer page →
Efficacy evidence
Retifanlimab binding to peripheral T cells (flow cytometry) in cynomolgus monkey studies
“These studies in monkeys included the evaluation of a pharmacodynamic endpoint – retifanlimab binding to peripheral T cells by flow cytometry”
Why that model
No cross-reactivity with non-primate PD-1, so in vivo studies limited to cynomolgus monkeys
“Retifanlimab cross reacts with PD-1 from cynomolgus and rhesus monkeys, but not with PD-1 from nonprimate species. Thus, in vivo studies were limited to cynomolgus monkeys with retifanlimab delivered by IV infusion.”
Reviewer's view of the efficacy data
EMA: no in vivo proof-of-concept models presented; not considered needed given experience with PD-1 inhibitors
“No in vivo models were presented to demonstrate proof of concept. These are not considered needed based on the experience with PD-1 inhibitors.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted
No animal reproductive or developmental toxicity studies; weight-of-evidence assessment instead
Why: Weight-of-evidence approach per ICH S6(R1) and ICH S9 · Within the guideline · Weight of evidence
“Embryo-fetal developmental toxicology studies were not conducted with retifanlimab. Rather, consistent with the alternative approach to providing information on the potential for reproductive toxicity described in ICH S6(R1) and ICH S9, the Applicant provided a weight-of-evidence assessment of the potential reproductive toxicity of retifanlimab.”
“The lack of carcinogenicity, genotoxicity, reproductive and developmental studies were adequately justified.”
Efficacy modelAcceptedBeyond the letter
No in vivo proof-of-concept models; mode of action supported in vitro only
Why: Not needed given experience with PD-1 inhibitors · Class precedent
“The mode of action of retifanlimab was supported by in vitro studies. No in vivo models were presented to demonstrate proof of concept.”
“These are not considered needed based on the experience with PD-1 inhibitors.”
Similar precedents
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