Imfinzi
durvalumab
Species
Monkey
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
Cynomolgus monkey only
“The cynomolgus monkey was found to be the only pharmacological relevant nonclinical species for evaluation of local and systemic toxicities of durvalumab.”
Why that species
Binds only human and cynomolgus monkey PD-L1; monkey the only relevant species
“Durvalumab was found to only bind to human and cynomolgus monkey PD-L1, and the cynomolgus monkey was found to be the only relevant nonclinical species for the safety and toxicity studies.”
Surrogate molecule
No surrogate in toxicology studies; a mouse anti-mouse PD-L1 surrogate was used in a syngeneic mouse pharmacology model
“For the PD studies, either a model of immunodeficient mice inoculated with a mixture of human tumour cell lines expressing B7- H1 (PD-L1) and human T-cells alloreactive to the human tumour cell lines or in a syngeneic mouse model using a mouse surrogate monoclonal antibody against mouse PD-L1.”
Study lengthopen answer page →
Longest pivotal study
13 weeks
“Two GLP repeat-dose IV toxicity studies were conducted with durvalumab, a 4-week (Study VMM0008) and a 13-week (Study VMM0033) repeat-dose toxicity study.”
Pivotal GLP studies
Monkey 4-week and 13-week studies: loading dose 30, 60 or 200 mg/kg, then weekly 15, 30 or 100 mg/kg
“in both studies a loading dose (double the maintenance dose) of 30, 60, or 200 mg/kg durvalumab was administered on Day 1, and followed by 4 or 13 weekly doses of 15, 30, or 100 mg/kg, respectively.”
Route in tox
Intravenous
“The IV route of administration was used for all in vivo toxicology studies as this is the intended route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted
“No genotoxicity studies were carried out.”
Carcinogenicity
Not conducted
“No carcinogenitity studies were carried out.”
Reproductive & developmental
Monkey reproduction study (dosing through delivery): premature delivery, fetal loss and increased neonatal deaths; placental transfer
“Administration of durvalumab resulted in premature delivery, fetal loss (abortion and stillbirth), and increase in neonatal deaths. Durvalumab was detected in infant serum on postpartum Day 1, indicating the presence of placental transfer of durvalumab.”
Safety pharmacology
Incorporated into repeat-dose monkey studies (neurologic, respiratory, ECG)
“Safety pharmacology endpoints were incorporated into the repeat-dose toxicology studies (neurologic, respiratory, and electrocardiographic).”
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 Imfinzi 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: NOAEL at the high dose (200/100 mg/kg) in the pivotal toxicity studies (EMA assessment report, p. 31)
NOAEL / key findings
NOAEL at the high dose (200/100 mg/kg) in the pivotal toxicity studies
“The selection of the high dose in all three studies is therefore also accepted as NOAEL (200/100 mg/kg) in the pivotal toxicity studies.”
Risksopen answer page →
Immune & cytokine safety
No cytokine release in a human whole blood assay
“In a human whole blood assay, durvalumab did not induce the release of any cytokine”
Biodistribution & persistence
Volume of distribution 40.5-73.0 mL/kg, consistent with residence mainly in plasma volume
“the volume of distribution is in the range of 40.5 to 73.0 mL/kg, which is expected for large protein molecules as these primarily resides in the plasma volume”
Modality-specific risk
Immune-mediated toxicity: multi-organ arteritis/periarteritis and inflammatory cell infiltration (PD-L1 role in peripheral tolerance)
“Intravenous (IV) administration of durvalumab caused multi-organ arteritis/periarteritis and inflammatory cell infiltration. The immune-mediated findings were consistent with the role of PD-L1 in regulating and maintaining peripheral tolerance.”