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.”
Species: general tox
Cynomolgus monkey only (up to 13 weeks)
“General toxicology studies included evaluation of durvalumab in Cynomolgus monkeys for up to 13 weeks.”
Species: DART
Cynomolgus monkey (enhanced pre- and postnatal development study)
“The potential effects of durvalumab on pregnancy outcome, embryo-fetal development, survival, and postnatal development of the offspring were evaluated in an enhanced pre-and postnatal development study in cynomolgus monkeys (ePPND study design).”
Species: carcinogenicity
Not conducted
“The carcinogenic and genotoxic potential of durvalumab have not been evaluated.”
Surrogate used in
Yes, pharmacology only: mouse anti-mouse PD-L1 surrogate in a syngeneic tumour model; toxicology used durvalumab
“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).”
Genotox: Ames
Not conducted (monoclonal antibody, not expected to interact with DNA)
“Since it is a monoclonal antibody and is not expected to interact with DNA, genetic toxicology studies were not conducted with durvalumab.”
Genotox: in vitro mammalian
Not conducted (monoclonal antibody, not expected to interact with DNA)
“Since it is a monoclonal antibody and is not expected to interact with DNA, genetic toxicology studies were not conducted with durvalumab.”
Genotox: in vivo
Not conducted (monoclonal antibody, not expected to interact with DNA)
“Since it is a monoclonal antibody and is not expected to interact with DNA, genetic toxicology studies were not conducted with durvalumab.”
Carcinogenicity model
Not conducted
“The carcinogenic and genotoxic potential of durvalumab have not been evaluated.”
Carcinogenicity timing
Not required; absence of carcinogenicity studies considered well justified
“The lack of carcinogenicity, mutagenicity, fertility and early embryonic development was well justified.”
hERG / QT
No stand-alone studies; no cardiovascular, respiratory or CNS changes in 4- and 13-week monkey studies
“The safety pharmacology endpoint assessments (Study VMM0008 and Study VMM0033) did not lead to any changes for either cardiovascular, respiratory or central nervous system measurements.”
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.”
Anti-drug antibodies: animals
ADAs in monkeys with variable impact on PK; ADA-affected animals excluded from PK summaries
“The presence of ADA had variable impact on pharmacokinetics and PK data from animals with obvious impact of ADAs were excluded from summary statistics calculations.”
Anti-drug antibodies: patients
Treatment-emergent ADA 3.6% (199/5,562); 8.5% of these neutralizing
“3.6% (199/5,562) of evaluable patients tested positive for treatment-emergent anti-durvalumab antibodies, and 8.5% (17/199) of treatment-emergent ADA positive patients had neutralizing antibodies against durvalumab.”
Label warnings
- Immune-Mediated Adverse Reactions
- Infusion-Related Reactions
- Complications of Allogeneic HSCT after IMFINZI
- 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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week cynomolgus monkey (IV) with 8-week treatment-free period
“MEDI4736: A 13 Week Repeat Dose Intravenous Toxicity Study in the Cynomolgus Monkey Followed by an 8 Week Treatment-Free Period”
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.”
DART package
Species: DART
Cynomolgus monkey (enhanced pre- and postnatal development study)
“The potential effects of durvalumab on pregnancy outcome, embryo-fetal development, survival, and postnatal development of the offspring were evaluated in an enhanced pre-and postnatal development study in cynomolgus monkeys (ePPND study design).”
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.”
PPND / ePPND: when
ePPND in cynomolgus monkey: completed before the marketing application
“The Applicant submitted a report from an enhanced pre- and postnatal developmental (ePPND) toxicology study with durvalumab in Cynomolgus monkeys conducted to characterize the potential risk of reproductive and developmental toxicity.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“The carcinogenic and genotoxic potential of durvalumab have not been evaluated.”
Carcinogenicity model
Not conducted
“The carcinogenic and genotoxic potential of durvalumab have not been evaluated.”
Carcinogenicity timing
Not required; absence of carcinogenicity studies considered well justified
“The lack of carcinogenicity, mutagenicity, fertility and early embryonic development was well justified.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey highest repeat-dose exposure 19.6x human AUC0-14 day at 10 mg/kg every two weeks
“Exposures at the highest dose levels in monkeys after repeat dosing (34900 μg.day/mL) exceeded (19.6 X) the estimated AUC0-14 day of 1773.2 µg*day/mL in humans at the clinically recommended dose of 10 mg/kg every two weeks.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Durvalumab in A375 and HPAC human tumour xenografts with human CD4+/CD8+ T cells; HPAC max tumour growth inhibition 74%
“The Applicant used A375 (human melanoma) and HPAC (human pancreatic adenocarcinoma) cells enriched for CD4+ and CD8+ T cells. Treatment with durvalumab reduced the tumour volume in the HPAC xenograft model, resulting in a maximum tumour growth inhibition of 74%.”
Why that model
Binds only human and cynomolgus monkey PD-L1; no rodent cross-reactivity for in vivo models with durvalumab
“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.”
Reviewer's view of the efficacy data
EMA: both xenograft and surrogate models showed dose-related tumour reduction; in vivo proof of concept accepted
“Both models showed dose related tumour reducing effects and in vivo proof of concept is accepted.”
Flexibilityopen answer page →
Flexibility accepted
DARTAcceptedBeyond the letter
No fertility and early embryonic development study; fertility assessed by reproductive organ weights and histopathology in the 13-week monkey study
Why: No adverse findings in sex organs of sexually mature monkeys; omission considered well justified · Weight of evidence
“The potential effects of durvalumab on reproduction and fertility were evaluated by the organ weights and histopathology of the male and female reproductive systems in the 13-week repeat-dose toxicity study in monkeys (sexually mature). No adverse durvalumab-related findings were reported in sex organs.”
“The lack of carcinogenicity, mutagenicity, fertility and early embryonic development was well justified.”
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