Imjudo
tremelimumab
Species
Monkey
Longest study
26 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
“These results support the monkey as the only pharmacologically relevant species.”
Why that species
Binds CTLA-4 on stimulated human and cynomolgus T cells; no binding to mouse, rat, hamster or rabbit T cells
“At a concentration of 10 µg/mL, tremelimumab bound human and cynomolgus T cells treated with phytohemagglutinin (PHA) to stimulate expression of CTLA‐4, but did not bind mouse, rat, hamster, or rabbit PHA‐stimulated T cells”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkeys
“The Applicant evaluated the safety of tremelimumab administered intravenously, the intended route of administration, using cynomolgus monkeys in GLP‐compliant 1‐ and 6‐month repeat‐dose toxicology studies.”
Species: general tox
Cynomolgus monkey only (1- and 6-month repeat-dose studies)
“The Applicant evaluated the safety of tremelimumab administered intravenously, the intended route of administration, using cynomolgus monkeys in GLP‐compliant 1‐ and 6‐month repeat‐dose toxicology studies.”
Species: DART
Cynomolgus monkey (embryo-fetal development during organogenesis)
“Once weekly IV administration of tremelimumab to pregnant monkeys during the period of organogenesis did not result in maternal toxicity or embryo‐fetal development toxicity at doses ≤30 mg/kg (approximately ≤4 times the clinical AUC);”
Species: carcinogenicity
Not conducted (generally not appropriate for antibody therapies)
“The Applicant did not conduct carcinogenicity or genetic toxicology studies as they are generally not appropriate for antibody therapies.”
Surrogate used in
Yes, pharmacology only: murine anti-mouse CTLA-4 surrogates in syngeneic tumour models; toxicology used tremelimumab
“demonstrating pharmacological activity of murine surrogates for tremelimumab and durvalumab in mouse syngeneic tumour models”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“Following repeat administration at doses up to 50 mg/kg for either 1‐month (5 doses) or 6‐months (26 doses), signs comprised intermittent diarrhea”
Pivotal GLP studies
1-month and 6-month IV cynomolgus monkey studies, weekly dosing at 5, 15 and 50 mg/kg
“The toxicokinetics of tremelimumab was evaluated in cynomolgus monkeys following IV administrations of tremelimumab in a single‐dose (10, 30, and 100 mg/kg), 1 month (5, 15, and 50 mg/kg/week;) and 6 month (5, 15, and 50 mg/kg/week) toxicologic studies”
Route in tox
Intravenous
“The Applicant evaluated the safety of tremelimumab administered intravenously, the intended route of administration, using cynomolgus monkeys in GLP‐compliant 1‐ and 6‐month repeat‐dose toxicology studies.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“No studies were conducted in accordance with ICH S6(R1).”
Carcinogenicity
Not conducted; generally not appropriate for antibody therapies
“The Applicant did not conduct carcinogenicity or genetic toxicology studies as they are generally not appropriate for antibody therapies.”
Reproductive & developmental
Monkey EFD (weekly, GD20 to GD48): no maternal toxicity, embryo-fetal mortality or malformations up to 30 mg/kg
“Under the conditions tested, there were no effects on maternal toxicity or embryo‐fetal mortality or malformations at doses up to 30 mg/kg administered once weekly during the period of organogenesis from GD20 to GD48 in an embryo‐fetal toxicity study in cynomolgus monkeys.”
Safety pharmacology
No cardiovascular, respiratory or CNS effects in monkeys up to 50 mg/kg weekly for up to 6 months
“The FDA agrees that there were no tremelimumab‐related effects on cardiovascular, respiration, or central nervous system parameters in male and female cynomolgus monkeys at doses up to 50 mg/kg administered once weekly for up to 6 months.”
Genotox: Ames
Not conducted (generally not appropriate for antibody therapies)
“The Applicant did not conduct carcinogenicity or genetic toxicology studies as they are generally not appropriate for antibody therapies.”
Genotox: in vitro mammalian
Not conducted (generally not appropriate for antibody therapies)
“The Applicant did not conduct carcinogenicity or genetic toxicology studies as they are generally not appropriate for antibody therapies.”
Genotox: in vivo
Not conducted (generally not appropriate for antibody therapies)
“The Applicant did not conduct carcinogenicity or genetic toxicology studies as they are generally not appropriate for antibody therapies.”
Carcinogenicity model
Not conducted
“The carcinogenic and genotoxic potential of tremelimumab-actl have not been evaluated.”
Carcinogenicity timing
Not required; acceptable given the uHCC indication
“Carcinogenic potential of tremelimumab was not evaluated, and this is acceptable given the indication sought in the treatment of unresectable hepatocellular carcinoma (uHCC).”
hERG / QT
No stand-alone studies; no dose-related ECG, heart rate, blood pressure or vital sign changes in monkey studies
“ECG, heart rate, blood pressure and vital signs (respiration rate and body temperature) was evaluated twice pre-dose and 5 min post dose in the GLP single dose study (tmax) and on several occasions during the dosing and recovery phase in the two repeat-dose studies. No dose-related changes from normal were observed in any study or on any occasion.”
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 Imjudo 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 5 mg/kg in 1-month study; no NOAEL in 6-month study, 15 mg/kg considered the maximum tolerated dose (FDA multi-discipline review, p. 42)
NOAEL / key findings
NOAEL 5 mg/kg in 1-month study; no NOAEL in 6-month study, 15 mg/kg considered the maximum tolerated dose
“A dose of 5 mg/kg was considered to be the no‐observed effect level (NOAEL) following 1‐month of dosing and following 6‐months of dosing a NOAEL was not established but 15 mg/kg was considered to be the maximum tolerated dose.”
Risksopen answer page →
Immune & cytokine safety
No TNF-α, IL-6 or IL-1β release from unstimulated human PBMC or whole blood in vitro
“In an in vitro cytokine release assay, treatment of unstimulated human PBMCs or whole blood cultures with soluble tremelimumab for up to 48 hours did not result in release of TNF‐α, IL‐6, or IL‐1β compared to untreated controls”
Biodistribution & persistence
Tissue cross-reactivity in monkey and human tissues: binding only to CTLA-4-expressing cells, similar between species
“In vitro tissue cross‐reactivity studies were conducted in both monkey (IM645; Module 4.2.3.7.7 ) and human (IM676; Module 4.2.3.7.7). Tremelimumab bound only to cells in tissues expected to contain CTLA‐4 expressing cells and were considered similar between species.”
Modality-specific risk
Immune-mediated adverse events (diarrhea, rash, hypothyroidism, anemia) mirroring monkey findings; infusion reactions
“Consistent with nonclinical findings, diarrhea, decreased appetite, rash, hypothyroidism, and anemia have been seen clinically and the IMJUDO (tremelimumab) label includes warnings for immune‐mediated adverse events and infusion reactions.”
Anti-drug antibodies: animals
ADAs in monkeys with limited impact on exposure; few animals showed declining exposure from neutralising ADAs
“Tremelimumab did give rise to antidrug antibodies in the monkeys, however with limited impact on exposure. Only few animals showed decreasing exposure over time due to neutralising antidrug antibodies.”
Anti-drug antibodies: patients
HIMALAYA: ADA 11% (20/182); 40% of these neutralizing
“11% (20/182) of patients tested positive for anti-tremelimumab-actl antibodies. Among the 20 patients who tested positive for ADAs 40% (8/20) tested positive for neutralizing antibodies against tremelimumab-actl.”
Label warnings
- Severe and Fatal Immune-Mediated Adverse Reactions
- Infusion-Related Reactions
- 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 Imjudo 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 5 mg/kg in 1-month study; no NOAEL in 6-month study, 15 mg/kg considered the maximum tolerated dose (FDA multi-discipline review, p. 42)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
6-month (26-week) IV cynomolgus monkey with recovery-phase animals (control and high dose); recovery length not stated
“Cynomolgus monkeys were administered a solution of tremelimumab in vehicle intravenously at doses of 5, 15, and 50 mg/kg/week for 6 months (the same dose levels as in the 1-month study). Six monkeys/sex were assigned to the 0 (control) and 50 mg/kg/week groups (with 4 monkeys/sex designated as main study monkeys and 2 monkeys/sex designated as recovery-phase monkeys).”
Pivotal GLP studies
1-month and 6-month IV cynomolgus monkey studies, weekly dosing at 5, 15 and 50 mg/kg
“The toxicokinetics of tremelimumab was evaluated in cynomolgus monkeys following IV administrations of tremelimumab in a single‐dose (10, 30, and 100 mg/kg), 1 month (5, 15, and 50 mg/kg/week;) and 6 month (5, 15, and 50 mg/kg/week) toxicologic studies”
DART package
Species: DART
Cynomolgus monkey (embryo-fetal development during organogenesis)
“Once weekly IV administration of tremelimumab to pregnant monkeys during the period of organogenesis did not result in maternal toxicity or embryo‐fetal development toxicity at doses ≤30 mg/kg (approximately ≤4 times the clinical AUC);”
Reproductive & developmental
Monkey EFD (weekly, GD20 to GD48): no maternal toxicity, embryo-fetal mortality or malformations up to 30 mg/kg
“Under the conditions tested, there were no effects on maternal toxicity or embryo‐fetal mortality or malformations at doses up to 30 mg/kg administered once weekly during the period of organogenesis from GD20 to GD48 in an embryo‐fetal toxicity study in cynomolgus monkeys.”
PPND / ePPND: when
Not conducted: PPND not performed, acceptable under ICH S9 (oncology)
“Pre- and postnatal development studies were not performed, and this is acceptable and in line with ICH S9.”
Carcinogenicity
Species: carcinogenicity
Not conducted (generally not appropriate for antibody therapies)
“The Applicant did not conduct carcinogenicity or genetic toxicology studies as they are generally not appropriate for antibody therapies.”
Carcinogenicity model
Not conducted
“The carcinogenic and genotoxic potential of tremelimumab-actl have not been evaluated.”
Carcinogenicity timing
Not required; acceptable given the uHCC indication
“Carcinogenic potential of tremelimumab was not evaluated, and this is acceptable given the indication sought in the treatment of unresectable hepatocellular carcinoma (uHCC).”
Safety marginopen answer page →
Safety margin at NOAEL
Chronic monkey study: no NOAEL; lowest dose 5 mg/kg/week gave exposure margin of 1-2 (potency-adjusted)
“No NOAEL was found in this study with animals treated with the lowest dose of 5 mg/kg/week requiring supportive care. This dose provided an exposure-based safety margin of 1-2 to clinically relevant exposure (taking species difference in potency into account).”
NOAEL / key findings
NOAEL 5 mg/kg in 1-month study; no NOAEL in 6-month study, 15 mg/kg considered the maximum tolerated dose
“A dose of 5 mg/kg was considered to be the no‐observed effect level (NOAEL) following 1‐month of dosing and following 6‐months of dosing a NOAEL was not established but 15 mg/kg was considered to be the maximum tolerated dose.”
Efficacy evidenceopen answer page →
Efficacy evidence
Surrogate anti-mouse CTLA-4 antibody in subcutaneous syngeneic mouse tumour models, alone and with anti-mouse PD-L1
“A surrogate tremelimumab anti‐CTLA‐4 antibody prolonged survival in multiple subcutaneous mouse tumor models when administered alone and demonstrated increased response rates when administered in combination with an anti‐mouse PD‐L1 antibody.”
Why that model
Tremelimumab binds human and cynomolgus CTLA-4 but not mouse, rat, hamster or rabbit T cells
“Tremelimumab also bound CTLA‐4 expressed on human and cynomolgus T cells stimulated to express CTLA‐4, but did not bind stimulated mouse, rat, hamster, or rabbit T cells;”
Reviewer's view of the efficacy data
EMA: no proof of principle in the indicated tumour type; relevance to uHCC not provided
“A proof of principle specific for the tumour type included in the indication was not demonstrated. Thus, the relevance for the current proposed indication, uHCC, was not provided.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
No NOAEL in the chronic monkey study; lowest dose gave an exposure margin of only 1-2
“No NOAEL was found in this study with animals treated with the lowest dose of 5 mg/kg/week requiring supportive care. This dose provided an exposure-based safety margin of 1-2 to clinically relevant exposure (taking species difference in potency into account).”
Efficacy modelQuestioned
No proof of principle in the indicated tumour type (unresectable hepatocellular carcinoma)
“A proof of principle specific for the tumour type included in the indication was not demonstrated. Thus, the relevance for the current proposed indication, uHCC, was not provided.”
Safety pharmacologyAccepted
No stand-alone safety pharmacology studies; endpoints in monkey toxicity studies; no dedicated CNS study
Why: Per guideline when non-human primate is the only relevant species · Within the guideline · No relevant species
“No stand-alone safety pharmacology studies were conducted for tremelimumab. This is acceptable and according to guideline, especially when non-human primate is the only relevant species.”
DARTAccepted
No pre- and postnatal development or juvenile studies; embryo-fetal study in monkeys only
Why: In line with ICH S9; indication limited to adults · Within the guideline
“Pre- and postnatal development studies were not performed, and this is acceptable and in line with ICH S9. No studies in juvenile animals were performed, and this is acceptable since the sought indication is only including adult patents.”
Similar precedents
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