Imjudo
tremelimumab
Sources:FDA multi-discipline review ↗
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.”
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.”
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.”