Yervoy
ipilimumab
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
“The cynomolgus monkey was selected as the toxicology species because ipilimumab binds specifically to macaque CTLA-4, but not to homologous CTLA-4 in other traditional toxicology species (mouse, rat, rabbit), and has pharmacologic activity only in primates.”
Why that species
Binds macaque CTLA-4 but not mouse, rat or rabbit CTLA-4; pharmacologically active only in primates
“The cynomolgus monkey was selected as the toxicology species because ipilimumab binds specifically to macaque CTLA-4, but not to homologous CTLA-4 in other traditional toxicology species (mouse, rat, rabbit), and has pharmacologic activity only in primates.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkey
“Since ipilimumab is administered intravenously to humans, the IV route was evaluated in all monkey studies.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“In a 6-month toxicity study in cynomolgus monkeys, ipilimumab in a dose of 10 mg/kg with monthly intervals (4 times over these 6 months) was not associated with adverse drug-related toxicity”
Pivotal GLP studies
GLP cynomolgus monkey IV studies: 1-month weekly, 10-week weekly, and 6-month monthly 10 mg/kg
“ipilimumab generally did not result in adverse toxicities in any other monkeys when administered IV at doses up to 30 mg/kg for 1 week, 10 mg/kg administered weekly for 1 month, 1 mg/kg weekly for 10 weeks, or 10 mg/kg monthly for up to 6 months.”
Route in tox
IV
“Since ipilimumab is administered intravenously to humans, the IV route was evaluated in all monkey studies.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted
“No standard genotoxicity battery of studies was performed with ipilimumab.”
Carcinogenicity
Not conducted; rodents not relevant and advanced cancer indication
“considering the lack of relevance of the rodent species for ipilimumab, the limited value of short-term carcinogenicity studies with homologous products (as reflected in the draft reviewed version of the guideline), and the advanced condition intended to be treated by ipilimumab, the lack of conventional carcinogenicity studies is acceptable.”
Reproductive & developmental
Monkey combined EFD/PPND: third-trimester dose-related increases in abortion, stillbirth, premature delivery and infant mortality
“Beginning in the third trimester, administration of ipilimumab at doses resulting in exposures approximately 2.6 to 7.2 times the human exposure at a dose of 3 mg/kg resulted in dose-related increases in abortion, stillbirth, premature delivery (with corresponding lower birth weight), and an increased incidence of infant mortality.”
Safety pharmacology
Incorporated into repeat-dose monkey studies up to 6 months; no cardiovascular, respiratory or neurologic findings
“No drug-related findings were observed in standard clinical evaluations of cardiovascular, respiratory or neurologic function (including behaviour, posture, coordination, neurologic exams that included peripheral and cranial nerve evaluations, peripheral reflexes, proprioception, or eye movements, and in the 1-month study, electrocardiograms) conducted in monkeys as part of the repeat-dose toxicity studies for up to 6 months with ipilimumab.”
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 Yervoy 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: Fatal colitis and persistent dermatitis/rash in two monkeys, considered immune-related adverse events of CTLA-4 blockade (EMA assessment report, p. 21)
NOAEL / key findings
Fatal colitis and persistent dermatitis/rash in two monkeys, considered immune-related adverse events of CTLA-4 blockade
“Fatal colitis and persistent dermatitis/rash observed in two animals along the toxicology programme were considered by the Applicant as immune-related adverse event (irAEs) linked with the intended pharmacologic basis of CTLA-4 blockade.”
Risksopen answer page →
Immune & cytokine safety
Generally not immunogenic in monkeys; ADA in 12% including weak responders
“Ipilimumab generally was not immunogenic in monkeys. When including the animals with a weak antibody response, a value of 12% was calculated for the frequency of anti-ipilimumab-Ab positive animals.”
Biodistribution & persistence
TCR: binding to activated lymphocytes expressing CTLA-4 in human and monkey tissues, and to placental connective tissue
“In tissue cross-reactivity studies, ipilimumab specifically bound to activated lymphocytes expressing CTLA-4 in several normal human and/or cynomolgus monkey tissues. In addition, ipilimumab bound specifically to connective tissue in human and cynomolgus monkey placenta and to connective tissue in cynomolgus monkey ovary; no specific binding was observed in human ovary.”
Modality-specific risk
Immune-related adverse events (colitis, dermatitis) from CTLA-4 blockade; no safety margin determined
“The most notable concern identified during non-clinical testing was a low incidence of serious irAEs, manifested as colitis or dermatitis, for which no safety margin could be determined.”