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.”
Species: general tox
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.”
Species: DART
Cynomolgus monkey (combined embryo-fetal and peri-postnatal study)
“In a combined study of embryo-fetal and peri-postnatal development, pregnant cynomolgus monkeys received ipilimumab every 3 weeks from the onset of organogenesis in the first trimester through parturition.”
Species: carcinogenicity
Not conducted
“Carcinogenicity studies for ipilimumab were not conducted.”
Surrogate used in
Yes: anti-mouse CTLA-4 mAb in a mouse anti-tumour study with dexamethasone; none in toxicology
“An assessment of the effect of dexamethasone on the anti-tumour activity of anti-mouse CTLA-4 monoclonal antibody (mAb) was made (study MDX-010-001-R).”
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.”
Genotox: Ames
Not conducted
“No standard genotoxicity battery of studies was performed with ipilimumab.”
Genotox: in vitro mammalian
Not conducted
“No standard genotoxicity battery of studies was performed with ipilimumab.”
Genotox: in vivo
Not conducted
“No standard genotoxicity battery of studies was performed with ipilimumab.”
Carcinogenicity model
Not conducted
“Carcinogenicity studies for ipilimumab were not conducted.”
Carcinogenicity timing
Not required: rodents not relevant, limited value of homologous studies, advanced disease
“In addition, 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.”
hERG / QT
No cardiovascular or ECG findings in monkey repeat-dose studies up to 6 months
“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.”
Anti-drug antibodies: animals
Anti-ipilimumab antibodies in 12% of monkeys, likely underestimated due to drug interference
“An anti-ipilimumab-antibody response was detected in 12% of the monkeys receiving ipilimumab, although it should be noted that this frequency is likely to be underestimated due to interference of (serum) ipilimumab with the antibody detection assay.”
Anti-drug antibodies: patients
1.1% of 1024 evaluable patients with unresectable or metastatic melanoma (binding antibodies)
“Eleven (1.1%) of 1024 evaluable patients with unresectable or metastatic melanoma tested positive for treatment-emergent binding antibodies against ipilimumab in an electrochemiluminescent (ECL) based assay.”
Label warnings
- Severe and Fatal Immune-Mediated Adverse Reactions
- Infusion-Related Reactions
- Complications of Allogeneic Hematopoietic Stem Cell Transplant after YERVOY
- Embryo-Fetal Toxicity
- Risks Associated When Administered in Combination with Nivolumab
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
6-month cynomolgus monkey (IV, 10 mg/kg monthly); recovery phase not stated
“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.”
DART package
Species: DART
Cynomolgus monkey (combined embryo-fetal and peri-postnatal study)
“In a combined study of embryo-fetal and peri-postnatal development, pregnant cynomolgus monkeys received ipilimumab every 3 weeks from the onset of organogenesis in the first trimester through parturition.”
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.”
PPND / ePPND: when
Combined embryo-fetal and pre/postnatal development study (ePPND design, cynomolgus monkey) ongoing at the marketing application
“a combined embryofoetal, pre/post-natal development study is ongoing. As indicated in the Risk Management Plan, final results of this study will be submitted when available.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Carcinogenicity studies for ipilimumab were not conducted.”
Carcinogenicity model
Not conducted
“Carcinogenicity studies for ipilimumab were not conducted.”
Carcinogenicity timing
Not required: rodents not relevant, limited value of homologous studies, advanced disease
“In addition, 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.”
Safety marginopen answer page →
Safety margin at NOAEL
No safety margin could be determined for serious irAEs (colitis, dermatitis) in monkeys
“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.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
MC-38 colon carcinoma in human CTLA-4 transgenic mice
“The MC-38 colon carcinoma tumour line was implanted into the human CTLA-4 transgenic mice to evaluate the anti-tumour activity of ipilimumab.”
Why that model
No binding to rat, mouse or rabbit CTLA-4; binds cynomolgus CTLA-4
“Ipilimumab did not show cross-reactivity with or binding to CTLA-4 from rats, mice or rabbits, but showed specific binding to cynomolgus monkey recombinant CTLA-4 and activated T-cells”
Reviewer's view of the efficacy data
EMA: relevance of transgenic and homologous mouse tumour studies limited, as antibody given at time of tumour inoculation
“For the current application the relevance of this study, and other cited anti-tumour studies using homologous mouse tumour models is limited because in all these studies the (blocking) CTLA-4 antibody was administered at the time or shortly after tumour inoculation”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted with a conditionBeyond the letter
No reproductive toxicity data at approval; monkey combined embryo-fetal/pre-postnatal study still ongoing
Why: Final results to be submitted post-authorisation under the Risk Management Plan
“a combined embryofoetal, pre/post-natal development study is ongoing. As indicated in the Risk Management Plan, final results of this study will be submitted when available.”
Safety marginQuestioned
No safety margin determined for serious immune-related colitis and dermatitis in monkeys
“Conclusion on the non-clinical aspects 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.”
Efficacy modelQuestioned
Mouse tumour models dosed at tumour inoculation, of limited relevance to established melanoma
“For the current application the relevance of this study, and other cited anti-tumour studies using homologous mouse tumour models is limited because in all these studies the (blocking) CTLA-4 antibody was administered at the time or shortly after tumour inoculation”
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