Libtayo
cemiplimab
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
“In in vitro studies, cemiplimab (REGN2810) bound to human and cynomolgus monkey PD-1 with similar affinity, but did not bind rodent PD-1, supporting the use of cynomolgus monkeys as the single pharmacologically relevant species for toxicity assessment.”
Why that species
Similar binding affinity to human and cynomolgus PD-1; no binding to mouse or rat PD-1
“REGN2810 exhibited similar binding affinity for human and cynomolgus monkey PD-1 (see Table 2), but did not bind mouse or rat PD-1, supporting the use of cynomolgus monkeys as a pharmacologically relevant species for toxicity assessment.”
Surrogate molecule
No surrogate; the clinical antibody was tested in cynomolgus monkey (huPD-1 knock-in mice used only for efficacy pharmacology)
“Since REGN2810 does not bind mouse PD-1, mice were genetically engineered to express a human/mouse PD-1 chimeric receptor (huPD-1 mice); these mice have a functional human PD-1 with expression regulated by the mouse PD-1 promoter.”
Species: general tox
Cynomolgus monkey only (4-, 13- and 26-week studies)
“The toxicity of cemiplimab was evaluated in the repeat dose toxicity studies of 4, 13 and 26-weeks duration in monkeys.”
Species: DART
Cynomolgus monkey (3-month fertility study)
“No effects on fertility assessment parameters or in the male and female reproductive organs were observed in a 3-month repeat dose fertility assessment study with sexually mature cynomolgus monkeys.”
Species: carcinogenicity
Not conducted (advanced cancer, ICH S9)
“Carcinogenicity studies were not conducted or required to support the use of an antibody in the currently proposed indication per ICH S9.”
Surrogate used in
No surrogate molecule; huPD-1 knock-in mice used for in vivo anti-tumor pharmacology with cemiplimab
“Since REGN2810 does not bind mouse PD-1, mice were genetically engineered to express a human/mouse PD-1 chimeric receptor (huPD-1 mice); these mice have a functional human PD-1 with expression regulated by the mouse PD-1 promoter.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“The Applicant evaluated the safety of cemiplimab in cynomolgus monkeys in GLP-compliant repeat-dose toxicology studies of up to 26 weeks duration.”
Pivotal GLP studies
Cynomolgus monkey studies of 4, 13 (fertility) and 26 weeks
“The toxicity of cemiplimab was evaluated in the repeat dose toxicity studies of 4, 13 and 26-weeks duration in monkeys. The 13-week study was dedicated to evaluation of fertility endpoints.”
Route in tox
Intravenous infusion, once weekly
“In the 26-week study, monkeys received once weekly intravenous (I.V.) administration of cemiplimab at doses up to 50 mg/kg”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“Not conducted per ICH S6.”
Carcinogenicity
Not conducted (advanced cancer, ICH S9)
“Carcinogenicity studies were not conducted or required to support the use of an antibody in the currently proposed indication per ICH S9.”
Reproductive & developmental
No embryo-fetal development studies; literature-based reproductive toxicity assessment (ICH S6(R1), S9)
“Embryo-fetal developmental toxicology studies were not conducted with cemiplimab. Rather, consistent with the alternative approach to providing information on the potential for reproductive toxicity described in ICH S6(R1) and ICH S9, the Applicant provided a literature”
Safety pharmacology
Integrated into repeat-dose monkey studies; no effects on CNS, heart rate, blood pressure, ECG or respiration
“During the toxicology studies, there were no drug-related effects observed in food consumption, body weights, CNS, body temperature effects, heart rate, blood pressure, ECG parameters or respiratory effects.”
Genotox: Ames
Not conducted (ICH S6)
“Not conducted per ICH S6.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Not conducted per ICH S6.”
Genotox: in vivo
Not conducted (ICH S6)
“Not conducted per ICH S6.”
Carcinogenicity model
Not conducted (advanced cancer indication, ICH S9)
“Carcinogenicity studies were not conducted or required to support the use of an antibody in the currently proposed indication per ICH S9.”
Carcinogenicity timing
Not required (ICH S9)
“Carcinogenicity studies were not conducted or required to support the use of an antibody in the currently proposed indication per ICH S9.”
hERG / QT
No hERG assay; no ECG, heart rate or blood pressure effects (telemetry) in repeat-dose monkey studies
“During the toxicology studies, there were no drug-related effects observed in food consumption, body weights, CNS, body temperature effects, heart rate, blood pressure, ECG parameters or respiratory effects.”
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 Libtayo 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 50 mg/kg/week (highest dose), excluding immunogenicity-related effects; two deaths in 26-week study from immune complex deposition (EMA assessment report, p. 33)
NOAEL / key findings
NOAEL 50 mg/kg/week (highest dose), excluding immunogenicity-related effects; two deaths in 26-week study from immune complex deposition
“The NOAEL was considered to be 50 mg/kg/week in all repeat-dose toxicity studies in monkeys, the highest dose administered. However, while setting this dose as the NOAEL any adverse reactions as a consequence of high immunogenicity was excluded. Given that in 26-week toxicity study in monkeys two animals died (one in 10 and 50 mg/kg dose groups in each) due to immune complex deposition and associated tissue damage.”
Risksopen answer page →
Immune & cytokine safety
Anti-drug antibodies in 53% of monkeys in 26-week study (92%, 33%, 33% at 2, 10, 50 mg/kg)
“ADAs were detected in 19/36 (53%) monkeys dosed with REGN2810 including 11/12 (92%), 4/12 (33%), and 4/12 (33%) monkeys dosed with 2, 10, and 50 mg/kg REGN2810, respectively.”
Biodistribution & persistence
No distribution, metabolism or excretion studies; tissue cross-reactivity study used to assess target distribution
“Traditional distribution, metabolism, and excretion studies were not conducted with cemiplimab because it is a monoclonal antibody; however, consistent with ICH S6(R1), the Applicant did include a tissue cross reactivity assay to assess distribution of the target”
Modality-specific risk
Immune-mediated adverse reactions such as pneumonitis, predicted by PD-1 blockade
“Based on clinical trials done to support the approval of cemiplimab in the proposed patient population, toxicities associated with cemiplimab are primarily immune-mediated adverse reactions, such as pneumonitis, that are predicted by its mechanism of action.”
Anti-drug antibodies: animals
ADA in 53% of monkeys in the 26-week study (92%, 33%, 33% at 2, 10, 50 mg/kg), inversely related to dose
“ADAs were detected in 19/36 (53%) monkeys dosed with REGN2810 including 11/12 (92%), 4/12 (33%), and 4/12 (33%) monkeys dosed with 2, 10, and 50 mg/kg REGN2810, respectively.”
Anti-drug antibodies: patients
2% of patients developed anti-cemiplimab antibodies; no clinically significant effect on PK
“During a treatment period ranging from 8 to 19 months in 5 clinical studies, 2% (22/1029) of LIBTAYO-treated patients developed anti-cemiplimab-rwlc antibodies. There was no clinically significant effect of anti-cemiplimab-rwlc antibodies on PK of cemiplimab-rwlc.”
Label warnings
- Severe and Fatal Immune-Mediated Adverse Reactions
- Infusion-Related Reactions
- Complications of Allogeneic HSCT
- 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 Libtayo 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 50 mg/kg/week (highest dose), excluding immunogenicity-related effects; two deaths in 26-week study from immune complex deposition (EMA assessment report, p. 33)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week cynomolgus monkey (IV) study with 12-week recovery
“Study REGN2810-TX-14153: 26-week IV toxicity and TK study with a 12-week recovery period.”
Pivotal GLP studies
Cynomolgus monkey studies of 4, 13 (fertility) and 26 weeks
“The toxicity of cemiplimab was evaluated in the repeat dose toxicity studies of 4, 13 and 26-weeks duration in monkeys. The 13-week study was dedicated to evaluation of fertility endpoints.”
DART package
Species: DART
Cynomolgus monkey (3-month fertility study)
“No effects on fertility assessment parameters or in the male and female reproductive organs were observed in a 3-month repeat dose fertility assessment study with sexually mature cynomolgus monkeys.”
Reproductive & developmental
No embryo-fetal development studies; literature-based reproductive toxicity assessment (ICH S6(R1), S9)
“Embryo-fetal developmental toxicology studies were not conducted with cemiplimab. Rather, consistent with the alternative approach to providing information on the potential for reproductive toxicity described in ICH S6(R1) and ICH S9, the Applicant provided a literature”
PPND / ePPND: when
Not conducted: checkpoint-inhibitor pregnancy risk already identified
“Since other checkpoint inhibitors have shown to induce abortion and premature delivery in monkeys, the risk is already identified,hence it is acceptable that no studies have been performed to test the potential of cemiplimab for carcinogenicity, genotoxicity, pre and postnatal development and juvenile studies.”
Carcinogenicity
Species: carcinogenicity
Not conducted (advanced cancer, ICH S9)
“Carcinogenicity studies were not conducted or required to support the use of an antibody in the currently proposed indication per ICH S9.”
Carcinogenicity model
Not conducted (advanced cancer indication, ICH S9)
“Carcinogenicity studies were not conducted or required to support the use of an antibody in the currently proposed indication per ICH S9.”
Carcinogenicity timing
Not required (ICH S9)
“Carcinogenicity studies were not conducted or required to support the use of an antibody in the currently proposed indication per ICH S9.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey 50 mg/kg/week (highest dose, NOAEL): ~5.5 to 25.5x human AUC at 350 mg Q3W
“at doses up to the high dose level of 50 mg/kg (approximately 5.5 to 25.5 times the human exposure by AUC at the human dose of 350 mg once every 3 weeks).”
NOAEL / key findings
NOAEL 50 mg/kg/week (highest dose), excluding immunogenicity-related effects; two deaths in 26-week study from immune complex deposition
“The NOAEL was considered to be 50 mg/kg/week in all repeat-dose toxicity studies in monkeys, the highest dose administered. However, while setting this dose as the NOAEL any adverse reactions as a consequence of high immunogenicity was excluded. Given that in 26-week toxicity study in monkeys two animals died (one in 10 and 50 mg/kg dose groups in each) due to immune complex deposition and associated tissue damage.”
Efficacy evidenceopen answer page →
Efficacy evidence
Syngeneic colorectal tumor xenografts in huPD-1 knock-in mice treated with cemiplimab
“The Applicant investigated the in vivo anti-tumor activity of REGN2810 in huPD-1 mice bearing syngeneic colorectal cancer xenografts”
Why that model
Cemiplimab does not bind mouse PD-1, so humanized PD-1 knock-in mice were required
“Since REGN2810 does not bind mouse PD-1, mice were genetically engineered to express a human/mouse PD-1 chimeric receptor (huPD-1 mice)”
Reviewer's view of the efficacy data
EMA: pharmacology, PK and toxicology studies adequate and acceptable
“In conclusion, the non-clinical studies (pharmacology, pharmacokinetics and toxicology), submitted for the marketing authorisation application for cemiplimab, were considered adequate and acceptable for the assessment of non-clinical aspects.”
Flexibilityopen answer page →
Flexibility accepted
DARTAcceptedBeyond the letter
No embryo-fetal development studies; literature review of PD-1/PD-L1 pathway reproductive risk instead
Why: Literature-based assessment of reproductive toxicity potential; FDA agreed the approach appeared reasonable · Weight of evidence
“Embryo-fetal development studies were not conducted with cemiplimab. Rather, the Applicant provided a scientific literature review and assessment of the reproductive toxicity potential of cemiplimab.”
“FDA agreed in September 2015 that this approach appeared reasonable.”
DARTAcceptedBeyond the letter
No pre- and postnatal development or juvenile studies
Why: Other checkpoint inhibitors already shown to induce abortion and premature delivery in monkeys; agreed at scientific advice · Class precedent
“Since other checkpoint inhibitors have shown to induce abortion and premature delivery in monkeys, the risk is already identified,hence it is acceptable that no studies have been performed to test the potential of cemiplimab for carcinogenicity, genotoxicity, pre and postnatal development and juvenile studies.”
“As also discussed during scientific advice, the lack of carcinogenicity, genotoxicity, fertility and pre/post-natal and juvenile development were agreed and are considered acceptable and well justified.”
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