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.”
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.”
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.”