Dupixent
dupilumab
Species
MonkeyMouse
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 (surrogate REGN646); mouse fertility study with surrogate REGN1103
“three pivotal repeat dose toxicity studies and an enhanced pre- and postnatal developmental toxicity study (ePPND) in cynomolgus monkey with REGN646 which is a fully human homologous antibody specific for cynomolgus monkey IL4Rα, and a subcutaneous fertility study in mice with REGN1103, a mouse homologous antibody that binds to IL4Rα.”
Why that species
Dupilumab does not cross-react with nonclinical species, so homologous surrogates for monkey and mouse were developed
“Because dupilumab does not cross-react with species used to evaluate nonclinical safety, the sponsor developed a fully human homologous antibody, REGN646,”
Surrogate molecule
Yes: REGN646 (anti-cynomolgus IL4Rα) for monkey repeat-dose and ePPND studies; REGN1103 (anti-mouse IL4Rα) for a mouse fertility study
“three pivotal repeat dose toxicity studies and an enhanced pre- and postnatal developmental toxicity study (ePPND) in cynomolgus monkey with REGN646 which is a fully human homologous antibody specific for cynomolgus monkey IL4Rα, and a subcutaneous fertility study in mice with REGN1103, a mouse homologous antibody that binds to IL4Rα.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“Repeated dose studies of up to 26 weeks duration were conducted with REGN646 in cynomolgus monkeys.”
Pivotal GLP studies
REGN646 in cynomolgus monkeys: 5-week IV infusion, 13-week SC, and 6-month IV and SC studies
“The three pivotal repeat dose toxicity studies, including a 5-week intravenous infusion (IV), a 13-week subcutaneous (SC) and a 6-month IV and SC studies, were conducted with REGN646”
Route in tox
Subcutaneous and intravenous
“once weekly IV or SC treatment with REGN646 at doses up to 100 mg/kg was well tolerated”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6)
“Genetic toxicology studies are not applicable to monoclonal antibodies and were not conducted with dupilumab based on ICH S6 guidance”
Carcinogenicity
Not conducted; assessment based on literature on the IL-4/IL-13 pathway in tumour development and nonclinical data for REGN646 and REGN1103
“No carcinogenicity studies were conducted. However, an assessment of the carcinogenic potential of dupilumab was made based on literature data on the role of the IL-4/IL-13 pathway in tumour development and on non-clinical data for both REGN646 and REGN1103.”
Reproductive & developmental
Mouse fertility study (surrogate) and monkey ePPND study: no adverse effects
“The effect of IL-4Rα blockade on reproductive and developmental toxicity was evaluated in a fertility study in mice which and in an ePPND study in cynomolgus monkeys. No adverse effects were noted.”
Safety pharmacology
Evaluated as part of the repeat-dose monkey toxicity studies (ICH S6(R1))
“In line with ICH S6(R1) safety pharmacology endpoints were evaluated as part of the repeat-dose toxicity studies in cynomolgus monkeys.”
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 Dupixent 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 outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: No adverse effects in repeat-dose studies; NOAEL was the highest dose in all studies (EMA assessment report, p. 20)
NOAEL / key findings
No adverse effects in repeat-dose studies; NOAEL was the highest dose in all studies
“In summary, no adverse effects were observed in the repeat-dose studies. In all studies, the NOAEL was the highest dose administered”
Risksopen answer page →
Immune & cytokine safety
No effect of REGN646 on antibody response to KLH immunization
“REGN646 treatment did not affect the development of an antibody response to immunization with KLH.”
Biodistribution & persistence
Distribution, metabolism and excretion studies not conducted (ICH S6(R1))
“In accordance with ICH S6 (R1), studies on distribution, metabolism and excretion were not conducted.”
Modality-specific risk
Theoretical carcinogenic potential; toxicology data do not suggest carcinogenic potential
“Overall, data from toxicology studies do not suggest carcinogenic potential for dupilumab.”