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.”
Species: general tox
Cynomolgus monkey only (surrogate REGN646): 5-week IV, 13-week SC and 6-month IV/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 in peripubertal adolescent cynomolgus monkeys”
Species: DART
Mouse (fertility, surrogate REGN1103) and cynomolgus monkey (ePPND, surrogate REGN646)
“A subcutaneous fertility study in young sexually mature male and female mice with REGN1103 and an enhanced pre- and postnatal developmental toxicity study (ePPND) in cynomolgus monkeys with REGN646 were reviewed under IND 107969.”
Species: carcinogenicity
Not conducted (with dupilumab or surrogates REGN646/REGN1103)
“No carcinogenicity studies were conducted with dupilumab or homologous monoclonal antibodies REGN646 and REGN1103 in any species.”
Surrogate used in
Yes: REGN646 (anti-monkey IL4Rα) for repeat-dose and ePPND studies; REGN1103 (anti-mouse IL4Rα) for mouse fertility study
“The sponsor submitted 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.”
Genotox: Ames
Not conducted (ICH S6)
“Genetic toxicology studies are not applicable to monoclonal antibodies and were not conducted with dupilumab based on ICH S6 guidance”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“Genetic toxicology studies are not applicable to monoclonal antibodies and were not conducted with dupilumab based on ICH S6 guidance”
Genotox: in vivo
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 model
Not conducted; labeling and postmarketing malignancy monitoring judged sufficient
“Adequate labeling based on published literature and animal data from the sponsor as well as post-marketing monitoring of malignancy in patients should be sufficient at this time.”
Carcinogenicity timing
Not required (Exec CAC concurrence, May 5, 2014)
“The Exec CAC committee members provided their concurrence via email that nonclinical carcinogenicity studies are not needed for dupilumab on May 5, 2014.”
hERG / QT
No blood pressure or ECG effects in monkey repeat-dose studies with REGN646 up to 100 mg/kg/week
“no effects on blood pressure and ECGs were detected in the repeat-dose toxicity studies in monkeys administered REGN646 IV doses up to 100 mg/kg/week for 5 weeks or 25 mg/kg/week for 6 months or weekly SC doses up to 100 mg/kg/week for 6 months.”
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
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
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.”
Anti-drug antibodies: animals
ADA to surrogate REGN646 in monkeys accelerated clearance, especially at low concentrations; no ADA-associated toxicity
“The presence of ADA in animals in the REGN646 monkey study clearly impacted the rate of drug clearance observed in the study especially at lower concentrations, and there was no evidence of toxicity associated with the occurrence of ADA.”
Anti-drug antibodies: patients
~7% ADA with DUPIXENT in 16-week and 52-week AD studies (placebo 2% and 8%)
“In the 16-week studies, approximately 7% of subjects treated with DUPIXENT and 2% of subjects on placebo developed antibodies to dupilumab, while in the 52-week study, approximately 7% of subjects treated with DUPIXENT + TCS and 8% of subjects on placebo + TCS developed antibodies to dupilumab.”
Label warnings
- Hypersensitivity
- Conjunctivitis, Keratitis, and Blepharitis
- Eosinophilic Conditions
- Acute Symptoms of Asthma or Chronic Obstructive Pulmonary Disease or Acute Deteriorating Disease
- Risk Associated with Abrupt Reduction of Corticosteroid Dosage
- Patients with Co-morbid Asthma
- Psoriasis
- Arthralgia and Psoriatic Arthritis
- Parasitic (Helminth) Infections
- Vaccinations
Hypersensitivity & infusion reactionsOcular toxicityPulmonary toxicityInfections
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 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
Use pharmacology data (target binding, receptor occupancy, in vitro human cells, PK/PD modelling) to estimate the lowest dose expected to have any biological effect (MABEL) and the active dose (PAD), and, for healthy volunteers, start at an exposure below the PAD unless robustly justified.
“these data should be used to determine the minimal anticipated biological effect level (MABEL) in humans and an estimation of the pharmacologically active dose (PAD) and/or anticipated therapeutic dose range (ATD) in humans.”
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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
6-month IV and SC cynomolgus monkey study (surrogate REGN646) with 3-month recovery
“6-Month Intravenous Infusion and Subcutaneous Toxicity Study of REGN646 in Cynomolgus Monkeys with a 3-Month Recovery Period (Study # REGN646-TX-10004)”
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”
DART package
Species: DART
Mouse (fertility, surrogate REGN1103) and cynomolgus monkey (ePPND, surrogate REGN646)
“A subcutaneous fertility study in young sexually mature male and female mice with REGN1103 and an enhanced pre- and postnatal developmental toxicity study (ePPND) in cynomolgus monkeys with REGN646 were reviewed under IND 107969.”
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.”
PPND / ePPND: when
ePPND in cynomolgus monkey (surrogate REGN646) completed before the marketing application
“The sponsor submitted 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.”
Carcinogenicity
Species: carcinogenicity
Not conducted (with dupilumab or surrogates REGN646/REGN1103)
“No carcinogenicity studies were conducted with dupilumab or homologous monoclonal antibodies REGN646 and REGN1103 in any species.”
Carcinogenicity model
Not conducted; labeling and postmarketing malignancy monitoring judged sufficient
“Adequate labeling based on published literature and animal data from the sponsor as well as post-marketing monitoring of malignancy in patients should be sufficient at this time.”
Carcinogenicity timing
Not required (Exec CAC concurrence, May 5, 2014)
“The Exec CAC committee members provided their concurrence via email that nonclinical carcinogenicity studies are not needed for dupilumab on May 5, 2014.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey ePPND NOAEL (surrogate REGN646) 100 mg/kg/week = 10x MRHD on a mg/kg basis
“The NOAEL for maternal and developmental toxicity was 100 mg/kg/week based on the results of this study, which is 10 times the maximum recommended human dose (MRHD) on a mg/kg basis.”
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”
Efficacy evidenceopen answer page →
Efficacy evidence
Transgenic mice expressing human IL-4 and IL-4Rα in type 2 immune response models; no atopic dermatitis model
“Although no preclinical models of atopic dermatitis were available a transgenic mouse expressing hIL-4 and hIL-4Rα was generated and used for proof of efficacy studies with dupilumab in models of type 2 immune responses.”
Why that model
No in vivo atopic dermatitis model, so classical IL-4/IL-13-mediated type 2 immune response models were used
“Due to the lack of an in vivo model of atopic dermatitis the proof of principle experiments have been performed using classical models of type 2 immune response which have been shown to be mediated at least in part through signalling via IL-4 and IL-13.”
Reviewer's view of the efficacy data
EMA: comprehensive basis for mechanism of action in AD and appropriateness of surrogate antibodies for toxicity studies
“Taken together the studies provide a comprehensive basis for the potential mechanism of action of dupilumab in atopic dermatitis as well as establishing the appropriateness of the surrogate antibodies for the toxicity studies.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesAcceptedBeyond the letter
All toxicology conducted with homologous surrogate antibodies (REGN646 in cynomolgus monkey, REGN1103 in mouse), not with dupilumab
Why: Dupilumab does not cross-react with IL-4Rα from nonclinical species · No relevant species
“Because dupilumab does not cross-react with species used to evaluate nonclinical safety, the toxicology studies were conducted with homologous anti-IL-4Rα monoclonal antibodies REGN646 and REGN1103 in cynomolgus monkeys and CD-1 mice, respectively, to identify potential hazards associated with inhibition of IL-4 and IL-13.”
“Given the lack of cross-reactivity of dupilumab with IL-4Rα from non-clinical species, surrogate mAbs were used, which is acceptable.”
CarcinogenicityAccepted
No carcinogenicity studies for a chronic non-oncology indication; weight-of-evidence assessment from IL-4/IL-13 literature and surrogate toxicity data
Why: Weight-of-evidence approach in accordance with ICH S6(R1); IL-4/IL-13 pathway literature · Weight of evidence · Within the guideline · Pharmacology or kinetics
“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.”
“The applied weight of evidence approach is in accordance with ICH S6(R1). It can be agreed that chronic treatment with dupilumab is not associated with an increased risk of cancer.”
Safety marginAcceptedBeyond the letter
No meaningful exposure multiples to human dupilumab exposure because toxicity studies used a surrogate antibody
Why: Chronic study Ctrough was 52x the in vitro IC90, showing sufficiently high exposure · Pharmacology or kinetics
“Given that the toxicity studies were conducted with a surrogate antibody a direct comparison of exposure multiples in the toxicity studies with exposure of dupilumab in humans is not considered meaningful.”
“However, the Ctrough at the end of treatment in the chronic toxicity study corresponds to 52x of IC90 determined for REGN646-mediated inhibition of IL-4-stimulated TARC section in vitro. This indicates that a sufficiently high exposure to REGN646 was maintained throughout the study.”
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