Exdensur
depemokimab
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 pharmacokinetics of depemokimab have been assessed in the Cynomolgus monkey, which is the only species relevant for the toxicity studies.”
Why that species
Binds cynomolgus IL-5 with high affinity (KD 23.9 pM vs 39.1 pM human); inhibits monkey and human IL-5 activity
“The difference in the affinity of depemokimab for human IL-5 (KD 39.1pM) and cynomolgus IL-5 (KD 23.9pM) was around two-fold less compared to mepolizumab that has equivalent affinities for human and cynomolgus IL-5 of 54.2 and 55.4pM respectively.”
Surrogate molecule
No surrogate for depemokimab; DART relied on mepolizumab data including rat anti-mouse IL-5 surrogate mouse EFD study
“In an embryo-fetal development mouse study, CD-1 mice received SB264091, a rat anti-human IL-5 surrogate monoclonal antibody (lgG2b), which cross reacts with human and murine IL-5.”
Species: general tox
Cynomolgus monkey only (pivotal 26-week study)
“Nonclinical safety was primarily evaluated in a 26-week toxicology study conducted in cynomolgus monkeys.”
Species: DART
Not conducted; DART risk assessed by weight-of-evidence
“No developmental and reproductive toxicity (DART) studies were conducted. The DART risk with depemokimab was assessed using a weight-of-evidence (WoE) approach.”
Species: carcinogenicity
Not conducted
“No carcinogenicity studies were conducted.”
Surrogate used in
Class data only: mepolizumab-program mouse EFD study used rat anti-IL-5 surrogate SB264091
“In an embryo-fetal development mouse study, CD-1 mice received SB264091, a rat anti-human IL-5 surrogate monoclonal antibody (lgG2b), which cross reacts with human and murine IL-5.”
Study lengthopen answer page →
Longest pivotal study
26 weeks
“A GLP-compliant repeat dose toxicity study in cynomolgus monkeys receiving depemokimab 10mg/kg and 100 mg/kg once every 3 months for 26 weeks has been performed.”
Pivotal GLP studies
GLP cynomolgus monkey 26-week SC study (10, 100 mg/kg every 13 weeks, 2 doses); 4-week single-dose study
“In the 26-week toxicology study conducted in monkeys, doses of 10 (low dose [LD]) and 100 (high dose [HD]) mg/kg were administered to adult male and female monkeys (4/sex/group) once every 13 weeks for a total of 2 doses.”
Route in tox
Subcutaneous
“Multiple dose toxicokinetics were determined in a 6 month repeat dose SC toxicity study in cynomolgus monkeys (3/sex/group) who received 2 doses of depemokimab (10 and 100 mg/kg bw) on Day 1 and during Week 14.”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (ICH S6(R1))
“No genotoxicity studies were conducted as monoclonal antibodies do not directly interact with DNA or other chromosomal material, which is in line with ICH S6(R1) guideline.”
Carcinogenicity
Not conducted; weight-of-evidence carcinogenicity assessment
“No carcinogenicity studies were conducted. The applicant conducted a weight-of-evidence (WoE) assessment to evaluate the potential of depemokimab to cause carcinogenicity.”
Reproductive & developmental
No DART studies conducted; risk assessed by weight-of-evidence
“No developmental and reproductive toxicity (DART) studies were conducted. The DART risk with depemokimab was assessed using a weight-of-evidence (WoE) approach.”
Safety pharmacology
No dedicated studies; CV endpoints in 26-week monkey study; ~7% QTc increase at 100 mg/kg (>70-fold clinical exposure)
“Cardiovascular parameters are specifically evaluated in toxicity study 2017N319933. In this study, an increase in QTc (approximately 7%) was observed in 4/6 animals at 100 mg/kg during Week 14 at an exposure that was >70-fold higher than clinical exposure.”
Genotox: Ames
Not conducted (ICH S6)
“No genotoxicity studies were conducted as monoclonal antibodies do not directly interact with DNA or other chromosomal material, which is in line with ICH S6(R1) guideline.”
Genotox: in vitro mammalian
Not conducted (ICH S6)
“No genotoxicity studies were conducted as monoclonal antibodies do not directly interact with DNA or other chromosomal material, which is in line with ICH S6(R1) guideline.”
Genotox: in vivo
Not conducted (ICH S6)
“No genotoxicity studies were conducted as monoclonal antibodies do not directly interact with DNA or other chromosomal material, which is in line with ICH S6(R1) guideline.”
Carcinogenicity model
Not conducted; weight-of-evidence assessment
“No carcinogenicity studies were conducted. The applicant conducted a weight-of-evidence (WoE) assessment to evaluate the potential of depemokimab to cause carcinogenicity.”
Carcinogenicity timing
Not required: FDA judged a monkey carcinogenicity study unnecessary; mepolizumab data used
“After reviewing the nonclinical data, it was decided that conducting a carcinogenicity study in monkeys for depemokimab would not be necessary. Carcinogenicity information can be taken from the mepolizumab program.”
hERG / QT
No hERG assay; ~7% QTc increase in 4/6 monkeys at 100 mg/kg (>70-fold clinical exposure)
“In this study, an increase in QTc (approximately 7%) was observed in 4/6 animals at 100 mg/kg during Week 14 at an exposure that was >70-fold higher than clinical exposure.”
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 Exdensur 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: NOAEL 10 mg/kg (EMA, QTc at 100 mg/kg) or 100 mg/kg (applicant); reduced eosinophils; vasculitis in single-dose study (EMA assessment report, p. 55)
NOAEL / key findings
NOAEL 10 mg/kg (EMA, QTc at 100 mg/kg) or 100 mg/kg (applicant); reduced eosinophils; vasculitis in single-dose study
“The NOAEL in the 26week repeat dose toxicity was considered by the Rapporteur to be 10 mg/kg instead of 100 mg/kg due to the increase in QTc at 100 mg/kg in 4/6 animals at 100 mg/kg, which is considered to be an adverse effect.”
Risksopen answer page →
Immune & cytokine safety
ADA in 6 monkeys, exposure reduced in one high-titer animal; immune-complex vasculitis in one monkey; no dedicated immunotoxicity studies
“While ADAs were detected in 6 animals in the 26-week repeat dose toxicity study, there was only one male at 10 mg/kg with a high ADA titre in which the depemokimab exposure was reduced.”
Biodistribution & persistence
No specific binding in human tissue cross-reactivity study; staining non-specific
“The applicant concluded that no specific positive staining was observed in any human tissues examined.”
Modality-specific risk
Eosinophil depletion with helminth infection risk; increased fetal exposure from YTE-extended half-life
“A class effect due to inhibition of IL-5/5R, and thereby eosinophils, are parasitic/helminth infections, a risk which is included in the Warnings and Precautions section of all approved anti-IL-5/5R biologic”
Anti-drug antibodies: animals
ADA in 6 monkeys in 26-week study; reduced exposure in one high-titre male
“While ADAs were detected in 6 animals in the 26-week repeat dose toxicity study, there was only one male at 10 mg/kg with a high ADA titre in which the depemokimab exposure was reduced.”
Anti-drug antibodies: patients
ADA 10% (66/691) in asthma patients on 100 mg every 6 months; 6% (4/66) of these neutralizing
“the incidence of ADA to depemokimab in patients treated with EXDENSUR 100 mg once every 6 months in SWIFT‑1, SWIFT‑2, and an open‑label extension was 10% (66/691). Among ADA‑positive patients, 6% (4/66) developed neutralizing antibodies.”
Label warnings
- Hypersensitivity Reactions
- Acute Asthma Symptoms or Deteriorating Disease
- Risk Associated With Abrupt Reduction of Corticosteroid Dosage
- Parasitic (Helminth) Infection
Hypersensitivity & infusion reactionsInfections
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 Exdensur 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: NOAEL 10 mg/kg (EMA, QTc at 100 mg/kg) or 100 mg/kg (applicant); reduced eosinophils; vasculitis in single-dose study (EMA assessment report, p. 55)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week cynomolgus monkey GLP study with 30-week recovery (off-dosing) period
“once every 3 months for 26 weeks has been performed. The control group and main dose groups contained 3 males and 3 females, but 2 males and 2 females were added to the control group and the group dosed with 10 mg/kg, respectively, for observation during a 30-week off-dosing period.”
Pivotal GLP studies
GLP cynomolgus monkey 26-week SC study (10, 100 mg/kg every 13 weeks, 2 doses); 4-week single-dose study
“In the 26-week toxicology study conducted in monkeys, doses of 10 (low dose [LD]) and 100 (high dose [HD]) mg/kg were administered to adult male and female monkeys (4/sex/group) once every 13 weeks for a total of 2 doses.”
DART package
Species: DART
Not conducted; DART risk assessed by weight-of-evidence
“No developmental and reproductive toxicity (DART) studies were conducted. The DART risk with depemokimab was assessed using a weight-of-evidence (WoE) approach.”
Reproductive & developmental
No DART studies conducted; risk assessed by weight-of-evidence
“No developmental and reproductive toxicity (DART) studies were conducted. The DART risk with depemokimab was assessed using a weight-of-evidence (WoE) approach.”
PPND / ePPND: when
Not conducted: monkey ePPND judged unnecessary (hazard identification only; mepolizumab data used)
“After reviewing the nonclinical data, it was decided that conducting an enhanced pre- and postnatal development (PPND) study in monkeys would not be necessary as the study only provides hazard identification.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No carcinogenicity studies were conducted.”
Carcinogenicity model
Not conducted; weight-of-evidence assessment
“No carcinogenicity studies were conducted. The applicant conducted a weight-of-evidence (WoE) assessment to evaluate the potential of depemokimab to cause carcinogenicity.”
Carcinogenicity timing
Not required: FDA judged a monkey carcinogenicity study unnecessary; mepolizumab data used
“After reviewing the nonclinical data, it was decided that conducting a carcinogenicity study in monkeys for depemokimab would not be necessary. Carcinogenicity information can be taken from the mepolizumab program.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOAEL 10 mg/kg (EMA, QTc at 100 mg/kg): 8.48x (asthma) and 9.65x (CRSwNP) human AUC; 10.9-12.0x Cmax
“The NOAEL in the 26week repeat dose toxicity was considered by the Rapporteur to be 10 mg/kg instead of 100 mg/kg due to the increase in QTc at 100 mg/kg in 4/6 animals at 100 mg/kg, which is considered to be an adverse effect. The exposure margin is 8.48 or 9.65 when based on AUC and 10.9 or 12.0 when based on Cmax (for patients with asthma or CRSwNP, respectively).”
NOAEL / key findings
NOAEL 10 mg/kg (EMA, QTc at 100 mg/kg) or 100 mg/kg (applicant); reduced eosinophils; vasculitis in single-dose study
“The NOAEL in the 26week repeat dose toxicity was considered by the Rapporteur to be 10 mg/kg instead of 100 mg/kg due to the increase in QTc at 100 mg/kg in 4/6 animals at 100 mg/kg, which is considered to be an adverse effect.”
Efficacy evidenceopen answer page →
Efficacy evidence
Prolonged blood eosinophil suppression in normal cynomolgus monkeys (39-week PK/PD study, 1 mg/kg)
“whereas the clearest effect was demonstrated following depemokimab 1 mg/kg treatment with a normalised EO ratio below 0.5 from day 2 to 155, showing a prolonged inhibition of eosinophil count.”
Why that model
No in vivo efficacy studies: depemokimab does not cross-react with mouse, rat, rabbit or dog IL-5
“No in vivo efficacy studies were conducted, what is agreed given the lack of cross reactivity with mouse, rat, rabbit and dog IL-5.”
Reviewer's view of the efficacy data
EMA: in vitro affinity/epitope data adequate; absence of in vivo efficacy studies agreed
“The applicant has demonstrated that the affinity of depemokimab for human IL-5 was around 2-10 fold higher than that of mepolizumab and that both antibodies share or have overlapping epitopes. No in vivo efficacy studies were conducted, what is agreed given the lack of cross reactivity with mouse, rat, rabbit and dog IL-5.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity study for a chronic non-oncology indication; weight-of-evidence assessment using mepolizumab and literature data
Why: Carcinogenicity information available from the mepolizumab program; updated weight of evidence agreed · Class precedent · Weight of evidence
“After reviewing the nonclinical data, it was decided that conducting a carcinogenicity study in monkeys for depemokimab would not be necessary. Carcinogenicity information can be taken from the mepolizumab program.”
“The applicant’s updated weight of evidence is agreed.”
DARTAccepted with a conditionBeyond the letter
No DART studies, including no monkey enhanced pre- and postnatal development study; mepolizumab reproductive data used instead
Why: Monkey ePPND study provides hazard identification only; postmarketing pregnancy safety study (DPSS) required · Class precedent · Weight of evidence
“After reviewing the nonclinical data, it was decided that conducting an enhanced pre- and postnatal development (PPND) study in monkeys would not be necessary as the study only provides hazard identification.”
“Additionally, based on the prolonged half-life with potential for increased fetal exposure in utero, the lack of pregnancy related nonclinical data for depemokimab, and the potential risk of adverse fetal outcomes with anti-IL-5 monoclonal antibodies, a PMR to conduct a worldwide DPSS will also be issued.”
DARTCriticised but acceptedBeyond the letter
In silico placental-transfer model, calibrated on a mepolizumab ePPND study, used to replace an in vivo study for the YTE-modified antibody
Why: Margins of safety adequate even if fetal concentrations exceed maternal maximal levels up to twofold · Class precedent · Pharmacology or kinetics
“The presented in silico model is intended to replace an in vivo study, it is therefore essential that all underlying assumptions are transparently described, thoroughly justified, and any potential concerns adequately addressed.”
“Even if foetal concentrations were to exceed maternal maximal levels by up to twofold, the margins of safety are considered adequate.”
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