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.”
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.”
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 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: 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”