Zenbexus
iberdomide
Species
MonkeyRat
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and monkey
“In addition, in the 28-day, 3- and 6- or 9-month repeat dose toxicity studies, there were no iberdomide-related electrocardiographic findings or CNS-related clinical observations in monkeys up to 1 mg/kg or CNS-related clinical observations in rats up to 50 mg/kg.”
Why that species
All metabolites formed in human hepatocytes were also formed in rat or monkey
“All metabolites formed in human hepatocytes were also formed in rat or monkey, the 2 animal species used for nonclinical safety testing.”
Surrogate molecule
No surrogate; the clinical compound (CC-220) was tested
“Study Title: A 4-Week Nasogastric Gavage Toxicity Study of CC-220 in Cynomolgus Monkeys with a 4-Week Recovery Period”
Study lengthopen answer page →
Longest pivotal study
39 (9-month cynomolgus monkey)
“Study Title: A 9-Month Nasogastric Gavage Toxicity Study in Cynomolgus Monkeys”
Pivotal GLP studies
Pivotal 9-month nasogastric gavage study in cynomolgus monkeys
“Study Title: A 9-Month Nasogastric Gavage Toxicity Study in Cynomolgus Monkeys”
Route in tox
Oral (nasogastric gavage)
“Route of administration: Nasogastric (gavage)”
Skipped studiesopen answer page →
Genotoxicity
In vitro chromosomal aberrations at ≥550 µg/mL; Ames and in vivo assays negative; not considered genotoxic
“Iberdomide showed increased chromosomal aberrations at ≥ 550 μg/mL in the in vitro clastogenicity assay; however, the results of the Ames assay and in vivo assays were negative for genotoxicity. Given the totality of the data, iberdomide is not considered genotoxic.”
Carcinogenicity
Not conducted; not warranted for the indication
“The FDA confirms that carcinogenicity studies were not conducted and not warranted for the proposed indication.”
Reproductive & developmental
Rat and rabbit EFD: embryo-fetal mortality, altered growth and structural abnormalities
“Oral administration of iberdomide in pregnant rats and rabbits during the period of organogenesis resulted in adverse developmental outcomes including embryo-fetal mortality, alterations to growth, and structural abnormalities.”
Safety pharmacology
Low potential for CV, CNS or respiratory effects; NOEL/NOAEL Cmax about 650-fold (rat) and 22-fold (monkey) above clinical Cmax
“The estimated total Cmax at the NOELs or NOAELs in the safety pharmacology studies were approximately 650- and 22-fold higher in rats and monkeys, respectively, than the estimated total Cmax of 6.22 ng/mL at 1 mg QD in RRMM patients. Results from these nonclinical studies indicate a low potential for CV, CNS, or respiratory effects in human subjects at the recommend human dose of 1 mg QD.”
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 Zenbexus 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 oncology small molecules (ICH S9)
In cancer patients the start dose should be pharmacologically active yet reasonably safe. A common small-molecule approach is one-tenth of the dose severely toxic to 10% of rodents, or one-sixth of the highest non-severely toxic dose in non-rodents.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: 9-month monkey NOAEL 0.12 mg/kg/day, about 0.95-fold the human steady-state AUC at 1 mg (FDA multi-discipline review, p. 61)
NOAEL / key findings
9-month monkey NOAEL 0.12 mg/kg/day, about 0.95-fold the human steady-state AUC at 1 mg
“In the 9-month monkey study, the NOAEL was 0.12 mg/kg/day with a mean AUC(0-24h) of 77.6 ng•h/mL 0.95-fold of the steady-state AUC(0-24h) of 81.36 ng•h/mL at 1 mg QD.”
Risksopen answer page →
Immune & cytokine safety
Immune suppression from lymphoid depletion; decreased neutrophils and lymphocytes, matching clinical neutropenia and infections
“Hematology changes (decreased neutrophils and lymphocytes), immune suppression from lymphoid depletion, and GI toxicity observed in the toxicology studies correlated with neutropenia, infections, and GI toxicity observed in patients in the clinical trials.”
Biodistribution & persistence
Prolonged retention in pigmented tissue (reversible melanin association); minimal brain distribution
“This longer presence in the pigmented tissue suggests a reversible association with melanin. There was minimal distribution of radioactivity into the brain of any animal used in the study”
Modality-specific risk
Thalidomide-like embryo-fetal toxicity (teratogenicity)
“Based on the primary mechanism of action, iberdomide has the same risk of embryo-fetal toxicity as thalidomide, a known human teratogen.”