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”
Species: general tox
Rat and cynomolgus monkey (28-day, 3-, 6- or 9-month studies)
“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.”
Species: DART
Rabbit (fertility/FEED) and rat and rabbit (EFD)
“The effects of iberdomide on fertility and embryo-fetal development were evaluated in fertility and early embryonic development (FEED) study in rabbits and embryo-fetal development (EFD) studies in rats and rabbits.”
Species: carcinogenicity
Not conducted
“No carcinogenicity studies have been conducted with iberdomide.”
Surrogate used in
No surrogate used; clinical compound (CC-220) 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.”
Genotox: Ames
Negative
“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.”
Genotox: in vitro mammalian
Human lymphocyte chromosomal aberration: positive at ≥550 µg/mL; overall 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.”
Genotox: in vivo
Rat bone marrow micronucleus and liver comet assays: negative
“In vivo, iberdomide was not clastogenic in a rat bone marrow micronucleus assay at the maximum tolerated dose of 500 mg/kg/day for 3 days (CC-220-TOX-1344). Under similar experimental conditions, iberdomide did not produce any liver cytotoxicity and did not induce any hepatocyte DNA damage (Comet assay) in rats”
Carcinogenicity model
Not conducted; not warranted for the proposed indication
“The FDA confirms that carcinogenicity studies were not conducted and not warranted for the proposed indication.”
Carcinogenicity timing
Not conducted; not warranted for the proposed indication
“The FDA confirms that carcinogenicity studies were not conducted and not warranted for the proposed indication.”
hERG / QT
hERG IC50 91.4 µM, >25,000-fold free Cmax at 1 mg QD; no ECG findings in monkeys
“The IC50 value for CC-17220 was 91.4 µM, that is >25,000-fold higher than the free fraction Cmax at steady-state at 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)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“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.”
Anti-drug antibodies: animals
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.
Anti-drug antibodies: patients
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.
Label warnings
Boxed warning: EMBRYO-FETAL TOXICITY and SERIOUS VENOUS AND ARTERIAL THROMBOEMBOLISM
- Embryo-Fetal Toxicity
- Zenbexus rems
- Serious Venous and Arterial Thromboembolism
- Neutropenia
- Infections
- Second Primary Malignancies
Thrombosis & embolismEmbryo-fetal toxicityCytopeniasInfectionsSecondary malignancy
US prescribing information, Boxed Warning and 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 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)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month cynomolgus monkey nasogastric gavage study; recovery not assessed
“Note testicular toxicity was only observed in the 9-month study where recovery was not assessed.”
Pivotal GLP studies
Pivotal 9-month nasogastric gavage study in cynomolgus monkeys
“Study Title: A 9-Month Nasogastric Gavage Toxicity Study in Cynomolgus Monkeys”
DART package
Species: DART
Rabbit (fertility/FEED) and rat and rabbit (EFD)
“The effects of iberdomide on fertility and embryo-fetal development were evaluated in fertility and early embryonic development (FEED) study in rabbits and embryo-fetal development (EFD) studies in rats and rabbits.”
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.”
PPND / ePPND: when
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.
Carcinogenicity
Species: carcinogenicity
Not conducted
“No carcinogenicity studies have been conducted with iberdomide.”
Carcinogenicity model
Not conducted; not warranted for the proposed indication
“The FDA confirms that carcinogenicity studies were not conducted and not warranted for the proposed indication.”
Carcinogenicity timing
Not conducted; not warranted for the proposed indication
“The FDA confirms that carcinogenicity studies were not conducted and not warranted for the proposed indication.”
Safety marginopen answer page →
Safety margin at NOAEL
9-month monkey NOAEL 0.12 mg/kg/day: 0.95-fold human steady-state AUC at 1 mg QD
“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.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Multiple myeloma xenograft models in mice, including lenalidomide-resistant models
“In vivo, iberdomide also demonstrated anti-tumor activity MM tumor xenograft models, including in models of lenalidomide resistance.”
Why that model
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.
Reviewer's view of the efficacy data
FDA agrees with the Applicant's assessment of the pharmacology data
“The FDA agrees with the Applicant’s assessment.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
No exposure margin at the 9-month monkey NOAEL (0.95-fold human steady-state AUC at 1 mg QD)
“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.”
RecoveryVerdict not stated
No recovery assessment in the 9-month monkey study, the only general toxicity study with testicular toxicity; reversibility assessed in a rabbit fertility study instead
Why: Recovery of testicular toxicity characterized in the rabbit FEED study
“Note testicular toxicity was only observed in the 9-month study where recovery was not assessed. Subsequently, testicular toxicity was characterized and recovery assessed in a rabbit FEED study (see Section 5.5.4).”
GenotoxicityAcceptedBeyond the letter
Positive in vitro chromosomal aberration assay at 550 µg/mL or more; judged non-genotoxic on totality of data
Why: Ames and in vivo assays negative · Weight of evidence
“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.”
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