Komzifti
ziftomenib
Species
MouseDog
Longest study
13 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse and dog
“The GLP-compliant repeat-dose toxicology studies with up to 13 weeks of dosing were conducted in mice and dogs with animals dosed twice daily via oral gavage.”
Why that species
In vitro metabolism in mouse and dog liver microsomes similar to human; no unique human metabolites
“In vitro metabolism in liver microsomes from the toxicological test species, mouse and dog, and humans was similar and there were no unique human metabolites.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the 13-week toxicology study in dogs, animals were given ziftomenib at doses of 6, 20, or 60 mg/kg/day.”
Species: general tox
Mouse and dog
“The GLP-compliant repeat-dose toxicology studies with up to 13 weeks of dosing were conducted in mice and dogs with animals dosed twice daily via oral gavage.”
Species: DART
Mouse (EFD only); no fertility studies
“Fertility studies in animals have not been conducted with ziftomenib.”
Species: carcinogenicity
Not conducted (not warranted for the indication)
“No carcinogenicity studies have been conducted with ziftomenib. The FDA’s Assessment: The FDA concurs. Carcinogenicity studies were not warranted for the proposed indication.”
Surrogate used in
No surrogate used; clinical compound tested in mouse and dog
“The GLP-compliant repeat-dose toxicology studies with up to 13 weeks of dosing were conducted in mice and dogs with animals dosed twice daily via oral gavage.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week mouse and dog)
“The GLP-compliant repeat-dose toxicology studies with up to 13 weeks of dosing were conducted in mice and dogs with animals dosed twice daily via oral gavage.”
Pivotal GLP studies
28-day and 13-week oral gavage studies in mice and dogs
“The definitive nonclinical safety program was comprised of 28-day and 13-week toxicity studies in mice and dogs, as well as the standard battery of genetic toxicology studies, in vitro and in vivo phototoxicity studies, and an embryofetal development study in mice.”
Route in tox
Oral gavage, twice daily
“The GLP-compliant repeat-dose toxicology studies with up to 13 weeks of dosing were conducted in mice and dogs with animals dosed twice daily via oral gavage.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro micronucleus and in vivo mouse bone marrow micronucleus assays
“Ziftomenib was not mutagenic in an in vitro bacterial reverse mutation assay and was not genotoxic in an in vitro micronucleus assay or in an in vivo mouse bone marrow micronucleus assay.”
Carcinogenicity
Not conducted (not warranted for the proposed indication)
“The FDA concurs. Carcinogenicity studies were not warranted for the proposed indication.”
Reproductive & developmental
EFD: cleft palate at high dose and skeletal malformations (ribs, skull, vertebrae) at all doses
“External malformations were elevated in the high-dose group fetuses and composed of cleft palates. Skeletal malformations were observed in all test article dose groups, notably in the ribs, skull, and vertebra.”
Safety pharmacology
hERG IC50 1.61 µM, Cav1.2 IC50 2.8 µM; lower blood pressure and longer PR interval in dogs
“The IC50 values for hERG and hCavl.2 inhibition were 1.61 and 2.8 μM, respectively. Dose-dependent lower blood pressure and longer PR intervals were seen after single doses of 40, 120, and 200 mg/kg/day in dogs”
Genotox: Ames
Negative (bacterial reverse mutation)
“Under the conditions of this study, ziftomenib was determined to be negative (nonmutagenic) in the bacterial reverse mutation assay.”
Genotox: in vitro mammalian
In vitro micronucleus in human peripheral blood lymphocytes: negative
“Under the conditions of this study, ziftomenib was considered negative (nonclastogenic/aneugenic) when evaluated in the in vitro micronucleus assay conducted in HPBLs.”
Genotox: in vivo
In vivo mouse bone marrow micronucleus: negative
“Ziftomenib was not mutagenic in an in vitro bacterial reverse mutation assay and was not genotoxic in an in vitro micronucleus assay or in an in vivo mouse bone marrow micronucleus assay.”
Carcinogenicity model
Not conducted (not warranted for the indication)
“No carcinogenicity studies have been conducted with ziftomenib. The FDA’s Assessment: The FDA concurs. Carcinogenicity studies were not warranted for the proposed indication.”
Carcinogenicity timing
Not conducted; not warranted for the proposed indication
“No carcinogenicity studies have been conducted with ziftomenib. The FDA’s Assessment: The FDA concurs. Carcinogenicity studies were not warranted for the proposed indication.”
hERG / QT
hERG inhibited near clinical exposure: free Cmax-ss ~0.049 µM is only 1.3-fold below the hERG IC50
“Given that ziftomenib has >99% protein binding, the free drug Cmax-ss will be approximately 0.049 µM, which is 1.3-fold lower than the IC50.”
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 Komzifti 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: Liver primary target (cholestasis, biliary hyperplasia); also lymph node, spleen, gall bladder, thymus, ovaries, bone marrow, adrenals (FDA multi-discipline review, p. 38)
NOAEL / key findings
Liver primary target (cholestasis, biliary hyperplasia); also lymph node, spleen, gall bladder, thymus, ovaries, bone marrow, adrenals
“The liver was the primary organ of toxicity, where elevated liver enzyme levels in the blood were observed along with discoloring and microscopic findings of cholestasis and biliary hyperplasia. Other organs of toxicity included the lymph node, spleen, gall bladder, thymus, ovaries, bone marrow, adrenal glands”
Risksopen answer page →
Immune & cytokine safety
Thymic white blood cell infiltration, vacuolation and lymphoid depletion, persisting after recovery
“Other target organs included the liver and the thymus, where white blood cell infiltration, vacuolation, and lymphoid depletion was noted microscopically. The microscopic findings persisted at the end of the recovery period.”
Biodistribution & persistence
Melanin binding in uveal tract of pigmented mice, with elimination over time
“Distribution trends were similar across pigmented and nonpigmented strains, except that radioactivity was distributed in the uveal tract, indicating binding to melanin-containing tissues with evidence of elimination of radioactivity from melanin containing tissues over time.”
Modality-specific risk
Proliferative findings: hyperplasia in multiple organs in 13-week mouse and dog studies
“In 13-week repeat-dose toxicity studies in mice and dogs, incidences of hyperplasia in a variety of organs occurred in several animals from both species.”
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 applicable; no immunogenicity assessments performed
“Immunogenicity The Applicant’s Position: Not applicable. No immunogenicity assessments were performed.”
Label warnings
Boxed warning: Differentiation syndrome
- Differentiation Syndrome
- QTc Interval Prolongation
- Embryo-Fetal Toxicity
CardiovascularEmbryo-fetal toxicity
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
US, Belgium, Canada, France, Germany, Italy, Spain and UK: first-in-human study KO-MEN-001 in patients with relapsed/refractory AML (52 centers)
“52 centers: 23 centers in the US 29 centers in Belgium, Canada, France, Germany, Italy, Spain, and the United Kingdom”
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 Komzifti 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: Liver primary target (cholestasis, biliary hyperplasia); also lymph node, spleen, gall bladder, thymus, ovaries, bone marrow, adrenals (FDA multi-discipline review, p. 38)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week mouse and dog (oral, twice daily); dog findings assessed after a 4-week recovery period
“Reversibility was not assessed at 20 mg/kg/day and findings were not reversible at 60 mg/kg/day after the 4-week recovery period. 13.2 Animal Toxicology and/or Pharmacology In 13-week repeat-dose toxicity studies in mice and dogs, incidences of hyperplasia in a variety of organs occurred in several animals from both species.”
Pivotal GLP studies
28-day and 13-week oral gavage studies in mice and dogs
“The definitive nonclinical safety program was comprised of 28-day and 13-week toxicity studies in mice and dogs, as well as the standard battery of genetic toxicology studies, in vitro and in vivo phototoxicity studies, and an embryofetal development study in mice.”
DART package
Species: DART
Mouse (EFD only); no fertility studies
“Fertility studies in animals have not been conducted with ziftomenib.”
Reproductive & developmental
EFD: cleft palate at high dose and skeletal malformations (ribs, skull, vertebrae) at all doses
“External malformations were elevated in the high-dose group fetuses and composed of cleft palates. Skeletal malformations were observed in all test article dose groups, notably in the ribs, skull, and vertebra.”
PPND / ePPND: when
No PPND study: DART in the definitive program limited to a mouse EFD study
“The definitive nonclinical safety program was comprised of 28-day and 13-week toxicity studies in mice and dogs, as well as the standard battery of genetic toxicology studies, in vitro and in vivo phototoxicity studies, and an embryofetal development study in mice.”
Carcinogenicity
Species: carcinogenicity
Not conducted (not warranted for the indication)
“No carcinogenicity studies have been conducted with ziftomenib. The FDA’s Assessment: The FDA concurs. Carcinogenicity studies were not warranted for the proposed indication.”
Carcinogenicity model
Not conducted (not warranted for the indication)
“No carcinogenicity studies have been conducted with ziftomenib. The FDA’s Assessment: The FDA concurs. Carcinogenicity studies were not warranted for the proposed indication.”
Carcinogenicity timing
Not conducted; not warranted for the proposed indication
“No carcinogenicity studies have been conducted with ziftomenib. The FDA’s Assessment: The FDA concurs. Carcinogenicity studies were not warranted for the proposed indication.”
Safety marginopen answer page →
Safety margin at NOAEL
No margin: EFD skeletal malformations at all doses, lowest ~0.3x human AUC at 600 mg QD
“Skeletal malformations were observed in all test article dose groups, notably in the ribs, skull, and vertebra. Exposures at the lowest dose were approximately 0.3 times the human exposure (AUC) at the recommended clinical dose of 600 mg once daily.”
NOAEL / key findings
Liver primary target (cholestasis, biliary hyperplasia); also lymph node, spleen, gall bladder, thymus, ovaries, bone marrow, adrenals
“The liver was the primary organ of toxicity, where elevated liver enzyme levels in the blood were observed along with discoloring and microscopic findings of cholestasis and biliary hyperplasia. Other organs of toxicity included the lymph node, spleen, gall bladder, thymus, ovaries, bone marrow, adrenal glands”
Efficacy evidenceopen answer page →
Efficacy evidence
AML xenografts (MV4-11, MOLM-13 cell lines and patient-derived cells) in immunocompromised mice and rats
“The in vivo anti-tumor activity of ziftomenib was evaluated in xenograft models using the human AML cell lines MV4-11 and MOLM-13 and patient-derived cells in immunocompromised rats and mice with oral administration and a variety of treatment durations.”
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: dose-dependent anti-tumor activity in vivo; supportive of the mechanism of action
“Overall, ziftomenib showed dose-dependent anti-tumor activity in these nonclinical in vivo models. These findings are supportive of the mechanism of action of ziftomenib as described in the label.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
Mouse embryo-fetal skeletal malformations at all doses; lowest dose about 0.3 times human AUC
“Skeletal malformations were observed in all test article dose groups, notably in the ribs, skull, and vertebra. Exposures at the lowest dose were approximately 0.3 times the human exposure (AUC) at the recommended clinical dose of 600 mg once daily.”
Safety marginVerdict not stated
Multi-organ hyperplasia in 13-week mouse and dog studies at exposures as low as 0.3 and 0.05 times human AUC
“The findings in the mouse study were observed at ≥ 12 mg/kg/day at exposures as low as 0.3 times the AUC at the recommended dose, and the findings in the dog study were observed at ≥ 6 mg/kg/day at exposures as low as 0.05 times the AUC at the recommended dose.”
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