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.”
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”
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)
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: 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.”