Inqovi
decitabine and cedazuridine
Sources:FDA multi-discipline review ↗
Species
MonkeyRatMouse
Longest study
13 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse and cynomolgus monkey (cedazuridine); rat (decitabine)
“In the general toxicology studies, cedazuridine (mice and cynomolgus monkeys) and decitabine (rats) were administered orally once daily for 5 to 7 days in 28-day cycles, similar to the clinical regimen.”
Why that species
Mouse and monkey CDA distribution and activity similar to human; CDA absent in rat
“A literature assessment submitted by the Applicant concluded that humans, mice, and cynomolgus monkeys have similar CDA tissue distribution and activity profiles, and CDA activity was notably absent in rats.”
Surrogate molecule
No surrogate; the clinical compounds were tested
“Pivotal studies of oral decitabine monotherapy were limited to a 13-week/4-cycle study conducted in rats only (up to 7.5 mg/kg/dose).”
Study lengthopen answer page →
Longest pivotal study
13 (92-day monkey, 4 cycles)
“A 92 Day Toxicity Study of E7727 Administered via Oral Gavage in Cynomolgus Monkeys Followed by a 21 Day Recovery”
Pivotal GLP studies
13-week/4-cycle oral cedazuridine studies in mouse and monkey
“Cedazuridine monotherapy was assessed in repeat-dose toxicity studies up to 13-weeks/4-cycles in duration in mice (up to 1000 mg/kg/dose) and cynomolgus monkeys (up to 200 mg/kg/dose).”
Route in tox
Oral, in 5-days-on/23-days-off cycles mirroring the clinical regimen
“The pivotal studies were conducted under GLP-compliance, and the test articles were administered by the oral route following dosing regimens comparable to the planned clinical treatment cycle of 5 consecutive dosing days followed by 23 non-dosing days.”
Skipped studiesopen answer page →
Genotoxicity
Cedazuridine positive in Ames and in vitro chromosome aberration assays; negative in in vivo micronucleus
“Cedazuridine was mutagenic in the Ames assay and genotoxic in the in vitro chromosome aberration assay, but not genotoxic in the in vivo micronucleus assay.”
Carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“Per ICH S9, we agree that carcinogenicity studies are not needed to support the approval of ASTX727 for the proposed indication.”
Reproductive & developmental
Not conducted (ICH S9); malformation or embryofetal lethality expected
“per ICH S9, reproductive and developmental toxicity studies are not needed for this class of drugs. These drugs are expected to cause malformation or embryofetal lethality.”
Safety pharmacology
Cedazuridine: no cardiovascular or respiratory findings in single-dose monkey study up to 200 mg/kg
“There were no cardiovascular or respiratory findings in a single-dose standalone safety pharmacology study in cynomolgus monkeys with oral doses of cedazuridine up to 200 mg/kg.”
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 Inqovi 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: Reversible myelosuppression; reversible reproductive tract effects from cedazuridine (FDA multi-discipline review, p. 61)
NOAEL / key findings
Reversible myelosuppression; reversible reproductive tract effects from cedazuridine
“In summary, the main repeat-dose toxicity findings from studies conducted in mice, rats, and monkeys were characterized by reversible myelosuppression (leukopenia, neutropenia, lymphopenia, and/or decreased platelet counts) due to decitabine, or both (ASTX727), reversible reproductive tract effects due to cedazuridine”
Risksopen answer page →
Immune & cytokine safety
Reversible thymic lymphoid depletion attributed to cedazuridine
“and thymic lymphoid depletion (cedazuridine, reversible) and testicular effects (partially reversible) due to decitabine.”
Biodistribution & persistence
Cedazuridine: low tissue distribution; highest in kidney, urinary bladder and GI tract
“Overall, cedazuridine did not show a strong tendency to distribute into tissues. The metabolic/excretory tissues (kidney, urinary bladder) as well as the tissues of the GI tract contained the highest distribution of [14C]-cedazuridine derived radioactivity.”
Modality-specific risk
Myelosuppression and embryo-fetal toxicity, unchanged from IV decitabine
“important risks of myelosuppression and embryo-fetal toxicity are unchanged from IV decitabine based on the data presented in the submission.”