Inqovi
decitabine and cedazuridine
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).”
Species: general tox
Mouse and cynomolgus monkey (cedazuridine); rat (oral decitabine)
“Toxicokinetics (TK) were also evaluated as part of the general toxicology studies for cedazuridine (in mice and cynomolgus monkeys) and decitabine (in rats).”
Species: DART
Not conducted for cedazuridine or the combination; relies on decitabine animal data in the decitabine injection label
“No stand-alone reproductive and developmental toxicology studies were conducted with cedazuridine or ASTX727. Decitabine is teratogenic, fetotoxic, and embryotoxic based on its mechanism of action and animal studies described in the product label for decitabine for injection”
Species: carcinogenicity
Not conducted
“No carcinogenicity studies have been conducted with ASTX727 or with its active components, cedazuridine and decitabine.”
Surrogate used in
No surrogate used; mice and monkeys chosen for human-like CDA profile (CDA absent in rats)
“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.”
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.”
Genotox: Ames
Cedazuridine positive (Ames)
“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.”
Genotox: in vitro mammalian
Positive: decitabine in L5178Y mouse lymphoma assay; cedazuridine in chromosomal aberration assay
“Decitabine increased mutation frequency in L5178Y mouse lymphoma cells, and mutations were produced in an E. coli lac-I transgene in colonic DNA of decitabine-treated mice. Decitabine also caused chromosomal rearrangements in larvae of fruit flies. Cedazuridine was genotoxic in a reverse bacterial mutation assay (Ames assay) and in an in vitro chromosomal aberration study using human lymphocytes.”
Genotox: in vivo
Decitabine positive: lac-I transgene mutations in colonic DNA of mice
“Decitabine increased mutation frequency in L5178Y mouse lymphoma cells, and mutations were produced in an E. coli lac-I transgene in colonic DNA of decitabine-treated mice.”
Carcinogenicity model
Not conducted; not warranted for the proposed indication
“Carcinogenicity studies were not conducted and are not warranted to support a marketing application for the proposed indication.”
Carcinogenicity timing
Not required for the indication (ICH S9); none conducted
“Per ICH S9, we agree that carcinogenicity studies are not needed to support the approval of ASTX727 for the proposed indication.”
hERG / QT
Cedazuridine hERG IC50 >300 μM; no effect on guinea pig papillary muscle action potentials
“The cumulative data from these studies indicate that cedazuridine does not have any effect on the cardiovascular system as evidenced by an in vitro concentration giving half-maximal inhibition (IC50) value of >300 μM for inhibition of hERG channel current and no effects on any action potential parameters in isolated papillary muscles from guinea pigs.”
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)
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: 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.”
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
- Myelosuppression
- Embryo-Fetal Toxicity
CytopeniasEmbryo-fetal toxicity
US prescribing information, 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 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)
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: Reversible myelosuppression; reversible reproductive tract effects from cedazuridine (FDA multi-discipline review, p. 61)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
92-day (4-cycle) cedazuridine study in cynomolgus monkey with 21-day recovery; mouse (cedazuridine) and rat (decitabine) studies of similar length
“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).”
DART package
Species: DART
Not conducted for cedazuridine or the combination; relies on decitabine animal data in the decitabine injection label
“No stand-alone reproductive and developmental toxicology studies were conducted with cedazuridine or ASTX727. Decitabine is teratogenic, fetotoxic, and embryotoxic based on its mechanism of action and animal studies described in the product label for decitabine for injection”
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.”
PPND / ePPND: when
Not conducted: reproductive and developmental studies not needed per ICH S9 (genotoxic, cytotoxic class)
“Cedazuridine and decitabine are genotoxic, and decitabine targets rapidly dividing cells in general toxicology studies; per ICH S9, reproductive and developmental toxicity studies are not needed for this class of drugs.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No carcinogenicity studies have been conducted with ASTX727 or with its active components, cedazuridine and decitabine.”
Carcinogenicity model
Not conducted; not warranted for the proposed indication
“Carcinogenicity studies were not conducted and are not warranted to support a marketing application for the proposed indication.”
Carcinogenicity timing
Not required for the indication (ICH S9); none conducted
“Per ICH S9, we agree that carcinogenicity studies are not needed to support the approval of ASTX727 for the proposed indication.”
Safety marginopen answer page →
Safety margin at NOAEL
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.
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”
Efficacy evidenceopen answer page →
Efficacy evidence
L1210 and KG-1 disseminated leukemia mouse models (oral cedazuridine plus oral decitabine)
“The in vivo effect of cedazuridine on the antitumor activity of orally administered decitabine was assessed in the L1210 and KG-1 disseminated leukemia mouse models.”
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: nonclinical data, together with the decitabine injection NDA data, adequate to support approval
“The nonclinical pharmacology, ADME/TK, and toxicology data submitted to this NOA, in combination with the nonclinical data submitted to support the approval of decitabine for injection (NOA 21790), are adequate to support the approval of ASTX727 for the proposed indication.”
Flexibilityopen answer page →
Flexibility accepted
Study lengthAcceptedBeyond the letter
Combination toxicology limited to one non-GLP 4-week (one-cycle) monkey study using separate capsules, not the fixed-dose tablet
Why: Disparate toxic dose levels of decitabine and cedazuridine · Other reason
“The toxicologic profiling of cedazuridine in combination with decitabine was limited to a non-GLP 4-week/1-cycle study in cynomolgus monkeys. This study did not evaluate the ASTX727 FDC drug product; instead, monkeys were orally administered separate gelatin capsules containing cedazuridine (1, 3, or 6 mg/kg/day) and decitabine (2 mg/kg/day).”
“Additional combination studies were not conducted due to the disparate toxic dose levels of decitabine and cedazuridine.”
Safety pharmacologyAcceptedBeyond the letter
No CNS safety pharmacology study; no safety pharmacology studies with the combination or decitabine
Why: FDA agreed with conclusions from the cedazuridine safety pharmacology studies · Pharmacology or kinetics
“CNS safety pharmacology studies were therefore not conducted.”
“The Regulatory Authorities’ Assessment: We agree with the Applicant’s conclusions for the safety pharmacology studies conducted with cedazuridine. We note that no safety pharmacology studies were conducted with ASTX727 or decitabine.”
OtherAcceptedBeyond the letter
Decitabine nonclinical package relies on data from the approved decitabine injection application
Why: Prior nonclinical data supporting approval of decitabine for injection · Class precedent
“The nonclinical pharmacology, ADME/TK, and toxicology data submitted to this NOA, in combination with the nonclinical data submitted to support the approval of decitabine for injection (NOA 21790), are adequate to support the approval of ASTX727 for the proposed indication.”
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