Modeyso
dordaviprone
Species
RatDog
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
Rat and dog
“The Applicant evaluated the safety of dordaviprone administered orally once or twice weekly in 28-day and 13-week GLP-compliant general toxicology studies using Sprague Dawley rats and Beagle dogs.”
Why that species
Standard rodent and non-rodent species per ICH S9
“in both rodents (Sprague-Dawley rats) and nonrodents (Beagle dogs) (Studies ONC201-TX-100, ONC201-TX-101; m4.2.3.2). This program was consistent with ICH S9, the guideline for nonclinical evaluation for anticancer pharmaceuticals (ICH 2010).”
Surrogate molecule
No surrogate; the clinical compound was tested
“The toxicity profile of orally administered dordaviprone was defined in GLP-regulated studies with once or twice (on 2 consecutive days) weekly administration for up to 13 weeks”
Species: general tox
Sprague Dawley rat and Beagle dog
“The Applicant evaluated the safety of dordaviprone administered orally once or twice weekly in 28-day and 13-week GLP-compliant general toxicology studies using Sprague Dawley rats and Beagle dogs.”
Species: DART
Rat and rabbit (non-GLP dose-range-finding EFD only)
“The FDA agreed that due to the significant findings in the non-GLP dose-range finding embryo-fetal development studies in rats and rabbits that additional GLP-compliant studies do not need to be conducted.”
Species: carcinogenicity
Not conducted (not warranted for H3 K27M-mutant diffuse glioma)
“The FDA agrees that carcinogenicity studies are not warranted for the current indication of pediatric and adult patients with H3 K27M-mutant diffuse glioma.”
Surrogate used in
No surrogate used; dordaviprone tested directly in rats and dogs
“The Applicant evaluated the safety of dordaviprone administered orally once or twice weekly in 28-day and 13-week GLP-compliant general toxicology studies using Sprague Dawley rats and Beagle dogs.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and dog)
“The Applicant evaluated the safety of dordaviprone administered orally once or twice weekly in 28-day and 13-week GLP-compliant general toxicology studies using Sprague Dawley rats and Beagle dogs.”
Pivotal GLP studies
28-day and 13-week oral (once or twice weekly) GLP studies in rats and dogs
“The Applicant evaluated the safety of dordaviprone administered orally once or twice weekly in 28-day and 13-week GLP-compliant general toxicology studies using Sprague Dawley rats and Beagle dogs.”
Route in tox
Oral (once or twice weekly)
“The weekly oral administration is consistent with the intended clinical route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro and in vivo micronucleus assays
“Dordaviprone was negative for mutagenicity in the Ames test and negative for clastogenicity in both the in vitro and in vivo micronucleus tests.”
Carcinogenicity
Not conducted; not warranted for the proposed indication
“Carcinogenicity studies have not been conducted with dordaviprone and are not warranted for the proposed indication.”
Reproductive & developmental
Rat and rabbit EFD: embryofetal mortality, growth alterations and malformations below human exposure
“In animal embryo-fetal development studies, oral administration of dordaviprone to pregnant rats and rabbits during the period of organogenesis caused embryofetal mortality, alterations to growth, and structural abnormalities at exposures below the human exposure at the highest recommended dose”
Safety pharmacology
hERG IC50 2.4 µM; no ECG changes in dogs
“Dordaviprone inhibited hERG potassium channel current with an IC50 of 2.4 µM in an in vitro safety pharmacology assessment. No changes were noted in ECG parameters in dogs”
Genotox: Ames
Negative
“Dordaviprone was not genotoxic in in vitro (Ames and micronucleus assay) and in vivo (mouse micronucleus) assays.”
Genotox: in vitro mammalian
Negative: in vitro micronucleus
“Dordaviprone was not genotoxic in in vitro (Ames and micronucleus assay) and in vivo (mouse micronucleus) assays.”
Genotox: in vivo
Negative: mouse micronucleus
“Dordaviprone was not genotoxic in in vitro (Ames and micronucleus assay) and in vivo (mouse micronucleus) assays.”
Carcinogenicity model
Not conducted (not warranted for H3 K27M-mutant diffuse glioma)
“The FDA agrees that carcinogenicity studies are not warranted for the current indication of pediatric and adult patients with H3 K27M-mutant diffuse glioma.”
Carcinogenicity timing
Not required for the indication
“The FDA agrees that carcinogenicity studies are not warranted for the current indication of pediatric and adult patients with H3 K27M-mutant diffuse glioma.”
hERG / QT
hERG IC50 2.4 µM
“Dordaviprone inhibited hERG potassium channel current with an IC50 of 2.4 µM in an in vitro safety pharmacology assessment.”
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 Modeyso 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: Rat NOAEL 125 mg/kg weekly; dog LOAEL 60 mg/kg weekly (reversible clinical signs); Cmax 1.9- and 3.9-fold human (FDA multi-discipline review, p. 58)
NOAEL / key findings
Rat NOAEL 125 mg/kg weekly; dog LOAEL 60 mg/kg weekly (reversible clinical signs); Cmax 1.9- and 3.9-fold human
“The Cmax plasma concentrations measured in rats (NOAEL; 125 mg/kg once weekly as the highest dose administered) and dogs (LOAEL; 60 mg/kg once weekly exhibiting adverse but reversible clinical signs) exceeded plasma concentrations observed in humans administered 625 mg dordaviprone by 1.9 and 3.9-fold, respectively.”
Risksopen answer page →
Immune & cytokine safety
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.
Biodistribution & persistence
Rat: distribution to uveal tract, eye, endocrine system, GI tract and meninges; minimal brain exposure
“Dordaviprone distributed to the uveal tract, eye, endocrine system, GI tract, and meninges in rats. Brain exposure was minimal for radiolabeled-dordaviprone in rats.”
Modality-specific risk
Dose-limiting CNS toxicity in rats and dogs
“CNS toxicity was observed in the 4-week repeat-dose GLP toxicity study in rats and the 13-week repeat-dose GLP toxicity study in dogs.”
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
- Hypersensitivity
- QTc Interval Prolongation
- Embryo-fetal Toxicity
Hypersensitivity & infusion reactionsCardiovascularEmbryo-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 Modeyso 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: Rat NOAEL 125 mg/kg weekly; dog LOAEL 60 mg/kg weekly (reversible clinical signs); Cmax 1.9- and 3.9-fold human (FDA multi-discipline review, p. 58)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week rat and dog (oral, once or twice weekly); recovery phase not stated
“The toxicity profile of orally administered dordaviprone was defined in GLP-regulated studies with once or twice (on 2 consecutive days) weekly administration for up to 13 weeks in both rodents (Sprague-Dawley rats) and nonrodents (Beagle dogs)”
Pivotal GLP studies
28-day and 13-week oral (once or twice weekly) GLP studies in rats and dogs
“The Applicant evaluated the safety of dordaviprone administered orally once or twice weekly in 28-day and 13-week GLP-compliant general toxicology studies using Sprague Dawley rats and Beagle dogs.”
DART package
Species: DART
Rat and rabbit (non-GLP dose-range-finding EFD only)
“The FDA agreed that due to the significant findings in the non-GLP dose-range finding embryo-fetal development studies in rats and rabbits that additional GLP-compliant studies do not need to be conducted.”
Reproductive & developmental
Rat and rabbit EFD: embryofetal mortality, growth alterations and malformations below human exposure
“In animal embryo-fetal development studies, oral administration of dordaviprone to pregnant rats and rabbits during the period of organogenesis caused embryofetal mortality, alterations to growth, and structural abnormalities at exposures below the human exposure at the highest recommended dose”
PPND / ePPND: when
Not conducted: PPND not required for advanced cancer (ICH S9)
“Dordaviprone is intended for the treatment of patients with advanced cancer; therefore, studies on fertility and pre- and postnatal development have not been conducted, as they are not required per ICH S9 guidelines for the nonclinical evaluation for anticancer pharmaceuticals (ICH 2010).”
Carcinogenicity
Species: carcinogenicity
Not conducted (not warranted for H3 K27M-mutant diffuse glioma)
“The FDA agrees that carcinogenicity studies are not warranted for the current indication of pediatric and adult patients with H3 K27M-mutant diffuse glioma.”
Carcinogenicity model
Not conducted (not warranted for H3 K27M-mutant diffuse glioma)
“The FDA agrees that carcinogenicity studies are not warranted for the current indication of pediatric and adult patients with H3 K27M-mutant diffuse glioma.”
Carcinogenicity timing
Not required for the indication
“The FDA agrees that carcinogenicity studies are not warranted for the current indication of pediatric and adult patients with H3 K27M-mutant diffuse glioma.”
Safety marginopen answer page →
Safety margin at NOAEL
Rat NOAEL AUC 75% of clinical AUC (dog LOAEL 70%)
“Shorter half-lives in nonclinical species compared to humans resulted in AUC plasma concentrations at these doses that were 75% and 70% clinical AUCs in rat and dogs, respectively.”
NOAEL / key findings
Rat NOAEL 125 mg/kg weekly; dog LOAEL 60 mg/kg weekly (reversible clinical signs); Cmax 1.9- and 3.9-fold human
“The Cmax plasma concentrations measured in rats (NOAEL; 125 mg/kg once weekly as the highest dose administered) and dogs (LOAEL; 60 mg/kg once weekly exhibiting adverse but reversible clinical signs) exceeded plasma concentrations observed in humans administered 625 mg dordaviprone by 1.9 and 3.9-fold, respectively.”
Efficacy evidenceopen answer page →
Efficacy evidence
Orthotopic intracranial (brainstem) tumor-bearing mice; survival and pharmacodynamic endpoints
“In mice bearing orthotopic intracranial (brainstem inoculated) tumors, the in vivo antitumor activity of dordaviprone was assessed by evaluating survival and pharmacodynamic endpoints.”
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
Increased lifespan in DIPG/DMG tumor-bearing mice, under the conditions tested
“Dordaviprone treatment of DIPG/DMG tumor-bearing mice in several studies increased lifespan compared to vehicle controls, under the conditions tested.”
Flexibilityopen answer page →
Flexibility accepted
DARTAcceptedBeyond the letter
Embryo-fetal development assessed only in non-GLP dose-range-finding studies in rats and rabbits; no definitive GLP studies
Why: Significant embryo-fetal findings already seen in the dose-range-finding studies · Weight of evidence
“The FDA agreed that due to the significant findings in the non-GLP dose-range finding embryo-fetal development studies in rats and rabbits that additional GLP-compliant studies do not need to be conducted.”
Safety marginVerdict not stated
Animal AUC at rat NOAEL and dog LOAEL only 75% and 70% of clinical AUC
“Shorter half-lives in nonclinical species compared to humans resulted in AUC plasma concentrations at these doses that were 75% and 70% clinical AUCs in rat and dogs, respectively.”
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