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”
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”
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)
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: 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.”