Rasonque
daraxonrasib
Sources:FDA multi-discipline review ↗
Species
MonkeyMouse
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 cynomolgus monkey
“Repeat-dose toxicology studies were conducted in mice (4-weeks and 13-weeks) and monkeys (4-weeks and 13-weeks).”
Why that species
Cross-species PK exposure, metabolic profiles, similar or identical CypA binding and identical KRAS GTPase-domain sequence
“Mice and cynomolgus monkeys were considered the relevant test species for in vivo toxicology studies based on cross-species PK exposures, metabolic profiles, similar (mouse) or identical (monkey) binding affinity to human cyclophilin A (CypA), and identical cross-species KRAS protein sequence in the guanosine 5' triphosphatase (GTPase) domain to which daraxonrasib binds.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Daraxonrasib was administered once daily by oral gavage in repeat-dose studies to mice and monkeys in toxicity studies for up to 13-weeks in duration.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week mouse and monkey)
“Daraxonrasib was administered once daily by oral gavage in repeat-dose studies to mice and monkeys in toxicity studies for up to 13-weeks in duration.”
Pivotal GLP studies
4-week and 13-week mouse and monkey oral gavage studies
“Repeat-dose toxicology studies were conducted in mice (4-weeks and 13-weeks) and monkeys (4-weeks and 13-weeks).”
Route in tox
Oral (gavage)
“Daraxonrasib was administered once daily by oral gavage in repeat-dose studies to mice and monkeys in toxicity studies for up to 13-weeks in duration.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human lymphocyte micronucleus and in vivo mouse micronucleus assays
“Daraxonrasib was not mutagenic in the GLP in vitro Ames assay, not clastogenic in the GLP in vitro micronucleus assay with human peripheral blood lymphocytes, and not genotoxic in the GLP in vivo micronucleus study in mice.”
Carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“Carcinogenicity studies were not conducted with daraxonrasib, consistent with ICH S9 recommendations for advanced cancer indications.”
Reproductive & developmental
Mouse EFD: embryo-fetal toxicity at ≥50 mg/kg/day (2.5x clinical exposure by AUC)
“In an embryo-fetal development study in mice (25, 50, and 75 mg/kg/day), daraxonrasib caused embryo-fetal toxicity at ≥50 mg/kg/day (2.5x exposure at the recommended dose based on AUC).”
Safety pharmacology
Monkey CV study: decreased heart rate, prolonged QT, shortened QTc and increased blood pressure at all doses (3, 10, 30 mg/kg)
“In a standalone good laboratory practice (GLP) cardiovascular study in monkey, daraxonrasib demonstrated decreased heart rate, prolonged QT, shortened QTc (secondary to heart rate decrease), and increased blood pressure at all dose levels tested (3, 10, and 30 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 Rasonque 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: Mouse 4-week STD10 50/30 mg/kg/day, 13-week NOAEL 25 mg/kg/day; monkey 4-week HNSTD 3 mg/kg/day (FDA multi-discipline review, p. 49)
NOAEL / key findings
Mouse 4-week STD10 50/30 mg/kg/day, 13-week NOAEL 25 mg/kg/day; monkey 4-week HNSTD 3 mg/kg/day
“The Severely Toxic Dose in 10% of animals (STD10) in the 4-week study in mice was 50/30 mg/kg/day, and the No Observed Adverse Effect Level (NOAEL) in the 13-week study in mice was 25 mg/kg/day. After 4-weeks of dosing in cynomolgus monkeys, the Highest Non-Severely Toxic Dose (HNSTD) was 3 mg/kg/day.”
Risksopen answer page →
Immune & cytokine safety
Monkey immune activation with fibrinogen elevation, thymic toxicity and myelosuppression
“Findings included GI toxicity, myelosuppression, thymic toxicity, electrolyte imbalance, and immune activation (elevated fibrinogen was secondary to immune activation).”
Biodistribution & persistence
Mouse QWBA: widespread distribution, highest in tissues of excretion and elimination
“In a mouse QWBA study, distribution of [14C]-daraxonrasib was widespread with the highest concentrations of radioactivity generally associated with tissues involved in excretion and elimination.”
Modality-specific risk
Bone marrow, gastrointestinal and immune/hematologic toxicity
“The primary target organs across both species included bone marrow, gastrointestinal tract and immune/hematologic systems.”