Rasonque
daraxonrasib
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.”
Species: general tox
Mouse and cynomolgus monkey (4- and 13-week)
“Repeat-dose toxicology studies were conducted in mice (4-weeks and 13-weeks) and monkeys (4-weeks and 13-weeks).”
Species: DART
Mouse (EFD only); no fertility studies
“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).”
Species: carcinogenicity
Not conducted (advanced cancer, ICH S9)
“Carcinogenicity studies were not conducted with daraxonrasib, consistent with ICH S9 recommendations for advanced cancer indications.”
Surrogate used in
No surrogate used; daraxonrasib tested directly in mice and monkeys
“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).”
Genotox: Ames
Negative
“Daraxonrasib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay, not clastogenic in an in vitro micronucleus assay in human peripheral blood lymphocytes, and not genotoxic in an in vivo mouse bone marrow micronuclei test.”
Genotox: in vitro mammalian
In vitro micronucleus (human peripheral blood lymphocytes): negative
“Daraxonrasib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay, not clastogenic in an in vitro micronucleus assay in human peripheral blood lymphocytes, and not genotoxic in an in vivo mouse bone marrow micronuclei test.”
Genotox: in vivo
Mouse bone marrow micronucleus: negative
“Daraxonrasib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay, not clastogenic in an in vitro micronucleus assay in human peripheral blood lymphocytes, and not genotoxic in an in vivo mouse bone marrow micronuclei test.”
Carcinogenicity model
Not conducted (advanced cancer, ICH S9)
“Carcinogenicity studies were not conducted with daraxonrasib, consistent with ICH S9 recommendations for advanced cancer indications.”
Carcinogenicity timing
Not required (ICH S9)
“FDA concurs. Carcinogenicity studies were not required for this Application per ICH S9.”
hERG / QT
hERG inhibition 13.3% at 0.8 µM and 36.0% at 2.7 µM; IC50 >2.7 µM
“daraxonrasib inhibited hERG current by 13.3% at 0.8 µM and 36.0% at 2.7 µM versus 0.4% in vehicle control. The IC50 for the inhibitory effect of daraxonrasib on hERG potassium current was not calculated but was estimated to be greater than 2.7 µM.”
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)
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: 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.”
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
- Dermatologic and Soft Tissue Toxicity
- Stomatitis and Oral Disorders
- Diarrhea
- Gastrointestinal Perforation
- Interstitial Lung Disease (ILD)/Pneumonitis
- Embryo-Fetal Toxicity
Skin reactionsGastrointestinalImmune-mediated reactionsPulmonary toxicityEmbryo-fetal toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
US: first-in-human study RMC-6236-001 in patients with advanced solid tumors, 16 US centers
“RMC-6236-001 NCT No. NCT05379985 16 centers in US Phase 1/1b, dose escalation and dose expansion”
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 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)
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: 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week mouse and cynomolgus monkey oral gavage studies, each with 4-week recovery
“A 13-Week Study of RMC-6236 by Oral Gavage Administration in CD-1® IGS Mice with a 4-Week Recovery Period (23- REV09-002P); A 13-Week Study of RMC-6236 by Oral Gavage Administration in Cynomolgus Monkey Followed by a 4-Week Recovery Period (23- REV09-003P)”
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).”
DART package
Species: DART
Mouse (EFD only); no fertility studies
“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).”
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).”
PPND / ePPND: when
Not conducted: not needed for advanced cancer indication (ICH S9)
“No reproductive and developmental toxicity studies to determine the effects of daraxonrasib in pre - and postnatal development, including maternal function, have been conducted or are needed to support the use of daraxonrasib in the currently proposed indication per ICH S9.”
Carcinogenicity
Species: carcinogenicity
Not conducted (advanced cancer, ICH S9)
“Carcinogenicity studies were not conducted with daraxonrasib, consistent with ICH S9 recommendations for advanced cancer indications.”
Carcinogenicity model
Not conducted (advanced cancer, ICH S9)
“Carcinogenicity studies were not conducted with daraxonrasib, consistent with ICH S9 recommendations for advanced cancer indications.”
Carcinogenicity timing
Not required (ICH S9)
“FDA concurs. Carcinogenicity studies were not required for this Application per ICH S9.”
Safety marginopen answer page →
Safety margin at NOAEL
13-week mouse and monkey studies: margin ~1x human AUC at recommended dose
“The safety margins reported for the 13-week repeat-dose toxicology studies in mouse and monkey are approximately 1 based on AUC at the recommended dose.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
KRAS G12X PDAC cell-line xenografts in mice (mean regressions 53%–93% at 25 mg/kg daily)
“In vivo cell-line derived xenograft (CDX) mouse models using mutant KRAS G12X pancreatic ductal adenocarcinoma (PDAC) cell lines demonstrated tumor regression with 25 mg/kg daraxonrasib administered daily via oral route of administration with mean tumor regressions of 53%–93%.”
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 generally agreed with the applicant's pharmacology position
“The FDA generally agrees with the Applicant’s position.”
Flexibilityopen answer page →
Flexibility accepted
DARTAccepted
Embryo-fetal assessment limited to a dose-range-finding study in mice; no definitive or second-species study
Why: Mouse range-finder showed clear embryo-fetal lethality and teratogenicity; consistent with ICH S9 · Within the guideline
“Consistent with International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use S9 guidance, since the dose-range finding (DRF) embryofetal development (EFD) study in mice showed clear evidence of EFD lethality and teratogenicity, the DRF in a single species is deemed sufficient to support marketing and a definitive study is not warranted.”
Safety marginVerdict not stated
13-week mouse and monkey studies give safety margins of about 1 based on AUC at the recommended dose
“The safety margins reported for the 13-week repeat-dose toxicology studies in mouse and monkey are approximately 1 based on AUC at the recommended dose.”
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