Rezurock
belumosudil
Species
RatDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“Consistent with the intended clinical route of administration and intended dosing schedule, daily oral administration of belumosudil was assessed in repeat-dose general toxicology studies for up to 26 weeks in rats and up to 39 weeks in dogs.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound was tested
“These studies were dosed orally (intended clinical route of administration) and utilized comparable and representative belumosudil drug substance.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“Consistent with the intended clinical route of administration and intended dosing schedule, daily oral administration of belumosudil was assessed in repeat-dose general toxicology studies for up to 26 weeks in rats and up to 39 weeks in dogs.”
Pivotal GLP studies
26-week rat and 39-week dog oral studies
“Consistent with the intended clinical route of administration and intended dosing schedule, daily oral administration of belumosudil was assessed in repeat-dose general toxicology studies for up to 26 weeks in rats and up to 39 weeks in dogs.”
Route in tox
Oral
“These studies were dosed orally (intended clinical route of administration) and utilized comparable and representative belumosudil drug substance.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosomal aberration and rat bone marrow micronucleus assays
“Belumosudil was not mutagenic in the in vitro bacterial reverse mutation test or clastogenic in either the in vitro chromosomal aberrations assay in human peripheral lymphocytes or in the vivo bone marrow micronucleus assay in rats.”
Carcinogenicity
6-month Tg(HRAS) transgenic mouse: no carcinogenic effect up to 15 (F) and 30 (M) mg/kg/day
“Belumosudil did not result in any carcinogenic effect in a 6-month CByB6F1-Tg (HRAS)2Jic hemizygous mouse study at oral doses up to 15 mg/kg/day in female and 30 mg/kg/day in male mice.”
Reproductive & developmental
Rabbit EFD: abortion, fetal loss, reduced fetal weight and skeletal/external malformations from 50 mg/kg/day
“Embryo-fetal findings occurred at doses ≥ 50 mg/kg/day and included spontaneous abortion, increased post-implantation loss, decreased percentage of live fetuses, decreased fetal body weight, and skeletal/external malformations.”
Safety pharmacology
hERG IC50 0.6 µM
“Belumosudil blocked hERG (human ether-à-go-go-related gene) current in a concentration-dependent manner with an IC50 of 0.6 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 Rezurock 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 small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: NOAEL margins below clinical exposure: 0.2-0.4x (9-month dog), 0.08x (rabbit EFD) (EMA assessment report, p. 62)
NOAEL / key findings
NOAEL margins below clinical exposure: 0.2-0.4x (9-month dog), 0.08x (rabbit EFD)
“In the rabbit embryo-foetal toxicity study, the NOAEL resulted in safety margin of 0.08, and dog 9-month repeat dose toxicity study NOAELs resulted in safety margins of 0.2 and 0.4, when compared to the expected clinical exposure.”
Risksopen answer page →
Immune & cytokine safety
Thymic lymphoid depletion with reduced thymus weight at high dose; not seen after recovery
“In addition, reduced thymus weights correlated with increased incidence and/or severity of thymic lymphoid depletion in HD males and females. Thymic lymphoid depletion was not observed in recovery males or females.”
Biodistribution & persistence
No appreciable brain radioactivity; melanin binding (uveal tract, pigmented skin)
“All tissues demonstrated clearance and no appreciable radioactivity was observed in the brain. Melanin-containing tissues (uveal tract and pigmented skin) demonstrated higher tissue retention, indicating some affinity of belumosudil for melanin.”
Modality-specific risk
Embryofetal toxicity with low safety margins
“In the rabbit embryo-foetal toxicity study, the NOAEL resulted in safety margin of 0.08, and dog 9-month repeat dose toxicity study NOAELs resulted in safety margins of 0.2 and 0.4, when compared to the expected clinical exposure.”