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.”
Species: general tox
Rat (up to 26 weeks) and dog (up to 39 weeks)
“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.”
Species: DART
Rat and rabbit
“Repeat-dose toxicity studies for belumosudil were conducted in rats and dogs, and in rats and rabbits for developmental and reproductive toxicity. The 6-month transgenic mouse model was used to investigate the carcinogenic properties of belumosudil.”
Species: carcinogenicity
Transgenic mouse (6-month); 2-year rat study ongoing
“A long-term rodent carcinogenicity study (6-month transgenic mice study) has been performed, and 2-year rat carcinogenicity study is currently ongoing.”
Surrogate used in
No surrogate used; clinical compound dosed orally
“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.”
Genotox: Ames
Negative
“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.”
Genotox: in vitro mammalian
Chromosomal aberration in human peripheral lymphocytes: negative
“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.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“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 model
6-month CByB6F1-Tg(HRAS)2Jic mouse: no carcinogenic effect up to 15 (F) / 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.”
Carcinogenicity timing
None at US marketing application; mouse and rat carcinogenicity studies required after approval (PMRs)
“PMR #9 Conduct a rodent carcinogenicity study in mice to evaluate the potential for carcinogenicity.”
hERG / QT
hERG IC50 well above unbound clinical Cmax (0.0055 µM)
“Considering unbound fraction (fu) of only 0.12% for belumosudil in human plasma (Study KDM/06), Cmax in human plasma corresponds to 2.5 ng/mL (0.0055 µM) unbound compound, which is significantly below IC50 for hERG inhibition.”
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.”
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
- Embryo-Fetal Toxicity
Embryo-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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week dog (oral) with 8-week recovery
“39 Week Oral Toxicity Study in Dogs with a 13 Week Interim Sacrifice and an 8 Week Recovery Period”
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.”
DART package
Species: DART
Rat and rabbit
“Repeat-dose toxicity studies for belumosudil were conducted in rats and dogs, and in rats and rabbits for developmental and reproductive toxicity. The 6-month transgenic mouse model was used to investigate the carcinogenic properties of belumosudil.”
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.”
PPND / ePPND: when
No PPND study; EMA accepted it as unnecessary given ROCK2 knockout placental dysfunction and foetal death
“Additionally, targeted ROCK2 receptor knockdown in homozygous knockout mice showed placental dysfunction, intrauterine growth retardation, and foetal death. Consequently, a PPND study is not considered necessary based on current knowledge.”
Carcinogenicity
Species: carcinogenicity
Transgenic mouse (6-month); 2-year rat study ongoing
“A long-term rodent carcinogenicity study (6-month transgenic mice study) has been performed, and 2-year rat carcinogenicity study is currently ongoing.”
Carcinogenicity model
6-month CByB6F1-Tg(HRAS)2Jic mouse: no carcinogenic effect up to 15 (F) / 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.”
Carcinogenicity timing
None at US marketing application; mouse and rat carcinogenicity studies required after approval (PMRs)
“PMR #9 Conduct a rodent carcinogenicity study in mice to evaluate the potential for carcinogenicity.”
Safety marginopen answer page →
Safety margin at NOAEL
Dog 9-month NOAEL margins 0.2-0.4x clinical exposure (rabbit EFD NOAEL 0.08x)
“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.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
cGVHD mouse models (lung and skin endpoints) and murine pulmonary fibrosis model
“In vivo studies in cGVHD mouse models demonstrated treatment with belumosudil resulted in improvement in cGVHD-related safety endpoints in the lung and skin. In addition, belumosudil reduced pulmonary fibrosis (one of the clinical manifestations of GVHD) and inflammation in a murine model of pulmonary fibrosis.”
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
EMA: in vitro and in vivo pharmacodynamic studies adequate to describe the mode of action
“The conducted in vitro and in vivo pharmacodynamic studies are considered adequate to describe the mode of action of belumosudil and its pharmacological effects in relation to its therapeutic target in the intended clinical indication.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity studies at US approval; waiver for chronic GVHD refused and rodent studies deferred to postmarketing requirements
Why: Waiver rejected: non-cancerous population with long life expectancy; studies required postmarketing
“The submission did not adequately address the carcinogenicity potential of belumosudil for chronic use. Given that the patient population includes subjects with non-cancerous conditions and long life expectancy, rodent studies should be conducted to determine the risk of carcinogenicity from belumosudil.”
“PMR #9 Conduct a rodent carcinogenicity study in mice to evaluate the potential for carcinogenicity.”
DARTAcceptedBeyond the letter
No pre- and postnatal development study
Why: ROCK2 knockout mice show placental dysfunction, growth retardation and foetal death · Pharmacology or kinetics · Weight of evidence
“Additionally, targeted ROCK2 receptor knockdown in homozygous knockout mice showed placental dysfunction, intrauterine growth retardation, and foetal death. Consequently, a PPND study is not considered necessary based on current knowledge.”
Safety marginVerdict not stated
Dog 9-month NOAEL margins 0.2 and 0.4, and rabbit embryo-fetal NOAEL margin 0.08, of clinical exposure
“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.”
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