Vanrafia
atrasentan
Species
RatDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Partial / alternative Partly stated
Speciesopen answer page →
Species
Rat and dog
“Pivotal chronic toxicology studies were conducted in rats for up to 6 months and dogs for up to 9 months.”
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
“Study Title: A 39-Week Repeat-Dose Study of Atrasentan in Dogs”
Species: general tox
Rat (26 weeks) and dog (39 weeks)
“General toxicity studies were conducted for durations of up to 26 weeks in rats and 39 weeks in dogs.”
Species: DART
Rat and rabbit (embryo-fetal development)
“In embryo-fetal developmental toxicity studies, treatment with atrasentan in pregnant rats and rabbits revealed teratogenicity”
Species: carcinogenicity
Sprague Dawley rat (104-week) and Tg rasH2 mouse (26-week)
“Two long-term studies were conducted to evaluate the carcinogenicity of atrasentan: a 26-week study in Model 001178-T (hemizygous) CByB6F1-Tg(HRAS)2Jic mice and a 104-week study in Sprague Dawley rats.”
Surrogate used in
No surrogate used; atrasentan tested in mouse, rat, dog and rabbit
“Nonclinical studies, including safety pharmacology, general toxicology, genetic toxicology, carcinogenicity, and reproductive and developmental toxicology were conducted to assess the safety of atrasentan in the mouse, rat, dog, and rabbit.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog)
“General toxicity studies were conducted for durations of up to 26 weeks in rats and 39 weeks in dogs.”
Pivotal GLP studies
26-week rat and 39-week dog studies
“General toxicity studies were conducted for durations of up to 26 weeks in rats and 39 weeks in dogs.”
Route in tox
Oral
“Methods: Animals were dosed by oral administration for 9 months.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosomal aberration and in vivo mouse micronucleus assays
“There was no evidence of mutagenicity or clastogenicity for atrasentan in in vitro bacteria reverse mutation and chromosomal aberration assays, or in an in vivo mouse micronucleus study.”
Carcinogenicity
2-year rat: benign uterine stromal polyps in females at 24 times the MRHD
“The carcinogenicity assessment of atrasentan in a 2-year rat study showed uterine stromal polyps in females at exposures 24 times the MRHD.”
Reproductive & developmental
Rat and rabbit EFD: teratogenic at exposures below the MRHD
“In animal reproduction studies, oral administration of atrasentan to pregnant rats and rabbits throughout organogenesis at doses that were below the maximum recommended human dose (MRHD) based on area under the curve (AUC) caused teratogenic effects in rats and rabbits”
Safety pharmacology
Dog telemetry: minimal QTc effect up to 51 times clinical Cmax
“In conscious dogs implanted with telemetry transmitters, atrasentan (≥10 mg/kg) showed minimal effects on heart rate-corrected QT interval at doses up to 51 times the maximal concentration achieved at the MRHD.”
Genotox: Ames
Negative
“There was no evidence of mutagenicity or clastogenicity for atrasentan in in vitro bacteria reverse mutation and chromosomal aberration assays, or in an in vivo mouse micronucleus study.”
Genotox: in vitro mammalian
Chromosomal aberration assay: negative
“There was no evidence of mutagenicity or clastogenicity for atrasentan in in vitro bacteria reverse mutation and chromosomal aberration assays, or in an in vivo mouse micronucleus study.”
Genotox: in vivo
Mouse micronucleus: negative
“There was no evidence of mutagenicity or clastogenicity for atrasentan in in vitro bacteria reverse mutation and chromosomal aberration assays, or in an in vivo mouse micronucleus study.”
Carcinogenicity model
104-week rat; 26-week Tg rasH2 mouse
“Two long-term studies were conducted to evaluate the carcinogenicity of atrasentan: a 26-week study in Model 001178-T (hemizygous) CByB6F1-Tg(HRAS)2Jic mice and a 104-week study in Sprague Dawley rats.”
Carcinogenicity timing
104-week Sprague Dawley rat and 26-week Tg(HRAS)2Jic (rasH2) mouse completed before the marketing application
“Two long-term studies were conducted to evaluate the carcinogenicity of atrasentan: a 26-week study in Model 001178-T (hemizygous) CByB6F1-Tg(HRAS)2Jic mice and a 104-week study in Sprague Dawley rats.”
hERG / QT
hERG IC10 ~2700-fold above Cmax at the MRHD
“Atrasentan induced concentration-dependent inhibition of human ether-à-go-go-related gene tail current with an estimated 10% inhibitory concentration of approximately 2700-fold higher than maximum plasma concentration (Cmax) at the MRHD.”
First doseopen answer page →
First-in-human starting dose
First-in-human single-dose study started at 139.5 mg; derivation not described
“Initially, the study was designed as a single dose, dose-escalating study with the starting dose of 139.5 mg.”
NOAEL / key findings
No NOAEL in rat or dog; male rat LOAEL 5 mg/kg/day for testicular degeneration
“In the chronic toxicology studies of atrasentan in the rat and dog, a no-observed-adverse-effect level (NOAEL) was not established. In male rats, the lowest dose tested, i.e., 5 mg/kg/day, was considered to be the lowest-observed-adverse-effect level (LOAEL) because of modest testicular degeneration”
Risksopen answer page →
Immune & cytokine safety
No immunosuppressive effect in 6-month rat and 9-month dog studies
“In addition, the repeat-dose toxicology studies in rats for up to 6 months and in dogs for up to 9 months do not suggest an immunosuppressive effect of atrasentan.”
Biodistribution & persistence
Rat: low levels in testes, eyes, bone marrow and fat; not detected in brain
“Low concentrations were observed in testes, eyes, bone marrow, and fat. Radioactivity was not detected in the brain.”
Modality-specific risk
Embryo-fetal toxicity (teratogenicity), an endothelin receptor antagonist class effect
“These findings are consistent with a class effect of developmental anomalies induced by endothelin receptor antagonists.”
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
Boxed warning: Embryo-fetal toxicity
- Embryo-Fetal Toxicity
- Hepatotoxicity
- Fluid Retention
- Decreased Sperm Counts
Embryo-fetal toxicityHepatotoxicityMetabolic & endocrine
US prescribing information, Boxed Warning and 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
First-in-human single-dose study started at 139.5 mg; derivation not described
“Initially, the study was designed as a single dose, dose-escalating study with the starting dose of 139.5 mg.”
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week (9-month) beagle dog with recovery groups (control and high dose); recovery length not stated
“Methods: Animals were dosed by oral administration for 9 months. Dose and frequency of dosing: 10, 30, 100 mg/kg/day Route of administration: Oral Formulation/vehicle: Atrasentan HCl powder in gelatin capsules. Species/strain: Beagle dog Number/sex/group: Five/sex/dose group Age: 6.5 to 7.5 months old Satellite groups: Recovery: two/sex (control and high-dose group)”
Pivotal GLP studies
26-week rat and 39-week dog studies
“General toxicity studies were conducted for durations of up to 26 weeks in rats and 39 weeks in dogs.”
DART package
Species: DART
Rat and rabbit (embryo-fetal development)
“In embryo-fetal developmental toxicity studies, treatment with atrasentan in pregnant rats and rabbits revealed teratogenicity”
Reproductive & developmental
Rat and rabbit EFD: teratogenic at exposures below the MRHD
“In animal reproduction studies, oral administration of atrasentan to pregnant rats and rabbits throughout organogenesis at doses that were below the maximum recommended human dose (MRHD) based on area under the curve (AUC) caused teratogenic effects in rats and rabbits”
PPND / ePPND: when
Rat PPND (GLP) completed and reviewed in the NDA
“13.1.7.3. Pre- and Postnatal Developmental Study Study Number/Title: R&D/15/0589 Peri- and Postnatal Development in Rats GLP compliance: Yes”
Carcinogenicity
Species: carcinogenicity
Sprague Dawley rat (104-week) and Tg rasH2 mouse (26-week)
“Two long-term studies were conducted to evaluate the carcinogenicity of atrasentan: a 26-week study in Model 001178-T (hemizygous) CByB6F1-Tg(HRAS)2Jic mice and a 104-week study in Sprague Dawley rats.”
Carcinogenicity model
104-week rat; 26-week Tg rasH2 mouse
“Two long-term studies were conducted to evaluate the carcinogenicity of atrasentan: a 26-week study in Model 001178-T (hemizygous) CByB6F1-Tg(HRAS)2Jic mice and a 104-week study in Sprague Dawley rats.”
Carcinogenicity timing
104-week Sprague Dawley rat and 26-week Tg(HRAS)2Jic (rasH2) mouse completed before the marketing application
“Two long-term studies were conducted to evaluate the carcinogenicity of atrasentan: a 26-week study in Model 001178-T (hemizygous) CByB6F1-Tg(HRAS)2Jic mice and a 104-week study in Sprague Dawley rats.”
Safety marginopen answer page →
Safety margin at NOAEL
No NOAEL established in chronic rat or dog studies
“In the chronic toxicology studies of atrasentan in the rat and dog, a no-observed-adverse-effect level (NOAEL) was not established.”
NOAEL / key findings
No NOAEL in rat or dog; male rat LOAEL 5 mg/kg/day for testicular degeneration
“In the chronic toxicology studies of atrasentan in the rat and dog, a no-observed-adverse-effect level (NOAEL) was not established. In male rats, the lowest dose tested, i.e., 5 mg/kg/day, was considered to be the lowest-observed-adverse-effect level (LOAEL) because of modest testicular degeneration”
Efficacy evidenceopen answer page →
Efficacy evidence
Spontaneous IgAN mouse (grouped-ddY): dose-dependent albuminuria reduction
“In a spontaneous IgAN mouse model (grouped-ddY mouse strain), treatment with atrasentan at doses of 10, 20, or 30 mg/kg/day for 5 days reduced albuminuria from baseline by 28, 62, and 63%, respectively.”
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: nonclinical pharmacology supports proof of concept for IgAN
“The nonclinical pharmacology data supports proof of concept for the treatment of IgAN.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
No NOAEL established in chronic rat or dog toxicity studies
“In the chronic toxicology studies of atrasentan in the rat and dog, a no-observed-adverse-effect level (NOAEL) was not established.”
OtherAcceptedBeyond the letter
No phototoxicity studies
Why: Low frequency of phototoxicity events in more than 2,000 patients on long-term atrasentan · Human data
“Phototoxicity studies have not been conducted with atrasentan.”
“further preclinical evaluation of phototoxicity risk for atrasentan was not considered necessary considering the low frequency of phototoxicity events observed following long-term administration of atrasentan in more than 2,000 patients with prostate cancer in an oncology program”
Similar precedents
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