Skyclarys
omaveloxolone
Species
MonkeyRat
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 cynomolgus monkey
“GLP-compliant general oral (gavage) toxicity studies of omaveloxolone were conducted in Sprague Dawley rat and cynomolgus monkey, with durations up to 26 and 39 weeks, respectively.”
Why that species
Monkey chosen as non-rodent because dogs develop species-specific GI toxicity with the related compound bardoxolone methyl
“Monkeys were chosen as the non-rodent non-clinical species in the omaveloxolone testing programme as dogs have previously been shown to develop species-specific gastrointestinal toxicity following repeated dosing with the chemically related substance, bardoxolone methyl.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Male and female cynomolgus monkeys (9-10/sex/group) were administered doses of 0 (sesame oil), 10, 30, or 100 mg/kg RTA 408 by daily oral gavage for 39 weeks with 4 weeks recovery;”
Species: general tox
Sprague Dawley rat (up to 26 weeks) and cynomolgus monkey (up to 39 weeks)
“GLP-compliant general oral (gavage) toxicity studies of omaveloxolone were conducted in Sprague Dawley rat and cynomolgus monkey, with durations up to 26 and 39 weeks, respectively.”
Species: DART
Rat (fertility, EFD, PPND) and rabbit (EFD)
“Male and female fertility were investigated in rats, including early embryonic development, however, no TK analysis was performed. Embryofetal developmental (EFD) toxicity in rats and rabbits were conducted, including TK analysis in both species. PPND toxicity was investigated in rats”
Species: carcinogenicity
Tg.rasH2 mouse (26-week) and Sprague Dawley rat (2-year)
“Carcinogenicity studies (26-week study in Tg.rasH2 mice and 2-year study in SD rats) are to be conducted as post-marketing requirements.”
Surrogate used in
No surrogate used; omaveloxolone tested directly in rats and monkeys
“GLP-compliant general oral (gavage) toxicity studies of omaveloxolone were conducted in Sprague Dawley rat and cynomolgus monkey, with durations up to 26 and 39 weeks, respectively.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week monkey)
“Oral toxicology studies of up to 26 and 39 weeks’ duration were conducted in Sprague Dawley (SD) rat and cynomolgus monkey, respectively.”
Pivotal GLP studies
26-week rat and 39-week cynomolgus monkey oral studies
“Oral toxicology studies of up to 26 and 39 weeks’ duration were conducted in Sprague Dawley (SD) rat and cynomolgus monkey, respectively.”
Route in tox
Oral (gavage)
“GLP-compliant general oral (gavage) toxicity studies of omaveloxolone were conducted in Sprague Dawley rat and cynomolgus monkey, with durations up to 26 and 39 weeks, respectively.”
Skipped studiesopen answer page →
Genotoxicity
Negative Ames; positive in vitro chromosomal aberration (human lymphocytes); negative in vivo rat micronucleus and comet assays
“Omaveloxolone was negative in a bacterial reverse mutation (Ames) assay, and positive in a chromosomal aberration assay in human peripheral blood lymphocytes but negative in in vivo (micronucleus and comet in rat) assays.”
Carcinogenicity
2-year rat: increased liver cholangioma/cholangiocarcinoma in high-dose females (1.9x human AUC)
“In a 2-year carcinogenicity study in rats, oral administration of omaveloxolone at levels of 0.1, 0.3, or 1 mg/kg/day in males and 0.3, 1, or 3 mg/kg/day in females resulted in increased incidences of liver cholangioma and combined cholangioma/cholangiocarcinoma in female rats at the highest dose tested (1.9 times the maximum recommended human dose of 150 mg/day based on AUC).”
Reproductive & developmental
Developmental toxicity (embryofetal death, growth impairment, offspring mortality and neurobehavioral deficits) at or below clinical exposure
“In animal studies, administration of omaveloxolone during pregnancy or throughout pregnancy and lactation produced evidence of developmental toxicity (embryofetal mortality and growth impairment, and mortality, growth impairment, and neurobehavioral deficits in offspring) at plasma exposures similar to or less than exposures in humans”
Safety pharmacology
Monkey single oral doses up to 100 mg/kg: no effects on blood pressure, heart rate or ECG including QTc
“Cardiovascular endpoints were assessed in cynomolgus monkeys administered single oral doses of RTA 408 up to 100 mg/kg. There were no drug effects on body temperature, blood pressure, heart rate, or ECG (PR, RR, QRS, and corrected QT intervals).”
Genotox: Ames
Negative
“Omaveloxolone was negative in a bacterial reverse mutation (Ames) assay, and positive in a chromosomal aberration assay in human peripheral blood lymphocytes but negative in in vivo (micronucleus and comet in rat) assays.”
Genotox: in vitro mammalian
Positive chromosomal aberration assay in human peripheral blood lymphocytes
“Omaveloxolone was negative in a bacterial reverse mutation (Ames) assay, and positive in a chromosomal aberration assay in human peripheral blood lymphocytes but negative in in vivo (micronucleus and comet in rat) assays.”
Genotox: in vivo
Negative rat micronucleus and comet assays
“Omaveloxolone was negative in a bacterial reverse mutation (Ames) assay, and positive in a chromosomal aberration assay in human peripheral blood lymphocytes but negative in in vivo (micronucleus and comet in rat) assays.”
Carcinogenicity model
2-year rat: liver cholangioma/cholangiocarcinoma in high-dose females (1.9x MRHD by AUC)
“In a 2-year carcinogenicity study in rats, oral administration of omaveloxolone at levels of 0.1, 0.3, or 1 mg/kg/day in males and 0.3, 1, or 3 mg/kg/day in females resulted in increased incidences of liver cholangioma and combined cholangioma/cholangiocarcinoma in female rats at the highest dose tested (1.9 times the maximum recommended human dose of 150 mg/day based on AUC).”
Carcinogenicity timing
26-week Tg.rasH2 mouse and 2-year rat studies: postmarketing requirements at US approval
“Carcinogenicity studies (26-week study in Tg.rasH2 mice and 2-year study in SD rats) are to be conducted as post-marketing requirements.”
hERG / QT
No meaningful hERG effect; no QT concern in monkey ECGs
“Omaveloxolone had no meaningful effect in the in vitro hERG assay and ECG parameters collected after single- and repeat-dose in monkeys identified no safety concern with regard to risk for QT prolongation at the doses tested.”
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 Skyclarys 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: Liver bile duct hyperplasia and kidney tubular degeneration at all doses; no NOAEL in 26-week rat (FDA pharmacology/toxicology review, p. 4)
NOAEL / key findings
Liver bile duct hyperplasia and kidney tubular degeneration at all doses; no NOAEL in 26-week rat
“Based on the liver (bile duct hyperplasia) and kidney (tubular degeneration/regeneration) findings at all doses (0, 0.3, 1, or 3 mg/kg) in the 26-week study, a NOAEL was not established in rats.”
Risksopen answer page →
Immune & cytokine safety
No dedicated immunotoxicity studies; not required for this small molecule
“Considering the type of molecule (small molecule), investigations of antigenicity and immunotoxicity are not required for omaveloxolone.”
Biodistribution & persistence
~3.41% oral bioavailability in monkey; wide tissue distribution including brain, highest in GI tract
“Following oral administration to monkeys, [14C]RTA 408 was approximately 3.41% bioavailable and was widely distributed to most tissues, including brain, between 8 and 30 h, with the highest concentrations observed in the gastrointestinal tract.”
Modality-specific risk
Major human metabolite M22 inadequately covered in rat and monkey general and reproductive toxicity studies (MIST)
“Therefore, M22 was not adequately tested in the general toxicology studies in rat and monkey or in any reproductive and developmental toxicology studies in rat.”
Anti-drug antibodies: animals
Not applicable (small molecule); antigenicity studies not required
“Considering the type of molecule (small molecule), investigations of antigenicity and immunotoxicity are not required for omaveloxolone.”
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
- Elevation of Aminotransferases
- Elevation of B-Type Natriuretic Peptide
- Lipid Abnormalities
Metabolic & endocrine
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 Skyclarys 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: Liver bile duct hyperplasia and kidney tubular degeneration at all doses; no NOAEL in 26-week rat (FDA pharmacology/toxicology review, p. 4)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week cynomolgus monkey (oral) with 4-week recovery
“Male and female cynomolgus monkeys (9-10/sex/group) were administered doses of 0 (sesame oil), 10, 30, or 100 mg/kg RTA 408 by daily oral gavage for 39 weeks with 4 weeks recovery; an interim 13-week sacrifice was included.”
Pivotal GLP studies
26-week rat and 39-week cynomolgus monkey oral studies
“Oral toxicology studies of up to 26 and 39 weeks’ duration were conducted in Sprague Dawley (SD) rat and cynomolgus monkey, respectively.”
DART package
Species: DART
Rat (fertility, EFD, PPND) and rabbit (EFD)
“Male and female fertility were investigated in rats, including early embryonic development, however, no TK analysis was performed. Embryofetal developmental (EFD) toxicity in rats and rabbits were conducted, including TK analysis in both species. PPND toxicity was investigated in rats”
Reproductive & developmental
Developmental toxicity (embryofetal death, growth impairment, offspring mortality and neurobehavioral deficits) at or below clinical exposure
“In animal studies, administration of omaveloxolone during pregnancy or throughout pregnancy and lactation produced evidence of developmental toxicity (embryofetal mortality and growth impairment, and mortality, growth impairment, and neurobehavioral deficits in offspring) at plasma exposures similar to or less than exposures in humans”
PPND / ePPND: when
PPND in rat completed before the marketing application
“PPND toxicity was investigated in rats and concentrations of omaveloxolone were determined in milk and in pup plasma samples.”
Carcinogenicity
Species: carcinogenicity
Tg.rasH2 mouse (26-week) and Sprague Dawley rat (2-year)
“Carcinogenicity studies (26-week study in Tg.rasH2 mice and 2-year study in SD rats) are to be conducted as post-marketing requirements.”
Carcinogenicity model
2-year rat: liver cholangioma/cholangiocarcinoma in high-dose females (1.9x MRHD by AUC)
“In a 2-year carcinogenicity study in rats, oral administration of omaveloxolone at levels of 0.1, 0.3, or 1 mg/kg/day in males and 0.3, 1, or 3 mg/kg/day in females resulted in increased incidences of liver cholangioma and combined cholangioma/cholangiocarcinoma in female rats at the highest dose tested (1.9 times the maximum recommended human dose of 150 mg/day based on AUC).”
Carcinogenicity timing
26-week Tg.rasH2 mouse and 2-year rat studies: postmarketing requirements at US approval
“Carcinogenicity studies (26-week study in Tg.rasH2 mice and 2-year study in SD rats) are to be conducted as post-marketing requirements.”
Safety marginopen answer page →
Safety margin at NOAEL
Rabbit EFD (no repeat-dose margin stated): maternal NOAEL 0.3x, developmental NOAEL 0.7x clinical exposure
“The maternal NOAEL is considered 3 mg/kg/day and the developmental NOAEL is considered 10 mg/kg/day in rabbits, corresponding to exposure margins of 0.3 and 0.7, respectively.”
NOAEL / key findings
Liver bile duct hyperplasia and kidney tubular degeneration at all doses; no NOAEL in 26-week rat
“Based on the liver (bile duct hyperplasia) and kidney (tubular degeneration/regeneration) findings at all doses (0, 0.3, 1, or 3 mg/kg) in the 26-week study, a NOAEL was not established in rats.”
Efficacy evidenceopen answer page →
Efficacy evidence
Nrf2 target-gene induction in healthy mice, rats and monkeys; no FA animal model
“The ability of omaveloxolone to induce expression of Nrf2 target genes in vivo was demonstrated using tissues collected from healthy omaveloxolone-treated mice, rats and monkeys.”
Why that model
No well-established FA animal models commercially available; tested in other rodent neurological disease models
“Because well-established animal models of FA are not commercially available, omaveloxolone was tested in several rodent models of neurological disease.”
Reviewer's view of the efficacy data
EMA: proof of concept and mechanism demonstrated despite limited in vivo efficacy studies
“Proof of concept, mechanism of action and mode of action of omaveloxolone were demonstrated despite a limited number of in vivo efficacy studies.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
Carcinogenicity studies (26-week Tg.rasH2 mouse, 2-year rat) deferred to post-marketing requirements
“Carcinogenicity studies (26-week study in Tg.rasH2 mice and 2-year study in SD rats) are to be conducted as post-marketing requirements.”
Impurity or metaboliteAccepted with a conditionBeyond the letter
Major human metabolite M22 not adequately covered in general or reproductive toxicology studies; EFD study of M22 required post-marketing
Why: M22 has minimal pharmacological activity and was negative in silico and in a non-GLP Ames assay · Pharmacology or kinetics
“Therefore, M22 was not adequately tested in the general toxicology studies in rat and monkey or in any reproductive and developmental toxicology studies in rat. M22 showed minimal pharmacological activity and was negative in in silico analysis and in a non-GLP Ames assay.”
“As a post-marketing requirement, the developmental toxicity of M22 should be evaluated in an embryofetal development (EFD) study in one species.”
Juvenile toxAcceptedBeyond the letter
No juvenile animal studies despite use from age 16; no justification provided by the applicant
Why: Target organs (GI tract, liver, kidney) already fully developed in patients aged 16-18 years · Weight of evidence
“No justification for omission of juvenile animal studies was provided by the applicant. However, considering the target organs of toxicity (gastrointestinal tract, liver and kidney) identified in the young and adult animals in pivotal repeat-dose toxicity studies, no higher sensitivity to toxicity in comparison to adults is expected as these organs are already fully developed in the proposed paediatric population (16-18 years”
Safety marginVerdict not stated
Rabbit embryo-fetal NOAELs below clinical exposure (maternal 0.3, developmental 0.7)
“The maternal NOAEL is considered 3 mg/kg/day and the developmental NOAEL is considered 10 mg/kg/day in rabbits, corresponding to exposure margins of 0.3 and 0.7, respectively.”
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