Oxbryta
voxelotor
Species
MonkeyRatMouse
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 (also mouse)
“Major findings associated with repeat-dose administration of voxelotor in mice, rats and Cynomolgus monkeys were changes in hematopoietic parameters and gastrointestinal (GI) intolerance that was attributed to local irritation.”
Why that species
Dogs dropped: exposure too low to reduce tissue O2 extraction, no erythroid changes
“The exposure in dogs in the 4-week study at the highest tolerated dose was not sufficiently high to cause decreased tissue O2 extraction and dogs did not have erythroid or bone marrow changes, therefore dogs were not further considered as test species.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In a fertility and early embryonic development study, voxelotor was administered orally to rats at 15, 50, and 250 mg/kg/day.”
Species: general tox
Mouse, rat and cynomolgus monkey
“Major findings associated with repeat-dose administration of voxelotor in mice, rats and Cynomolgus monkeys were changes in hematopoietic parameters and gastrointestinal (GI) intolerance that was attributed to local irritation.”
Species: DART
Rat (fertility, EFD, pre/postnatal, juvenile) and rabbit (EFD)
“Reproductive and developmental toxicity of voxelotor was studied in the fertility and early embryonic development (FEED) study in rats, embryo-foetal developmental (EFD) toxicity studies in rats and rabbits, pre-and postnatal developmental toxicity study in rats and a dose-range finding study in juvenile rats.”
Species: carcinogenicity
Rat (2-year) and transgenic mouse (26-week)
“Carcinogenicity of voxelotor was studied in the 2-year study with rats study (PRC-16-009) and the 26-week study with transgenic mice (study PRC-17-006).”
Surrogate used in
No surrogate used; voxelotor-Hb binding in animals expected to match humans
“Affinity and dissociation constants for voxelotor to Hb for human HbS, HbA and HbF and for the animal equivalents and it is not expected that the voxelotor-Hb binding is different or not-reversible in animals.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week monkey)
“The prolonged QT and QTc intervals could have been related to the poor condition of the animals, as they were not seen in the 39-week study at comparable (slightly lower) exposure levels.”
Pivotal GLP studies
26-week rat oral gavage study with 4-week recovery
“0, 15, 50 and 250 mg/kg/day, oral gavage 26 weeks with 4 weeks recovery”
Route in tox
Oral or nasogastric gavage
“0, 15, 30 and 60 mg/kg/day, oral or nasogastric gavage 39 weeks with 4 weeks recovery”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, rat Comet and rat micronucleus assays
“Voxelotor was not genotoxic in the reverse mutation bacterial (Ames) test, rat Comet assay, or rat micronucleus assay.”
Carcinogenicity
2-year rat and 26-week transgenic mouse; hepatocellular adenoma and pheochromocytoma in high-dose female rats
“Carcinogenicity of voxelotor was studied in the 2-year study with rats study (PRC-16-009) and the 26-week study with transgenic mice (study PRC-17-006). In rats, increased incidence of hepatocellular adenoma and adrenal pheochromocytoma was seen in high-dose females (100 mg/kg/day).”
Reproductive & developmental
Rat and rabbit EFD: no developmental effects at maternally toxic doses
“Voxelotor did not have an effect on the embryo-foetal development in either rats or rabbits at dose levels causing maternal toxicity.”
Safety pharmacology
hERG IC50 >10 μM, >70-fold clinical Cmax after protein-binding correction
“The IC50 for the inhibitory effect of voxelotor on hERG potassium current was not calculated but is greater than 10 μM. The IC50 for inhibition of hERG potassium channel currents, corrected for protein binding is greater than 70-fold the maximum plasma concentration of voxelotor in patients receiving 1500 mg, once daily.”
Genotox: Ames
Negative
“Voxelotor was not genotoxic in the reverse mutation bacterial (Ames) test, rat Comet assay, or rat micronucleus assay.”
Genotox: in vitro mammalian
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.
Genotox: in vivo
Rat Comet and rat micronucleus: negative
“Voxelotor was not genotoxic in the reverse mutation bacterial (Ames) test, rat Comet assay, or rat micronucleus assay.”
Carcinogenicity model
2-year rat; 26-week transgenic mouse
“Carcinogenicity of voxelotor was studied in the 2-year study with rats study (PRC-16-009) and the 26-week study with transgenic mice (study PRC-17-006).”
Carcinogenicity timing
2-year rat and 26-week transgenic mouse studies completed and assessed with the marketing application
“Carcinogenicity of voxelotor was studied in the 2-year study with rats study (PRC-16-009) and the 26-week study with transgenic mice (study PRC-17-006).”
hERG / QT
hERG IC50 >10 µM, >70-fold clinical Cmax after protein-binding correction
“The IC50 for the inhibitory effect of voxelotor on hERG potassium current was not calculated but is greater than 10 μM. The IC50 for inhibition of hERG potassium channel currents, corrected for protein binding is greater than 70-fold the maximum plasma concentration of voxelotor in patients receiving 1500 mg, once daily.”
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 Oxbryta 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: Erythrocytosis, marrow hypercellularity and splenic haematopoiesis (exaggerated pharmacology) (EMA assessment report, p. 50)
NOAEL / key findings
Erythrocytosis, marrow hypercellularity and splenic haematopoiesis (exaggerated pharmacology)
“Hematologic changes included increased RBCs, reticulocytes, and haematocrit, with increased cellularity of bone marrow and extramedullary haematopoiesis in spleen consistent with exaggerated pharmacology of voxelotor in normal animals.”
Risksopen answer page →
Immune & cytokine safety
Immunosuppression: opportunistic infections in monkeys, reduced IgG/IgM titres, delayed antibody response
“2) The immunosuppressive action of voxelotor, manifested as increased mortality due to opportunistic infections in monkeys, significantly reduced IgG (rats, monkeys) and IgM (monkeys) titres, delayed antibody response (monkeys)”
Biodistribution & persistence
Crosses blood-brain barrier at ≥30-fold lower than blood; no melanin binding
“Radioactivity was found to cross the blood brain barrier, but exposure was at least 30-fold lower than in the blood. As pigmented and non-pigmented skin were similarly labelled, it is concluded that there is no melanin binding.”
Modality-specific risk
Compensatory erythropoiesis, immunosuppression and GI toxicity at low safety margins
“The applicant has agreed to include the compensatory erythropoiesis, immunosuppression and adverse gastro-intestinal tract effects action as important non-clinical safety findings in Part II module SII and as identified risks in Part II module SVII of the Risk Management Plan)”
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
- Hypersensitivity Reactions
- Laboratory Test Interference
Hypersensitivity & infusion reactions
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 Oxbryta 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: Erythrocytosis, marrow hypercellularity and splenic haematopoiesis (exaggerated pharmacology) (EMA assessment report, p. 50)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week cynomolgus monkey GLP oral/nasogastric gavage study with 4-week recovery
“PRC-16-007, GLP Monkey, Cynomolgus, 6/sex/dose (controls and high-dose – 4/sex/dose terminated immediately after dosing, 2/sex/dose recovery group), 4/sex/dose (low- and mid-dose) 0, 15, 30 and 60 mg/kg/day, oral or nasogastric gavage 39 weeks with 4 weeks recovery”
Pivotal GLP studies
26-week rat oral gavage study with 4-week recovery
“0, 15, 50 and 250 mg/kg/day, oral gavage 26 weeks with 4 weeks recovery”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal, juvenile) and rabbit (EFD)
“Reproductive and developmental toxicity of voxelotor was studied in the fertility and early embryonic development (FEED) study in rats, embryo-foetal developmental (EFD) toxicity studies in rats and rabbits, pre-and postnatal developmental toxicity study in rats and a dose-range finding study in juvenile rats.”
Reproductive & developmental
Rat and rabbit EFD: no developmental effects at maternally toxic doses
“Voxelotor did not have an effect on the embryo-foetal development in either rats or rabbits at dose levels causing maternal toxicity.”
PPND / ePPND: when
PPND in rat completed and assessed with the marketing application
“In the pre- and post-natal developmental toxicity study reduced pup viability index and reduced F1 generation body weight (in males until post-pairing day 55, in females until maturation day 7) was seen at the dose level of 250 mg/kg/day.”
Carcinogenicity
Species: carcinogenicity
Rat (2-year) and transgenic mouse (26-week)
“Carcinogenicity of voxelotor was studied in the 2-year study with rats study (PRC-16-009) and the 26-week study with transgenic mice (study PRC-17-006).”
Carcinogenicity model
2-year rat; 26-week transgenic mouse
“Carcinogenicity of voxelotor was studied in the 2-year study with rats study (PRC-16-009) and the 26-week study with transgenic mice (study PRC-17-006).”
Carcinogenicity timing
2-year rat and 26-week transgenic mouse studies completed and assessed with the marketing application
“Carcinogenicity of voxelotor was studied in the 2-year study with rats study (PRC-16-009) and the 26-week study with transgenic mice (study PRC-17-006).”
Safety marginopen answer page →
Safety margin at NOAEL
No margin: adverse effects in animals at exposures comparable to or below anticipated clinical exposure
“A number of adverse effects were observed in the test animals at dose levels comparable or even lower than the anticipated clinical exposure.”
NOAEL / key findings
Erythrocytosis, marrow hypercellularity and splenic haematopoiesis (exaggerated pharmacology)
“Hematologic changes included increased RBCs, reticulocytes, and haematocrit, with increased cellularity of bone marrow and extramedullary haematopoiesis in spleen consistent with exaggerated pharmacology of voxelotor in normal animals.”
Efficacy evidenceopen answer page →
Efficacy evidence
SCD (SS) mouse model: increased Hb-O2 affinity and reduced ex vivo RBC sickling
“All voxelotor-treated SS mice exhibited an increase in Hb-O2 affinity and a decrease in the ex vivo RBC sickling, the effect was dose dependent”
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: primary pharmacodynamic studies adequately showed voxelotor binds and stabilises oxygenated Hb
“Overall, the primary pharmacodynamic studies provided adequate evidence that voxelotor binds to and stabilises oxygen loaded Hb, but also affects the dissociation of O2 from voxelotor bound Hb.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginAccepted with a conditionBeyond the letter
Adverse effects in animals at exposures comparable to or below anticipated clinical exposure
Why: Compensatory erythropoiesis to be evaluated as an identified risk in the PSUR
“A number of adverse effects were observed in the test animals at dose levels comparable or even lower than the anticipated clinical exposure.”
“However, as the safety margins between the preclinical studies and the anticipated clinical exposure are very low, the applicant has agreed to include compensatory erythropoiesis as an identified risk to be evaluated in the PSUR.”
Juvenile toxVerdict not stated
Only a dose-range-finding juvenile rat study; no definitive juvenile toxicity study
Why: Effects in juvenile animals consistent with those in adult animals · Weight of evidence
“As the observed effects in juvenile animals were consistent with the effects seen in adult animals, no full study was conducted.”
SpeciesVerdict not stated
Dog dropped after 4 weeks; monkey used as the chronic non-rodent species
Why: Dog exposure at highest tolerated dose too low to reduce tissue O2 extraction · Pharmacology or kinetics
“The exposure in dogs in the 4-week study at the highest tolerated dose was not sufficiently high to cause decreased tissue O2 extraction and dogs did not have erythroid or bone marrow changes, therefore dogs were not further considered as test species.”
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