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.”
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.”
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)”