Voydeya
danicopan
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
“Toxicological characterization of danicopan was evaluated in beagle dogs (5 days, 2-weeks, 13- weeks, 13-weeks, and 9 months), wistar han (WH) rats (14 days, 28-days, 13-weeks, and 6- months)”
Why that species
Dog selected as non-rodent safety species; rat (pharmacologically inactive) used to assess off-target toxicity
“The dog was selected as the nonrodent nonclinical safety species (repeat-dose toxicology), and the off-target activity/toxicity of danicopan was assessed in rats.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the 6-month toxicity study in rats (species not pharmacologically sensitive to danicopan), hypertrophy in liver, thyroid and adrenal gland was observed at doses of 1000 mg/kg/day (~26-fold above human exposure at 200 mg three times a day based on AUC).”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“No danicopan-related effects were observed on heart rate, RR, PR, QT, QTc (using Van de Water’s formula) intervals, and QRS complex duration at the approximate time to maximum concentration (Tmax) in a repeat-dose oral toxicity study in beagle dogs dosed up to 150 mg/kg/day (75 mg/kg, BID) for 39 weeks (ACH-15-057, GLP-compliant).”
Pivotal GLP studies
6-month rat and 9-month dog studies
“Toxicological characterization of danicopan was evaluated in beagle dogs (5 days, 2-weeks, 13- weeks, 13-weeks, and 9 months), wistar han (WH) rats (14 days, 28-days, 13-weeks, and 6- months)”
Route in tox
Oral
“The pivotal repeat-dose oral toxicology studies were conducted in accordance with GLP regulations”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human lymphocyte micronucleus and in vivo rat micronucleus assays
“Danicopan was not genotoxic in the Ames bacterial reverse mutation assay, in vitro micronucleus assay in human peripheral blood lymphocytes, or in the in vivo micronucleus assay in rats.”
Carcinogenicity
6-month TgRasH2 mouse and 2-year rat: not carcinogenic (rat exposure 15-23x MRHD)
“Danicopan was not carcinogenic in the 6-month carcinogenicity study in the TgRasH2 mouse model. Danicopan was not carcinogenic in the 2-year rat carcinogenicity study at exposures 15- to 23-times the exposure at the MRHD (based on AUC).”
Reproductive & developmental
Rabbit (pharmacologically active): no embryo-fetal effects up to 18x and no postnatal effects up to 9x MRHD exposure
“There were no effects on early embryonic development and fetal development in NZW rabbits (where danicopan is pharmacodynamically active) up to a mean maternal systemic exposure 18-times the exposure at the MRHD (based on AUC) or during post-natal development up to a mean maternal systemic exposure 9-times the exposure at the MRHD (based on AUC).”
Safety pharmacology
Dog telemetry (single doses up to 500 mg/kg): no hemodynamic or ECG effects
“A cardiovascular safety assessment of danicopan was conducted in conscious telemetry-instrumented male beagle dogs after single oral (gavage) doses up to 500 mg/kg and no effects on hemodynamic or electrocardiogram endpoints were observed for up to 24 hrs postdosing (ACH-15-072, GLP-compliant).”
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 Voydeya 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: Dog: cholestatic liver injury, 150 mg/kg/day not tolerated in 39-week study; bile duct hypertrophy/hyperplasia at ≥75 mg/kg/day (EMA assessment report, p. 25)
NOAEL / key findings
Dog: cholestatic liver injury, 150 mg/kg/day not tolerated in 39-week study; bile duct hypertrophy/hyperplasia at ≥75 mg/kg/day
“In the 39-week toxicity study, danicopan at the dose of 150 mg/kg/day was not tolerated due to cholestatic liver injury. Hypertrophy/hyperplasia of the bile duct was observed in males at greater than or equal to 75 mg/kg/day.”
Risksopen answer page →
Immune & cytokine safety
Alternative-pathway blockade may impair serum bactericidal activity (meningococcal infection risk) when antibody titers are low
“results suggests that when anti-Nm antibody titers are low (i.e., prevaccination), CAP-mediated amplification is required to elicit effective SBA, and hence, there is an increased risk of danicopan promoting bacterial infections under these conditions.”
Biodistribution & persistence
Crosses blood-retina barrier; binds melanin in uvea/RPE and skin of pigmented animals
“Distribution studies in either pigmented rats or pigmented rabbits showed that danicopan crosses the blood-retina barrier, enters the neural retina (a tissue that does not contain melanin), and associates with ocular tissues containing melanin (e.g., uvea and choroid-retinal pigment epithelium) and with the skin in pigmented rats.”
Modality-specific risk
Hepatobiliary (cholestatic) liver injury
“Multiple lines of evidence from the nonclinical data suggest that there is an increased risk of hepatobiliary liver injury associated with the administration of danicopan.”