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).”
Species: general tox
Wistar Han rat (up to 6 months) and beagle dog (up to 9 months)
“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)”
Species: DART
NZW rabbit (fertility, EFD, pre/postnatal), the pharmacologically active species
“Danicopan is pharmacologically active in the rabbit and is therefore considered toxicologically relevant for the assessment of fertility and early embryonic developmental (FEED) toxicity, Embryo/Fetal Developmental (EFD) toxicity and Pre- and Post-natal Developmental (PPND) toxicity.”
Species: carcinogenicity
Rat (2-year) and TgRasH2 mouse (6-month)
“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).”
Surrogate used in
No surrogate used; dog and rabbit chosen as pharmacologically relevant species
“Beagle dogs and NZW rabbits are considered pharmacologically relevant nonclinical species for toxicological evaluations based on the in vitro/in vivo/ex vivo assessments of danicopan PD activity.”
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).”
Genotox: Ames
Negative
“Danicopan demonstrated no potential for genotoxicity in a bacterial reverse mutation (Ames) assay, an in vitro micronucleus assay employing human peripheral blood lymphocytes, and in a 28-day in vivo bone marrow micronucleus assessment in male and female WH rats.”
Genotox: in vitro mammalian
Negative: in vitro micronucleus in human peripheral blood lymphocytes
“Danicopan demonstrated no potential for genotoxicity in a bacterial reverse mutation (Ames) assay, an in vitro micronucleus assay employing human peripheral blood lymphocytes, and in a 28-day in vivo bone marrow micronucleus assessment in male and female WH rats.”
Genotox: in vivo
Negative: 28-day rat bone marrow micronucleus
“Danicopan demonstrated no potential for genotoxicity in a bacterial reverse mutation (Ames) assay, an in vitro micronucleus assay employing human peripheral blood lymphocytes, and in a 28-day in vivo bone marrow micronucleus assessment in male and female WH rats.”
Carcinogenicity model
2-year rat and 6-month TgRasH2 mouse; both negative (rat at 15-23x MRHD AUC)
“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).”
Carcinogenicity timing
2-year WH rat and TgRasH2 mouse studies completed before the marketing application
“Danicopan was not carcinogenic at any dose assessed in WH rats and hemizygous TgRasH2 mice.”
hERG / QT
hERG IC50 >10 µM; 106-fold above free Cmax at MRHD (200 mg TID)
“An IC50 for the inhibitory effect of danicopan on hERG potassium channel current could not be calculated but was estimated to be greater than 10µM. Based on the in vitro protein binding data, the highest danicopan concentration assessed in this assay (10µM) is 106-fold higher than the estimated free-fraction concentration of danicopan (0.094µM) at the MRHD (200 mg, TID).”
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.”
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: Serious infections caused by encapsulated bacteria
- Serious Infections Caused by Encapsulated Bacteria
- Voydeya rems
- Hepatic Enzyme Increases
- Monitoring of PNH Manifestations After VOYDEYA Discontinuation
- Hyperlipidemia
InfectionsHepatotoxicityMetabolic & 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
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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week oral gavage GLP study in beagle dogs with 13-week recovery
“A 39-Week Study of Danicopan by Oral Gavage in the Beagle Dog With a 13-Week Recovery Period (ACH-16-057, GLP)”
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)”
DART package
Species: DART
NZW rabbit (fertility, EFD, pre/postnatal), the pharmacologically active species
“Danicopan is pharmacologically active in the rabbit and is therefore considered toxicologically relevant for the assessment of fertility and early embryonic developmental (FEED) toxicity, Embryo/Fetal Developmental (EFD) toxicity and Pre- and Post-natal Developmental (PPND) toxicity.”
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).”
PPND / ePPND: when
PPND in NZW rabbit (pharmacologically active species) completed before the marketing application
“The pre- and post-natal development (PPND) study conducted in NZW rabbits resulted in no overt maternal toxicity (F0) at doses up to 250 mg/kg/day (HD)”
Carcinogenicity
Species: carcinogenicity
Rat (2-year) and TgRasH2 mouse (6-month)
“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).”
Carcinogenicity model
2-year rat and 6-month TgRasH2 mouse; both negative (rat at 15-23x MRHD AUC)
“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).”
Carcinogenicity timing
2-year WH rat and TgRasH2 mouse studies completed before the marketing application
“Danicopan was not carcinogenic at any dose assessed in WH rats and hemizygous TgRasH2 mice.”
Safety marginopen answer page →
Safety margin at NOAEL
Dog 39-week NOAEL: 5x the AUC at the MRHD (200 mg TID)
“At the NOAEL, the sex-averaged exposure (50 μg.hr/mL, AUC0-24, Day 273) represents a 5x exposure multiple of the exposure at the MRHD (200 mg (TID), 10.5 μg.hr/mL AUC0-24hr).”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Ex vivo alternative-pathway inhibition (80-90%) in serum of orally dosed cynomolgus monkeys
“In serum derived from cynomolgus monkeys administered single oral or multiple oral doses of danicopan, an ex vivo analysis revealed that significant (80% to 90%, at concentrations greater than or equal to 258nM) and concentration-dependent inhibition of AP activity was achieved in monkeys.”
Why that model
No cross-reactivity with rodents; monkey, dog and rabbit selected as nonclinical efficacy species
“Based on the pharmacology data (and the lack of cross reactivity to rodent species), the cynomolgus monkey, beagle dog, and New Zealand white (NZW) rabbit were selected as the nonclinical efficacy species.”
Reviewer's view of the efficacy data
EMA: inter- and intra-species variability in AP activity adds uncertainty to interpreting the pharmacology data
“The significant variability noted inter- and intra-species was attributed to the intrinsic AP activity for each individual. This aspect should be considered for the interpretation of the pharmacological data, considering the potential uncertainty when results are interpreted.”
Flexibilityopen answer page →
Flexibility accepted
SpeciesVerdict not stated
Rat (pharmacologically inactive) used only for off-target toxicity; DART conducted in rabbit, a pharmacologically active species
Why: Danicopan not pharmacologically active in rats · No relevant species
“Rabbit species was selected for DART studies, based on the absence of pharmacological activity of rats.”
CarcinogenicityVerdict not stated
Carcinogenicity assessed only in rodents (rasH2 mouse, rat), species not pharmacologically relevant for danicopan
“Both studies were concluded as negative, although rodent species are not considered pharmacologically relevant for danicopan.”
Safety marginQuestioned
Applicant's dog 39-week NOAEL (75 mg/kg/day) disputed: bile duct hypertrophy/hyperplasia at that dose considered damage
“The Applicant argued that the isolated biliary findings at 75 mg/kg/day in the absence of corresponding clinical pathology correlates are not considered adverse and represent the study NOAEL. However, although the findings at this dose were less in severity and magnitude, the damage is clearly observed.”
Juvenile toxVerdict not stated
Only a dose range-finding juvenile study in dogs; no definitive juvenile animal study
“The applicant presented the results of a Dose range finding Juvenile animal studie (DRF JAS) in dogs, although no definitive JAS has been performed.”
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