Ongentys
opicapone
Species
MonkeyRat
Longest study
52 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
“In the subchronic and chronic toxicity studies in rat (up to 6 months) and monkey (up to 52 weeks) and in the carcinogenicity studies in mouse and rat, opicapone was tested at doses up to 1000 mg/kg/day, which was identified as the NOAEL in all three species.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound was tested
“No effects on ECG parameters were reported in cynomolgus monkeys administered BIA 9-1067 at daily oral doses of 100, 300, or 1000 mg/kg for 52 weeks.”
Study lengthopen answer page →
Longest pivotal study
52 (52-week monkey)
“Study title: 52-week oral (gavage) toxicity study in the Cynomolgus monkey with an 8-week recovery period.”
Pivotal GLP studies
Chronic studies in rat (up to 6 months) and monkey (up to 52 weeks)
“In the subchronic and chronic toxicity studies in rat (up to 6 months) and monkey (up to 52 weeks) and in the carcinogenicity studies in mouse and rat, opicapone was tested at doses up to 1000 mg/kg/day, which was identified as the NOAEL in all three species.”
Route in tox
Oral gavage, once daily
“The oral route of administration (gavage) with a once daily regimen was used in the toxicology studies as this is the intended human therapeutic route.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration (human lymphocytes) and mouse micronucleus assays
“Opicapone was negative in a standard battery of genetic toxicology (Ames, in vitro chromosomal aberration in peripheral human lymphocytes, in vivo CD-1 mouse micronucleus) assays.”
Carcinogenicity
Mouse and rat carcinogenicity studies: no drug-related tumors
“No drug-related tumors were observed in mouse or rat.”
Reproductive & developmental
Rat fertility, EFD and PPND: no adverse effects up to 1000 mg/kg/day
“In the reproductive and developmental toxicology studies in rat, opicapone was tested at oral doses up to 1000 mg/kg/day, using standard study designs. No adverse effects on fertility or on embryofetal (EFD) or pre- and postnatal development (PPND) were observed.”
Safety pharmacology
No relevant hERG or Purkinje fiber effects; no ECG, respiratory or behavioral effects in rat and monkey
“BIA 9-1067 had no relevant effects on hERG-mediated currents in HEK cells or on action potential of isolated Purkinje fibers. In vivo administration in rat and monkey resulted in no test-article effects on electrocardiograms, respiratory function, or behavior.”
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 Ongentys 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: 6-month rat NOAEL 500 mg/kg/day; increased bilirubin without histologic change at 1000 mg/kg/day (FDA pharmacology/toxicology review, p. 88)
NOAEL / key findings
6-month rat NOAEL 500 mg/kg/day; increased bilirubin without histologic change at 1000 mg/kg/day
“In the 6-month study in rat, the MD (500 mg/kg/day) was the NOAEL due to increased bilirubin levels (in the absence of histologic changes) at the HD of 1000 mg/kg/day.”
Risksopen answer page →
Immune & cytokine safety
Slight increase in T-helper lymphocytes in rats, with no functional change (sheep RBC response)
“In all dosed groups there was a slight increase in the Thelper (CD3+/CD4+)lymphocyte populations, with no alteration in function or response to sheep RBC’s.”
Biodistribution & persistence
Rat QWBA: highest in liver and kidney; brain below limit of quantification
“the highest tissue levels were found in the liver, kidney cortex, and renal medulla (7163, 4243, and 3806 ng equiv/g, respectively). Concentrations in brain were found to be below the limit of quantification at all time points.”
Modality-specific risk
Embryofetal toxicity: structural (blood vessel and skeletal) abnormalities in rabbit EFD study
“In the EFD study in rabbit (0, 100, 175, and 225 mg/kg/day), increases in structural (blood vessel and skeletal) abnormalities were observed.”