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.”
Species: general tox
Rat (up to 6 months) and cynomolgus 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.”
Species: DART
Rat and rabbit (embryo-fetal development; no teratogenicity)
“Definitive developmental and embryo-fetal toxicity studies were completed in female rats and rabbits. There was no evidence of teratogenicity in either species, at any dose level.”
Species: carcinogenicity
Wistar rat and CD-1 mouse (104-week)
“Lifetime (104-week) bioassays of BIA 9-1067 were conducted in Wistar Han rats and CD-1 mice.”
Surrogate used in
No surrogate used
“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.”
Genotox: Ames
Negative (opicapone and metabolite BIA 9-1079)
“BIA 9-1067 and metabolite BIA 9-1079 were negative in genetic toxicology (Ames, in vitro chromosomal aberration in human peripheral blood lymphocytes, and in vivo mouse micronucleus) studies.”
Genotox: in vitro mammalian
Human peripheral blood lymphocyte chromosomal aberration: negative
“BIA 9-1067 and metabolite BIA 9-1079 were negative in genetic toxicology (Ames, in vitro chromosomal aberration in human peripheral blood lymphocytes, and in vivo mouse micronucleus) studies.”
Genotox: in vivo
Mouse micronucleus: negative
“BIA 9-1067 and metabolite BIA 9-1079 were negative in genetic toxicology (Ames, in vitro chromosomal aberration in human peripheral blood lymphocytes, and in vivo mouse micronucleus) studies.”
Carcinogenicity model
104-week Wistar Han rat and CD-1 mouse: no drug-related neoplasms
“Sufficient numbers of animals survived through 104 weeks in both studies, and there were no drug-related neoplasms in either study. Under the conditions of these studies, BIA 9-1067 was found to be non-carcinogenic.”
Carcinogenicity timing
Mouse and rat long-term carcinogenicity studies completed before the marketing application
“Two long term carcinogenicity studies have been completed with Opicapone. Mice were dosed with oral opicapone at 100, 500/375 and 1000/500 mg/kg/day and rats were dosed with 100, 500 and 1000 mg/kg/day).”
hERG / QT
No relevant effect on hERG currents or Purkinje fiber action potential up to 10 µM
“At concentrations up to 10 µM BIA 9-1067 had no relevant effects on hERG-mediated currents in HEK cells or on action potential of isolated Purkinje fibers.”
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.”
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
- Cardiovascular Effects with Concomitant Use of Drugs Metabol ized by Catechol-O-Methyltransferase (COMT)
- Falling Asleep During Activities of Daily Living and Somnolence
- Hypotension/Syncope
- Dyskinesia
- Hallucinations and Psychosis
- Impulse Control / Compulsive Disorders
- Withdrawal- E mergent Hyperpyrexia and Confusion
CardiovascularSkin 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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
52-week cynomolgus monkey oral (gavage) GLP study with 8-week recovery
“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.”
DART package
Species: DART
Rat and rabbit (embryo-fetal development; no teratogenicity)
“Definitive developmental and embryo-fetal toxicity studies were completed in female rats and rabbits. There was no evidence of teratogenicity in either species, at any dose level.”
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.”
PPND / ePPND: when
PPND in rat completed and reviewed with the marketing application; no adverse effects
“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.”
Carcinogenicity
Species: carcinogenicity
Wistar rat and CD-1 mouse (104-week)
“Lifetime (104-week) bioassays of BIA 9-1067 were conducted in Wistar Han rats and CD-1 mice.”
Carcinogenicity model
104-week Wistar Han rat and CD-1 mouse: no drug-related neoplasms
“Sufficient numbers of animals survived through 104 weeks in both studies, and there were no drug-related neoplasms in either study. Under the conditions of these studies, BIA 9-1067 was found to be non-carcinogenic.”
Carcinogenicity timing
Mouse and rat long-term carcinogenicity studies completed before the marketing application
“Two long term carcinogenicity studies have been completed with Opicapone. Mice were dosed with oral opicapone at 100, 500/375 and 1000/500 mg/kg/day and rats were dosed with 100, 500 and 1000 mg/kg/day).”
Safety marginopen answer page →
Safety margin at NOAEL
6-month rat NOAEL ≥21x human AUC at MRHD; 28-day studies ≥7x
“Exposure (AUC) at the NOAEL in 28-day studies and the MTD in rabbit exceeded exposures at the MRHD by not less than 7-fold and in the 6-month rat study by not less than 21-fold.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
MPTP-lesioned cynomolgus monkeys: augmented L-DOPA/benserazide effects on motor activity
“In MPTP-lesioned cynomolgus monkeys with stable Parkinsonian-like symptoms, BIA 9-1067 was found to augment the effects of L-DOPA/benserazide (a DDI) on motor activity.”
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
FDA: in primate PD model, beneficial only with levodopa/benserazide, no effect alone
“In a primate model of Parkinson’s disease, BIA 9-1067 alone did not affect Parkinson-like behavior but, when administered with levodopa and benserazide, BIA 9-1067 had a beneficial effect when compared to levodopa/benserazide alone.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginCriticised but acceptedBeyond the letter
Rabbit embryofetal study: no exposure margin for maternal or developmental toxicity (<1 to 1 times human AUC)
Why: Adjunct only to levodopa preparations restricted in pregnancy, or for women without childbearing potential · Other reason
“In pregnant rabbits maternal toxicity was evident already at exposure levels far below the human exposure at the recommended daily dose of 50 mg (AUC), while embryo-fetal development was not negatively influenced up to an AUC in the range of the human exposure, resulting in no safety margin either for the does (<1 time) or for the offspring (<1 to 1 time).”
“Due to the fact that opicapone is indicated as adjunctive therapy only to preparations of levodopa/benserazide or levodopa/carbidopa, all products with restricted use during pregnancy (“should not be used during pregnancy without using contraception measures”), or in female patients without childbearing potential, the deficiency of the rabbit study was agreed to be of minor concern and the issue was considered resolved.”
DARTCriticised but acceptedBeyond the letter
Rat PPND study did not assess neurobehavioral development with a complex learning and memory task
“In the PPND study, effects on neurobehavioral development were not assessed using a complex learning and memory task, such as the Biel or Cincinnati water maze, and were, therefore, marginally acceptable.”
DARTAccepted with a conditionBeyond the letter
No embryofetal study of opicapone combined with levodopa/carbidopa; known levodopa/carbidopa teratogenicity addressed in labeling
Why: Levodopa/carbidopa teratogenicity already known · Class precedent
“Adverse development effects of opicapone given in combination with levodopa/carbidopa (LD/CD) were not assessed; however, LD/CD is known to cause visceral and skeletal malformations in rabbits. This information should be included in labeling because opicapone is to be indicated as an adjunct to LD/CD.”
Juvenile toxAcceptedBeyond the letter
No juvenile, local tolerance, immunotoxicity or dependence studies
“No juvenile, local tolerance, immunotoxicology or dependence studies have been conducted with Opicapone. The absence of these studies has been adequately justified.”
Impurity or metaboliteAcceptedBeyond the letter
Major human metabolite BIA 9-1103 not measured in rodent toxicity studies; exposure extrapolated from other toxicokinetic studies
Why: Rat exposure gives adequate margin of safety over expected human metabolite AUC; mouse exposure on the low side · Pharmacology or kinetics
“Although no sampling of BIA 9-1103 was undertaken, the applicant has sought to address this by extrapolating the expected level of BIA 9-1103 in mice and rats using metabolite exposures observed in other completed TK studies.”
“Relative exposures in mice look on the low side (AUC0-t of 2.81 μg•h/mL at 1000 mg/kg in single dose study), however in the rat (AUC0-t of 35.3 to 182 μg•h/mL ) this has a adequate margin of safety compared to the expected human AUC0-t of 4.00 μg•h/mL. In the end, the toxicological cover for the major human metabolite can be accepted.”
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