Orladeyo
berotralstat
Species
MonkeyRat
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 monkey
“General toxicity studies included chronic oral toxicity studies in rats and monkeys (treatment durations of up to 26 and 39 weeks, respectively).”
Why that species
Kallikrein inhibition in rat and monkey plasma comparable to human
“monkey and rat plasma with mean EC50s of 5.4, 5.2, and 7.2 nM (Study BR-7353-005-REV-01), supporting the suitability of monkey and rat as the non-clinical species used for toxicology studies.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Cynomolgus monkeys (4/sex/dose) were dosed by oral gavage with 0, 1, 2.5, 7.5, and 20 mg/kg/day berotralstat for 39 weeks.”
Species: general tox
Rat (up to 26 weeks) and monkey (up to 39 weeks)
“General toxicity studies included chronic oral toxicity studies in rats and monkeys (treatment durations of up to 26 and 39 weeks, respectively).”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“The completed package of reproductive and developmental toxicity for BCX7353 includes a fertility and early embryonic development study in male and female rats, embryo-foetal development (EFD) studies in rats and in rabbits, and a pre- and post-natal development study in rats.”
Species: carcinogenicity
Rat (2-year) and Tg.RasH2 mouse (26-week)
“The carcinogenicity potential of berotralstat was evaluated in a 2-year traditional bioassay in rats and a 26-week study in B6F1 Tg.RasH2 mice.”
Surrogate used in
No surrogate used; berotralstat inhibits rat and monkey plasma kallikrein, supporting these species
“Furthermore, BCX7353 was shown to inhibit kallikrein activity ex-vivo, in activated human plasma from healthy human volunteers and in monkey and rat plasma with mean EC50s of 5.4, 5.2, and 7.2 nM (Study BR-7353-005-REV-01), supporting the suitability of monkey and rat as the non-clinical species used for toxicology studies.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month monkey)
“General toxicity studies included chronic oral toxicity studies in rats and monkeys (treatment durations of up to 26 and 39 weeks, respectively).”
Pivotal GLP studies
Up to 26-week rat and 39-week monkey oral studies
“General toxicity studies included chronic oral toxicity studies in rats and monkeys (treatment durations of up to 26 and 39 weeks, respectively).”
Route in tox
Oral gavage
“Cynomolgus monkeys were dosed by oral gavage with 0, 30, 55, and 80 mg/kg/day berotralstat for up to 273 days.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human lymphocyte chromosomal aberration and rat micronucleus assays
“Berotralstat produced negative results in the bacterial reverse gene mutation assay, an in vitro chromosomal aberration assay in human peripheral blood lymphocytes, and an in vivo micronucleus assay in rats.”
Carcinogenicity
2-year rat and 26-week Tg.rasH2 mouse: no evidence of tumorigenicity
“No evidence of tumorigenicity was found in mice or rats. The carcinogenicity potential of berotralstat was evaluated in a 2-year traditional bioassay in rats and a 26-week study in B6F1 Tg.RasH2 mice.”
Reproductive & developmental
Rat fertility, rat and rabbit EFD, rat PPND: not teratogenic; no effect on fertility or PPND
“Berotralstat was nonteratogenic in pregnant rats and rabbits dosed with the drug during the organogenesis period. Berotralstat did not affect the fertility or PPND of rats.”
Safety pharmacology
No CV effects in conscious monkeys at 15 mg/kg; decreased blood pressure and increased RR, PR, QRS and QTc at 50-150 mg/kg
“A single dose of 15 mg/kg BCX7353 had no adverse effects on the cardiovascular system in conscious monkeys (Study 806-135). However, doses of 50 and 150 mg/kg decreased blood pressure (diastolic, systolic and mean) and increased ECG intervals, including RR, PR, QRS and QTc.”
Genotox: Ames
Negative
“Berotralstat produced negative results in the bacterial reverse gene mutation assay, an in vitro chromosomal aberration assay in human peripheral blood lymphocytes, and an in vivo micronucleus assay in rats.”
Genotox: in vitro mammalian
Chromosomal aberration in human peripheral blood lymphocytes: negative
“Berotralstat produced negative results in the bacterial reverse gene mutation assay, an in vitro chromosomal aberration assay in human peripheral blood lymphocytes, and an in vivo micronucleus assay in rats.”
Genotox: in vivo
Rat micronucleus: negative
“Berotralstat produced negative results in the bacterial reverse gene mutation assay, an in vitro chromosomal aberration assay in human peripheral blood lymphocytes, and an in vivo micronucleus assay in rats.”
Carcinogenicity model
2-year rat bioassay; 26-week Tg.RasH2 mouse; no tumorigenicity
“No evidence of tumorigenicity was found in mice or rats. The carcinogenicity potential of berotralstat was evaluated in a 2-year traditional bioassay in rats and a 26-week study in B6F1 Tg.RasH2 mice.”
Carcinogenicity timing
2-year rat bioassay and 26-week Tg.RasH2 mouse study completed and reviewed with the NDA
“No evidence of tumorigenicity was found in mice or rats. The carcinogenicity potential of berotralstat was evaluated in a 2-year traditional bioassay in rats and a 26-week study in B6F1 Tg.RasH2 mice.”
hERG / QT
hERG inhibited in vitro, IC50 0.29 µM
“BCX7353 was shown to inhibit the hERG channel in vitro, with an IC50 of 0.29 μM.”
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 Orladeyo 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: Monkey target organs: kidney, liver, intestine, lung, spleen, lymph nodes and bone marrow (FDA multi-discipline review, p. 36)
NOAEL / key findings
Monkey target organs: kidney, liver, intestine, lung, spleen, lymph nodes and bone marrow
“The target organs of toxicity of berotralstat in monkeys were the kidney, liver, intestine, lung, spleen, lymph nodes, and bone marrow.”
Risksopen answer page →
Immune & cytokine safety
Foamy macrophages/histiocytes in spleen, thymus and intestine (phospholipidosis)
“Phospholipidosis-related findings included vacuoles in the epithelium and mucosa of the intestine, kidney, and choroid plexus (rats); foamy macrophages and histiocytes in the spleen, thymus, and intestine; and foamy Kupffer cells in the liver.”
Biodistribution & persistence
Binds melanin-containing tissues; highest late radioactivity in uveal tract of pigmented rats
“BCX7353 was found to bind to melanin-containing tissues. At 1440 hours post-dose, the highest concentration of radioactivity was quantified in the uveal tract of the eye.”
Modality-specific risk
Phospholipidosis and cardiovascular effects (QT prolongation)
“Toxicity studies indicated that berotralstat can result in phospholipidosis and affect the cardiovascular (CV) system of animals.”
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
- Risk of QTc Interval Prolongation with Higher-Than-Recommended Dosages
Cardiovascular
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 Orladeyo 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: Monkey target organs: kidney, liver, intestine, lung, spleen, lymph nodes and bone marrow (FDA multi-discipline review, p. 36)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month (39-week) cynomolgus monkey oral gavage study with 13-week recovery
“Study Title/Number: A 9-Month Study of BCX7353 by Oral Gavage in the Cynomolgus Monkey with a 13-Week Recovery Period (#806-162)”
Pivotal GLP studies
Up to 26-week rat and 39-week monkey oral studies
“General toxicity studies included chronic oral toxicity studies in rats and monkeys (treatment durations of up to 26 and 39 weeks, respectively).”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“The completed package of reproductive and developmental toxicity for BCX7353 includes a fertility and early embryonic development study in male and female rats, embryo-foetal development (EFD) studies in rats and in rabbits, and a pre- and post-natal development study in rats.”
Reproductive & developmental
Rat fertility, rat and rabbit EFD, rat PPND: not teratogenic; no effect on fertility or PPND
“Berotralstat was nonteratogenic in pregnant rats and rabbits dosed with the drug during the organogenesis period. Berotralstat did not affect the fertility or PPND of rats.”
PPND / ePPND: when
PPND in rat completed and reviewed with the NDA; no effect on PPND
“Berotralstat was nonteratogenic in pregnant rats and rabbits dosed with the drug during the organogenesis period. Berotralstat did not affect the fertility or PPND of rats.”
Carcinogenicity
Species: carcinogenicity
Rat (2-year) and Tg.RasH2 mouse (26-week)
“The carcinogenicity potential of berotralstat was evaluated in a 2-year traditional bioassay in rats and a 26-week study in B6F1 Tg.RasH2 mice.”
Carcinogenicity model
2-year rat bioassay; 26-week Tg.RasH2 mouse; no tumorigenicity
“No evidence of tumorigenicity was found in mice or rats. The carcinogenicity potential of berotralstat was evaluated in a 2-year traditional bioassay in rats and a 26-week study in B6F1 Tg.RasH2 mice.”
Carcinogenicity timing
2-year rat bioassay and 26-week Tg.RasH2 mouse study completed and reviewed with the NDA
“No evidence of tumorigenicity was found in mice or rats. The carcinogenicity potential of berotralstat was evaluated in a 2-year traditional bioassay in rats and a 26-week study in B6F1 Tg.RasH2 mice.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey chronic NOAEL (30 mg/kg/day) ~1.5x human AUC at 150 mg QD
“30 mg/kg/day. At this NOAEL, the AUC0-24 was 3950 ng.h/mL, which represents a narrow safety margins of 1.5, over the exposure in humans receiving daily 150 mg doses of BCX7353.”
NOAEL / key findings
Monkey target organs: kidney, liver, intestine, lung, spleen, lymph nodes and bone marrow
“The target organs of toxicity of berotralstat in monkeys were the kidney, liver, intestine, lung, spleen, lymph nodes, and bone marrow.”
Efficacy evidenceopen answer page →
Efficacy evidence
Ex vivo kallikrein inhibition in plasma from HAE patients
“Finally, BCX7353 was shown to inhibit kallikrein activity ex-vivo from subjects with HAE, with a range of EC50s slightly higher than in normal human plasma, ranging from 11.7 to 20.0 nM, and a mean EC50 of 15.9 ± 0.57 nM (Study BR-7353-006-REV-01).”
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
EMA: limited in vitro package without in vivo studies accepted as sufficient proof of concept
“A limited primary pharmacodynamics package was presented and no in vivo studies were included, but the scientific rationale for inhibiting plasma kallikrein activity in the treatment of in HAE is accepted, and the in vitro proof of concept data are considered sufficient non-clinical data to support the use of BCX7353 in HAE.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginCriticised but acceptedBeyond the letter
Narrow NOAEL exposure margins in chronic studies: 3.8 in rat and 1.5 in monkey
Why: Margins considered acceptable to support 150 mg once daily, despite decreased survival in the rat carcinogenicity study
“Hence, the safety margin based on exposures at the NOAELs in the chronic toxicity studies in rat (20mg/kg/day) and monkey (30mg/kg/day) is 3.8 and 1.5 respectively.”
“While these safety margins could be considered acceptable to support berotralstat 150 mg once daily (QD) administered to humans, BCX-7353-related decreased survival was noted in WH rats administered 20mg/kg/day in the 104-week carcinogenicity study”
DARTQuestioned
Rabbit embryo-fetal studies of limited value: low exposure and inadequate pharmacological activity in rabbits
“However, considering the inadequate pharmacological activity in rabbits, these data are considered insufficient evidence of lack of toxicity in non-rodent species and the rabbit data will not be included in the SmPC.”
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