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.”
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.”
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.”