Tavneos
avacopan
Species
MonkeyRat
Longest study
44 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Hamster, rat and cynomolgus monkey
“The Sponsor conducted oral toxicology studies up to 26 weeks in rats, 13 weeks in hamsters, and 44 weeks in monkeys.”
Why that species
Hamster and monkey pharmacologically relevant (on- and off-target toxicity); rat not pharmacologically relevant, off-target toxicity only
“The hamster and monkey were pharmacologically relevant species and could assess both potential on-target and off-target toxicity. However, the rat was not a pharmacologically relevant and could only assess potential off-target toxicity.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the 13-week toxicology study in hamster, CCX168 was administered at doses of 0 (vehicle), 10, 30, 100 and 1000 (500 mg/kg BID) mg/kg/day.”
Study lengthopen answer page →
Longest pivotal study
44 (44-week monkey)
“The Sponsor conducted oral toxicology studies up to 26 weeks in rats, 13 weeks in hamsters, and 44 weeks in monkeys.”
Pivotal GLP studies
13-week hamster, 26-week rat and 44-week cynomolgus monkey oral studies
“The Sponsor conducted oral toxicology studies up to 26 weeks in rats, 13 weeks in hamsters, and 44 weeks in monkeys.”
Route in tox
Oral (gavage; nasogastric intubation in monkeys weeks 1-5)
“administered by nasogastric intubation (Weeks 1-5). Starting at Week 6, the route of administration was switched to oral gavage (Weeks 6-44).”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, mouse lymphoma and in vivo rat bone marrow micronucleus assays
“Avacopan was negative in all assays including the in vitro bacterial mutagenicity study (Ames test), in vitro mouse lymphoma forward-mutation assay, and in vivo rat bone marrow micronucleus study.”
Carcinogenicity
2-year rat and hamster: no tumorigenic potential up to 100 mg/kg/day (~3x and ~6x MRHD AUC)
“Two-year carcinogenicity studies in Sprague-Dawley rats and Syrian hamsters were conducted to assess the carcinogenic potential of avacopan. Avacopan demonstrated no tumorigenic potential in a study with rats that received oral doses up to 100 mg/kg/day (approximately 3 times the MRHD in adults on an AUC basis) and a study in hamsters that received oral doses up to 100 mg/kg/day (approximately 6 times the MRHD in adults on an AUC basis).”
Reproductive & developmental
Hamster and rabbit EFD: no fetal harm or malformations up to 1000 and 200 mg/kg/day
“In embryofetal development studies with hamsters and rabbits, no fetal harm or malformations were observed with oral doses of CCX168 up 1000 and 200 mg/kg/day.”
Safety pharmacology
Monkey telemetry: no blood pressure or ECG (incl. QTc) effects up to 50 mg/kg
“In the telemetry study in conscious monkeys, there were no effects on cardiovascular (blood pressure) and electrocardiographic parameters (P, PR, QRS, QT and QTc intervals, and R amplitude) following single oral doses up to 50 mg/kg, the highest dose tested.”
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 Tavneos 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: No dose-limiting toxicity or target organs identified; NOAEL was the high dose (FDA multi-discipline review, p. 383)
NOAEL / key findings
No dose-limiting toxicity or target organs identified; NOAEL was the high dose
“No dose-limiting toxicity or target organs of toxicity were identified. The NOAEL was considered as the high dose.”
Risksopen answer page →
Immune & cytokine safety
No effect on monkey TDAR, peripheral immunophenotyping or lymphoid organ histology
“In monkeys, avacopan had no effect on T-cell dependent antibody responses or on relative or absolute values for peripheral blood immunophenotyping (total T lymphocytes, helper T lymphocytes, cytotoxic T lymphocytes, B lymphocytes, or natural killer cells).”
Biodistribution & persistence
Rat QWBA: slowly reversible association with melanin-containing tissues of the eye
“Distribution trends in the pigmented uveal tract suggested that [14C]-avacopan-related radioactivity associated with the melanin-containing tissues of the eye; this association was slowly reversible.”
Modality-specific risk
Low AUC exposure margins (~4-fold in hamster and monkey, 15-fold in rat)
“The AUC exposure margins relative to the human AUC exposure are approximately 4, 15 and 4 in hamsters, rats and monkeys, respectively.”