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.”
Species: general tox
Rat (26-week), hamster (13-week) and monkey (44-week)
“The Sponsor conducted oral toxicology studies up to 26 weeks in rats, 13 weeks in hamsters, and 44 weeks in monkeys.”
Species: DART
Hamster (fertility, EFD) and rabbit (EFD)
“Fertility and reproductive performance were unaffected in a fertility and early embryonic development study with male and female hamsters that received oral doses of CCX168 up to 1000 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.”
Species: carcinogenicity
Sprague-Dawley rat and Syrian hamster (2-year)
“Two-year carcinogenicity studies in Sprague-Dawley rats and Syrian hamsters were conducted to assess the carcinogenic potential of avacopan.”
Surrogate used in
Transgenic human C5aR knock-in mouse used for in vivo pharmacology; no surrogate molecule
“Therefore, a human C5a receptor knock in (hC5aR KI) transgenic mouse strain was generated, where the murine C5aR gene was replaced by the human C5aR gene.”
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.”
Genotox: Ames
Negative
“Avacopan was not mutagenic or clastogenic in the following assays: in vitro bacterial reverse mutation (Ames) test, in vitro mouse lymphoma assay, and in vivo rat micronucleus test.”
Genotox: in vitro mammalian
Mouse lymphoma assay: negative
“Avacopan was not mutagenic or clastogenic in the following assays: in vitro bacterial reverse mutation (Ames) test, in vitro mouse lymphoma assay, and in vivo rat micronucleus test.”
Genotox: in vivo
Rat micronucleus: negative
“Avacopan was not mutagenic or clastogenic in the following assays: in vitro bacterial reverse mutation (Ames) test, in vitro mouse lymphoma assay, and in vivo rat micronucleus test.”
Carcinogenicity model
2-year Sprague-Dawley rat; 2-year Syrian hamster
“Two-year carcinogenicity studies in Sprague-Dawley rats and Syrian hamsters were conducted to assess the carcinogenic potential of avacopan.”
Carcinogenicity timing
2-year rat and hamster studies completed and reviewed under the NDA
“The 2-year carcinogenicity studies in rat and hamster were reviewed under NDA 214487”
hERG / QT
No hERG inhibition up to 6.9 µM; metabolite CCX168-M1 inhibited 38% at 3 µM
“In vitro, CCX168 did not inhibit hERG channel current in HEK293 cells, stably expressing hERG, at concentrations up to 6.9 µM. CCX168-M1 inhibited hERG channel currents by 38% at 3 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 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.”
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 applicable (small molecule)
“Immunogenicity Not applicable”
Label warnings
- Hepatotoxicity
- Hypersensitivity Reactions
- Hepatitis B Virus (HBV) Reactivation
- Serious Infections
HepatotoxicityHypersensitivity & infusion reactionsInfections
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
44-week cynomolgus monkey with 6-week recovery
“Avacopan has been evaluated in repeat-dose toxicity studies in hamsters (up to 13 weeks with 4 weeks recovery), rats (up to 26 weeks with 6 weeks recovery) and monkeys (up to 44 weeks with 6 weeks recovery).”
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.”
DART package
Species: DART
Hamster (fertility, EFD) and rabbit (EFD)
“Fertility and reproductive performance were unaffected in a fertility and early embryonic development study with male and female hamsters that received oral doses of CCX168 up to 1000 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.”
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.”
PPND / ePPND: when
PPND in hamster completed and reviewed in the NDA
“In a pre- and post-natal development study with hamsters, there were no effects of CCX168-treatment of the F0 mothers at doses up to 1000 mg/kg/day on growth, physical, and neurological development as well as reproductive performance of the F1 generation.”
Carcinogenicity
Species: carcinogenicity
Sprague-Dawley rat and Syrian hamster (2-year)
“Two-year carcinogenicity studies in Sprague-Dawley rats and Syrian hamsters were conducted to assess the carcinogenic potential of avacopan.”
Carcinogenicity model
2-year Sprague-Dawley rat; 2-year Syrian hamster
“Two-year carcinogenicity studies in Sprague-Dawley rats and Syrian hamsters were conducted to assess the carcinogenic potential of avacopan.”
Carcinogenicity timing
2-year rat and hamster studies completed and reviewed under the NDA
“The 2-year carcinogenicity studies in rat and hamster were reviewed under NDA 214487”
Safety marginopen answer page →
Safety margin at NOAEL
Pivotal toxicology AUC margins ~4x (hamster, monkey) and ~15x (rat) human AUC at 30 mg b.i.d.
“Exposures of avacopan reached in the pivotal toxicology studies exceeded the expected exposures reached with 30 mg b.i.d. in humans. The AUC exposure margins relative to the human AUC exposure are approximately 4, 15 and 4 in hamsters, rats and monkeys, respectively.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Anti-MPO ANCA glomerulonephritis model in hC5aR knock-in mice
“In the ANCA disease model in hC5aR KI mice, avacopan caused dose-dependent and significant reductions in the incidence of glomerular crescent formation and necrosis relative to vehicle-treated mice”
Why that model
Avacopan has little or no potency at mouse/rat C5aR, so a human C5aR knock-in mouse was generated
“As avacopan retains little, if any, potency for C5aR expressed by mice or rats, the applicant generated a human C5aR knock-in (hC5aR KI) mouse strain in which the mouse C5aR gene was replaced with the human C5aR gene.”
Reviewer's view of the efficacy data
EMA: in vitro and in vivo pharmacology support clinical use; models and dose ranges relevant
“Overall, in vitro and in vivo primary pharmacology data support the intended clinical use. Moreover, the in vivo models and the avacopan dose ranges studied are considered relevant for the clinical situation.”
Flexibilityopen answer page →
Flexibility accepted
Safety pharmacologyAcceptedBeyond the letter
Respiratory, renal, CNS safety pharmacology and TDAR studies done only in rats, a pharmacologically non-relevant species
Why: Standard clinical observations in the chronic monkey study sufficient · Other reason
“The T cell dependent antibody response (TDAR) assay, respiratory, renal, and CNS safety pharmacology studies were conducted in rats, a pharmacologically non-relevant species for CCX168.”
“The Division agreed that these studies are not required and that standard clinical observations in the chronic monkey study would be sufficient to fulfill the safety pharmacology study requirements.”
OtherCriticised but acceptedBeyond the letter
No dose-limiting effects or target organs in chronic studies; maximum feasible doses with only about 4- to 15-fold AUC margins
Why: Maximum feasible doses given dose volume, formulation concentration and tolerability constraints · Pharmacology or kinetics
“No dose-limiting effects or target organ of toxicity were noted in the chronic studies and therefore, the toxicology of avacopan is not considered fully explored. However, the maximum dose levels employed were the maximum feasible dose levels based on dose volume and formulation concentration constraints, and/or formulation tolerability.”
“The AUC exposure margins relative to the human AUC exposure are approximately 4, 15 and 4 in hamsters, rats and monkeys, respectively.”
SpeciesAcceptedBeyond the letter
Hamster used as the main rodent species for general, reproductive and carcinogenicity studies
Why: Justified by pharmacology and pharmacokinetic data · Pharmacology or kinetics
“The selection of the main toxicology species, hamster and Cynomolgus monkeys is justified based on pharmacology and pharmacokinetic data.”
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