Fotivda
tivozanib
Species
MonkeyRat
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and cynomolgus monkey
“The selection of animal models to be used in toxicology and safety pharmacology studies (rats and monkeys) was based on PK and/or metabolic profiles of tivozanib.”
Why that species
Metabolic profile: monkey liver microsomal metabolism most similar to human, followed by rat
“Comparison of the metabolic profile of tivozanib in liver microsomes showed that monkey most closely resembled the human, followed by the rat. These data provided support for species selection.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Oral administration of tivozanib in rats for 26 weeks produced non-adverse decreases in body weights, abnormal whitening of the teeth and changes in hematology/clinical chemistry at 0.08 mg/kg/day.”
Species: general tox
Rat (up to 26 weeks) and cynomolgus monkey (up to 39 weeks)
“Single-oral and intravenous (IV) dose toxicity studies in CD-1 mice and Sprague-Dawley (SD) rats were conducted followed by oral repeat-dose studies in SD rats (up to 26 weeks) and cynomolgus monkeys (up to 39 weeks).”
Species: DART
Rat and rabbit (embryo-fetal development)
“Tivozanib was shown to be teratogenic, embryotoxic and foetotoxic in pregnant rats at dose levels 5 times lower than the recommended clinical dose (based on a 60 kg human). Studies in pregnant rabbits showed no effect on maternal health or embryo foetal development at doses approximately 0.6 times the human exposure at the recommended dose”
Species: carcinogenicity
Not conducted
“Carcinogenicity studies have not been conducted with tivozanib.”
Surrogate used in
No surrogate used; rats and monkeys selected on tivozanib PK/metabolic profiles
“The selection of animal models to be used in toxicology and safety pharmacology studies (rats and monkeys) was based on PK and/or metabolic profiles of tivozanib.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week monkey)
“In a 39-week oral toxicity study in monkeys, the highest dose tested 0.1 mg/kg/day (HED=1.95 g/day; 1. 5-fold of the recommended human dose) was well tolerated.”
Pivotal GLP studies
Up to 26-week rat and 39-week cynomolgus monkey oral studies
“Single-oral and intravenous (IV) dose toxicity studies in CD-1 mice and Sprague-Dawley (SD) rats were conducted followed by oral repeat-dose studies in SD rats (up to 26 weeks) and cynomolgus monkeys (up to 39 weeks).”
Route in tox
Oral
“The oral route was utilized in nonclinical studies as this is the intended clinical route of exposure.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro CHO cytogenetic and in vivo mouse bone marrow micronucleus assays
“Tivozanib was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro cytogenetic assay in Chinese hamster ovary cells or in an in vivo mouse bone marrow micronucleus assay.”
Carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“As it is intended for advanced Renal Cell Carcinoma, in accordance with ICH S9 Nonclinical Evaluation for Anticancer Pharmaceuticals, carcinogenicity studies are not required.”
Reproductive & developmental
Rat fertility: increased epididymis/testis weights at ≥0.03 mg/kg/day; reduced mating and infertility at ≥0.3 mg/kg/day
“In animal studies assessing mating and fertility parameters, oral doses ≥ 0.03 mg/kg/day (0.2 times the maximum recommended clinical dose on a mg/m 2 basis) in rats were associated with increased epididymis and testis weights, and doses ≥ 0.3 mg/kg/day (2 times the maximum recommended clinical dose on a mg/m 2 basis) reduced mating and produced infertility.”
Safety pharmacology
Telemetered monkeys: increased blood pressure at 3 mg/kg; no effects on heart rate, QT/QTc or QRS
“A dose of 3 mg/kg resulted in increases in systolic, diastolic and mean arterial blood pressure 90 minutes post-dose. There were no test article-related effects on heart rates, RR, PR, QT, QTcF, QTcQ intervals and the QRS duration at any dose level.”
Genotox: Ames
Negative
“Tivozanib was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro cytogenetic assay in Chinese hamster ovary cells or in an in vivo mouse bone marrow micronucleus assay.”
Genotox: in vitro mammalian
CHO chromosomal aberration assay unreliable (cytotoxic); abnormal division with hyperdiploid cells
“An in Vitro Chromosomal Aberration Assay in CHO Cells (Study RCK0002) was considered unreliable as the test material was very toxic to the cells in this treatment, and it appears that it may have caused cells to undergo abnormal cell division leading to diploid cells and hyperdiploid cells (cells with greater than the normal diploid count but not polyploidy).”
Genotox: in vivo
Negative: in vivo mouse bone marrow micronucleus
“Tivozanib was not mutagenic in a bacterial reverse mutation (Ames) assay and was not clastogenic in an in vitro cytogenetic assay in Chinese hamster ovary cells or in an in vivo mouse bone marrow micronucleus assay.”
Carcinogenicity model
Not conducted (advanced RCC, ICH S9)
“As it is intended for advanced Renal Cell Carcinoma, in accordance with ICH S9 Nonclinical Evaluation for Anticancer Pharmaceuticals, carcinogenicity studies are not required.”
Carcinogenicity timing
Not required for advanced renal cell carcinoma per ICH S9
“As it is intended for advanced Renal Cell Carcinoma, in accordance with ICH S9 Nonclinical Evaluation for Anticancer Pharmaceuticals, carcinogenicity studies are not required.”
hERG / QT
No hERG inhibition in vitro; no QT/QTc changes in monkey repeat-dose studies
“The lack of QT and QTc changes are consistent with findings in the in vitro study indicating that tivozanib hydrochloride does not inhibit the hERG channel.”
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 Fotivda 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 oncology small molecules (ICH S9)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Rat and monkey targets: adrenal, GI (stomach, duodenum, pancreas), kidney, bone, liver, brain, pituitary, heart, incisors, ovaries/uterus (FDA multi-discipline review, p. 29)
NOAEL / key findings
Rat and monkey targets: adrenal, GI (stomach, duodenum, pancreas), kidney, bone, liver, brain, pituitary, heart, incisors, ovaries/uterus
“The predominant toxicities in both species were associated with the following systems/organs: adrenal gland, gastrointestinal system (stomach, duodenum, and pancreas), kidney, bone (femur and tibia), liver, brain, pituitary gland, heart, incisors and reproductive system (ovaries and uterus).”
Risksopen answer page →
Immune & cytokine safety
Lymphoid depletion of thymus, lymph nodes and spleen
“gastric system (stomach, duodenum and pancreas), reproductive system (ovary and corpora lutea) and lymphoid organs (lymphoid depletion of thymus, lymph nodes and spleen).”
Biodistribution & persistence
Melanin binding to choroid of eye in pigmented rats, declining over 120 hours
“In pigmented rats, melanin binding to the choroid layer of the eye was apparent and levels decreased steadily over 120 hours post-dose.”
Modality-specific risk
Embryo-fetal toxicity: malformations and embryo-fetal death below clinical dose
“In embryo-fetal developmental studies, oral administration of tivozanib to pregnant animals during the period of organogenesis caused maternal toxicity, fetal malformations and embryo- fetal death at doses below the maximum recommended clinical dose on a mg/m 2 basis [see DATA ] .”
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
- Hypertension and Hypertensive Crisis
- Cardiac Failure
- Cardiac Ischemia and Arterial Thromboembolic Events
- Venous Thromboembolic Events
- Hemorrhagic Events
- Proteinuria
- Gastrointestinal Perforation and Fistula Formation
- Thyroid Dysfunction
- Risk of Impaired Wound Healing
- Reversible Posterior Leukoencephalopathy Syndrome
- Embryo-Fetal Toxicity
- Allergic Reactions to Tartrazine (FD&C Yellow No.5)
CardiovascularThrombosis & embolismBleedingNephrotoxicityGastrointestinalMetabolic & endocrineInfectionsNeurotoxicityEmbryo-fetal toxicityHypersensitivity & infusion 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 Fotivda 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 oncology small molecules (ICH S9)
HNSTD/STD10 is the method used for anticancer drugs in patients: the start dose is one-sixth of the highest non-severely toxic dose (HNSTD) in non-rodents, or one-tenth of the dose severely toxic to 10% of rodents (STD10), scaled by body surface area. The aim is a dose that is pharmacologically active yet reasonably safe.
“A common approach for many small molecules is to set a start dose at 1/10 the Severely Toxic Dose in 10% of the animals (STD 10) in rodents. If the non-rodent is the most appropriate species, then 1/6 the Highest Non-Severely Toxic Dose (HNSTD) is considered an appropriate starting dose.”
This product's starting point
NOAEL / key findings: Rat and monkey targets: adrenal, GI (stomach, duodenum, pancreas), kidney, bone, liver, brain, pituitary, heart, incisors, ovaries/uterus (FDA multi-discipline review, p. 29)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week oral cynomolgus monkey study with 6-week recovery; well tolerated at all doses
“In a 39-Week Oral Toxicity Study (1458-006) in Cynomolgus Monkeys With a 6-Week Recovery tivozanib hydrochloride was well tolerated when administered daily to both male and female cynomolgus monkeys at all dose levels evaluated.”
Pivotal GLP studies
Up to 26-week rat and 39-week cynomolgus monkey oral studies
“Single-oral and intravenous (IV) dose toxicity studies in CD-1 mice and Sprague-Dawley (SD) rats were conducted followed by oral repeat-dose studies in SD rats (up to 26 weeks) and cynomolgus monkeys (up to 39 weeks).”
DART package
Species: DART
Rat and rabbit (embryo-fetal development)
“Tivozanib was shown to be teratogenic, embryotoxic and foetotoxic in pregnant rats at dose levels 5 times lower than the recommended clinical dose (based on a 60 kg human). Studies in pregnant rabbits showed no effect on maternal health or embryo foetal development at doses approximately 0.6 times the human exposure at the recommended dose”
Reproductive & developmental
Rat fertility: increased epididymis/testis weights at ≥0.03 mg/kg/day; reduced mating and infertility at ≥0.3 mg/kg/day
“In animal studies assessing mating and fertility parameters, oral doses ≥ 0.03 mg/kg/day (0.2 times the maximum recommended clinical dose on a mg/m 2 basis) in rats were associated with increased epididymis and testis weights, and doses ≥ 0.3 mg/kg/day (2 times the maximum recommended clinical dose on a mg/m 2 basis) reduced mating and produced infertility.”
PPND / ePPND: when
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.
Carcinogenicity
Species: carcinogenicity
Not conducted
“Carcinogenicity studies have not been conducted with tivozanib.”
Carcinogenicity model
Not conducted (advanced RCC, ICH S9)
“As it is intended for advanced Renal Cell Carcinoma, in accordance with ICH S9 Nonclinical Evaluation for Anticancer Pharmaceuticals, carcinogenicity studies are not required.”
Carcinogenicity timing
Not required for advanced renal cell carcinoma per ICH S9
“As it is intended for advanced Renal Cell Carcinoma, in accordance with ICH S9 Nonclinical Evaluation for Anticancer Pharmaceuticals, carcinogenicity studies are not required.”
Safety marginopen answer page →
Safety margin at NOAEL
9-month monkey NOAEL ~0.5-fold RCC patient exposure; 6-month rat NOAEL ~2-fold
“This exposure corresponds approximately to an exposure in humans that is 2-fold below the exposure obtain at the NOAEL in the 6-month rat study and is greater than the exposure observed at the NOAEL in the 9-month monkey study (the exposure in monkeys was approximately 0.5-fold that of RCC patients).”
NOAEL / key findings
Rat and monkey targets: adrenal, GI (stomach, duodenum, pancreas), kidney, bone, liver, brain, pituitary, heart, incisors, ovaries/uterus
“The predominant toxicities in both species were associated with the following systems/organs: adrenal gland, gastrointestinal system (stomach, duodenum, and pancreas), kidney, bone (femur and tibia), liver, brain, pituitary gland, heart, incisors and reproductive system (ovaries and uterus).”
Efficacy evidenceopen answer page →
Efficacy evidence
Human and murine tumor xenografts in mice and rats (tumor growth inhibition, anti-angiogenesis)
“In vivo pharmacodynamic studies in mice and rats bearing human or murine xenograft tumors demonstrated that tivozanib inhibited tumor growth at a dose of 0.2 mg/kg in rats, via inhibition of angiogenesis and vascular permeability.”
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: potent, selective VEGF-pathway inhibitor with strong anti-tumour activity across tumour types
“Primary pharmacology studies conducted at both molecular and cellular levels and in tumour models have demonstrated that tivozanib hydrochloride is a potent and highly selective inhibitor of the VEGF pathway that exerts strong anti-tumour activities in a broad spectrum of tumour types by blocking tumour angiogenesis.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
Exposure at the 9-month monkey NOAEL about 0.5-fold that of RCC patients (no margin)
“This exposure corresponds approximately to an exposure in humans that is 2-fold below the exposure obtain at the NOAEL in the 6-month rat study and is greater than the exposure observed at the NOAEL in the 9-month monkey study (the exposure in monkeys was approximately 0.5-fold that of RCC patients).”
OtherAcceptedBeyond the letter
No secondary pharmacodynamic or pharmacodynamic drug interaction studies
Why: High selectivity of tivozanib for the VEGF pathway · Pharmacology or kinetics
“No secondary pharmacodynamic and pharmacodynamic drug interaction studies were performed by the applicant, which is considered acceptable, considering the high level of selectivity of tivozanib hydrochloride for the VEGF pathway.”
Similar precedents
FruzaqlaSmall molecules · fruquintinib · VEGFR1-3Rodent + dog or minipig · 13 wkAugtyroSmall molecules · repotrectinib · ROS1/TRKMonkey + rodent · 13 wkGavretoSmall molecules · pralsetinib · RETMonkey + rodent · 13 wkHyrnuoSmall molecules · sevabertinib · HER2 (mutant)Monkey + rodent · 13 wkIbtroziSmall molecules · taletrectinib · ROS1Monkey + rodent · 12 wkOrgovyxSmall molecules · relugolix · GnRH receptorMonkey + rodent · 39 wk