Fruzaqla
fruquintinib
Species
RatDog
Longest study
13 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 dog
“Overall, the toxicity profile determined in rat and dog in the non-GLP studies (4-week studies and 26 or 39-week studies with an intermediate 13-week analysis) appears affected a larger number of target organs than the one observed in GLP pivotal studies (two 13-week studies).”
Why that species
Metabolite profile: dog metabolites mostly represent human; rat has the same metabolites in a different ratio
“The species comparison suggests that metabolites in dog represent mostly the metabolites in human but that the rat also has same metabolites present, although in a different ratio.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In a 13-week repeat-dose toxicology study in dogs, animals were orally administered fruquintinib at 0, 0.03, 0.06, or 0.12 mg/kg daily with a 4-week recovery period.”
Species: general tox
Rat and dog (13-week GLP pivotal studies)
“Overall, the toxicity profile determined in rat and dog in the non-GLP studies (4-week studies and 26 or 39-week studies with an intermediate 13-week analysis) appears affected a larger number of target organs than the one observed in GLP pivotal studies (two 13-week studies).”
Species: DART
Rat only (3 studies, one GLP)
“The reproductive and development toxicity study program consisted of 3 rat studies, one (8449387) being GLP-compliant.”
Species: carcinogenicity
Not conducted (advanced cancer, ICH S9)
“Carcinogenicity studies were not performed and are not required for pharmaceuticals intended for the treatment of advanced cancer (ICH S9).”
Surrogate used in
No surrogate used; fruquintinib tested directly
“In a 13-week repeat-dose toxicology study in dogs, animals were orally administered fruquintinib at 0, 0.03, 0.06, or 0.12 mg/kg daily with a 4-week recovery period.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week rat and dog GLP studies)
“Given the indication was in the scope of ICH S9 guideline, the two 13-week GLP compliant studies could be considered as the only pivotal studies in the submitted non-clinical package.”
Pivotal GLP studies
Two 13-week GLP pivotal studies in rat and dog; longer earlier studies were non-GLP
“Overall, the toxicity profile determined in rat and dog in the non-GLP studies (4-week studies and 26 or 39-week studies with an intermediate 13-week analysis) appears affected a larger number of target organs than the one observed in GLP pivotal studies (two 13-week studies).”
Route in tox
Oral
“In a 13-week repeat-dose toxicology study in rats, animals were orally administered fruquintinib at 0, 0.3, 0.6, or 1.2 mg/kg daily with a 4-week recovery period.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro CHO chromosome aberration and in vivo rat micronucleus assays
“Fruquintinib was not mutagenic in the in vitro bacterial reverse mutation assay or clastogenic in the in vitro chromosomal aberration assay in Chinese hamster ovary (CHO) cells. The in vivo bone marrow micronucleus assay in rats was negative.”
Carcinogenicity
Not conducted (advanced cancer indication, ICH S9)
“Carcinogenicity studies were not performed and are not required for pharmaceuticals intended for the treatment of advanced cancer (ICH S9).”
Reproductive & developmental
Rat EFD: teratogenicity and embryo lethality at exposures below clinical exposure
“In an embryo-fetal developmental study in pregnant rats, oral administration of fruquintinib during the period of organogenesis resulted in teratogenicity and embryo lethality at exposures below the clinical exposure (see Data ) .”
Safety pharmacology
No significant cardiovascular or respiratory effects in dogs or neurobehavioral effects in rodents
“Fruquintinib did not have a toxicologically significant effect on cardiovascular or respiratory function in dogs or neurobehavioral function in rats.”
Genotox: Ames
Negative (bacterial reverse mutation)
“Fruquintinib was not mutagenic in the in vitro bacterial reverse mutation assay or clastogenic in the in vitro chromosomal aberration assay in Chinese hamster ovary (CHO) cells. The in vivo bone marrow micronucleus assay in rats was negative.”
Genotox: in vitro mammalian
Chromosomal aberration in CHO cells: negative
“Fruquintinib was not mutagenic in the in vitro bacterial reverse mutation assay or clastogenic in the in vitro chromosomal aberration assay in Chinese hamster ovary (CHO) cells. The in vivo bone marrow micronucleus assay in rats was negative.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Fruquintinib was not mutagenic in the in vitro bacterial reverse mutation assay or clastogenic in the in vitro chromosomal aberration assay in Chinese hamster ovary (CHO) cells. The in vivo bone marrow micronucleus assay in rats was negative.”
Carcinogenicity model
Not conducted (advanced cancer, ICH S9)
“Carcinogenicity studies were not performed and are not required for pharmaceuticals intended for the treatment of advanced cancer (ICH S9).”
Carcinogenicity timing
Not conducted; not warranted for the advanced colorectal cancer indication
“Carcinogenicity studies were not warranted to support marketing of fruquintinib for the current indication.”
hERG / QT
No hERG inhibition: IC50 >13.08 μM, >380-fold unbound human Cmax
“Fruquintinib did not inhibit hERG channels, resulting in an IC50 value of >13.08 μM, based on the actual concentrations. IC50 for M11 was > 6.05 µM. These IC50 values are more than 380- and 1000-fold greater than the unbound human steady-state Cmax at the proposed therapeutic dose of 5 mg daily of fruquintinib”
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 Fruzaqla 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: Target organs: liver, kidney, adrenal gland, thymus, spleen, bone marrow and femur (EMA assessment report, p. 40)
NOAEL / key findings
Target organs: liver, kidney, adrenal gland, thymus, spleen, bone marrow and femur
“The identified target organs of fruquintinib toxicity were liver, kidney, adrenal gland, thymus, spleen, bone marrow (sternum), and femur.”
Risksopen answer page →
Immune & cytokine safety
Immune system (thymus, spleen, lymph nodes) a target organ in dog studies
“The non-GLP dog studies identified liver, kidney, GI-tract, adrenal gland, and immune system (thymus and spleen, and lymph nodes in the 39-week study) as target organs.”
Biodistribution & persistence
Wide distribution; highest in GI tract, bladder, uveal tract and pigmented skin (melanin)
“Following a single oral dose of radiolabeled fruquintinib, wide distribution of fruquintinib was observed with the highest radioactivity observed in the esophagus, large intestine, small intestine, stomach, bladder, uveal tract, and pigmented skin.”
Modality-specific risk
Low exposure margins: 13-week rat and dog NOAEL AUC ratios 0.3 and 0.05
“The safety margins (total AUC ratio) derived from the GLP-compliant 13-week rat and dog study NOAELs are 0.3 and 0.05, 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
Label warnings
- Hypertension
- Hemorrhagic Events
- Infections
- Gastrointestinal Perforation
- Hepatotoxicity
- Proteinuria
- Palmar-Plantar Erythrodysesthesia (PPE)
- Posterior Reversible Encephalopathy Syndrome (PRES)
- Impaired Wound Healing
- Arterial Thromboembolic Events
- Allergic Reactions to FD&C Yellow No. 5 (Tartrazine) and No. 6 (Sunset Yellow FCF)
- Embryo-Fetal Toxicity
CardiovascularBleedingInfectionsGastrointestinalHepatotoxicityNephrotoxicityNeurotoxicityThrombosis & embolismHypersensitivity & infusion reactionsEmbryo-fetal toxicity
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 Fruzaqla 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: Target organs: liver, kidney, adrenal gland, thymus, spleen, bone marrow and femur (EMA assessment report, p. 40)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week dog (non-GLP), recovery not stated; longest GLP studies 13-week rat and dog
“Three pivotal repeat dose toxicity studies were conducted in Beagle dogs with fruquintinib in National Shanghai Center for New Drug Safety Evaluation and Research (4 and 39-weeks non-GLP, 2009 and 2012) and Covance Pharmaceutical R&D (Shanghai) Co., Ltd (Covance - Shanghai; 13-week GLP study, 2021).”
Pivotal GLP studies
Two 13-week GLP pivotal studies in rat and dog; longer earlier studies were non-GLP
“Overall, the toxicity profile determined in rat and dog in the non-GLP studies (4-week studies and 26 or 39-week studies with an intermediate 13-week analysis) appears affected a larger number of target organs than the one observed in GLP pivotal studies (two 13-week studies).”
DART package
Species: DART
Rat only (3 studies, one GLP)
“The reproductive and development toxicity study program consisted of 3 rat studies, one (8449387) being GLP-compliant.”
Reproductive & developmental
Rat EFD: teratogenicity and embryo lethality at exposures below clinical exposure
“In an embryo-fetal developmental study in pregnant rats, oral administration of fruquintinib during the period of organogenesis resulted in teratogenicity and embryo lethality at exposures below the clinical exposure (see Data ) .”
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 (advanced cancer, ICH S9)
“Carcinogenicity studies were not performed and are not required for pharmaceuticals intended for the treatment of advanced cancer (ICH S9).”
Carcinogenicity model
Not conducted (advanced cancer, ICH S9)
“Carcinogenicity studies were not performed and are not required for pharmaceuticals intended for the treatment of advanced cancer (ICH S9).”
Carcinogenicity timing
Not conducted; not warranted for the advanced colorectal cancer indication
“Carcinogenicity studies were not warranted to support marketing of fruquintinib for the current indication.”
Safety marginopen answer page →
Safety margin at NOAEL
13-week NOAEL AUC margins: rat 0.3x, dog 0.05x human exposure
“The safety margins (total AUC ratio) derived from the GLP-compliant 13-week rat and dog study NOAELs are 0.3 and 0.05, respectively.”
NOAEL / key findings
Target organs: liver, kidney, adrenal gland, thymus, spleen, bone marrow and femur
“The identified target organs of fruquintinib toxicity were liver, kidney, adrenal gland, thymus, spleen, bone marrow (sternum), and femur.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human tumor xenografts in BALB/c nude mice (BGC-823, HT-29, Caki-1, NCI-H460)
“Fruquintinib demonstrated dose-dependent and reproducible tumour growth inhibition for the following human xenograft models in BALB/c nude mice: BGC-823, HT-29, Caki-1, and NCI-H460.”
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
FDA: nonclinical pharmacology and toxicology data adequate to support approval
“The nonclinical pharmacology and toxicology data submitted to this NDA are adequate to support the approval of fruquintinib for the proposed indication.”
Flexibilityopen answer page →
Flexibility accepted
GLPCriticised but accepted
Most single- and repeat-dose studies non-GLP; only two 13-week GLP bridging studies (rat, dog) considered pivotal
Why: Advanced-cancer indication under ICH S9; supportive toxicity profile consistent with marketed anti-VEGFR products · Within the guideline · Class precedent
“All other single- or repeated-dose studies are claimed as non-GLP compliant. Given the indication was in the scope of ICH S9 guideline, the two 13-week GLP compliant studies could be considered as the only pivotal studies in the submitted non-clinical package.”
“However, it is acknowledged that an extended toxicity profile is consistent with those obtained for already marketed anti-VEGFR1, 2 and 3 products, and the use of toxicity profile obtained from the supportive studies therefore is accepted.”
DARTAccepted
Embryo-fetal development studied in rat only (no second species)
Why: Clear malformations and embryo-fetal lethality at low doses in rat (ICH S9) · Within the guideline
“The absence of second species in the embryo-foetal development studies can be accepted as clearly positive results for the induction of malformations and embryo-foetal lethality was demonstrated after administration of low doses of fruquintinib in rat studies (ICH S9).”
Safety marginVerdict not stated
No exposure margin: 13-week NOAEL AUC ratios 0.3 (rat) and 0.05 (dog); EFD 0.02
“The safety margins (total AUC ratio) derived from the GLP-compliant 13-week rat and dog study NOAELs are 0.3 and 0.05, respectively. For the embryo-foetal development, the safety factor derived from the NOEAL is 0.02.”
Safety pharmacologyAcceptedBeyond the letter
CNS and respiratory safety pharmacology studies non-GLP; cardiovascular exposure margins very limited
Why: Large clinical experience addresses uncertainties from limited exposure margins · Human data
“Similarly, the dedicated study to assess respiratory function (0849PH1) was declared as non-GLP compliant; fruquintinib had no effect on respiratory system.”
“Nevertheless, the current clinical experience is sufficient to address the uncertainties raised by the limited margins of exposures and this issue need to be assessed in clinical safety with the current large clinical experience.”
Similar precedents
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