Inrebic
fedratinib
Species
RatDog
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 dog
“Repeat‐dose toxicology studies of up to 6‐month in rats and 9‐month in dogs were conducted.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound was tested
“In the rat study, fedratinib was administered at 0, 3, 10, or 30 mg/kg/day.”
Species: general tox
Rat (up to 6 months) and dog (up to 9 months)
“Repeat‐dose toxicology studies of up to 6‐month in rats and 9‐month in dogs were conducted.”
Species: DART
Rat (fertility, EFD, PPND) and rabbit (EFD)
“Developmental and reproductive toxicology studies in rats and rabbits showed the following: There were no remarkable fedratinib-related effects on fertility and early embryonic development.”
Species: carcinogenicity
Tg rasH2 mouse (6-month); no 2-year rat study
“In a 6-month carcinogenicity study in transgenic Tg.RasH2 mice, there were no neoplasms that were attributed to treatment with fedratinib. No 2-year carcinogenicity study in rats was performed.”
Surrogate used in
No surrogate used; fedratinib tested directly in rats and dogs
“Repeat‐dose toxicology studies of up to 6‐month in rats and 9‐month in dogs were conducted.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog)
“Repeat‐dose toxicology studies of up to 6‐month in rats and 9‐month in dogs were conducted.”
Pivotal GLP studies
6-month rat and 9-month dog repeat-dose studies
“Repeat‐dose toxicology studies of up to 6‐month in rats and 9‐month in dogs were conducted.”
Route in tox
Oral gavage
“A 9‐Month Toxicity Study of TG101348 Administered by Oral Gavage to Dogs”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro CHO chromosomal aberration and rat micronucleus assays
“Fedratinib was not mutagenic in a bacterial reverse mutation (Ames) assay, or clastogenic in an in vitro chromosomal aberration assay in Chinese hamster ovary cells or in vivo in a micronucleus test in rats.”
Carcinogenicity
6-month Tg.rasH2 mouse: no drug-related neoplasms; no 2-year rat study
“In a 6-month carcinogenicity study in transgenic Tg.RasH2 mice, there were no neoplasms that were attributed to treatment with fedratinib. No 2-year carcinogenicity study in rats was performed.”
Reproductive & developmental
Rat fertility: no remarkable effects; rat EFD: maternal toxicity at mid and high doses
“There were no remarkable fedratinib‐related effects in the FEED study. In the EFD study in rats, fedratinib was maternally toxic at the middle and high dose levels with lower gestational body weight gain and decreased gravid uterine weights.”
Safety pharmacology
No significant cardiovascular or respiratory effects in dogs; no clear CNS effects in rats (non-dose-dependent miosis)
“In vivo, fedratinib was not associated with toxicologically significant effects on cardiovascular or respiratory parameters in dogs. There were no clear drug‐related CNS effects in rats; eye miosis and lack of pupillary responses were observed but were non‐dose‐dependent.”
Genotox: Ames
Negative
“Fedratinib was not mutagenic in a bacterial reverse mutation (Ames) assay, or clastogenic in an in vitro chromosomal aberration assay in Chinese hamster ovary cells or in vivo in a micronucleus test in rats.”
Genotox: in vitro mammalian
Negative: chromosomal aberration assay in CHO cells
“Fedratinib was not mutagenic in a bacterial reverse mutation (Ames) assay, or clastogenic in an in vitro chromosomal aberration assay in Chinese hamster ovary cells or in vivo in a micronucleus test in rats.”
Genotox: in vivo
Negative: rat micronucleus test
“Fedratinib was not mutagenic in a bacterial reverse mutation (Ames) assay, or clastogenic in an in vitro chromosomal aberration assay in Chinese hamster ovary cells or in vivo in a micronucleus test in rats.”
Carcinogenicity model
6-month Tg rasH2 mouse (negative); 2-year rat not performed
“In a 6-month carcinogenicity study in transgenic Tg.RasH2 mice, there were no neoplasms that were attributed to treatment with fedratinib. No 2-year carcinogenicity study in rats was performed.”
Carcinogenicity timing
6-month Tg rasH2 mouse completed before the marketing application; 2-year rat not performed (waived)
“In a 6-month carcinogenicity study in transgenic Tg.RasH2 mice, there were no neoplasms that were attributed to treatment with fedratinib. No 2-year carcinogenicity study in rats was performed.”
hERG / QT
Unbound human Cmax (~0.35 µM) below the hERG IC50; dedicated clinical QT study showed no effect
“Therefore, the unbound Cmax in humans of around 0.35 µM is below the IC50 for hERG channel inhibition. Further, a dedicated clinical QT study was performed which showed no effect on the cardiac action potential.”
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 Inrebic 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 targets: bone marrow and liver; also lymphoid tissues, lungs and heart (EMA assessment report, p. 34)
NOAEL / key findings
Rat targets: bone marrow and liver; also lymphoid tissues, lungs and heart
“In rats, the main target organs of toxicity included the bone marrow and liver. Effects were also observed in the lymphoid tissues, lungs and heart.”
Risksopen answer page →
Immune & cytokine safety
Bone marrow hypoplasia and lymphocyte depletion (spleen, thymus, lymph nodes) in all species; immunosuppressive
“In conclusion, fedratinib-related effects on the bone marrow (hypoplasia) and lymphoid tissues (lymphocyte depletion in the spleen, thymus and lymph nodes) in all three species are likely symptoms of exaggerated pharmacology and indicate clear immunosuppressive properties of fedratinib”
Biodistribution & persistence
Whole-body distribution in rats incl. melanin-containing skin and eyes; ocular elimination ~40 days
“Radiolabeled [14C]‐fedratinib was distributed throughout the whole body of the rat, including to the skin and eyes (i.e. melanin‐containing tissues). Elimination from the eyes was approximately 40 days.”
Modality-specific risk
Thiamine transporter (ThTr-1/ThTr-2) inhibition and thiamine levels, assessed in vitro and in rats
“The ability of fedratinib to inhibit human thiamine transporters ThTr‐1 and ThTr‐2 was evaluated using biochemical assays, and to change thiamine levels was assessed in a GLP‐ compliant 28‐day repeat‐dose pharmacodynamic study in rats.”
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
Boxed warning: Encephalopathy including wernicke's
- Encephalopathy, Including Wernicke's
- Anemia and Thrombocytopenia
- Gastrointestinal Toxicity
- Hepatic Toxicity
- Amylase and Lipase Elevation
- Uveitis
- Major Adverse Cardiac Events (MACE)
- Thrombosis
- Secondary Malignancies
- Symptom Exacerbation Following Interruption or Discontinuation of Treatment
NeurotoxicityThrombocytopeniaCytopeniasGastrointestinalHepatotoxicityOcular toxicityCardiovascularThrombosis & embolismSecondary malignancy
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Country not named; first-in-human dose escalation was in patients with myelofibrosis
“The IND for fedratinib was opened in October 2007 by TargeGen with a first-in-human (FIH) Phase 1 dose-escalation study in patients with MF”
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 Inrebic 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 targets: bone marrow and liver; also lymphoid tissues, lungs and heart (EMA assessment report, p. 34)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month (39-week) dog oral study; no recovery phase described (6-month rat)
“Repeat‐dose toxicology studies of up to 6‐month in rats and 9‐month in dogs were conducted.”
Pivotal GLP studies
6-month rat and 9-month dog repeat-dose studies
“Repeat‐dose toxicology studies of up to 6‐month in rats and 9‐month in dogs were conducted.”
DART package
Species: DART
Rat (fertility, EFD, PPND) and rabbit (EFD)
“Developmental and reproductive toxicology studies in rats and rabbits showed the following: There were no remarkable fedratinib-related effects on fertility and early embryonic development.”
Reproductive & developmental
Rat fertility: no remarkable effects; rat EFD: maternal toxicity at mid and high doses
“There were no remarkable fedratinib‐related effects in the FEED study. In the EFD study in rats, fedratinib was maternally toxic at the middle and high dose levels with lower gestational body weight gain and decreased gravid uterine weights.”
PPND / ePPND: when
Rat PPND completed before the marketing application
“In the PPND study, fedratinib‐related effects were limited to decreased body weight parameters.”
Carcinogenicity
Species: carcinogenicity
Tg rasH2 mouse (6-month); no 2-year rat study
“In a 6-month carcinogenicity study in transgenic Tg.RasH2 mice, there were no neoplasms that were attributed to treatment with fedratinib. No 2-year carcinogenicity study in rats was performed.”
Carcinogenicity model
6-month Tg rasH2 mouse (negative); 2-year rat not performed
“In a 6-month carcinogenicity study in transgenic Tg.RasH2 mice, there were no neoplasms that were attributed to treatment with fedratinib. No 2-year carcinogenicity study in rats was performed.”
Carcinogenicity timing
6-month Tg rasH2 mouse completed before the marketing application; 2-year rat not performed (waived)
“In a 6-month carcinogenicity study in transgenic Tg.RasH2 mice, there were no neoplasms that were attributed to treatment with fedratinib. No 2-year carcinogenicity study in rats was performed.”
Safety marginopen answer page →
Safety margin at NOAEL
No safety margin: exposures in mice, rats and dogs were below human exposure
“In TK, low exposure levels were obtained in mice, rats and dogs following repeated administration, resulting in no safety margin.”
NOAEL / key findings
Rat targets: bone marrow and liver; also lymphoid tissues, lungs and heart
“In rats, the main target organs of toxicity included the bone marrow and liver. Effects were also observed in the lymphoid tissues, lungs and heart.”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse models of JAK2V617F-driven myeloproliferative disease: survival up to 100% at 42 days; reduced WBC, hematocrit, splenomegaly, fibrosis
“In vivo studies in mouse models of JAK2V617F-driven myeloproliferative disease showed that twice daily oral doses of fedratinib at 60 or 120 mg/kg blocked phosphorylation of STAT3/5, increased survival to 100% at the highest dose after 42 days of treatment, and improved disease-associated symptoms, including reduction of white blood cells, hematocrit, splenomegaly, and fibrosis.”
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: proof of concept shown, but mouse efficacy required exposures higher than those reached in humans
“Numerous in vivo mouse models were used to evaluate the efficacy of fedratinib. Although proof of concept is shown in these studies, it appears that in mice a higher exposure to fedratinib than the exposure reached in humans is required to result in an effect on tumour cells.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
No long-term rodent carcinogenicity study; sponsor ICH S9 rationale rejected, waiver granted on low rodent exposure
Why: Low tolerability of rodents to fedratinib limits exposures, so rodent carcinogenicity studies lack value · Pharmacology or kinetics
“No long-term carcinogenicity study has been conducted, and this was justified by the applicant by referring to ICH guideline S9 (treatment of advanced cancer). However, this is not applicable to fedratinib and instead ICH S1 applies.”
“The applicant justified to the lack of value of rodent carcinogenicity studies, due to the low tolerability of rodents to fedratinib, resulting in low exposures in the studies. This is agreed, and therefore carcinogenicity studies can be waived.”
DARTAccepted with a conditionBeyond the letter
Rat and rabbit embryo-fetal studies at exposures well below clinical exposure
Why: JAK inhibitor class effect; pregnancy contraindication added to SmPC · Class precedent
“Although no teratogenic effects were observed in rat or rabbit embryo-foetal toxicity studies, the exposure to fedratinib in these studies was well below the clinical exposure. The relevance of these studies for human safety is therefore limited.”
“Due to this class effect and since other JAK inhibitors have a contraindication for pregnancy, a contraindication for pregnancy has been included in section 4.3 of the SmPC of Inrebic.”
Safety marginVerdict not stated
No safety margin: repeat-dose exposures in mice, rats and dogs below human exposure
“Toxicokinetic data In TK, low exposure levels were obtained in mice, rats and dogs following repeated administration, resulting in no safety margin.”
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