Jesduvroq
daprodustat
Species
MonkeyRatDog
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 cynomolgus monkey (dog in studies up to 13 weeks)
“General toxicology studies of 4- and 13-weeks duration were conducted in Sprague Dawley rats and Beagle Dogs with rats receiving daily oral doses by gavage and dogs by capsule. A 13-week toxicity study was also conducted in the cynomolgus monkey with daily dosing by oral gavage.”
Why that species
Monkey forms the three major human metabolites (M2, M3, M13) at ≥1x human exposure; rodents and dog do not
“The 3 major circulating human metabolites (M2, M3, and M13) were present in rabbit and monkey plasma with an animal:human AUC ratio of at least 1X in monkeys (comparing the 50 mg/kg MTD dose in the 39-week toxicity study and human exposure at the 48 mg three times a week (TIW) human dose).”
Surrogate molecule
No surrogate; the clinical compound was tested
“Title/ Study No.: GSK1278863A: A 26-week Oral (Gavage) Toxicity Study in the Rat/ 2011N126130”
Species: general tox
Sprague Dawley rat, beagle dog and cynomolgus monkey (oral)
“General toxicology studies of 4- and 13-weeks duration were conducted in Sprague Dawley rats and Beagle Dogs with rats receiving daily oral doses by gavage and dogs by capsule. A 13-week toxicity study was also conducted in the cynomolgus monkey with daily dosing by oral gavage.”
Species: DART
Rat and rabbit (embryo-fetal development)
“Daprodustat administered orally to pregnant rats and rabbits during the period of organogenesis was associated with adverse fetal outcomes, including embryonic and fetal loss and reduced fetal weight, at doses that caused maternal toxicity and polycythemia”
Species: carcinogenicity
Rat (2-year) and mouse (2-year, with SC major human metabolites)
“Daprodustat was not carcinogenic in two-year carcinogenicity studies when administered orally at doses of 0.02, 0.1, 0.8, or 4 mg/kg/day (males) / 7 mg/kg/day (females) in rats (up to 3 times the MRHD based on body surface area) and 0.2, 0.8, or 3 mg/kg/day (including subcutaneous injection of major human metabolites of daprodustat) in mice”
Surrogate used in
No surrogate molecule; human metabolite cocktail given SC to mice (carcinogenicity) and rats (pre/postnatal study)
“The metabolites were not detected in mouse, rat, or dog plasma, and were administered SC as a metabolite cocktail to mice and rats in a mouse carcinogenicity study and rat pre-and post-natal development study to achieve at least 1X human exposure.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week monkey)
“Title/ Study No.: GSK1278863A: A 39-week Oral (Gavage) Toxicity Study in the Cynomolgus Monkey with a 6-week Recovery Period /2011N126131”
Pivotal GLP studies
39-week cynomolgus monkey oral gavage study with 6-week recovery; 26-week rat study
“Title/ Study No.: GSK1278863A: A 39-week Oral (Gavage) Toxicity Study in the Cynomolgus Monkey with a 6-week Recovery Period /2011N126131”
Route in tox
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human lymphocyte chromosomal aberration and in vivo rat bone marrow micronucleus assays
“Daprodustat was negative for mutagenic or clastogenic potential in the in vitro bacterial reverse mutation assay, the in vitro human lymphocyte chromosomal aberration assay, and the in vivo rat bone marrow micronucleus assay.”
Carcinogenicity
2-year rat and 2-year mouse (with major human metabolites): not carcinogenic
“Daprodustat was not carcinogenic in two-year carcinogenicity studies when administered orally at doses of 0.02, 0.1, 0.8, or 4 mg/kg/day (males) / 7 mg/kg/day (females) in rats (up to 3 times the MRHD based on body surface area) and 0.2, 0.8, or 3 mg/kg/day (including subcutaneous injection of major human metabolites of daprodustat) in mice”
Reproductive & developmental
Rat and rabbit EFD: embryofetal loss and reduced fetal weight at maternally toxic, polycythemic doses
“Daprodustat administered orally to pregnant rats and rabbits during the period of organogenesis was associated with adverse fetal outcomes, including embryonic and fetal loss and reduced fetal weight, at doses that caused maternal toxicity and polycythemia ( see Data ).”
Safety pharmacology
No effect on hERG (up to 47.66 µM), neurobehavioral or respiratory function (up to 20 mg/kg)
“Daprodustat had no effect on hERG channel activity (up to 47.66µM), neurobehavioral, and respiratory activity (up to 20 mg/kg).”
Genotox: Ames
Negative with and without S9
“Daprodustat was not mutagenic in the bacterial mutation assay, when tested in either the presence or absence of S9-mix”
Genotox: in vitro mammalian
Human lymphocyte chromosomal aberration assay: negative
“Daprodustat was negative for mutagenic or clastogenic potential in the in vitro bacterial reverse mutation assay, the in vitro human lymphocyte chromosomal aberration assay, and the in vivo rat bone marrow micronucleus assay.”
Genotox: in vivo
Rat bone marrow micronucleus: small positive response, judged not direct genotoxicity (mechanism-related)
“The result was positive, but it is not considered to be a direct genotoxic response based on the small magnitude of the response and the mechanism of action of GSK1278863A which can contribute to the positive result.”
Carcinogenicity model
2-year rat and 2-year mouse (mouse co-dosed SC with major human metabolites); not carcinogenic
“Daprodustat was not carcinogenic in two-year carcinogenicity studies when administered orally at doses of 0.02, 0.1, 0.8, or 4 mg/kg/day (males) / 7 mg/kg/day (females) in rats (up to 3 times the MRHD based on body surface area) and 0.2, 0.8, or 3 mg/kg/day (including subcutaneous injection of major human metabolites of daprodustat) in mice”
Carcinogenicity timing
2-year rat and 2-year mouse completed before the marketing application
“Daprodustat was not carcinogenic in two-year carcinogenicity studies when administered orally at doses of 0.02, 0.1, 0.8, or 4 mg/kg/day (males)/ 7 mg/kg/day (females) in rats and 0.2, 0.8, or 3 mg/kg/day (including subcutaneous injection of major human metabolites of daprodustat) in mice”
hERG / QT
No hERG effect up to 47.66 µM
“Daprodustat had no effect on hERG channel activity (up to 47.66µM), neurobehavioral, and respiratory activity (up to 20 mg/kg).”
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 Jesduvroq 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: 39-week monkey NOAEL 3 mg/kg/day; choroid plexus, kidney and stomach findings at ≥10 mg/kg/day (FDA integrated review, p. 257)
NOAEL / key findings
39-week monkey NOAEL 3 mg/kg/day; choroid plexus, kidney and stomach findings at ≥10 mg/kg/day
“The NOAEL is determined at 3 mg/kg/day based on the microscopic findings in choroid plexus, kidney, and stomach at ≥10 mg/kg/day.”
Risksopen answer page →
Immune & cytokine safety
Thymic lymphoid atrophy in the 13-week monkey study
“In monkeys, there were fewer organs of toxicity (only bone marrow [erythroid hypercellulartity], lung [alveolar hemorrhage], thymus [lymphoid atrophy], and stomach”
Biodistribution & persistence
Rat QWBA: uveal tract and pigmented skin radioactivity undetectable by Day 7; no irreversible melanin binding
“Radioactivity concentrations in the uveal tract, pigmented skin, and meninges peak at 1h or 4h declining steadily afterwards until undetectable by Day 7. This finding suggests no irreversible binding to melanin-containing tissues.”
Modality-specific risk
Exaggerated pharmacology: polycythemia with thrombosis, hemorrhage and mortality in rats
“Cause of death appeared related to hemorrhage, systemic thrombosis and/or necrosis and thrombosis of various organs including the heart, lung, kidney, and cecum. These findings are consistent with the drug’s primary pharmacology and secondary impact on hemodynamics.”
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: INCREASED RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, and THROMBOSIS OF VASCULAR ACCESS
- Increased Risk of Death, Myocardial Infarction, Stroke, Venous Thromboembolism, and Thrombosis of Vascular Access
- Risk of Hospitalization for Heart Failure
- Hypertension
- Gastrointestinal Erosion
- Serious Adverse Events in Patients with Anemia Due to Chronic Kidney Disease and Not on Dialysis
- Malignancy
Thrombosis & embolismCardiovascularGastrointestinalNephrotoxicityCytopeniasSecondary 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; initial IND protocol was a single ascending oral dose study in healthy subjects
“The initial IND included the protocol titled PHX111427: A Phase I, Randomized, Single-Blind, Placebo-Controlled, Dose-Escalation Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Single Oral Doses of GSK1278863A in Healthy Subjects.”
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 Jesduvroq 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: 39-week monkey NOAEL 3 mg/kg/day; choroid plexus, kidney and stomach findings at ≥10 mg/kg/day (FDA integrated review, p. 257)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week cynomolgus monkey oral study with 6-week recovery
“GSK1278863A: A 39-week Oral (Gavage) Toxicity Study in the Cynomolgus Monkey with a 6-week Recovery Period”
Pivotal GLP studies
39-week cynomolgus monkey oral gavage study with 6-week recovery; 26-week rat study
“Title/ Study No.: GSK1278863A: A 39-week Oral (Gavage) Toxicity Study in the Cynomolgus Monkey with a 6-week Recovery Period /2011N126131”
DART package
Species: DART
Rat and rabbit (embryo-fetal development)
“Daprodustat administered orally to pregnant rats and rabbits during the period of organogenesis was associated with adverse fetal outcomes, including embryonic and fetal loss and reduced fetal weight, at doses that caused maternal toxicity and polycythemia”
Reproductive & developmental
Rat and rabbit EFD: embryofetal loss and reduced fetal weight at maternally toxic, polycythemic doses
“Daprodustat administered orally to pregnant rats and rabbits during the period of organogenesis was associated with adverse fetal outcomes, including embryonic and fetal loss and reduced fetal weight, at doses that caused maternal toxicity and polycythemia ( see Data ).”
PPND / ePPND: when
Rat PPND completed before the marketing application
“In a pre- and postnatal development study, pregnant rats were dosed orally with daprodustat from implantation until weaning (gestation day 6 to lactation day 21)”
Carcinogenicity
Species: carcinogenicity
Rat (2-year) and mouse (2-year, with SC major human metabolites)
“Daprodustat was not carcinogenic in two-year carcinogenicity studies when administered orally at doses of 0.02, 0.1, 0.8, or 4 mg/kg/day (males) / 7 mg/kg/day (females) in rats (up to 3 times the MRHD based on body surface area) and 0.2, 0.8, or 3 mg/kg/day (including subcutaneous injection of major human metabolites of daprodustat) in mice”
Carcinogenicity model
2-year rat and 2-year mouse (mouse co-dosed SC with major human metabolites); not carcinogenic
“Daprodustat was not carcinogenic in two-year carcinogenicity studies when administered orally at doses of 0.02, 0.1, 0.8, or 4 mg/kg/day (males) / 7 mg/kg/day (females) in rats (up to 3 times the MRHD based on body surface area) and 0.2, 0.8, or 3 mg/kg/day (including subcutaneous injection of major human metabolites of daprodustat) in mice”
Carcinogenicity timing
2-year rat and 2-year mouse completed before the marketing application
“Daprodustat was not carcinogenic in two-year carcinogenicity studies when administered orally at doses of 0.02, 0.1, 0.8, or 4 mg/kg/day (males)/ 7 mg/kg/day (females) in rats and 0.2, 0.8, or 3 mg/kg/day (including subcutaneous injection of major human metabolites of daprodustat) in mice”
Safety marginopen answer page →
Safety margin at NOAEL
Rat embryo-fetal NOAEL 7 mg/kg/day = 3x MRHD (body surface area); no repeat-dose margin stated
“No adverse effects were observed at doses less than or equal to 7 mg/kg/day (3 times the MRHD based on body surface area).”
NOAEL / key findings
39-week monkey NOAEL 3 mg/kg/day; choroid plexus, kidney and stomach findings at ≥10 mg/kg/day
“The NOAEL is determined at 3 mg/kg/day based on the microscopic findings in choroid plexus, kidney, and stomach at ≥10 mg/kg/day.”
Efficacy evidenceopen answer page →
Efficacy evidence
Normal Sprague-Dawley rats: dose-related increases in RBC, hemoglobin and hematocrit
“Daprodustat treatment resulted in dose-related increases in RBC parameters (up to 18%, 22%, and 26% of RBC, hemoglobin, and hematocrit, respectively) that were evident by Day 8 and further increased on Day 22.”
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
Reviewer: in vitro and in vivo studies show increased EPO leading to increased RBC parameters
“Treatment of daprodustat in vitro and in vivo pharmacology studies showed that daprodustat increases erythropoietin (EPO) levels (mRNA and protein), which results in an increase of red blood cell (RBC) parameters.”
Flexibilityopen answer page →
Flexibility accepted
Impurity or metaboliteVerdict not stated
Major human metabolites M2, M3 and M13 not formed in rodents; given SC as a metabolite cocktail in mouse carcinogenicity and rat pre/postnatal studies
Why: Achieve at least 1X human metabolite exposure in rodent studies · Pharmacology or kinetics
“The metabolites were not detected in mouse, rat, or dog plasma, and were administered SC as a metabolite cocktail to mice and rats in a mouse carcinogenicity study and rat pre-and post-natal development study to achieve at least 1X human exposure.”
GenotoxicityAcceptedBeyond the letter
Uncertain genotoxic potential of major metabolite M13 after mouse lymphoma and initial mouse liver comet assays
Why: Division concluded M13 was not genotoxic
“Genotoxicity studies paused based on the uncertainty about the genotoxic potential of the M13 metabolite of GSK 1278863 following the results of mouse lymphoma assay and the initial mouse liver comet assay”
“The Division concluded that the M13 metabolite was not genotoxic and agreed with the Sponsor to re-initiate clinical trials of GSK 12788863”
Similar precedents
VafseoSmall molecules · vadadustat · HIF prolyl hydroxylaseRodent + dog or minipig · 39 wkLupkynisSmall molecules · voclosporin · CalcineurinMonkey + rodent · 39 wkKerendiaSmall molecules · finerenone · Mineralocorticoid receptorRodent + dog or minipig · 39 wkAvmapki Fakzynja Co-packSmall molecules · avutometinib and defactinib · RAF/MEK clamp; FAKMonkey + rodent · 13 wkBaxfendySmall molecules · baxdrostat · Aldosterone synthase (CYP11B2)Monkey + rodent · 39 wkCibinqoSmall molecules · abrocitinib · JAK1Monkey + rodent · 39 wk