Duvyzat
givinostat
Species
MonkeyRatMouseDog
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 monkey (supporting 13-week mouse and 4-week dog)
“The toxicity of givinostat was investigated after single and repeated i.v. and oral administration for up to 13 weeks in mice, 26 weeks in rats 4 weeks in dogs and 39 weeks in monkeys.”
Why that species
Mouse and rat: pharmacologically responsive rodents; monkey chosen because dogs had poor gastrointestinal tolerability
“Mice and rats were chosen as pharmacologically responsive rodent species, whereas monkeys were selected due to the limited gastrointestinal tolerability of givinostat in the 4 weeks repeat-dose toxicity study in dogs.”
Surrogate molecule
No surrogate; the clinical compound was tested
“The toxicity of orally administered givinostat was investigated in single and repeat-dose studies for up to 13 weeks in mice, 26 weeks in rats 4 weeks in dogs and 39 weeks in monkeys.”
Species: general tox
Rat (26-week) and cynomolgus monkey (39-week); supporting mouse (13-week) and dog (4-week)
“The toxicity of givinostat was investigated after single and repeated i.v. and oral administration for up to 13 weeks in mice, 26 weeks in rats 4 weeks in dogs and 39 weeks in monkeys.”
Species: DART
Rat (fertility, EFD, pre/postnatal, juvenile) and rabbit (EFD)
“These investigations are complemented by genotoxicity evaluations, reproductive and developmental toxicity studies in rats and rabbits including also juvenile animals.”
Species: carcinogenicity
Mouse and 2-year rat studies required postmarketing
“PMR 4575-1 Conduct a carcinogenicity study of givinostat in mouse. • Final Protocol Submission: 12/2022 (submitted) • Study Completion: 12/2024 • Final Report Submission: 12/2025 PMR 4575-2 Conduct a 2-year carcinogenicity study of givinostat in rat.”
Surrogate used in
No surrogate used; givinostat itself tested in mdx mice
“In both models, daily oral administration of givinostat delayed decreases in treadmill exhaustion, grip strength, and muscle fibrosis and adipocyte infiltration.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week monkey)
“At the same high dose in a 39-week monkey study, findings consisted of transient gait abnormalities and decreased grip strength, increases in ALT and bilirubin, bile duct hyperplasia, and reduced bone marrow cellularity; reduced thymus weight was seen at all doses (0, 5, 12, and 30 mg/kg).”
Pivotal GLP studies
26-week rat and 39-week monkey oral studies (plus 13-week mouse and 4-week dog)
“The toxicity of orally administered givinostat was investigated in single and repeat-dose studies for up to 13 weeks in mice, 26 weeks in rats 4 weeks in dogs and 39 weeks in monkeys.”
Route in tox
Oral (daily)
“All general toxicity and reproductive and development toxicology studies were GLP-compliant and conducted using daily oral administration.”
Skipped studiesopen answer page →
Genotoxicity
Positive in Ames; negative in mouse lymphoma, human lymphocyte chromosome aberration and in vivo Big Blue rat (Pig-a) assays
“Givinostat was positive in a bacterial reverse mutation (Ames) assay, and negative in an in vitro mammalian cell (mouse lymphoma) mutation assay, an in vitro chromosomal aberration assay in mammalian (human lymphocytes) cells, and an in vivo gene mutation assay (with Pig-a endpoints) in Big Blue transgenic rats.”
Carcinogenicity
Not conducted; deferred to postmarketing given the DMD indication
“The Applicant was therefore informed in a Type C meeting (May 11, 2020) that, due to the nature of the proposed indication (i.e., DMD), carcinogenicity studies for givinostat may be deferred until post approval.”
Reproductive & developmental
Decreased fetal weight and structural variations after organogenesis dosing; embryofetal and offspring mortality and offspring neurobehavioral changes in pre/postnatal study
“In animal studies, oral administration of givinostat during organogenesis resulted in decreased fetal body weight and increased structural variations; oral administration during pregnancy and lactation resulted in increased embryofetal and offspring mortality and neurobehavioral changes in the offspring.”
Safety pharmacology
hERG IC50 1.4 µM; slight APD prolongation in rabbit Purkinje fibres at ≥3 µM; no heart rate, ECG or respiratory effects in dogs and monkeys
“Givinostat inhibited hERG currents with an IC50 of 1.4 µM and slightly prolonged action potential duration in rabbit Purkinje fibres at ≥3 µM during simulated bradycardia conditions in vitro, but did not significantly alter heart rate, ECG and respiratory parameters in dogs and monkeys.”
Genotox: Ames
Positive
“Givinostat was positive in a bacterial reverse mutation (Ames) assay, and negative in an in vitro mammalian cell (mouse lymphoma) mutation assay, an in vitro chromosomal aberration assay in mammalian (human lymphocytes) cells, and an in vivo gene mutation assay (with Pig-a endpoints) in Big Blue transgenic rats.”
Genotox: in vitro mammalian
Mouse lymphoma mutation assay and human lymphocyte chromosomal aberration: negative
“Givinostat was positive in a bacterial reverse mutation (Ames) assay, and negative in an in vitro mammalian cell (mouse lymphoma) mutation assay, an in vitro chromosomal aberration assay in mammalian (human lymphocytes) cells, and an in vivo gene mutation assay (with Pig-a endpoints) in Big Blue transgenic rats.”
Genotox: in vivo
Big Blue transgenic rat gene mutation assay with Pig-a endpoint: negative
“Givinostat was positive in a bacterial reverse mutation (Ames) assay, and negative in an in vitro mammalian cell (mouse lymphoma) mutation assay, an in vitro chromosomal aberration assay in mammalian (human lymphocytes) cells, and an in vivo gene mutation assay (with Pig-a endpoints) in Big Blue transgenic rats.”
Carcinogenicity model
Not conducted before approval; mouse study required postmarketing
“PMR 4575-1 Conduct a carcinogenicity study of givinostat in mouse.”
Carcinogenicity timing
Mouse and 2-year rat carcinogenicity studies not conducted before the marketing application; postmarketing requirements
“PMR 4575-1 Conduct a carcinogenicity study of givinostat in mouse. • Final Protocol Submission: 12/2022 (submitted) • Study Completion: 12/2024 • Final Report Submission: 12/2025 PMR 4575-2 Conduct a 2-year carcinogenicity study of givinostat in rat.”
hERG / QT
hERG IC50 1.4 µM; slight APD prolongation in rabbit Purkinje fibres at ≥3 µM; no heart rate or ECG effects in dogs and monkeys
“Givinostat inhibited hERG currents with an IC50 of 1.4 µM and slightly prolonged action potential duration in rabbit Purkinje fibres at ≥3 µM during simulated bradycardia conditions in vitro, but did not significantly alter heart rate, ECG and respiratory parameters in dogs and monkeys.”
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 Duvyzat 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: Transient CNS signs (rat, monkey); decreased WBC and bone marrow myeloid series (rat); bile duct hyperplasia and thymic atrophy (monkey) (FDA integrated review, p. 133)
NOAEL / key findings
Transient CNS signs (rat, monkey); decreased WBC and bone marrow myeloid series (rat); bile duct hyperplasia and thymic atrophy (monkey)
“Primary toxicities included transient CNS signs in rat and monkey, decreases in WBC counts and bone myeloid series in rats, and bile duct hyperplasia and thymic atrophy in monkeys.”
Risksopen answer page →
Immune & cytokine safety
Lymphoid depletion with atrophy of thymus, lymph nodes, bone marrow and spleen; partially reversible
“This lymphoid depletion led to atrophies of thymus, lymph nodes, bone marrow and spleen. This interference of givinostat with the white blood cell lineage likely reflects its anti-inflammatory activity and was partially reversible in rats and monkeys.”
Biodistribution & persistence
Rat: mainly GI tract and elimination organs (liver, kidney, bladder); no significant brain distribution
“In rats, givinostat primarily distributed into gastrointestinal tract tissue (intestine > duodenum > stomach) and in organs involved in elimination (liver > kidney > bladder), but not significantly into the brain.”
Modality-specific risk
No exposure-based safety margins at repeat-dose NOAELs relative to therapeutic doses
“However, no relevant Cmax- and AUC-based safety margins could be established for givinostat at the respective NOAELs in subchronic and chronic toxicity studies in mice, rats and monkeys compared to the envisaged therapeutic human doses of 25 to 70 mg bid in DMD patients.”
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
- Hematological Changes
- Increased Triglycerides
- Gastrointestinal Disturbances
- QTc Prolongation
CytopeniasGastrointestinalCardiovascular
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 Duvyzat 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: Transient CNS signs (rat, monkey); decreased WBC and bone marrow myeloid series (rat); bile duct hyperplasia and thymic atrophy (monkey) (FDA integrated review, p. 133)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week oral monkey study with 8-week recovery
“Bile duct, thymus, and bone marrow histopathology remained present after recovery periods of 4 or 8 weeks in the 13 and 39-week studies, respectively, but appeared to be resolving.”
Pivotal GLP studies
26-week rat and 39-week monkey oral studies (plus 13-week mouse and 4-week dog)
“The toxicity of orally administered givinostat was investigated in single and repeat-dose studies for up to 13 weeks in mice, 26 weeks in rats 4 weeks in dogs and 39 weeks in monkeys.”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal, juvenile) and rabbit (EFD)
“These investigations are complemented by genotoxicity evaluations, reproductive and developmental toxicity studies in rats and rabbits including also juvenile animals.”
Reproductive & developmental
Decreased fetal weight and structural variations after organogenesis dosing; embryofetal and offspring mortality and offspring neurobehavioral changes in pre/postnatal study
“In animal studies, oral administration of givinostat during organogenesis resulted in decreased fetal body weight and increased structural variations; oral administration during pregnancy and lactation resulted in increased embryofetal and offspring mortality and neurobehavioral changes in the offspring.”
PPND / ePPND: when
PPND in rat completed before the marketing application
“In a pre- and postnatal development study in rat, administration of givinostat (0, 40, 80, and 160 mg/kg) from GD 6 to postnatal day (PND) 20 resulted in reduced number of litters with liveborn pups, increases in stillborn pups, total litter loss, and decreases in pups surviving to PND 21.”
Carcinogenicity
Species: carcinogenicity
Mouse and 2-year rat studies required postmarketing
“PMR 4575-1 Conduct a carcinogenicity study of givinostat in mouse. • Final Protocol Submission: 12/2022 (submitted) • Study Completion: 12/2024 • Final Report Submission: 12/2025 PMR 4575-2 Conduct a 2-year carcinogenicity study of givinostat in rat.”
Carcinogenicity model
Not conducted before approval; mouse study required postmarketing
“PMR 4575-1 Conduct a carcinogenicity study of givinostat in mouse.”
Carcinogenicity timing
Mouse and 2-year rat carcinogenicity studies not conducted before the marketing application; postmarketing requirements
“PMR 4575-1 Conduct a carcinogenicity study of givinostat in mouse. • Final Protocol Submission: 12/2022 (submitted) • Study Completion: 12/2024 • Final Report Submission: 12/2025 PMR 4575-2 Conduct a 2-year carcinogenicity study of givinostat in rat.”
Safety marginopen answer page →
Safety margin at NOAEL
No relevant AUC- or Cmax-based margins at repeat-dose NOAELs (mouse, rat, monkey) vs human doses of 25 to 70 mg bid
“However, no relevant Cmax- and AUC-based safety margins could be established for givinostat at the respective NOAELs in subchronic and chronic toxicity studies in mice, rats and monkeys compared to the envisaged therapeutic human doses of 25 to 70 mg bid in DMD patients.”
NOAEL / key findings
Transient CNS signs (rat, monkey); decreased WBC and bone marrow myeloid series (rat); bile duct hyperplasia and thymic atrophy (monkey)
“Primary toxicities included transient CNS signs in rat and monkey, decreases in WBC counts and bone myeloid series in rats, and bile duct hyperplasia and thymic atrophy in monkeys.”
Efficacy evidenceopen answer page →
Efficacy evidence
B10.mdx (mild) and D2.mdx (severe) mouse models of DMD; DMD patient-derived fibroblasts
“Studies were conducted in the C57BL/10ScSn-Dmdmdx/J (i.e., B10.mdx) and D2.B10-Dmdmdx/J (i.e., D2.mdx) mice which were intended to model the IAAM (mild) and VTTT (severe) haplotypes, respectively, in DMD.”
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: only temporary improvement in mdx mice apart from reduced fibrosis; the mild mdx phenotype limits the model
“Hence, givinostat treatment only temporarily improved the muscle deficiencies of mdx mice, except the alleviation of muscular fibrosis. Nevertheless, the mdx phenotype is rather mild”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
Mouse and two-year rat carcinogenicity studies deferred to after approval as postmarketing requirements
Why: Nature of the indication (DMD) and negligible in vivo mutation risk · Serious disease · Weight of evidence
“The Applicant was therefore informed in a Type C meeting (May 11, 2020) that, due to the nature of the proposed indication (i.e., DMD), carcinogenicity studies for givinostat may be deferred until post approval.”
“PMR 4575-2 Conduct a 2-year carcinogenicity study of givinostat in rat.”
GenotoxicityAcceptedBeyond the letter
Positive Ames result accepted after a follow-up transgenic rat (Big Blue, Pig-a) mutagenesis assay
Why: In vivo transgenic rat assay showed negligible in vivo mutation risk · Weight of evidence
“Based on a review of these data by the PTCC Genetic Toxicology Subcommittee, it was determined that the risk of in vivo mutation was negligible for givinostat.”
Safety marginAccepted with a conditionBeyond the letter
No Cmax- or AUC-based safety margins at repeat-dose NOAELs in mice, rats and monkeys
“However, no relevant Cmax- and AUC-based safety margins could be established for givinostat at the respective NOAELs in subchronic and chronic toxicity studies in mice, rats and monkeys compared to the envisaged therapeutic human doses of 25 to 70 mg bid in DMD patients.”
“For this reason, non-clinical repeat-dose toxicity studies cannot significantly support the clinical safety of givinostat, which is adequately reflected in section 5.3 of the SmPC.”
Similar precedents
EvrysdiSmall molecules · risdiplam · SMN2 splicingMonkey + rodent · 39 wkZokinvySmall molecules · lonafarnib · FarnesyltransferaseMonkey + rodent · 52 wkAgamreeSmall molecules · vamorolone · Glucocorticoid receptor (dissociative)Rodent + dog or minipig · 39 wkGomekliSmall molecules · mirdametinib · MEK1/2Rodent + dog or minipig · 13 wkSohonosSmall molecules · palovarotene · RARγRodent + dog or minipig · 39 wkAvmapki Fakzynja Co-packSmall molecules · avutometinib and defactinib · RAF/MEK clamp; FAKMonkey + rodent · 13 wk