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.”
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.”
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.”