Givlaari
givosiran
Species
MonkeyRatRabbit
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 (both pharmacologically active); rabbit inactive (EFD only)
“In addition to being pharmacologically active in humans, based on the nonclinical data described below, givosiran is also pharmacologically active in both rats and monkeys but is not pharmacologically active in rabbits.”
Why that species
Lead duplex has complete sequence homology to human and monkey ALAS1; ALAS1 knockdown shown in rat and monkey
“This parent duplex, with complete sequence homology to human and monkey ALAS1, and is therefore expected to be pharmacologically active in each of the indicated species.”
Surrogate molecule
No surrogate; clinical siRNA tested in rat, monkey and (non-responsive) rabbit
“Pharmacodynamics measurement on GD 22 indicated that givosiran did not reduce hepatic ALAS1 transcript levels in pregnant rabbits at any dose level, confirming that givosiran is not pharmacologically active in rabbits.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“In a 39-week monkey study, cynomolgus monkeys were subcutaneously administered vehicle or givosiran (10, 30, or 100 mg/kg) once weekly for 39 weeks followed by a 13-week recovery period.”
Pivotal GLP studies
Rat 26-week SC weekly (with male fertility arm), monkey 39-week SC weekly, both with 13-week recovery
“Dawley rats were subcutaneously administered vehicle or givosiran (3, 10, or 30 mg/kg) once weekly for 26 weeks followed by a 13-week recovery period.”
Route in tox
Subcutaneous, once weekly (vs monthly clinical schedule)
“The studies were conducted using the subcutaneous route of administration, which is consistent with the intended clinical route of administration; however, animals were dosed once weekly instead of the once monthly dose schedule used to treat patients.”
Skipped studiesopen answer page →
Genotoxicity
Conducted: Ames, human lymphocyte chromosome aberration, rat micronucleus; all negative
“Givosiran was not mutagenic in the in vitro bacterial reverse mutation test or clastogenic in the in vitro chromosomal aberrations assay in human peripheral blood lymphocytes or in the in vivo bone marrow micronucleus assay in rats.”
Carcinogenicity
Conducted: 26-week Tg.rasH2 mouse negative; 2-year rat (post-approval) showed hepatocellular adenomas in males at 100 mg/kg
“A statistically significant increase in hepatocellular adenomas occurred in males at 100 mg/kg/month, the clinical significance of which is uncertain.”
Reproductive & developmental
Full DART: rat fertility/EFD, rabbit EFD (postimplantation loss with maternal toxicity), rat PPND; no malformations
“Givosiran showed marked maternal toxicity in rabbits (including mean maternal body weight loss) and resulted in increased post-implantation loss as a result of increased early resorptions and a low incidence of skeletal variations.”
Safety pharmacology
Standalone GLP CV/respiratory telemetry study in monkey (single 150 mg/kg SC); no clear effects
“A safety pharmacology study assessed the effects of a single subcutaneous dose of 150 mg/kg givosiran on cardiovascular and respiratory function in male telemetered cynomolgus monkeys.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
Liver primary target in rat and monkey (single-cell necrosis, enzyme increases); no adverse findings at 3.5x (rat) and 26.3x (monkey) exposure
“No adverse findings were associated with chronic, weekly administration of givosiran to rats and monkeys at doses that achieved exposure multiples of 3.5- and 26.3 fold, respectively when compared to exposures achieved in patients receiving the maximum recommended human dose.”
Risksopen answer page →
Immune & cytokine safety
Low ADA incidence: rat negative, one monkey ADA-positive; no dedicated antigenicity studies
“All samples in the rat were negative. In the monkey study one sample was positive at 30 mg/kg/week (on day 169) and 3 samples were positive at 100 mg/kg/week, all from one animal (on days 85, 169 and 253).”
Biodistribution & persistence
Rat QWBA: liver, kidney cortex, lymph nodes highest; long liver/kidney half-lives; persists in liver, kidney, injection site at 28 days
“Quantitative whole-body autoradiography confirmed that givosiran is distributed to a limited number of tissues, with high exposures observed in the liver, kidneys, kidney cortex, and lymph nodes.”
Modality-specific risk
Hepatotoxicity, renal oligonucleotide accumulation (basophilic granules), injection-site reactions; off-target hybridization screened
“Tubular basophilic granules were observed in the kidney and may be related to accumulation of polyanionic oligonucleotide molecules in lysosomes.”