Qfitlia
fitusiran
Sources:FDA integrated review ↗
Species
MonkeyRatMouseDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Partial / alternative Partial / alternative
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Healthy rat and cynomolgus monkey (GLP); hemophilia A mouse, hemophilia A dog and induced-HA monkey models
“Repeat-dose toxicology studies were conducted in healthy rats for up to 26 weeks, healthy monkeys for up to 39 weeks, and in hemophilia mice for up to 26 weeks.”
Why that species
Antithrombin mRNA sequence highly conserved, so fitusiran is pharmacologically active in mouse, rat, monkey and dog
“Fitusiran is pharmacologically active in mice, rats, monkeys, and dogs because the antithrombin mRNA sequences are highly conserved across species.”
Surrogate molecule
No surrogate; clinical siRNA active in rodent and monkey; hemophilia animal models added to assess on-target risk
“To address the limitations of studies in healthy animals, the Applicant conducted extensive studies in animal models of hemophilia”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“Repeat-dose toxicology studies were conducted in healthy rats for up to 26 weeks, healthy monkeys for up to 39 weeks, and in hemophilia mice for up to 26 weeks.”
Pivotal GLP studies
GLP SC weekly: rat 26-week with FEED (13-wk recovery), monkey 39-week (13-wk recovery), 7-week rat and monkey studies, 26-week hemophilia A mouse
“A 26-Week Subcutaneous Injection Toxicity, Toxicokinetic, and Fertility and Early Embryonic Development (to Implantation) Study in the Rat Followed By a 13-Week Recovery Period”
Route in tox
SC (weekly dosing)
“Animals were dosed once weekly by the SC route.”
Skipped studiesopen answer page →
Genotoxicity
Conducted: bacterial reverse mutation, in vitro chromosomal aberration (human lymphocytes), rat bone-marrow micronucleus; all negative
“Fitusiran was not mutagenic or clastogenic in a battery of genetic toxicity studies”
Carcinogenicity
Conducted: 2-year rat and 26-week Tg-rasH2 mouse studies; not carcinogenic
“In a 2-year carcinogenicity study in Sprague Dawley rats, fitusiran was not carcinogenic up to the highest dose tested”
Reproductive & developmental
Male fertility/early embryonic development in 26-week rat study (no effects); no female reproductive or EFD studies (hemophilia almost exclusively male)
“Fitusiran was not tested in reproduction studies in female animals because hemophilia A and B occur almost exclusively in males.”
Safety pharmacology
Dedicated: hERG assay and GLP telemetry monkey CV/respiratory study (up to 10 mg/kg SC); no effects
“In a GLP safety pharmacology study that evaluated both cardiovascular and respiratory function, male telemetered cynomolgus monkeys were subcutaneously administered a single dose of vehicle”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
Rat 26-wk NOAEL 1 mg/kg/wk females, 0.5 mg/kg/wk males (fatal clotting at 1); monkey 39-wk 0.5 mg/kg/wk tolerated; thrombosis, hepatic necrosis, injection-site findings
“The no observed adverse effect level (NOAEL) was the high dose (HD) of 1 mg/kg/week in females, based on the absence of toxicity, and the MD of 0.5 mg/kg/week in males, based on severe clotting.”
Risksopen answer page →
Immune & cytokine safety
No ADA in monkeys (0.1-1 mg/kg/week); injection-site hypersensitivity-type skin reactions in rats and monkeys at all doses
“Fitusiran increased the incidence of hypersensitivity reactions (skin redness/dryness/scab/discharge at the injection site) in rats and monkeys at all doses tested.”
Biodistribution & persistence
Rapid hepatic uptake and slow liver clearance (liver t1/2 ~55-60 h); liver >> kidney, spleen; negligible exposure in brain, heart
“Fitusiran distributed mainly to liver (the primary target organ of pharmacology), followed by kidney and spleen.”
Modality-specific risk
Exaggerated pharmacology: excessive clotting/thrombosis with AT lowering; hepatobiliary toxicity at high doses; injection-site hypersensitivity
“A major risk of fitusiran is anticipated to be excessive clotting related to exaggerated pharmacology.”