Qfitlia
fitusiran
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”
Species: general tox
Rat and cynomolgus monkey (healthy), plus hemophilia A mouse
“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.”
Species: DART
Rat (male fertility within 26-week study only); no EFD studies in rats or rabbits as hemophilia is X-linked
“Because hemophilia is primarily an X-linked disease, no embryo-fetal toxicity studies in rats and rabbits have been performed.”
Species: carcinogenicity
Rat (2-year) and TgRasH2 mouse (26-week)
“The Sponsor submitted final reports for carcinogenicity studies of fitusiran 1. A 26-week study in TgRasH2 mouse study-at3-glp17-001.pdf, 2. A 2-year study in rats study-car0186.pdf.”
Surrogate used in
No surrogate used; fitusiran is active in mouse, rat, dog and monkey
“Fitusiran is pharmacologically active in mice, rats, dogs, and cynomolgus monkeys, as the AT mRNA target sequence is fully conserved (mice, rats, monkeys) or highly conserved (dogs) with the human sequence.”
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”
Genotox: Ames
Negative (bacterial reverse mutation)
“Fitusiran was not mutagenic or clastogenic in a battery of genetic toxicity studies (i.e., in vitro bacterial reverse mutation assay, in vitro chromosomal aberration assay in human peripheral blood lymphocytes; in vivo bone marrow micronucleus test in rats).”
Genotox: in vitro mammalian
Chromosomal aberration in human peripheral blood lymphocytes: negative
“Fitusiran was not mutagenic or clastogenic in a battery of genetic toxicity studies (i.e., in vitro bacterial reverse mutation assay, in vitro chromosomal aberration assay in human peripheral blood lymphocytes; in vivo bone marrow micronucleus test in rats).”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Fitusiran was not mutagenic or clastogenic in a battery of genetic toxicity studies (i.e., in vitro bacterial reverse mutation assay, in vitro chromosomal aberration assay in human peripheral blood lymphocytes; in vivo bone marrow micronucleus test in rats).”
Carcinogenicity model
2-year rat and 26-week TgRasH2 mouse
“The Sponsor submitted final reports for carcinogenicity studies of fitusiran 1. A 26-week study in TgRasH2 mouse study-at3-glp17-001.pdf, 2. A 2-year study in rats study-car0186.pdf.”
Carcinogenicity timing
26-week TgRasH2 mouse and 2-year rat studies completed; final reports submitted with the marketing application
“The Sponsor submitted final reports for carcinogenicity studies of fitusiran 1. A 26-week study in TgRasH2 mouse study-at3-glp17-001.pdf, 2. A 2-year study in rats study-car0186.pdf.”
hERG / QT
No hERG inhibition up to 10 μM
“Fitusiran did not inhibit hERG at up to 10μM in a GLP-compliant study.”
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 Qfitlia 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 oligonucleotides 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: 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 (FDA integrated review, p. 153)
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.”
Anti-drug antibodies: animals
No ADA in monkeys at 0.1-1.0 mg/kg/week, including after 8-week recovery
“Antidrug antibodies (ADAs) were not detected in any monkey administered fitusiran at doses ranging from 0.1 to 1.0 mg/kg/week during the dosing period or following an 8-week recovery period.”
Anti-drug antibodies: patients
3.4% (10 of 290 adults), low-titer and mostly transient; no clinically significant effect
“During QFITLIA treatment (up to 250 weeks) in four studies, 10 out of 290 adults with hemophilia (3.4%) developed ADAs. All patients had low ADA titers, and the majority of patients had transient ADAs.”
Label warnings
Boxed warning: Thrombotic events and acute and recurrent gallbladder disease
- Thrombotic Events
- Acute and Recurrent Gallbladder Disease
- Hepatotoxicity
Thrombosis & embolismHepatotoxicity
US prescribing information, Boxed Warning and 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 Qfitlia 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 oligonucleotides 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: 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 (FDA integrated review, p. 153)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week cynomolgus monkey (SC, weekly) with 13-week recovery
“A 39-Week Subcutaneous Injection Toxicity and Toxicokinetic Study in the Cynomolgus Monkey Followed by a 13-Week Recovery Period (AT3-NCD14-007)”
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”
DART package
Species: DART
Rat (male fertility within 26-week study only); no EFD studies in rats or rabbits as hemophilia is X-linked
“Because hemophilia is primarily an X-linked disease, no embryo-fetal toxicity studies in rats and rabbits have been performed.”
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.”
PPND / ePPND: when
No PPND study: no reproduction studies in female animals because hemophilia A and B occur almost exclusively in males
“Fitusiran was not tested in reproduction studies in female animals because hemophilia A and B occur almost exclusively in males.”
Carcinogenicity
Species: carcinogenicity
Rat (2-year) and TgRasH2 mouse (26-week)
“The Sponsor submitted final reports for carcinogenicity studies of fitusiran 1. A 26-week study in TgRasH2 mouse study-at3-glp17-001.pdf, 2. A 2-year study in rats study-car0186.pdf.”
Carcinogenicity model
2-year rat and 26-week TgRasH2 mouse
“The Sponsor submitted final reports for carcinogenicity studies of fitusiran 1. A 26-week study in TgRasH2 mouse study-at3-glp17-001.pdf, 2. A 2-year study in rats study-car0186.pdf.”
Carcinogenicity timing
26-week TgRasH2 mouse and 2-year rat studies completed; final reports submitted with the marketing application
“The Sponsor submitted final reports for carcinogenicity studies of fitusiran 1. A 26-week study in TgRasH2 mouse study-at3-glp17-001.pdf, 2. A 2-year study in rats study-car0186.pdf.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey 39-week top dose 0.5 mg/kg/week (tolerated) is below the MRHD on a BSA dose basis
“In monkeys with normal coagulation at baseline, fitusiran administration at up to 0.5 mg/kg/week (representing a dose below the MRHD based on BSA comparisons) for 39 weeks decreased AT protein and activity up to 74% and 71%, respectively, and all doses were well-tolerated.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Hemophilia A and B knockout mice, genetic hemophilia A dog and antibody-induced hemophilia A monkey
“The HA and HB mouse proof of concept data were further corroborated by studies in a genetic dog model of HA and in an HA monkey model where hemophilia was induced using an anti-FVIII monoclonal antibody (MAb).”
Why that model
Antithrombin mRNA target conserved across mouse, rat, monkey (fully) and dog (highly), so the clinical siRNA works in disease models
“Fitusiran is pharmacologically active in mice, rats, dogs, and cynomolgus monkeys, as the AT mRNA target sequence is fully conserved (mice, rats, monkeys) or highly conserved (dogs) with the human sequence.”
Reviewer's view of the efficacy data
FDA: hemophilia mouse studies provided important proof of concept and supported clinical development
“Studies in mouse hemophilia models provided important proof of concept data and supported the initiation of clinical development of fitusiran for the treatment of hemophilia.”
Flexibilityopen answer page →
Flexibility accepted
DARTVerdict not stated
No reproduction studies in female animals (no embryo-fetal or pre/postnatal studies); male fertility assessed within 26-week rat study
Why: Hemophilia A and B occur almost exclusively in males · Other reason
“Fitusiran was not tested in reproduction studies in female animals because hemophilia A and B occur almost exclusively in males.”
Safety marginVerdict not stated
Chronic monkey top dose 0.5 mg/kg/week, below the MRHD on a body-surface-area dose basis
“In monkeys with normal coagulation at baseline, fitusiran administration at up to 0.5 mg/kg/week (representing a dose below the MRHD based on BSA comparisons) for 39 weeks decreased AT protein and activity up to 74% and 71%, respectively, and all doses were well-tolerated.”
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