Tegsedi
inotersen
Species
MonkeyRatMouse
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse, rat and cynomolgus monkey; monkey the only pharmacologically relevant species
“Inotersen is pharmacologically active in cynomolgus monkey but not rodent or rabbit.”
Why that species
Target sequence conserved in monkey; 8 mismatches in rodents and 4 in rabbit
“The target sequence of inotersen is conserved between monkeys and humans, but contains 8 mismatches in rodents and 4 mismatches in rabbits.”
Surrogate molecule
Yes: mouse (ISIS 401724) and rat (ISIS 594799) TTR-specific surrogate ASOs in tox, repro and carcinogenicity studies
“For this reason, mouse- and rat-specific analogues of inotersen were included in the toxicology evaluations in order to distinguish toxicity associated with reduction of the target (TTR) from toxicities related to the chemistry of the oligonucleotide”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“In the 39-week study, inotersen was administered at doses of 0, 3, 6, 10, and 20 mg/kg once weekly.”
Pivotal GLP studies
SC: mouse 13- and 26-week; rat 26-week; cynomolgus monkey 13-week and 39-week, with recovery
“Pivotal toxicity studies were conducted in CD-1 mouse (13-week [30-day interim] + 13-week recovery, 26-week + 13-week recovery), Sprague-Dawley rat (26-week), and cynomolgus monkey (13-week + 13-week recovery, 39-week [26-week interim] + 26-week recovery).”
Route in tox
Subcutaneous (clinical route) in all species
“In all species, inotersen was administered by subcutaneous injection.”
Skipped studiesopen answer page →
Genotoxicity
Conducted; negative (Ames, CHL chromosomal aberration, mouse micronucleus)
“Inotersen was negative in an adequate standard battery of in vitro (Ames, chromosomal aberration in Chinese hamster lung cells) and in vivo (CD-1 mouse micronucleus at single doses up to 2000 mg/kg SC) assays.”
Carcinogenicity
26-week rasH2 mouse (inotersen + surrogate) negative; 2-year rat study as postmarketing requirement
“In transgenic (TgRasH2) mice, subcutaneous administration of inotersen (0, 10, 30, or 80 mg/kg) or a species-specific surrogate (ISIS 401724; 30 mg/kg) weekly for 26 weeks resulted in no drug-related increase in tumors.”
Reproductive & developmental
Full battery in mouse (FEED/EFD, PPND, with surrogate) and rabbit EFD; only reduced fetal weight at rabbit high dose
“A full battery of reproductive and development studies was conducted in CD-1 mouse and New Zealand White rabbit.”
Safety pharmacology
Standalone core battery: mouse CNS, telemetered monkey CV/respiratory, hERG; no adverse effects
“No adverse effects of inotersen were observed on a core battery of safety pharmacology parameters in CNS in CD-1 mouse (CNS) or cynomolgus monkey (cardiovascular and respiratory) following acute SC doses of up to 300 or 40 mg/kg, respectively.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
Monkey 39-wk NOAEL 6 mg/kg/wk (severe thrombocytopenia); rat NOAEL 5 mg/kg (glomerulopathy); margins <=~2-fold
“The NOAEL was 6 mg/kg/week, based on the severe thrombocytopenia observed at 10 and 20 mg/kg/week.”
Risksopen answer page →
Immune & cytokine safety
Monkey perivascular inflammation with ADA, CRP, IL-6, TNFa, IgG/IgM rises; complement Bb activation; ADA in some monkeys
“In the same study, five other animals across the three lowest dose groups showed perivascular mixed cell infiltration in multiple organs, associated with increases in anti-drug antibody, CRP, IL-6, MIP-1β, TNFα, and serum IgG and IgM”
Biodistribution & persistence
Rapid plasma-to-tissue distribution; high levels in kidney, liver, lymph nodes, injection site, bone marrow
“High concentrations of inotersen were detected in kidneys, liver, mesenteric lymph nodes, injection site and bone marrow.”
Modality-specific risk
Thrombocytopenia (monkey, clinically translated) and renal glomerular toxicity; PS-ASO class pro-inflammatory effects
“In the 39-week monkey study, severe thrombocytopenia associated with petechiae, bruising, and internal hemorrhages was observed within the first 11-14 weeks of dosing in two animals (one in each of the two highest dose groups), necessitating early euthanasia.”