Oxlumo
lumasiran
Species
MonkeyRatRabbit
Longest study
36 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 cynomolgus monkey (both pharmacologically relevant); rabbit for EFD
“The target site of lumasiran in the HAO1 mRNA is conserved across mammalian species and both rodent and monkey are pharmacologically relevant species.”
Why that species
HAO1 target site conserved across mammals; active in rodents, lagomorphs and NHP
“Lumasiran is pharmacologically active in both rodents, lagomorphs and nonhuman primates.”
Surrogate molecule
No surrogate; clinical siRNA pharmacologically active in rodent and monkey tox species
“The target site of lumasiran in the HAO1 mRNA is conserved across mammalian species and both rodent and monkey are pharmacologically relevant species.”
Study lengthopen answer page →
Longest pivotal study
36 weeks
“Chronic administration of lumasiran was assessed in good laboratory practice (GLP) repeat-dose toxicology studies up to 25- and 36-weeks in rats and monkeys, respectively.”
Pivotal GLP studies
Rat 25-week SC monthly; monkey 36-week SC every 4 weeks (10 doses); plus 8-week weekly monkey study
“Dose and frequency of dosing: 30, 100, or 300 mg/kg lumasiran once every 4 weeks for a total of 10 doses Route of administration: SC”
Route in tox
Subcutaneous, weekly or monthly, matching clinical route
“Dose and frequency of dosing: 0, 20, 50 and 200 mg/kg Once/month for 25 weeks Route of administration: SC”
Skipped studiesopen answer page →
Genotoxicity
Conducted: Ames, human lymphocyte chromosome aberration, rat micronucleus; all negative
“Lumasiran was not genotoxic in an in vitro bacterial reverse mutation (Ames) assay, in vitro chromosomal aberration assay in cultured human peripheral blood lymphocytes, or in vivo micronucleus assay in rats.”
Carcinogenicity
Postmarketing requirement; later completed: 26-week Tg-rasH2 mouse and 2-year rat both negative
“Lumasiran was not carcinogenic in transgenic Tg-rasH2 mice following monthly subcutaneous administration of lumasiran for 26 weeks at doses of 150, 500, or 1500 mg/kg.”
Reproductive & developmental
Full DART: rat fertility, rat and rabbit EFD, rat PPND, plus juvenile rat study; no serious effects
“Reproductive toxicology studies did not reveal any serious fertility or teratogenic effects of lumasiran.”
Safety pharmacology
Standalone monkey CV/respiratory telemetry (10, 100 mg/kg weekly x4), no effects; CNS in 8-week monkey study
“In a standalone cardiovascular safety pharmacology study in the monkey, the administration of lumasiran at 10 and 100 mg/kg weekly for a total of four doses had no immediate or delayed effects on clinical observations, qualitative or quantitative electrocardiogram parameters,”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
NOAELs = highest doses (200 mg/kg rat, 300 mg/kg monkey monthly); non-adverse liver, kidney, coagulation, injection site, lymph node findings
“The no observed adverse effect levels (NOAELs) in the chronic repeat-dose toxicity studies with once monthly dosing were the highest doses tested, 200 and 300 mg/kg for rats and monkeys, respectively.”
Risksopen answer page →
Immune & cytokine safety
Low-titre ADA in 3/36 monkeys, no impact on exposure or tox; no ADA in rats; not immunostimulatory
“A low incidence, 3 out of 36 treated monkeys in the 36- week repeat-dose toxicity study (GO1-GLP15-036) were confirmed to have a low titre of anti-lumasiran antibodies.”
Biodistribution & persistence
Rat: liver, kidney cortex/medulla highest; not detected in brain/spinal cord; long liver half-life (585 h) in monkey
“Relatively high tissue concentrations (in descending order) were observed in the liver, kidney cortex, kidney medulla, cecum, salivary gland, bone marrow, thyroid and pancreas.”
Modality-specific risk
Rodent-specific hepatocellular changes (vacuolation, necrosis); renal basophilic granules; GalNAc-siRNA class effects (ISR, LFTs, ADA)
“AEs or toxicities associated with GalNAC-conjugated siRNA products include injection site reactions, ALT and AST elevations, mild increases in serum creatinine and decreases in eGFR, positive ADA, and hypersensitivity (including anaphylactic reactions).”