Rivfloza
nedosiran
Sources:FDA integrated review ↗
Species
MonkeyMouse
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Cynomolgus monkey (relevant) plus mouse (nedosiran inactive; off-target assessment)
“Nedosiran is inactive in the mouse because the LDHA mRNA sequence is different from humans, and hence, the toxicology of nedosiran was studied in the mouse to assess off-target hybridization effects.”
Why that species
LDHA mRNA target sequence 100% homologous in monkey; not conserved in mouse
“The monkey is considered a pharmacologically relevant model because the LDHA mRNA target sequence has 100% homology with humans.”
Surrogate molecule
Yes: mouse-active analog DCR-m355 used in pharmacology and mouse reproductive studies
“The effects of knockdown of LDHA mRNA were also assessed in genetically or chemically induced mouse models of PH using the pharmacologically active mouse-specific analog DCR-m355.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“General toxicity studies were conducted for durations up to 26 weeks in juvenile mice and 39 weeks in juvenile and adult monkeys.”
Pivotal GLP studies
26-week juvenile mouse and 39-week juvenile/young adult cynomolgus monkey, SC once every 4 weeks
“Repeat dose toxicology studies were conducted in mice for up to 26 weeks and monkeys for up to 39 weeks.”
Route in tox
Subcutaneous, once every 4 weeks (mimicking clinical monthly dosing)
“The animals were dosed once every 4 weeks to mimic the clinical monthly dosing frequency.”
Skipped studiesopen answer page →
Genotoxicity
Conducted; negative (Ames, in vitro micronucleus, in vivo mouse micronucleus)
“Nedosiran was negative in the bacterial reverse mutation assay and did not induce micronuclei in mammalian cells in vitro or in vivo (Table 48).”
Carcinogenicity
Not conducted pre-approval; deferred to postmarketing (TgRasH2 and 2-year studies)
“The carcinogenic potential of nedosiran has not been assessed. The Agency agrees that carcinogenicity studies can be conducted postmarketing.”
Reproductive & developmental
Mouse FEED/EFD/PPND clean; rabbit EFD: fetal loss and malformations at >=0.7-2x MRHD (unexplained, off-target)
“Higher postimplantation loss and lower numbers of live fetuses were observed at doses of ≥6 mg/kg/dose (0.7x the MRHD, based on body surface area), and fetal cardiovascular and skeletal malformations were observed at a dose of 20 mg/kg/dose (2x the MRHD).”
Safety pharmacology
Stand-alone in vitro hERG plus CNS/respiratory/CV studies in conscious monkeys; no significant effects
“Nedosiran had no significant adverse effect on central nervous system, respiratory, or cardiovascular function of cynomolgus monkeys at doses up to 300 mg/kg.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
Juvenile monkey NOAEL 100 mg/kg (29x AUC); Kupffer/macrophage basophilic hypertrophy in liver, lymph nodes, testes, injection sites
“The NOAEL for nedosiran in the most sensitive and relevant species, the juvenile monkey, is 100 mg/kg, with a corresponding AUC0-48h 400 µg·h/mL, which is approximately 29-fold higher”
Risksopen answer page →
Immune & cytokine safety
No cytokine or complement activation in 39-week monkey study; nonclinical ADA not assessed
“No test article-related effect on cytokine activation was evident at any time point evaluated.”
Biodistribution & persistence
Mainly liver, less kidney; other tissues <2% of liver; long liver half-life (12-23 days)
“Nedosiran is distributed primarily to the liver, and to a lesser extent to the kidney.”
Modality-specific risk
Oligonucleotide accumulation in Kupffer cells/macrophages (class effect); GalNAc-siRNA hepatic, renal, injection-site risks
“The hypertrophic changes in the Kupffer cell/macrophage in the liver may be due to accumulation of the test article and are considered a class effect of oligonucleotides.”