Redemplo
plozasiran
Sources:FDA integrated review ↗
Species
MonkeyRat
Longest study
37 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat (off-target toxicity) and cynomolgus monkey (pharmacologically relevant)
“Monkeys were deemed the most pharmacologically relevant species to evaluate on-target safety profile of plozasiran.”
Why that species
Antisense strand fully complementary to monkey and human ApoC-III mRNA, 7 mismatches to rodent; rat only suitable for off-target toxicity
“The antisense strand of plozasiran is fully complementary to monkey and human ApoC-III mRNAs, whereas plozasiran has seven sequence mismatches to the rodent ApoC-III mRNA transcript.”
Surrogate molecule
Yes: rodent-specific surrogate AD06313 used in rat embryo-fetal/repro studies; clinical molecule in general tox
“A follow-up EFD study was conducted with single dose SC administration of plozasiran or the rodent-specific surroga”
Study lengthopen answer page →
Longest pivotal study
37 weeks
“Q4W in rats (15, 30, and 120 mg/kg) and monkeys (30, 90, and 180 mg/kg) for durations up to 24- and 37-weeks, respectively”
Pivotal GLP studies
24-week rat and 37-week monkey SC Q4W repeat-dose toxicity studies
“Repeat-dose general toxicology studies with plozasiran were conducted with SC administration (consistent with the clinical route) Q4W in rats”
Route in tox
Subcutaneous, Q4W
“Repeat-dose general toxicology studies with plozasiran were conducted with SC administration (consistent with the clinical route) Q4W in rats”
Skipped studiesopen answer page →
Genotoxicity
Conducted: Ames, in vitro chromosomal aberration (TK6), in vivo mouse micronucleus; not genotoxic
“Plozasiran was not genotoxic when tested in the in vitro bacterial mutation (Ames) assay, in vitro chromosomal aberration assay in cultured TK6 lymphoblastoid cells, and in vivo micronucleus assay in mice.”
Carcinogenicity
Conducted: 26-week Tg.rasH2 mouse negative; 2-year rat study ongoing
“In the 26-week study in Tg.rasH2 mice, administration of plozasiran by the SC route Q8W up to 120 mg/kg (~50-fold clinical dose, based on AUC) did not increase the incidence of tumors in male or female mice.”
Reproductive & developmental
Conducted in rat: fertility (NOAEL 50 mg/kg), EFD (NOAEL 60 mg/kg), PPND (pup survival reduced at 24 mg/kg and above); no rabbit
“The NOAEL for male and female fertility was 50 mg/kg (19-fold the human dose, based on BSA).”
Safety pharmacology
Standalone monkey CV study (single SC dose up to 300 mg/kg); hERG not warranted
“Plozasiran had no adverse effect on cardiovascular function in conscious cynomolgus monkeys following a single dose of SC injection up to 300 mg/kg.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
Rat NOAEL 120 mg/kg Q4W (47x MRHD); monkey NOAEL 180 mg/kg (140x, top dose); liver, kidney, lymph node, injection-site changes
“The NOAEL was considered 180 mg/kg/Q4W (140-fold MRHD, BSA), the highest dose tested, based on the absence of significant toxicity.”
Risksopen answer page →
Immune & cytokine safety
Proinflammatory cytokines induced in human whole blood in vitro at high concentrations; none in rat/monkey studies
“No induction of proinflammatory cytokines or inflammation were noted in the completed rat and monkey toxicity studies at doses higher than the plasma concentrations expected at MRHD”
Biodistribution & persistence
High liver concentration (>100-fold other sites), liver half-life ~4-5 days in rats
“revealed high liver concentration (>100-fold) compared to other sites and a prolonged liver elimination half-life (~4 to 5 days)”
Modality-specific risk
Hybridization-independent off-target toxicity from siRNA tissue accumulation: liver, lymph nodes, injection sites; no on-target toxicity
“All toxicology findings with chronic SC administration of plozasiran in rats and monkeys were associated with hybridization”