Tryngolza
olezarsen
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
Mouse (with surrogate) and cynomolgus monkey
“The general toxicity of olezarsen has been characterized in repeat-dose toxicity studies in CD-1 mice and cynomolgus monkeys in studies of up to 26- and 39-weeks duration, respectively, with once-weekly SC injections.”
Why that species
Full sequence complementarity to human and cynomolgus apoC-III mRNA; mouse sequence diverges
“Olezarsen exhibits full complementarity to the apoC-III mRNA transcript of humans and cynomolgus monkeys.”
Surrogate molecule
Yes: mouse-specific GalNAc3 ASO ISIS 838707 in mouse pharmacology and 26-week mouse tox
“In wild-type mice, a mouse-specific apoC-III surrogate ASO was used (ISIS 838707, a murine”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“In a 39-week monkey toxicity study that included a 26-week recovery period, olezarsen induced a marked reduction in platelet count (>98% decrease) in a single male animal at the 12 mg/kg/wk”
Pivotal GLP studies
GLP weekly SC: CD-1 mouse 26 weeks (13-wk recovery); cynomolgus monkey 39 weeks (26-wk recovery)
“The nonclinical evaluation of the safety of olezarsen included repeat-dose general toxicology studies of up to 26 and 39-weeks in duration with 13 and 26-week recovery periods in mice and monkeys, respectively”
Route in tox
Subcutaneous (once weekly)
“once-weekly SC injections. These studies included 13- and 26-week recovery periods in the mouse and monkey, respectively.”
Skipped studiesopen answer page →
Genotoxicity
Conducted; negative (Ames, chromosomal aberration, mouse micronucleus)
“Olezarsen was not mutagenic in vitro or in vivo.”
Carcinogenicity
Not conducted with olezarsen; relied on volanesorsen lifetime mouse/rat studies (tumors of uncertain relevance)
“Carcinogenicity studies were not conducted with olezarsen, but lifetime carcinogenicity studies were conducted for the active unconjugated ASO, volanesorsen, in both mice and rats.”
Reproductive & developmental
Mouse FEED study with olezarsen; EFD and PPND bridged from volanesorsen (mice/rabbits)
“The Agency agreed that embryofetal development and pre-/postnatal development evaluations conducted with the unconjugated active ASO component of olezarsen in mice and/or rabbits were adequate to support a marketing application.”
Safety pharmacology
Stand-alone in vitro hERG and single ascending-dose SC monkey CV/respiratory/CNS study; no relevant effects
“Other than a transient increase in heart rate at the highest dose at 360 minutes, there were no effects on cardiovascular, respiratory, or central nervous system functioning observed.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
Monkey NOAEL 6 mg/kg/wk (6x BSA margin); mouse NOAEL 2 mg/kg/wk; liver, kidney, injection site, thrombocytopenia
“Drug-related effects consistent with the expected toxicities of an ASO with a phosphorothioate backbone were evident in the liver, kidney, and spleen.”
Risksopen answer page →
Immune & cytokine safety
Complement activation (Bb up, C3 down) in monkeys; MCP-1/CRP/IFN-gamma increases; ADAs in 25-62.5% of monkeys
“Dose-dependent increases in complement Bb were seen at all dosages.”
Biodistribution & persistence
Rapid distribution to liver and kidney; ASGPR-mediated liver uptake saturates at high doses
“Distribution to tissues in mouse and monkey was responsible for the initial rapid plasma clearance, with the highest concentrations present in liver and kidney.”
Modality-specific risk
ASO class: thrombocytopenia, hepatic effects, injection site reactions, hypersensitivity/complement activation
“Potentially clinically relevant observations from repeat-dose toxicity studies with olezarsen (also observed with volanesorsen, the unconjugated ASO) included thrombocytopenia, effects on the liver, injection site reactions, and hypersensitivity/inflammatory responses”