Tryngolza
olezarsen
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”
Species: general tox
CD-1 mouse 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.”
Species: DART
Mice and/or rabbits for EFD and pre-/postnatal studies with the unconjugated ASO (volanesorsen)
“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.”
Species: carcinogenicity
Mouse and rat lifetime studies with unconjugated volanesorsen; none with olezarsen
“Carcinogenicity studies were not conducted with olezarsen, but lifetime carcinogenicity studies were conducted for the active unconjugated ASO, volanesorsen, in both mice and rats.”
Surrogate used in
Yes: mouse-specific apoC-III surrogate ASO for mouse pharmacology and repeat-dose toxicity
“Non-clinical studies were mainly conducted in monkeys, except for some cases where a mouse specific surrogate inhibitor of apoC-III mRNA was used for pharmacodynamic (PD) and repeated-dose toxicity studies in mouse.”
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.”
Genotox: Ames
Negative (no mutagenic potential in bacterial systems)
“Overall, this test concluded that olezarsen does not possess mutagenic potential in bacterial systems.”
Genotox: in vitro mammalian
Chromosome aberration in CHL cells: negative
“Consequently, olezarsen was considered negative for clastogenicity, meaning it did not cause chromosomal damage in CHL cells up to the highest concentration tested.”
Genotox: in vivo
In vivo micronucleus assay: negative
“For genotoxicity, the studies conducted did not show any mutagenic or clastogenic potential, with negative results in the Ames test, chromosome aberration assay, and in vivo micronucleus assay.”
Carcinogenicity model
Not conducted with olezarsen; lifetime mouse and rat studies of unconjugated volanesorsen relied on
“Carcinogenicity studies were not conducted with olezarsen, but lifetime carcinogenicity studies were conducted for the active unconjugated ASO, volanesorsen, in both mice and rats.”
Carcinogenicity timing
Not required for olezarsen: volanesorsen carcinogenicity data accepted by FDA and EMA
“they determined that no additional carcinogenicity studies were required for olezarsen, and that the data from volanesorsen’s carcinogenicity studies were sufficient to support olezarsen.”
hERG / QT
Minimal hERG reduction (<2%) at 30 and 300 µM; IC50 >300 µM
“At concentrations of 30 and 300 µM, minimal reductions (<2%) in hERG current were noted. The IC50 was considered >300µM (greater than 1000 times the human exposure).”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Tryngolza don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oligonucleotides outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Monkey NOAEL 6 mg/kg/wk (6x BSA margin); mouse NOAEL 2 mg/kg/wk; liver, kidney, injection site, thrombocytopenia (FDA integrated review, p. 220)
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”
Anti-drug antibodies: animals
ADAs in 25.0-62.5% of monkeys after 9 months (2-30 mg/kg)
“However, regarding immunogenicity, the incidence of anti-drug antibodies (ADA) was notable, with 25.0% to 62.5% of monkeys developing antibodies after 9 months of treatment at doses between 2 to 30 mg/kg.”
Anti-drug antibodies: patients
42% (18/43) of FCS patients developed treatment-emergent ADAs through 53 weeks
“In Trial 1, among patients with FCS treated with TRYNGOLZA, 18 of 43 patients (42%) developed treatment-emergent anti-drug antibodies (ADAs) through 53 weeks of treatment.”
Label warnings
- Hypersensitivity Reactions
- Liver Enzyme Abnormalities
Hypersensitivity & infusion reactionsHepatotoxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Tryngolza don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oligonucleotides outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Monkey NOAEL 6 mg/kg/wk (6x BSA margin); mouse NOAEL 2 mg/kg/wk; liver, kidney, injection site, thrombocytopenia (FDA integrated review, p. 220)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week monkey study with 26-week recovery
“In a 39-week monkey toxicity study that included a 26-week recovery period, olezarsen induced a marked reduction in platelet count (>98% decrease)”
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”
DART package
Species: DART
Mice and/or rabbits for EFD and pre-/postnatal studies with the unconjugated ASO (volanesorsen)
“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.”
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.”
PPND / ePPND: when
Not conducted with olezarsen: waived; mouse PPND with unconjugated volanesorsen relied on
“Studies evaluating embryofetal development and pre-/postnatal development were not conducted with olezarsen as there were no effects on parameters evaluated in these studies conducted with the unconjugated ASO volanesorsen.”
Carcinogenicity
Species: carcinogenicity
Mouse and rat lifetime studies with unconjugated volanesorsen; none with olezarsen
“Carcinogenicity studies were not conducted with olezarsen, but lifetime carcinogenicity studies were conducted for the active unconjugated ASO, volanesorsen, in both mice and rats.”
Carcinogenicity model
Not conducted with olezarsen; lifetime mouse and rat studies of unconjugated volanesorsen relied on
“Carcinogenicity studies were not conducted with olezarsen, but lifetime carcinogenicity studies were conducted for the active unconjugated ASO, volanesorsen, in both mice and rats.”
Carcinogenicity timing
Not required for olezarsen: volanesorsen carcinogenicity data accepted by FDA and EMA
“they determined that no additional carcinogenicity studies were required for olezarsen, and that the data from volanesorsen’s carcinogenicity studies were sufficient to support olezarsen.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOAEL 6 mg/kg/wk ~6x MRHD (80 mg/month) by BSA
“This NOAEL of 6 mg/kg/wk gives a 6x safety margin based on BSA relative to maximum recommended human dose of 80 mg/month.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Human apoC-III transgenic mice, wild-type CD-1 mice (mouse surrogate) and cynomolgus monkeys; primary hepatocytes in vitro
“Olezarsen was evaluated in vitro in primary hepatocytes, transgenic mice expressing human apoC-III, wild-type (normal) CD-1 mice and cynomolgus monkeys.”
Why that model
Surrogate needed in wild-type mice due to mouse/human apoC-III mRNA sequence divergence
“due to the divergence in sequence between mouse and human apoC-III mRNA”
Reviewer's view of the efficacy data
FDA: animal models gave reasonable proof-of-concept supporting human trials
“Results from these animal models provide reasonable proof-of-concept that supported the initiation of human trials as assessed using a clinically translatable and monitorable pharmacological endpoint, plasma TG.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityCriticised but acceptedBeyond the letter
No carcinogenicity studies with olezarsen; lifetime mouse and rat studies of unconjugated same-sequence ASO volanesorsen relied on
Why: Volanesorsen data accepted by FDA and EMA as applicable; absence of direct olezarsen data leaves some uncertainty · Class precedent
“Carcinogenicity studies were not conducted with olezarsen, but lifetime carcinogenicity studies were conducted for the active unconjugated ASO, volanesorsen, in both mice and rats.”
“This rationale was accepted by both regulatory authorities (US FDA and EMA CHMP) and is considered applicable to humans, though the absence of direct carcinogenicity data for olezarsen itself does leave some uncertainty.”
DARTAcceptedBeyond the letter
No embryofetal or pre-/postnatal development studies with olezarsen; bridged from volanesorsen mouse/rabbit studies
Why: No effects in the same studies with unconjugated active ASO volanesorsen · Class precedent
“Studies evaluating embryofetal development and pre-/postnatal development were not conducted with olezarsen as there were no effects on parameters evaluated in these studies conducted with the unconjugated ASO volanesorsen.”
“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.”
Juvenile toxAcceptedBeyond the letter
No juvenile animal toxicity studies with olezarsen; volanesorsen data relied on
Why: Available volanesorsen data considered sufficient · Class precedent
“In conclusion, based on the available data from volanesorsen, no additional juvenile toxicity studies for olezarsen are warranted at this time.”
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