Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)Canada: first-in-human study in healthy volunteers
Waylivra: what was done before first-in-human, and what came after?
volanesorsen · APOC3 (ASO)
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 Waylivra 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 39-week NOAEL 3 mg/kg (per EMA table); thrombocytopenia, kidney/liver basophilic granules, inflammatory cytokines, injection-site findings (EMA assessment report, p. 35)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week cynomolgus monkey (SC); recovery duration not stated
“Volanesorsen plasma PK following SC administration in male and female monkeys were further studied in the 39-week toxicity study (study 304801-AS11).”
Pivotal GLP studies
GLP SC repeat-dose: monkey 13- and 39-week, rat 26-week, mouse 13- and 26-week studies; 2-year mouse and rat carcinogenicity
“Volanesorsen plasma PK following SC administration in male and female monkeys were further studied in the 39-week toxicity study (study 304801-AS11).”
DART package
Species: DART
Mouse (fertility/EFD and pre/postnatal, Segment I/II/III) and rabbit (EFD, Segment II)
“Reproductive and developmental toxicity studies were conducted in mice (Segment I/II/III), and rabbits (Segment II)”
Reproductive & developmental
Conducted: mouse fertility/EFD (Seg I/II) and peri-postnatal, rabbit EFD (Seg II); no untoward effects attributed to apoC-III reduction
“Reproductive and developmental toxicity studies were conducted in mice (Segment I/II/III), and rabbits (Segment II)”
PPND / ePPND: when
PPND in mouse (volanesorsen and murine apoC-III surrogate) completed before the marketing application
“An assessment of pre- and postnatal toxicity was performed using subcutaneous administration of volanesorsen or the murine-specific apoC-III inhibitor (ISIS 440670) on alternate days to pregnant female mice at doses up to 87.5 mg/kg/wk from Day 6 of gestation to Day 21 postpartum.”
Carcinogenicity
Species: carcinogenicity
Mouse and rat (2-year)
“The carcinogenic potential of volanesorsen was assessed in 2-yr repeated dose studies in mice (Study No. 304801-AS15) and rats (Study No. 304801-AS16).”
Carcinogenicity model
2-year mouse and rat
“The carcinogenic potential of volanesorsen was assessed in 2-yr repeated dose studies in mice (Study No. 304801-AS15) and rats (Study No. 304801-AS16).”
Carcinogenicity timing
2-year mouse and rat studies completed before the marketing application
“Two-year carcinogenicity studies were conducted in mice and rats. Test article-related neoplastic findings were above the historical control ranges, and it is likely that the neoplasms are secondary to chronic inflammation.”
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