Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)Canada: first-in-human study in healthy volunteers
Defitelio: what was done before first-in-human, and what came after?
defibrotide · Fragmented DNA oligonucleotides
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 Defitelio 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: 13-week rat: adverse findings in kidneys, liver and lymphoid tissues; prolonged PT (rat) and APTT (rat and dog) (FDA pharmacology/toxicology review, p. 4)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week dog study, pre-dating GLP (longest pivotal GLP study: 13 weeks); recovery not stated
“Of the 8 studies three pre-date implementation of GLP standards: 4 weeks in rats and 13/26 weeks in dogs.”
Pivotal GLP studies
Rat continuous IV infusion for 9 weeks; dog IV infusion of 2 h every 6 hours, 4 times daily, for 13 weeks
“Rats were given defibrotide by continuous iv infusion for 9 weeks. Dogs were given defibrotide by i.v. infusion of 2 h duration every 6 hours 4 times daily for 13 weeks.”
DART package
Species: DART
Rat and rabbit (IV EFD; not evaluable due to maternal mortality, abortion and resorption)
“Embryo-Fetal toxicity assessment was attempted in rats and rabbits, but was not possible because of high maternal mortality, abortion, and fetal resorption at all doses.”
Reproductive & developmental
Rabbit embryo-fetal toxicity: fewer implantations and viable fetuses at doses about equal to the clinical dose (mg/m2)
“Exposure to defibrotide was associated with embryo-fetal toxicity (decreased number of implantations and viable fetuses compared to controls) in pregnant rabbits at doses approximately equivalent to the recommended clinical dose on a mg/m2 basis.”
PPND / ePPND: when
Rat pre- and postnatal study (non-GLP, i.m., 1970s) completed before the marketing application; not fully reviewed
“Fertility and pre- and post-natal toxicology studies were conducted in the rat; however, the studies were not fully reviewed for the following reasons: non-GLP studies conducted in 1970’s with a route of administration (i.m.) different from the proposed clinical route (i.v.)”
Carcinogenicity
Species: carcinogenicity
Mouse and rat (oral route)
“Two studies in mice and rats were conducted to review the potential long-term/carcinogenicity effects of defibrotide. The studies were performed to GLP standards and used the oral route of administration.”
Carcinogenicity model
No IV carcinogenicity studies; oral studies inadequate for assessment
“No carcinogenicity studies have been conducted with defibrotide administered by the intravenous route and the oral studies were inadequate to conduct an assessment of the potential for carcinogenicity.”
Carcinogenicity timing
No IV carcinogenicity studies; oral mouse and rat studies inadequate; none required for approval
“No carcinogenicity studies have been conducted with defibrotide administered by the intravenous route and the oral studies were inadequate to conduct an assessment of the potential for carcinogenicity.”
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