Kynamro
mipomersen · APOB (ASO)Applicant estimated safe starting dose from nonclinical results; method not specified
Defitelio: how was the first human dose set?
defibrotide · Fragmented DNA oligonucleotides
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)
NOAEL / key findings
13-week rat: adverse findings in kidneys, liver and lymphoid tissues; prolonged PT (rat) and APTT (rat and dog)
“Target organs of toxicity were identified in a 13-week rat toxicology study, which included adverse findings in the kidneys, liver and lymphoid tissues. Defibrotide also prolonged prothrombin time (PT) in rats, in addition to activated partial thromboplastin time (APTT) in rats and dogs.”
Same question, other oligonucleotides
Zanvastro
zilganersen · GFAP (ASO)Starting-dose rationale not stated; FDA capped clinical IT dose at 25 mg (~1/10 mouse/monkey NOAEL), later 50 mg Q12W
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