Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)Canada: first-in-human study in healthy volunteers
Onpattro: what was done before first-in-human, and what came after?
patisiran · TTR (siRNA)
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 Onpattro 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: Liver (single-cell necrosis, vacuolation) drove NOAELs in all species; also spleen, bone marrow, lymph nodes, adrenal (EMA assessment report, p. 40)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week monkey IV study (every 3 weeks); recovery phase not stated
“Intravenous administration of patisiran-LC (0, 0.3, 1, or 2 mg/kg) to adult monkeys every three weeks for 39 weeks produced no adverse effects on male reproductive organs or on sperm morphology or count.”
Pivotal GLP studies
Monkey 6-week (q2w) and 39-week (q3w) IV; rat 6-week and 26-week IV; plus luciferase-LNP control arms
“It is noted that no single cell necrosis or adverse findings are found in the 26-week rat study.”
DART package
Species: DART
Rat (with rodent-specific surrogate) and rabbit
“In animal studies, intravenous administration of patisiran lipid complex (patisiran-LC) to pregnant rabbits resulted in developmental toxicity (embryofetal mortality and reduced fetal body weight) at doses that were also associated with maternal toxicity. No adverse developmental effects were observed when patisiran-LC or a rodent-specific (pharmacologically active) surrogate were administered to pregnant rats (see Data ).”
Reproductive & developmental
Full DART: rat fertility/EFD and PPND (with rodent surrogate), rabbit EFD; no adverse effects in rat
“No adverse developmental effects were observed when patisiran-LC or a rodent-specific (pharmacologically active) surrogate were administered to pregnant rats (see Data ).”
PPND / ePPND: when
PPND with patisiran-LNP and rodent surrogate AF-011-18534 completed before the marketing application; NOAEL 1.5 mg/kg
“Prenatal and postnatal development, including maternal function: The NOAEL for maternal toxicity and for viability and growth in the offspring for patisiran-LNP and AF-011-18534 were 1.5 mg/kg, the highest dose tested for patisiran-LNP”
Carcinogenicity
Species: carcinogenicity
TgRasH2 mouse (26-week); no 2-year rat study
“A 2-year carcinogenicity study of patisiran-LNP in rats was not conducted because of the technical challenges of long term IV administration of patisiran-LNP, and the immunogenicity (development of ADA) that was observed in the 26-week chronic rat study. However, a 26-week carcinogenicity was performed in TgRasH2 mice.”
Carcinogenicity model
26-week TgRasH2 mouse; 2-year rat not conducted (long-term IV challenges, ADA in rats)
“A 2-year carcinogenicity study of patisiran-LNP in rats was not conducted because of the technical challenges of long term IV administration of patisiran-LNP, and the immunogenicity (development of ADA) that was observed in the 26-week chronic rat study. However, a 26-week carcinogenicity was performed in TgRasH2 mice.”
Carcinogenicity timing
26-week TgRasH2 mouse completed before the marketing application; 2-year rat not conducted
“A 2-year carcinogenicity study of patisiran-LNP in rats was not conducted because of the technical challenges of long term IV administration of patisiran-LNP, and the immunogenicity (development of ADA) that was observed in the 26-week chronic rat study. However, a 26-week carcinogenicity was performed in TgRasH2 mice.”
Same question, other oligonucleotides
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lumasiran · HAO1 (siRNA)UK: single ascending dose in healthy subjects (Study 001 Part A)
Zanvastro
zilganersen · GFAP (ASO)United States and other countries: ION373-CS1, the single combined first clinical and pivotal trial in AxD patients
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Spinraza
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Viltepso
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fomivirsen · CMV IE2 mRNA (ASO)Not stated in public reviews
Vyondys 53
golodirsen · DMD exon 53 (PMO)Not stated in public reviews
Wainua
eplontersen · TTR (ASO)Not stated in public reviews
Waylivra
volanesorsen · APOC3 (ASO)Not stated in public reviews