Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)Canada: first-in-human study in healthy volunteers
Amvuttra: what was done before first-in-human, and what came after?
vutrisiran · 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 Amvuttra 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: NOAEL = high doses (150 mg/kg rat, 300 mg/kg monkey monthly); ~600x/~4400x human AUC; non-adverse liver, kidney, lymph node findings (FDA pharmacology/toxicology review, p. 9)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month SC cynomolgus monkey study (and 6-month rat); no recovery phase
“Given the generally mild effects, recovery periods did not follow the dosing phases of the 6 and 9 months toxicity studies.”
Pivotal GLP studies
Rat 13-week and 26-week SC monthly; monkey 13-week and 9-month (40-week) SC every 4 weeks
“Frequency of dosing: Every 4 weeks, Day 1 to Day 281 Route of administration: SC injection to the dorsal region”
DART package
Species: DART
SD rat (fertility, EFD, pre/postnatal) and New Zealand White rabbit (EFD)
“GLP-compliant studies consisted of a fertility and early embryonic development (to implantation) study, an embryofetal development study, and a pre- and postnatal development study in SD rat, and an embryofetal development study in New Zealand White rabbit.”
Reproductive & developmental
Rat fertility (with surrogate), rat and rabbit EFD, rat PPND; rat EFD toxicity at maternally hepatotoxic doses
“The LD was the NOAEL for maternal and developmental toxicity.”
PPND / ePPND: when
GLP PPND in rat completed and submitted with the marketing application; no adverse effects
“In a GLP pre- and postnatal development study in rat, SC administration of vutrisiran (0, 5, 10, or 20 mg/kg on GD 7, 13, and 19, and lactation days 6, 12, and 18) resulted in no adverse effects.”
Carcinogenicity
Species: carcinogenicity
Rat and mouse (2-year)
“Per prior agreement, 2-year carcinogenicity studies of vutrisiran in rat and mouse are to be conducted as post-marketing requirements.”
Carcinogenicity model
Rat SC every 4 or 12 weeks for 99 (males) / 86-87 (females) weeks: no increase in tumors
“Subcutaneous administration of vutrisiran to male rats (0, 4, 7.5, or 15 mg/kg once every 4 weeks or 15 mg/kg once every 12 weeks) for 99 weeks and to female rats (0, 6, 12.5, or 25 mg/kg once every 4 weeks or 25 mg/kg once every 12 weeks) for 86-87 weeks resulted in no increase in tumors.”
Carcinogenicity timing
2-year rat and mouse studies ongoing at approval; final reports to be submitted post approval
“The potential carcinogenicity of vutrisiran is being assessed in ongoing 2-year studies in rat and mouse; final reports will be submitted post approval per prior agreement with the Division.”
Same question, other oligonucleotides
Givlaari
givosiran · ALAS1 (siRNA)US, UK and Sweden: 6 clinical study centers (4 US, 1 UK, 1 Sweden)
Oxlumo
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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