Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)Canada: first-in-human study in healthy volunteers
Vitravene: what was done before first-in-human, and what came after?
fomivirsen · CMV IE2 mRNA (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 Vitravene 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 115 µg intravitreal with triamcinolone: no ocular alterations; transient IOP decrease in 3/6 (FDA review, p. 24)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
3-month study: 8 doses of 115 ug every other week
“No intact fomivirsen was observed in any of tissues (kidney, liver, ovary, and uterus) following 1, 3, or 8 doses of 10 uM (115 ug) fomivirsen administered every-other-week for three months.”
Pivotal GLP studies
Cynomolgus monkey multiple-dose intravitreal ocular toxicity and systemic exposure study, with prophylactic corticosteroid
“To evaluate the effects of ISIS 2922 on ocular tissues in cynomolgus monkeys that have received prophylactic corticosteroid treatment and to determine the systemic exposure (i.e. plasma, kidney, liver, and uterus concentrations) following multiple intravitreal injection.”
DART package
Species: DART
Not conducted: no reproductive toxicology information provided
“No information was provided.”
Reproductive & developmental
Not conducted; no reproductive toxicology information provided
“No information was provided.”
PPND / ePPND: when
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.
Carcinogenicity
Species: carcinogenicity
Not conducted (waiver requested)
“A waiver from performing carcinogenicity studies was requested by the sponsor.”
Carcinogenicity model
Not conducted: waiver citing lack of meaningful systemic exposure
“A waiver from performing carcinogenicity studies was requested by the sponsor. The sponsor stated that "lack of meaningful systemic exposure, additional systemic toxicity studies are neither relevant nor useful for assessing the safety profile of this compound".”
Carcinogenicity timing
Not required: FDA accepted the carcinogenicity waiver (local treatment of CMV retinitis)
“fomivirsen is indicated for the local treatment of CMV retinitis in AIDS patients and the dosing schedule stated in the labeling?, the review division would accept the request from the sponsor for a waiver of carcinogenicity studies on fomivirsen.”
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
Amondys 45
casimersen · DMD exon 45 (PMO)Not stated in public reviews
Amvuttra
vutrisiran · TTR (siRNA)Not stated in public reviews
Defitelio
defibrotide · Fragmented DNA oligonucleotidesNot stated in public reviews
Exondys 51
eteplirsen · DMD exon 51 (PMO)Not stated in public reviews
Hibsago
bepirovirsen · HBV RNA (ASO)Not stated in public reviews
Izervay
avacincaptad pegol · C5 (aptamer)Not stated in public reviews
Kynamro
mipomersen · APOB (ASO)Not stated in public reviews
Leqvio
inclisiran · PCSK9 (siRNA)Not stated in public reviews
Macugen
pegaptanib · VEGF-165 (aptamer)Not stated in public reviews
Onpattro
patisiran · TTR (siRNA)Not stated in public reviews
Qalsody
tofersen · SOD1 (ASO)Not stated in public reviews
Qfitlia
fitusiran · Antithrombin / SERPINC1 (siRNA)Not stated in public reviews
Redemplo
plozasiran · APOC3 (siRNA)Not stated in public reviews
Rivfloza
nedosiran · LDHA (siRNA)Not stated in public reviews
Rytelo
imetelstat · Telomerase (oligo)Not stated in public reviews
Spinraza
nusinersen · SMN2 (ASO)Not stated in public reviews
Tegsedi
inotersen · TTR (ASO)Not stated in public reviews
Tryngolza
olezarsen · APOC3 (ASO)Not stated in public reviews
Viltepso
viltolarsen · DMD exon 53 (PMO)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