Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)Canada: first-in-human study in healthy volunteers
Qfitlia: what was done before first-in-human, and what came after?
fitusiran · Antithrombin / SERPINC1 (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 Qfitlia 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: Rat 26-wk NOAEL 1 mg/kg/wk females, 0.5 mg/kg/wk males (fatal clotting at 1); monkey 39-wk 0.5 mg/kg/wk tolerated; thrombosis, hepatic necrosis, injection-site findings (FDA integrated review, p. 153)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week cynomolgus monkey (SC, weekly) with 13-week recovery
“A 39-Week Subcutaneous Injection Toxicity and Toxicokinetic Study in the Cynomolgus Monkey Followed by a 13-Week Recovery Period (AT3-NCD14-007)”
Pivotal GLP studies
GLP SC weekly: rat 26-week with FEED (13-wk recovery), monkey 39-week (13-wk recovery), 7-week rat and monkey studies, 26-week hemophilia A mouse
“A 26-Week Subcutaneous Injection Toxicity, Toxicokinetic, and Fertility and Early Embryonic Development (to Implantation) Study in the Rat Followed By a 13-Week Recovery Period”
DART package
Species: DART
Rat (male fertility within 26-week study only); no EFD studies in rats or rabbits as hemophilia is X-linked
“Because hemophilia is primarily an X-linked disease, no embryo-fetal toxicity studies in rats and rabbits have been performed.”
Reproductive & developmental
Male fertility/early embryonic development in 26-week rat study (no effects); no female reproductive or EFD studies (hemophilia almost exclusively male)
“Fitusiran was not tested in reproduction studies in female animals because hemophilia A and B occur almost exclusively in males.”
PPND / ePPND: when
No PPND study: no reproduction studies in female animals because hemophilia A and B occur almost exclusively in males
“Fitusiran was not tested in reproduction studies in female animals because hemophilia A and B occur almost exclusively in males.”
Carcinogenicity
Species: carcinogenicity
Rat (2-year) and TgRasH2 mouse (26-week)
“The Sponsor submitted final reports for carcinogenicity studies of fitusiran 1. A 26-week study in TgRasH2 mouse study-at3-glp17-001.pdf, 2. A 2-year study in rats study-car0186.pdf.”
Carcinogenicity model
2-year rat and 26-week TgRasH2 mouse
“The Sponsor submitted final reports for carcinogenicity studies of fitusiran 1. A 26-week study in TgRasH2 mouse study-at3-glp17-001.pdf, 2. A 2-year study in rats study-car0186.pdf.”
Carcinogenicity timing
26-week TgRasH2 mouse and 2-year rat studies completed; final reports submitted with the marketing application
“The Sponsor submitted final reports for carcinogenicity studies of fitusiran 1. A 26-week study in TgRasH2 mouse study-at3-glp17-001.pdf, 2. A 2-year study in rats study-car0186.pdf.”
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
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
Vitravene
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