Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)Canada: first-in-human study in healthy volunteers
Hibsago: what was done before first-in-human, and what came after?
bepirovirsen · HBV RNA (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 Hibsago 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 not stated; 2-year mouse: hepatocellular carcinomas at ≥10 mg/kg; liver adenomas and hemangiosarcomas at 30 mg/kg (males)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
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.
Pivotal GLP studies
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.
DART package
Species: DART
Mouse and rabbit (animal reproduction studies)
“In animal reproduction studies, no adverse developmental or reproductive effects were observed when bepirovirsen was administered subcutaneously to mice and rabbits at less than 1 (mouse) and approximately 3 (rabbits) times the maximum recommended human dose (MRHD), based on body surface area (BSA) comparisons (see Data).”
Reproductive & developmental
Mouse and rabbit: no adverse developmental or reproductive effects at <1x (mouse) and ~3x (rabbit) MRHD, BSA
“In animal reproduction studies, no adverse developmental or reproductive effects were observed when bepirovirsen was administered subcutaneously to mice and rabbits at less than 1 (mouse) and approximately 3 (rabbits) times the maximum recommended human dose (MRHD), based on body surface area (BSA) comparisons (see Data).”
PPND / ePPND: when
Pre- and postnatal development in mouse (GD 6 to LD 21) completed, described in the approved label
“No adverse effects on embryofetal development, parturition, or on the postnatal development of the offspring were observed following subcutaneous administration of bepirovirsen to pregnant mice during organogenesis and throughout pregnancy and lactation [Gestation day (GD) 0 to 15 and from GD 6 to lactation day (LD) 21], at 0.7 times the MRHD based on BSA comparison.”
Carcinogenicity
Species: carcinogenicity
Mouse (2-year, subcutaneous)
“In a 2-year carcinogenicity study in mice, bepirovirsen sodium was administered by subcutaneous injection weekly at doses of 3, 10, and 30 mg/kg (approximately 0.05, 0.2, and 0.5 times the RHD, respectively, based on BSA comparison).”
Carcinogenicity model
2-year mouse, weekly subcutaneous 3, 10, 30 mg/kg (about 0.05-0.5x RHD, BSA)
“In a 2-year carcinogenicity study in mice, bepirovirsen sodium was administered by subcutaneous injection weekly at doses of 3, 10, and 30 mg/kg (approximately 0.05, 0.2, and 0.5 times the RHD, respectively, based on BSA comparison).”
Carcinogenicity timing
2-year subcutaneous mouse study completed, described in the approved label
“In a 2-year carcinogenicity study in mice, bepirovirsen sodium was administered by subcutaneous injection weekly at doses of 3, 10, and 30 mg/kg (approximately 0.05, 0.2, and 0.5 times the RHD, respectively, based on BSA comparison).”
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
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
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