Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)Canada: first-in-human study in healthy volunteers
Viltepso: what was done before first-in-human, and what came after?
viltolarsen · DMD exon 53 (PMO)
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 Viltepso 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 60 mg/kg/wk IV in monkey (39-wk) and mouse (26-wk); renal tubular vacuolation/dilation; mouse deaths at 1000 mg/kg (FDA pharmacology/toxicology review, p. 47)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week IV cynomolgus monkey study with 8-week recovery
“Monkey: Viltolarsen was administered by IV injection for 12 weeks (+4-week recovery) and 39 weeks (+8-week recovery)”
Pivotal GLP studies
Weekly IV: male mouse 13 and 26 weeks; male monkey 12 and 39 weeks; juvenile male mouse PND 7-70
“The pivotal IV toxicity studies were conducted in male CD-1 mouse (13 and 26 weeks) and male cynomolgus monkey (12 and 39 weeks).”
DART package
Species: DART
Male CD-1 mouse fertility and early embryonic development only; EFD and pre/postnatal studies not conducted (male population)
“Embryofetal development and pre- and postnatal development studies were not conducted, as agreed to by the Division, because of the intended patient population, which is almost exclusively male. A fertility and early embryonic development study was conducted in male CD-1 mice, which were mated with untreated females.”
Reproductive & developmental
Male mouse fertility study only (no effects); EFD/PPND waived for male population; juvenile mouse study
“Embryofetal development and pre- and postnatal development studies were not conducted, as agreed to by the Division, because of the intended patient population, which is almost exclusively male.”
PPND / ePPND: when
Not conducted: waived because the patient population is almost exclusively male
“Embryofetal development and pre- and postnatal development studies were not conducted, as agreed to by the Division, because of the intended patient population, which is almost exclusively male.”
Carcinogenicity
Species: carcinogenicity
Not conducted pre-approval; 26-week Tg.rasH2 mouse and 2-year rat required as PMRs
“If the application is approved, a 26-week carcinogenicity study in Tg.rasH2 mouse and a 2-year carcinogenicity study in rat should be conducted as PMRs.”
Carcinogenicity model
Not conducted; SPA protocols for 26-week Tg.rasH2 mouse and 2-year rat reviewed by the Division and Executive CAC
“Protocols for a 26-week study in Tg.rasH2 mouse and a 2-year study in rat were submitted for review under Special Protocol Assessment and were reviewed by the Division and the Executive CAC under IND 127474 (Minutes dated July 12, 2018, and August 9, 2019, respectively).”
Carcinogenicity timing
Not conducted before approval; 26-week Tg.rasH2 mouse and 2-year rat studies are postmarketing requirements
“If the application is approved, a 26-week carcinogenicity study in Tg.rasH2 mouse and a 2-year carcinogenicity study in rat should be conducted as PMRs.”
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
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