Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)Canada: first-in-human study in healthy volunteers
Spinraza: what was done before first-in-human, and what came after?
nusinersen · SMN2 (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 Spinraza 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 neurotoxicity NOAEL 0.3 mg/dose; hippocampal neuronal vacuolation/necrosis; no CSF-based safety margin (FDA pharmacology/toxicology review, p. 89)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
53-week (one year) juvenile cynomolgus monkey study with 26-week recovery
“ISIS 396443: A one year (53 weeks) repeat dose toxicity study in juvenile cynomolgus monkeys with a 26-week recovery phase”
Pivotal GLP studies
14- and 53-week IT bolus juvenile monkey; 13-week SC juvenile mouse; single-dose IT adult monkey
“The toxicity and pharmacokinetics (PK) of ISIS 396443 were evaluated following single IT bolus doses (up to 7 mg) in adult monkeys or following repeated IT bolus doses (weekly or every other week) for 14 (0.3, 1, or 3 mg/dose) and 53 (0.3, 1, or 4 mg/dose) weeks in juvenile monkeys.”
DART package
Species: DART
Mouse and rabbit
“Developmental and reproductive toxicity studies in mice and rabbit showed no fetal effects related to treatment with nusinersen.”
Reproductive & developmental
Mouse fertility/EFD and rabbit EFD (SC): no clear toxicity; PPND ongoing as PMR
“No clear evidence of reproductive or developmental toxicity was seen in mouse and rabbit studies, and ISIS 396443 was negative for genotoxicity in a standard battery of in vitro and in vivo assays.”
PPND / ePPND: when
PPND study ongoing at approval; submission is a postmarketing requirement
“A pre- and postnatal development study is ongoing; submission of the study should be a post-marketing requirement.”
Carcinogenicity
Species: carcinogenicity
Mouse (2-year SC study, conducted after approval)
“Administration of nusinersen (0, 5, 15, or 50 mg/kg) to male and female mice by subcutaneous injection, once every two weeks for 2 years, resulted in an increase in the incidence of vascular tumors (combined hemangioma and hemangiosarcoma) at the highest dose tested.”
Carcinogenicity model
2-year SC mouse study: increased vascular tumors (hemangioma/hemangiosarcoma) at the highest dose
“Administration of nusinersen (0, 5, 15, or 50 mg/kg) to male and female mice by subcutaneous injection, once every two weeks for 2 years, resulted in an increase in the incidence of vascular tumors (combined hemangioma and hemangiosarcoma) at the highest dose tested.”
Carcinogenicity timing
No carcinogenicity study before approval; 2-year carcinogenicity study is a postmarketing requirement
“the sponsor should conduct a 2-year carcinogenicity study as a postmarketing requirement.”
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
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