Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)Canada: first-in-human study in healthy volunteers
Wainua: what was done before first-in-human, and what came after?
eplontersen · TTR (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 Wainua 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 NOAEL 25 mg/kg Q4W (39 wk; 134x AUC margin); basophilic granules liver/kidney/lymph nodes; one monkey thrombocytopenia (FDA integrated review, p. 50)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month (39-week) cynomolgus monkey (SC) with 3-month recovery
“Study 682884-AS05, 9-Month Repeat Dose Toxicity Study of ION-682884 in Cynomolgus Monkeys With a 3-Month Recovery Phase (GLP)”
Pivotal GLP studies
GLP SC studies: mouse 13 and 26 weeks; cynomolgus monkey 13 weeks and 9 months (39 weeks)
“The nonclinical studies of eplontersen submitted to the NDA included general toxicology studies of up to 26 weeks (mouse) and 9 months (monkey) in duration”
DART package
Species: DART
Mouse (combined fertility and EFD); no second-species EFD or PPND
“The potential for adverse effects on fertility and embryofetal development (EFD) was assessed in a combined fertility and EFD study in mouse”
Reproductive & developmental
Combined fertility/EFD study in mouse (with surrogate); no adverse effects; no 2nd species, PPND or juvenile
“Potential effect of eplontersen on embryo-foetal development in a second species, pre- and post-natal development or juvenile toxicity were not investigated.”
PPND / ePPND: when
No PPND for eplontersen; not required because identical-sequence inotersen was tested in mouse PPND and rabbit EFD
“As eplontersen harbours the identical sequence of inotersen, which had been also tested with respect to embryo-foetal development in rabbits and in a pre-/postnatal development study in mice (see EPAR of “Tegsedi”, the previous CHMP advice is confirmed that further reproduction and developmental toxicity studies are not required for eplontersen.”
Carcinogenicity
Species: carcinogenicity
Tg.rasH2 mouse (26-week); no 2-year rat study
“Based on the negative outcome of this investigation in Tg.rasH2 mice, the lack of genotoxicity, immunosuppressive or proliferative findings in other toxicity studies, as well as the similarity of eplontersen and inotersen, which was not carcinogenic in rats, the lack of a 2 years rat carcinogenicity study is acceptable”
Carcinogenicity model
26-week Tg.rasH2 mouse, SC up to 1500 mg/kg/month; not tumorigenic
“Eplontersen was not tumorigenic following s.c. injections up to 1500 mg/kg/month in a GLP-compliant 26 weeks carcinogenicity study in transgenic Tg.rasH2 mice.”
Carcinogenicity timing
26-week Tg.rasH2 mouse not assessed at the marketing application; postmarketing requirement
“The carcinogenic potential of eplontersen has not been assessed. A 26-week carcinogenicity study in the tg.ratH2 mouse will be a post-marketing 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
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
Waylivra
volanesorsen · APOC3 (ASO)Not stated in public reviews