Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)Canada: first-in-human study in healthy volunteers
Macugen: what was done before first-in-human, and what came after?
pegaptanib · VEGF-165 (aptamer)
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 Macugen 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 3 mg/eye dog, 2 mg/eye rabbit; rat IV NOAEL 1 mg/kg/day (nephropathy, PEG vacuolated macrophages) (EMA assessment report, p. 10)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month beagle dog intravitreal study with 6-week recovery
“Dogs/Beagle 5-7/sex/group. Reversibility 2/sex in control and 3 mg groups. 0, 0.3, 1, 3 in 100µl/eye, IVT 9 months with 6 week recovery”
Pivotal GLP studies
6-month IVT rabbit and 9-month IVT dog (every 2 weeks, 6-week recovery); 13-week IV rat
“From the total of studies performed, the 6-month rabbit and 9-month dog studies are considered pivotal.”
DART package
Species: DART
Mouse (definitive IV EFD) and rabbit (IVT range-finding EFD only)
“The reproductive toxicology program included range-finding embryo-foetal development studies in rabbit and mouse and a final embryo-foetal development study in the mouse.”
Reproductive & developmental
Limited: mouse IV EFD (not teratogenic; developmental NOAEL 6.5 mg/kg); rabbit IVT range-finding only
“The reproductive toxicology program included range-finding embryo-foetal development studies in rabbit and mouse and a final embryo-foetal development study in the mouse.”
PPND / ePPND: when
No PPND study: reproductive program limited to embryo-foetal development studies in mouse and rabbit
“The reproductive toxicology program included range-finding embryo-foetal development studies in rabbit and mouse and a final embryo-foetal development study in the mouse.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Carcinogenicity studies were not conducted.”
Carcinogenicity model
Not conducted: very low systemic exposure and difficulty achieving both high systemic and intraocular exposure
“The main argument considered by the CHMP in order to accept the lack of carcinogenicity studies was due to the very low systemic exposure obtained in the clinical population together with the apparent difficulty to perform relevant study obtaining both high systemic and intraocular exposure.”
Carcinogenicity timing
Not required: CHMP accepted no carcinogenicity studies given very low systemic exposure
“The main argument considered by the CHMP in order to accept the lack of carcinogenicity studies was due to the very low systemic exposure obtained in the clinical population together with the apparent difficulty to perform relevant study obtaining both high systemic and intraocular exposure.”
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
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