Givlaari
givosiran · ALAS1 (siRNA)US, UK and Sweden: 6 clinical study centers (4 US, 1 UK, 1 Sweden)
Dawnzera: what was done before first-in-human, and what came after?
donidalorsen · Prekallikrein / KLKB1 (ASO)
Before first-in-human
First-in-human: where
Canada: first-in-human study in healthy volunteers
“A phase 1 study, Protocol No. ISIS 721744-CS1, was previously conducted in Canada to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of ISIS 721744 in healthy volunteers.”
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 Dawnzera 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 6 mg/kg/week (platelet reductions at higher doses; ~29-fold margin); mouse NOAEL top dose; liver and kidney target organs (EMA assessment report, p. 31)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week SC cynomolgus monkey study (13-week interim) with 26-week treatment-free recovery
“The plasma TK profile of SC administration of donidalorsen was evaluated in a GLP-compliant 13-week interim/39-week repeat-dose toxicity study in Cynomolgus monkeys with a 26-week treatment-free recovery period.”
Pivotal GLP studies
13- and 26-week SC studies in CD-1 mice; 13-week interim/39-week SC study in cynomolgus monkeys with 26-week recovery
“plasma TK profile of SC administration of donidalorsen was evaluated in a GLP-compliant 13-week interim/39-week repeat-dose toxicity study in Cynomolgus monkeys with a 26-week treatment-free recovery period”
DART package
Species: DART
CD-1 mouse only (combined fertility/EFD and pre-/postnatal studies); no rabbit study
“Reproductive and developmental toxicity studies were conducted in one species only, namely CD-1 mice”
Reproductive & developmental
Conducted in mice only: combined fertility/EFD and PPND studies (with surrogate group); NOAEL top dose; no rabbit EFD
“Reproductive and developmental toxicity studies were conducted in one species only, namely CD-1 mice”
PPND / ePPND: when
PPND in mouse completed and submitted with the marketing application
“This review evaluates the GLP-compliant reproductive and developmental toxicology studies with ISIS 721744 (i.e., combined fertility and developmental toxicity study in mice and PPND study in mice) to support the safety of ISIS 721744 for marketing approval.”
Carcinogenicity
Species: carcinogenicity
Tg.rasH2 mouse (27-week, completed) and SD rat (2-year, ongoing)
“The carcinogenicity assessment for donidalorsen includes a completed 27-week study in Tg.rasH2 mice and a 2-year study in SD rats that is ongoing with the final report due in Q4 2025.”
Carcinogenicity model
27-week Tg.rasH2 mouse (completed); 2-year SD rat (ongoing)
“The carcinogenicity assessment for donidalorsen includes a completed 27-week study in Tg.rasH2 mice and a 2-year study in SD rats that is ongoing with the final report due in Q4 2025.”
Carcinogenicity timing
27-week Tg.rasH2 mouse completed; 2-year SD rat ongoing at approval, final report due Q4 2025
“The carcinogenicity assessment for donidalorsen includes a completed 27-week study in Tg.rasH2 mice and a 2-year study in SD rats that is ongoing with the final report due in Q4 2025.”
Same question, other oligonucleotides
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
Wainua
eplontersen · TTR (ASO)Not stated in public reviews
Waylivra
volanesorsen · APOC3 (ASO)Not stated in public reviews