Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)Canada: first-in-human study in healthy volunteers
Tegsedi: what was done before first-in-human, and what came after?
inotersen · 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 Tegsedi 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 39-wk NOAEL 6 mg/kg/wk (severe thrombocytopenia); rat NOAEL 5 mg/kg (glomerulopathy); margins <=~2-fold (FDA pharmacology/toxicology review, p. 70)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week cynomolgus monkey (SC) with 26-week recovery
“A 39-Week Repeat Subcutaneous Dose Toxicity Study of ISIS 420915 in Cynomolgus Monkeys with a 26-Week Interim Necropsy and a 26-Week Recovery”
Pivotal GLP studies
SC: mouse 13- and 26-week; rat 26-week; cynomolgus monkey 13-week and 39-week, with recovery
“Pivotal toxicity studies were conducted in CD-1 mouse (13-week [30-day interim] + 13-week recovery, 26-week + 13-week recovery), Sprague-Dawley rat (26-week), and cynomolgus monkey (13-week + 13-week recovery, 39-week [26-week interim] + 26-week recovery).”
DART package
Species: DART
Mouse (CD-1) and rabbit (New Zealand White)
“A full battery of reproductive and development studies was conducted in CD-1 mouse and New Zealand White rabbit.”
Reproductive & developmental
Full battery in mouse (FEED/EFD, PPND, with surrogate) and rabbit EFD; only reduced fetal weight at rabbit high dose
“A full battery of reproductive and development studies was conducted in CD-1 mouse and New Zealand White rabbit.”
PPND / ePPND: when
PPND in mouse completed before the marketing application
“The reproductive and developmental toxicity of inotersen was assessed in a fertility and embryofetal development study in mouse, an embryofetal development study in rabbit, and a pre- and postnatal development study in mouse.”
Carcinogenicity
Species: carcinogenicity
Transgenic rasH2 mouse (short-term); 2-year rat study ongoing, results post approval
“No carcinogenic potential was identified in a short-term carcinogenicity study in transgenic rasH2 mice. A 2 year carcinogenicity study in rats is currently ongoing and results will be submitted post approval.”
Carcinogenicity model
26-week TgRasH2 mouse with inotersen and mouse surrogate ISIS 401724: no drug-related tumors
“In transgenic (TgRasH2) mice, subcutaneous administration of inotersen (0, 10, 30, or 80 mg/kg) or a species-specific surrogate (ISIS 401724; 30 mg/kg) weekly for 26 weeks resulted in no drug-related increase in tumors.”
Carcinogenicity timing
rasH2 mouse study completed; 2-year rat study ongoing at approval, results submitted post approval
“No carcinogenic potential was identified in a short-term carcinogenicity study in transgenic rasH2 mice. A 2 year carcinogenicity study in rats is currently ongoing and results will be submitted post approval.”
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
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