Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)Canada: first-in-human study in healthy volunteers
Tryngolza: what was done before first-in-human, and what came after?
olezarsen · APOC3 (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 Tryngolza 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/wk (6x BSA margin); mouse NOAEL 2 mg/kg/wk; liver, kidney, injection site, thrombocytopenia (FDA integrated review, p. 220)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week monkey study with 26-week recovery
“In a 39-week monkey toxicity study that included a 26-week recovery period, olezarsen induced a marked reduction in platelet count (>98% decrease)”
Pivotal GLP studies
GLP weekly SC: CD-1 mouse 26 weeks (13-wk recovery); cynomolgus monkey 39 weeks (26-wk recovery)
“The nonclinical evaluation of the safety of olezarsen included repeat-dose general toxicology studies of up to 26 and 39-weeks in duration with 13 and 26-week recovery periods in mice and monkeys, respectively”
DART package
Species: DART
Mice and/or rabbits for EFD and pre-/postnatal studies with the unconjugated ASO (volanesorsen)
“The Agency agreed that embryofetal development and pre-/postnatal development evaluations conducted with the unconjugated active ASO component of olezarsen in mice and/or rabbits were adequate to support a marketing application.”
Reproductive & developmental
Mouse FEED study with olezarsen; EFD and PPND bridged from volanesorsen (mice/rabbits)
“The Agency agreed that embryofetal development and pre-/postnatal development evaluations conducted with the unconjugated active ASO component of olezarsen in mice and/or rabbits were adequate to support a marketing application.”
PPND / ePPND: when
Not conducted with olezarsen: waived; mouse PPND with unconjugated volanesorsen relied on
“Studies evaluating embryofetal development and pre-/postnatal development were not conducted with olezarsen as there were no effects on parameters evaluated in these studies conducted with the unconjugated ASO volanesorsen.”
Carcinogenicity
Species: carcinogenicity
Mouse and rat lifetime studies with unconjugated volanesorsen; none with olezarsen
“Carcinogenicity studies were not conducted with olezarsen, but lifetime carcinogenicity studies were conducted for the active unconjugated ASO, volanesorsen, in both mice and rats.”
Carcinogenicity model
Not conducted with olezarsen; lifetime mouse and rat studies of unconjugated volanesorsen relied on
“Carcinogenicity studies were not conducted with olezarsen, but lifetime carcinogenicity studies were conducted for the active unconjugated ASO, volanesorsen, in both mice and rats.”
Carcinogenicity timing
Not required for olezarsen: volanesorsen carcinogenicity data accepted by FDA and EMA
“they determined that no additional carcinogenicity studies were required for olezarsen, and that the data from volanesorsen’s carcinogenicity studies were sufficient to support olezarsen.”
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
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