Amondys 45
casimersen · DMD exon 45 (PMO)No reproductive and developmental toxicity studies; male reproductive organs and sperm evaluated in chronic studies instead
Wainua: what flexibility did regulators accept, and why?
eplontersen · TTR (ASO)
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
Carcinogenic potential not assessed at FDA approval; 26-week Tg.rasH2 mouse study made a 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.”
CarcinogenicityAcceptedBeyond the letter
No two-year rat carcinogenicity study; 26-week Tg.rasH2 mouse study plus data from same-sequence inotersen
Why: Negative Tg.rasH2 study, no genotoxic or proliferative findings, and inotersen (same sequence) not carcinogenic in rats · Class precedent · Weight of evidence
“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”
DARTAcceptedBeyond the letter
No rabbit embryo-fetal or pre/postnatal studies; combined mouse fertility/embryo-fetal study only, with inotersen data used instead
Why: Identical sequence to inotersen, which was tested in rabbit embryo-fetal and mouse pre/postnatal studies · Class precedent
“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.”
Same question, other oligonucleotides
Amvuttra
vutrisiran · TTR (siRNA)No carcinogenicity studies at approval; rat and mouse studies deferred to postmarketing requirements
Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)No rabbit embryo-fetal study with donidalorsen; DART in mice only, rabbit data leveraged from the unconjugated analogue ISIS 546254
Defitelio
defibrotide · Fragmented DNA oligonucleotidesFertility and pre/postnatal studies only from 1970s non-GLP intramuscular rat studies; not fully reviewed
Exondys 51
eteplirsen · DMD exon 51 (PMO)No carcinogenicity studies before approval; transgenic mouse and rat studies deferred to postmarketing requirements
Givlaari
givosiran · ALAS1 (siRNA)2-year rat carcinogenicity study still ongoing at approval; only the 26-week Tg-rasH2 mouse study completed
Hibsago
bepirovirsen · HBV RNA (ASO)No exposure margin in mouse fertility study: no adverse effects up to 0.7 times the MRHD (BSA)
Izervay
avacincaptad pegol · C5 (aptamer)Ocular toxicity studies in rabbit and dog, species in which the aptamer has very low activity; no monkey ocular study
Kynamro
mipomersen · APOB (ASO)Mipomersen inactive in rodents and only partly active in monkey; pivotal rodent studies added a species-specific surrogate arm
Leqvio
inclisiran · PCSK9 (siRNA)No juvenile toxicology study
Macugen
pegaptanib · VEGF-165 (aptamer)No carcinogenicity studies for a chronic intravitreal therapy
Onpattro
patisiran · TTR (siRNA)No 2-year rat carcinogenicity study; 26-week TgRasH2 mouse study only
Oxlumo
lumasiran · HAO1 (siRNA)Rat 2-year and transgenic mouse 6-month carcinogenicity studies incomplete at approval; deferred to postmarketing requirements
Qalsody
tofersen · SOD1 (ASO)No carcinogenicity studies before approval; carcinogenic potential to be assessed post-approval
Qfitlia
fitusiran · Antithrombin / SERPINC1 (siRNA)No reproduction studies in female animals (no embryo-fetal or pre/postnatal studies); male fertility assessed within 26-week rat study
Redemplo
plozasiran · APOC3 (siRNA)2-year rat carcinogenicity study ongoing at approval; completion to be submitted postmarketing
Rivfloza
nedosiran · LDHA (siRNA)No carcinogenicity assessment before approval; studies deferred to postmarketing
Rytelo
imetelstat · Telomerase (oligo)No carcinogenicity studies before approval; ICH S9 waiver claim not accepted by FDA; mouse and rat studies required postmarketing
Spinraza
nusinersen · SMN2 (ASO)No chronic rodent toxicity study to assess systemic exposure
Tegsedi
inotersen · TTR (ASO)2-year rat carcinogenicity study not submitted before approval; required post-marketing
Tryngolza
olezarsen · APOC3 (ASO)No carcinogenicity studies with olezarsen; lifetime mouse and rat studies of unconjugated same-sequence ASO volanesorsen relied on
Viltepso
viltolarsen · DMD exon 53 (PMO)No carcinogenicity studies before approval; Tg.rasH2 mouse and two-year rat studies required as postmarketing requirements
Vitravene
fomivirsen · CMV IE2 mRNA (ASO)No carcinogenicity studies; waiver requested citing lack of meaningful systemic exposure
Vyondys 53
golodirsen · DMD exon 53 (PMO)No carcinogenicity studies before approval; 26-week transgenic mouse and 2-year rat studies deferred post-approval
Waylivra
volanesorsen · APOC3 (ASO)Mouse and rat carcinogenicity studies of limited value: high toxicity-related mortality and early termination of study groups
Zanvastro
zilganersen · GFAP (ASO)No carcinogenicity studies before approval; completion required as postmarketing requirements