Amondys 45
casimersen · DMD exon 45 (PMO)No reproductive and developmental toxicity studies; male reproductive organs and sperm evaluated in chronic studies instead
Tryngolza: what flexibility did regulators accept, and why?
olezarsen · APOC3 (ASO)
Flexibility accepted
CarcinogenicityCriticised but acceptedBeyond the letter
No carcinogenicity studies with olezarsen; lifetime mouse and rat studies of unconjugated same-sequence ASO volanesorsen relied on
Why: Volanesorsen data accepted by FDA and EMA as applicable; absence of direct olezarsen data leaves some uncertainty · Class precedent
“Carcinogenicity studies were not conducted with olezarsen, but lifetime carcinogenicity studies were conducted for the active unconjugated ASO, volanesorsen, in both mice and rats.”
“This rationale was accepted by both regulatory authorities (US FDA and EMA CHMP) and is considered applicable to humans, though the absence of direct carcinogenicity data for olezarsen itself does leave some uncertainty.”
DARTAcceptedBeyond the letter
No embryofetal or pre-/postnatal development studies with olezarsen; bridged from volanesorsen mouse/rabbit studies
Why: No effects in the same studies with unconjugated active ASO volanesorsen · Class precedent
“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.”
“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.”
Juvenile toxAcceptedBeyond the letter
No juvenile animal toxicity studies with olezarsen; volanesorsen data relied on
Why: Available volanesorsen data considered sufficient · Class precedent
“In conclusion, based on the available data from volanesorsen, no additional juvenile toxicity studies for olezarsen are warranted at this time.”
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
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
Wainua
eplontersen · TTR (ASO)Carcinogenic potential not assessed at FDA approval; 26-week Tg.rasH2 mouse study made a postmarketing requirement
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