Amondys 45
casimersen · DMD exon 45 (PMO)No reproductive and developmental toxicity studies; male reproductive organs and sperm evaluated in chronic studies instead
Defitelio: what flexibility did regulators accept, and why?
defibrotide · Fragmented DNA oligonucleotides
Flexibility accepted
DARTVerdict not stated
Fertility and pre/postnatal studies only from 1970s non-GLP intramuscular rat studies; not fully reviewed
“Fertility and pre- and post-natal toxicology studies were conducted in the rat; however, the studies were not fully reviewed for the following reasons: non-GLP studies conducted in 1970’s with a route of administration (i.m.) different from the proposed clinical route (i.v.)”
DARTQuestioned
Intravenous embryo-fetal studies in rats and rabbits non-GLP and not evaluable due to maternal toxicity
“These studies provided very limited information about defibrotide effects on embryo-foetal development as they could not be evaluated; the studies performed were also non GLP-compliant.”
“The pharmacokinetic and toxicological aspects of the non-clinical dossier are limited in their relevance to this application and a number of the older studies presented pre-date GLP.”
CarcinogenicityVerdict not stated
No intravenous carcinogenicity studies; oral rat and mouse studies inadequate to assess carcinogenic potential
“No carcinogenicity studies have been conducted with defibrotide administered by the intravenous route and the oral studies were inadequate to conduct an assessment of the potential for carcinogenicity.”
Efficacy modelQuestioned
Pharmacological rationale not established nonclinically; no extrapolation to clinical data on pharmacological plausibility
“Based on the provided data, the CHMP concluded that the pharmacological rationale for the use of defibrotide has not been established; therefore, no extrapolations to clinical data can be made based on “pharmacological plausibility”.”
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
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
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