Amondys 45
casimersen · DMD exon 45 (PMO)No reproductive and developmental toxicity studies; male reproductive organs and sperm evaluated in chronic studies instead
Givlaari: what flexibility did regulators accept, and why?
givosiran · ALAS1 (siRNA)
Flexibility accepted
CarcinogenicityVerdict not stated
2-year rat carcinogenicity study still ongoing at approval; only the 26-week Tg-rasH2 mouse study completed
“There was no evidence of carcinogenicity in the 26-week conducted in f Tg-rasH2 mice. A longer, 2-year carcinogenicity study in Sprague Dawley rats (AS1-GLP18-007), currently ongoing, will be submitted upon its completion.”
Juvenile toxAcceptedBeyond the letter
No dedicated juvenile animal studies; young monkeys (13 to 17 months old) in the 39-week study used to support adolescents
Why: Monkeys aged 13 to 17 months at study start cover the developmental age of adolescents 12 years and older · Weight of evidence
“Dedicated studies were not conducted in juvenile animals. In the chronic monkey GLP toxicology study, givosiran was administered once weekly at dose levels between 10 and 100 mg/kg for 39 weeks, followed by a 13-week recovery phase.”
“At initiation of the treatment, monkeys were 13 to 17 months old. Monkeys at 24 to 36 months old are generally considered the corresponding development age of adolescent up to 12 years of age in human.”
OtherVerdict not stated
Repeat-dose toxicity studies dosed once weekly rather than the once-monthly clinical schedule
“The studies were conducted using the subcutaneous route of administration, which is consistent with the intended clinical route of administration; however, animals were dosed once weekly instead of the once monthly dose schedule used to treat patients.”
SpeciesVerdict not stated
Rabbit embryo-fetal study conducted in a pharmacologically inactive species (no hepatic ALAS1 knockdown)
“Pharmacodynamics measurement on GD 22 indicated that givosiran did not reduce hepatic ALAS1 transcript levels in pregnant rabbits at any dose level, confirming that givosiran is not pharmacologically active in rabbits.”
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
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