Amondys 45
casimersen · DMD exon 45 (PMO)No reproductive and developmental toxicity studies; male reproductive organs and sperm evaluated in chronic studies instead
Kynamro: what flexibility did regulators accept, and why?
mipomersen · APOB (ASO)
Flexibility accepted
SpeciesAcceptedBeyond the letter
Mipomersen inactive in rodents and only partly active in monkey; pivotal rodent studies added a species-specific surrogate arm
Why: apoB mRNA sequence differences abolish or reduce mipomersen activity in animal species · No relevant species · Pharmacology or kinetics
“Species-specific differences in the nucleotide sequence of apoB mRNA caused a reduction (monkey) or complete loss (mouse, rat, dog and rabbit) of the intended pharmacological activity of mipomersen in these species.”
“In general, the nonclinical program has not identified any toxicity specifically associated with reduction in apoB100 expression (via use of species-specific surrogates) that was not also seen with mipomersen (which is only partially active in monkeys and not active in rodents or rabbits).”
Safety pharmacologyAcceptedBeyond the letter
Cardiovascular safety study conducted in monkeys instead of dogs
Why: Monkey model shown to be suitable for the preclinical development · Other reason
“The CHMP noted that monkeys instead of dogs were used in the cardiovascular safety study. However, taking into account the suitability of the monkey model showed for the preclinical development it is considered acceptable.”
Safety marginVerdict not stated
Chronic monkey NOAEL (10 mg/kg/week) corresponds to anticipated clinical exposure at 200 mg/week; no margin
“In a chronic monkey study, multi-focal intimal hyperplasia with mixed inflammatory infiltrates was evident in vascular beds in 2 of 6 monkeys treated for 12 months with 30 mg/kg/week with a no-observed-adverse-effect-level (NOAEL) of 10 mg/kg/week (clinical exposures anticipated from a 200 mg/wk dose based on body surface area comparisons across species).”
Efficacy modelQuestioned
Hepatic lipids not measured in the most hypercholesterolaemic mouse models despite steatosis concern
“While none of the pharmacology studies revealed a clear potential for apoB antisense inhibitors to cause or exacerbate hepatic steatosis, it is notable that studies in the models that have the greatest degree of hypercholesterolemia (the LDLr- Deficient Mouse, the Human ApoB transgenic/LDLr-Deficient Mouse, and the ApoE-Deficient Mouse) failed to assess hepatic lipid levels.”
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
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