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Precedia/Oligonucleotides/Waylivra/Flexibility

Waylivra: what flexibility did regulators accept, and why?

volanesorsen · APOC3 (ASO)
Check my plan vs. these
Flexibility accepted
CarcinogenicityCriticised but acceptedBeyond the letter
Mouse and rat carcinogenicity studies of limited value: high toxicity-related mortality and early termination of study groups
Why: No genotoxicity; tumours most likely secondary to chronic inflammation · Weight of evidence
“However, given the high mortality due to toxicity of volanesorsen, the value of these studies is limited.”
✓ VerifiedEMA assessment report, p. 43Source ↗
“Taking into account the lack of a genotoxic effect of volanesorsen and the likelihood that most tumours were secondary to chronic inflammation, volanesorsen has little carcinogenic risk for patients, despite the early termination of study groups in the mouse and rat study.”
✓ VerifiedEMA assessment report, p. 43Source ↗
DARTVerdict not stated
Mouse pre/postnatal study run with both volanesorsen and a murine-specific apoC-III ASO surrogate (ISIS 440670)
“An assessment of pre- and postnatal toxicity was performed using subcutaneous administration of volanesorsen or the murine-specific apoC-III inhibitor (ISIS 440670) on alternate days to pregnant female mice at doses up to 87.5 mg/kg/wk from Day 6 of gestation to Day 21 postpartum.”
✓ VerifiedEMA assessment report, p. 39Source ↗

Same question, other oligonucleotides

Amondys 45

casimersen · DMD exon 45 (PMO)
No reproductive and developmental toxicity studies; male reproductive organs and sperm evaluated in chronic studies instead

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 oligonucleotides
Fertility 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

Wainua

eplontersen · TTR (ASO)
Carcinogenic potential not assessed at FDA approval; 26-week Tg.rasH2 mouse study made a postmarketing requirement

Zanvastro

zilganersen · GFAP (ASO)
No carcinogenicity studies before approval; completion required as postmarketing requirements

Summary across all 27 oligonucleotides →