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Precedia/Oligonucleotides/Redemplo/Flexibility

Redemplo: what flexibility did regulators accept, and why?

plozasiran · APOC3 (siRNA)
Check my plan vs. these
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
2-year rat carcinogenicity study ongoing at approval; completion to be submitted postmarketing
Why: Unmet medical need associated with familial chylomicronemia syndrome · Rare disease / unmet need
“The 2-year rat carcinogenicity study is ongoing, and the Agency recommends that completion of this study should be submitted postmarketing (after approval) considering the unmet medical need associated with the FCS clinical indication.”
✓ VerifiedFDA integrated review, p. 103Source ↗
SpeciesAcceptedBeyond the letter
Rat lacks full ApoC-III sequence homology (seven mismatches), so suitable only for off-target toxicity; monkey the pharmacologically relevant species
Why: Monkeys deemed the most pharmacologically relevant species for on-target safety · No relevant species
“The antisense strand of plozasiran is fully complementary to monkey and human ApoC-III mRNAs, whereas plozasiran has seven sequence mismatches to the rodent ApoC-III mRNA transcript. Moderate pharmacodynamic activity was observed in rats only at toxic doses; however, the lack of full rat mRNA sequence homology makes this species suitable only for assessing off-target toxicity.”
✓ VerifiedFDA integrated review, p. 102Source ↗
“Monkeys were deemed the most pharmacologically relevant species to evaluate on-target safety profile of plozasiran.”
✓ VerifiedFDA integrated review, p. 102Source ↗
DARTVerdict not stated
Rat embryo-fetal study tested a rodent-specific surrogate siRNA (AD06313) alongside plozasiran
“In pregnant rats, daily treatment with plozasiran or a rodent-specific surrogate (AD06313) during the period of organogenesis did not result in fetal malformations or teratogenicity at any dose up to 60 mg/kg/day plozasiran (23-fold MRHD), the highest dose tested.”
✓ VerifiedFDA integrated review, p. 103Source ↗

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

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

Summary across all 27 oligonucleotides →