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Precedia/Oligonucleotides/Viltepso/Flexibility

Viltepso: what flexibility did regulators accept, and why?

viltolarsen · DMD exon 53 (PMO)
Check my plan vs. these
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity studies before approval; Tg.rasH2 mouse and two-year rat studies required as postmarketing requirements
“If the application is approved, a 26-week carcinogenicity study in Tg.rasH2 mouse and a 2-year carcinogenicity study in rat should be conducted as PMRs.”
✓ VerifiedFDA pharmacology/toxicology review, p. 5Source ↗
“Carcinogenicity was not evaluated but is to be assessed as a postmarketing requirement. The nonclinical data support approval vitolarsen.”
✓ VerifiedFDA pharmacology/toxicology review, p. 47Source ↗
DARTAcceptedBeyond the letter
No embryo-fetal or pre/postnatal development studies; male mouse fertility study only
Why: Patient population almost exclusively male · Other reason
“Embryofetal development and pre- and postnatal development studies were not conducted, as agreed to by the Division, because of the intended patient population, which is almost exclusively male.”
✓ VerifiedFDA pharmacology/toxicology review, p. 3Source ↗

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

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 →