Amondys 45
casimersen · DMD exon 45 (PMO)No reproductive and developmental toxicity studies; male reproductive organs and sperm evaluated in chronic studies instead
Amvuttra: what flexibility did regulators accept, and why?
vutrisiran · TTR (siRNA)
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity studies at approval; rat and mouse studies deferred to postmarketing requirements
Why: Serious indication with limited life expectancy; deferral previously agreed · Serious disease
“Carcinogenicity studies were not submitted in the NDA but are to be conducted post-approval (as PMRs), as agreed to by the division (DN1), if vutrisiran is approved.”
“Considering the proposed vutrisiran treatment of a serious indication with limited life-expectancy, the delayed completion of carcinogenicity studies post approval has been previously accepted (EMEA/H/SA/3876/1/2018/PA/III, 2018).”
DARTAccepted with a conditionBeyond the letter
Target-mediated reproductive and developmental effects not evaluated; rat and rabbit lack TTR sequence homology
Why: No sequence homology in rat or rabbit; Vitamin A deficiency effects on reproduction well known; supplementation recommended · No relevant species · Weight of evidence
“Target-mediated effects on reproductive function and development were not evaluated in rat or rabbit because of the lack of sequence homology;”
“The effects of Vitamin A deficiency on reproductive function and embryofetal development are well known (e.g., Clagett-Dame M, Knutson D. Nutrients 2011, 3, 385-428; doi:10.3390/nu3040385), and Vitamin A supplementation is to be recommended in patients with hTTR treated with vutrisiran.”
RecoveryVerdict not stated
No recovery periods in the 6-month rat and 9-month monkey toxicity studies
Why: Generally mild effects · Other reason
“Given the generally mild effects, recovery periods did not follow the dosing phases of the 6 and 9 months toxicity studies.”
OtherAccepted
No single-dose toxicity studies conducted
Why: In accordance with prevailing ICH and European guidance · Within the guideline
“Single dose toxicity studies have not been conducted with vutrisiran, which is endorsed in accordance with prevailing ICH and European guidance (EMA/CPMP/ICH/286/1995; EMA/CHMP/SWP/81714/2010).”
Same question, other oligonucleotides
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
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