Amondys 45
casimersen · DMD exon 45 (PMO)No reproductive and developmental toxicity studies; male reproductive organs and sperm evaluated in chronic studies instead
Zanvastro: what flexibility did regulators accept, and why?
zilganersen · GFAP (ASO)
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity studies before approval; completion required as postmarketing requirements
Why: Benefit:risk and unmet medical need · Rare disease / unmet need
“Carcinogenicity No new studies were provided. The Division agreed these studies can be completed as post-marketing requirements (PMRs) given the benefit:risk and unmet medical need.”
DARTAccepted with a conditionBeyond the letter
Rabbit embryo-fetal and pre/postnatal development studies deferred to postmarketing
“An embryofetal development study in rabbit will be needed but may be conducted as a postmarketing requirement.”
“5053-4: Conduct a pre- and postnatal development (PPND) study of zilganersen and the mouse surrogate (ISIS 713812) to evaluate maternal and offspring toxicity.”
SpeciesVerdict not stated
No GFAP knockdown in monkey toxicity study due to a single sequence mismatch with monkey GFAP mRNA
“No meaningful changes in GFAP mRNA levels were observed in brain or spinal cord tissues, likely due to the single mismatch between zilganersen and monkey GFAP mRNA.”
First doseAccepted with a conditionBeyond the letter
Clinical intrathecal dose capped at 25 mg (about 1/10 of mouse and monkey NOAELs) after unexplained deaths in a mouse ICV study
Why: Additional nonclinical data allowed an increase to 50 mg every 12 weeks
“The FDA placed protocol ION373-CS1 on hold for IT doses of ION373 exceeding 25 mg, which is approximately 1/10th the NOAELs in mouse and monkey, due to unexplained deaths in female mice in the 9- week ICV toxicity study.”
“Following nonclinical data review, Ionis was permitted to increase the maximum dose and dosing frequency to 50 mg every 12 weeks for Study ION373-CS1.”
Impurity or metaboliteAccepted with a conditionBeyond the letter
13-week intrathecal toxicity study of leachables with local CNS concerns required postmarketing
“5053-5: Conduct a 13-week intrathecal toxicity study for detected leachables with local CNS toxicity concerns including butylated hydroxytoluene (BHT) (0.65 µg/day), boron (6.6 µg/day),”
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
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