Amondys 45
casimersen · DMD exon 45 (PMO)No reproductive and developmental toxicity studies; male reproductive organs and sperm evaluated in chronic studies instead
Vyondys 53: what flexibility did regulators accept, and why?
golodirsen · DMD exon 53 (PMO)
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity studies before approval; 26-week transgenic mouse and 2-year rat studies deferred post-approval
Why: Seriousness of the indication · Serious disease
“If the NDA is approved, carcinogenicity studies in two species (26-week in transgenic mouse, 2-year in rat) are to be conducted post-approval, as previously agreed to by the division.”
“As previously agreed to by the division, carcinogenicity studies in two species may be conducted post-approval (as PMRs), based on the seriousness of the indication.”
DARTAcceptedBeyond the letter
No fertility or embryo-fetal/pre- and postnatal studies; male fertility assessed by reproductive organ histopathology and sperm in general toxicity studies, plus juvenile rat study
Why: Patient population almost exclusively male · Other reason
“No developmental and reproductive toxicity studies were conducted with golodirsen because the patient population is almost entirely male.”
“Reproductive and developmental studies (except for the juvenile animal study) were not required because of the intended patient population, which is almost exclusively male.”
Safety marginAccepted with a conditionBeyond the letter
Small margin for renal toxicity: human AUC at 30 mg/kg only 2.6-fold below the juvenile rat NOAEL
Why: Kidney function is monitorable in patients · Other reason
“At the recommended human dose of 30 mg/kg, plasma exposure (AUC of ∼90 µg*hr/mL) is only 2.6-fold lower than that at the no-adverse-effect-level in the most sensitive species (juvenile rat).”
“However, because kidney function is monitorable, the nonclinical data are considered adequate to support approval of golodirsen for the treatment of DMD in patients with mutations amenable to exon 53 skipping therapies.”
Efficacy modelVerdict not stated
No in vivo study of exon 53 skipping with golodirsen; in vitro patient myoblast data only
“No in vivo nonclinical studies were conducted to assess the extent of exon 53 skipping by golodirsen.”
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
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