Amondys 45
casimersen · DMD exon 45 (PMO)No reproductive and developmental toxicity studies; male reproductive organs and sperm evaluated in chronic studies instead
Spinraza: what flexibility did regulators accept, and why?
nusinersen · SMN2 (ASO)
Flexibility accepted
Study lengthAccepted with a conditionBeyond the letter
No chronic rodent toxicity study to assess systemic exposure
Why: Postmarketing carcinogenicity study in one species to provide chronic toxicity data
“A less-than standard battery of nonclinical studies (no chronic toxicity study in rodent [to assess systemic exposure], pre- and postnatal development (PPND) study in rodent, or carcinogenicity studies in mouse and rat) was conducted to support approval of nusinersen.”
“Completion of the ongoing PPND study and a carcinogenicity study in one species (which will provide chronic toxicity data) should be post-marketing requirements.”
CarcinogenicityAccepted with a conditionBeyond the letter
No carcinogenicity studies before approval; waiver requested, parenteral study in one species required postmarketing
Why: Lifetime intrathecal rodent studies infeasible; waiver rejected because of significant systemic exposure in patients · Other reason
“Carcinogenicity studies were not conducted. The sponsor has requested a waiver based on the infeasibility of conducting lifetime studies in rodents by the IT route, but given the significant systemic exposure documented in clinical studies, it is recommended that a parenteral study in one species be conducted postmarketing.”
DARTAccepted with a conditionBeyond the letter
Pre- and postnatal development study incomplete at approval; deferred to postmarketing requirement
“A pre- and postnatal development study is ongoing; submission of the study should be a post-marketing requirement.”
Safety marginCriticised but acceptedBeyond the letter
No CSF-based safety margin for hippocampal neurotoxicity in the 53-week juvenile monkey study
Why: Seriousness of the indication and apparently substantial clinical efficacy · Serious disease
“The no-effect dose (0.3 mg) for neurotoxicity in the 53-week monkey study was associated with csf levels (12 ng/mL) generally less than that in SMA patients (7-35 ng/mL); therefore, there is no safety margin based on csf levels.”
“However, considering the seriousness of the indication and the apparently substantial evidence of efficacy in the clinical trials in SMA patients, there is no objection to approval of the NDA from a pharmacology/toxicology standpoint.”
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
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