Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)Canada: first-in-human study in healthy volunteers
Rivfloza: what was done before first-in-human, and what came after?
nedosiran · LDHA (siRNA)
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Rivfloza don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for oligonucleotides outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Juvenile monkey NOAEL 100 mg/kg (29x AUC); Kupffer/macrophage basophilic hypertrophy in liver, lymph nodes, testes, injection sites (FDA integrated review, p. 51)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month (39-week) cynomolgus monkey (SC, every 4 weeks; juvenile and young adult) with 8-week recovery
“At the injection sites, minimal to mild macrophage basophilic hypertrophy was observed in the subcutaneous tissues in the juvenile mice and monkeys, which resolved following an 8-week recovery period, indicating hybridization-independent effects. Findings in Young Adult Monkeys In the young adult cynomolgus monkey study, nedosiran was tested at one dose level of 300 mg/kg once every 4 weeks for 9 months.”
Pivotal GLP studies
26-week juvenile mouse and 39-week juvenile/young adult cynomolgus monkey, SC once every 4 weeks
“Repeat dose toxicology studies were conducted in mice for up to 26 weeks and monkeys for up to 39 weeks.”
DART package
Species: DART
Mouse (fertility, EFD, PPND; plus mouse-active analog) and rabbit (EFD)
“In an embryo-fetal development study in mice, no maternal or developmental toxicities were observed with nedosiran at doses up to 2000 mg/kg/dose (58x the maximum recommended human dose (MRHD) or with the mouse active analog DCR-m355.”
Reproductive & developmental
Mouse FEED/EFD/PPND clean; rabbit EFD: fetal loss and malformations at >=0.7-2x MRHD (unexplained, off-target)
“Higher postimplantation loss and lower numbers of live fetuses were observed at doses of ≥6 mg/kg/dose (0.7x the MRHD, based on body surface area), and fetal cardiovascular and skeletal malformations were observed at a dose of 20 mg/kg/dose (2x the MRHD).”
PPND / ePPND: when
PPND in mouse (nedosiran and mouse-active analog) completed before the marketing application; no adverse effects on offspring
“In a pre- and postnatal study in mice, subcutaneous administration of nedosiran (0, 250, 500, or 1000 mg/kg/dose) or a mouse-specific (pharmacologically active) analog (10 mg/kg/dose) from implantation to weaning did not have adverse effects on the growth, viability, development, and reproductive performance of the offspring.”
Carcinogenicity
Species: carcinogenicity
Not conducted pre-approval; 2-year study in one rodent species required postmarketing
“Complete a long-term (2-year) GLP carcinogenicity study of nedosiran by subcutaneous injection in one rodent species.”
Carcinogenicity model
Not conducted pre-approval; TgRasH2 mouse and 2-year rodent studies to follow
“The carcinogenic potential of nedosiran has not been assessed. The Agency agrees that carcinogenicity studies can be conducted postmarketing.”
Carcinogenicity timing
Not assessed at approval; transgenic mouse and long-term rodent carcinogenicity studies to be conducted postmarketing
“The carcinogenic potential of nedosiran has not been assessed. The Agency agrees that carcinogenicity studies can be conducted postmarketing.”
Same question, other oligonucleotides
Givlaari
givosiran · ALAS1 (siRNA)US, UK and Sweden: 6 clinical study centers (4 US, 1 UK, 1 Sweden)
Oxlumo
lumasiran · HAO1 (siRNA)UK: single ascending dose in healthy subjects (Study 001 Part A)
Zanvastro
zilganersen · GFAP (ASO)United States and other countries: ION373-CS1, the single combined first clinical and pivotal trial in AxD patients
Amondys 45
casimersen · DMD exon 45 (PMO)Not stated in public reviews
Amvuttra
vutrisiran · TTR (siRNA)Not stated in public reviews
Defitelio
defibrotide · Fragmented DNA oligonucleotidesNot stated in public reviews
Exondys 51
eteplirsen · DMD exon 51 (PMO)Not stated in public reviews
Hibsago
bepirovirsen · HBV RNA (ASO)Not stated in public reviews
Izervay
avacincaptad pegol · C5 (aptamer)Not stated in public reviews
Kynamro
mipomersen · APOB (ASO)Not stated in public reviews
Leqvio
inclisiran · PCSK9 (siRNA)Not stated in public reviews
Macugen
pegaptanib · VEGF-165 (aptamer)Not stated in public reviews
Onpattro
patisiran · TTR (siRNA)Not stated in public reviews
Qalsody
tofersen · SOD1 (ASO)Not stated in public reviews
Qfitlia
fitusiran · Antithrombin / SERPINC1 (siRNA)Not stated in public reviews
Redemplo
plozasiran · APOC3 (siRNA)Not stated in public reviews
Rytelo
imetelstat · Telomerase (oligo)Not stated in public reviews
Spinraza
nusinersen · SMN2 (ASO)Not stated in public reviews
Tegsedi
inotersen · TTR (ASO)Not stated in public reviews
Tryngolza
olezarsen · APOC3 (ASO)Not stated in public reviews
Viltepso
viltolarsen · DMD exon 53 (PMO)Not stated in public reviews
Vitravene
fomivirsen · CMV IE2 mRNA (ASO)Not stated in public reviews
Vyondys 53
golodirsen · DMD exon 53 (PMO)Not stated in public reviews
Wainua
eplontersen · TTR (ASO)Not stated in public reviews
Waylivra
volanesorsen · APOC3 (ASO)Not stated in public reviews