Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)Canada: first-in-human study in healthy volunteers
Amondys 45: what was done before first-in-human, and what came after?
casimersen · DMD exon 45 (PMO)
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 Amondys 45 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: Kidney tubular basophilia/vacuolation, degeneration; juvenile rat NOAEL 300 mg/kg (4x AUC); no kidney no-effect dose in mouse/rat (FDA pharmacology/toxicology review, p. 75)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week IV study in male cynomolgus monkeys with 8-week recovery
“SRP-4045: A 39-week intravenous infusion toxicity study in male cynomolgus monkeys with an 8-week recovery period”
Pivotal GLP studies
12-wk IV, 22-wk IV (terminated) and 26-wk SC mouse; 12-wk and 39-wk IV monkey; 10-wk IV juvenile rat
“general toxicology (12-, 22-, and 26-week IV in mouse; 12- and 39-week IV in monkey) studies”
DART package
Species: DART
Not conducted (patient population extremely rare in females)
“Reproductive and developmental toxicology studies were not required because of the intended patient population (extremely rare in females), and carcinogenicity studies may be conducted post-approval, as previously agreed to by the division, because of the seriousness of the indication.”
Reproductive & developmental
Not conducted (patients extremely rare in females); male reproductive endpoints in tox studies; juvenile rat
“Reproductive and developmental toxicology studies were not required because of the intended patient population (extremely rare in females), and carcinogenicity studies may be conducted post-approval”
PPND / ePPND: when
No PPND study: reproductive and developmental studies not required because patients are extremely rare in females
“Reproductive and developmental toxicology studies were not required because of the intended patient population (extremely rare in females)”
Carcinogenicity
Species: carcinogenicity
Male Tg.rasH2 mouse (26-week SC) and male rat (up to 104 weeks IV)
“Administration of casimersen to male transgenic (Tg.rasH2) mice (0, 100, 300, or 1000 mg/kg) weekly for 26 weeks by subcutaneous injection and to male rats (0, 125, 250, or 500 mg/kg) for up to 104 weeks by intravenous injection resulted in no increase in neoplasms.”
Carcinogenicity model
26-week Tg.rasH2 mouse (SC) and up to 104-week rat (IV); no increase in neoplasms
“Administration of casimersen to male transgenic (Tg.rasH2) mice (0, 100, 300, or 1000 mg/kg) weekly for 26 weeks by subcutaneous injection and to male rats (0, 125, 250, or 500 mg/kg) for up to 104 weeks by intravenous injection resulted in no increase in neoplasms.”
Carcinogenicity timing
Mouse and rat carcinogenicity studies deferred to postmarketing requirements; not conducted before approval
“Carcinogenicity assessments were not conducted. PMRs covering the carcinogenicity assessments are recommended.”
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
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
Rivfloza
nedosiran · LDHA (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