Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)Canada: first-in-human study in healthy volunteers
Exondys 51: what was done before first-in-human, and what came after?
eteplirsen · DMD exon 51 (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 Exondys 51 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 degeneration in all species; monkey NOAEL 320 mg/kg (~20x AUC); juvenile rat NOAEL 300 mg/kg (6x); bone density loss (FDA pharmacology/toxicology review, p. 91)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week IV male cynomolgus monkey with 8-week recovery
“39-Week Intravenous Injection Toxicity and Toxicokinetic Study of Eteplirsen in Sexually Mature Male Cynomolgus Monkeys with an 8-Week Recovery”
Pivotal GLP studies
39-week IV male monkey; 10-week IV juvenile rat (PND14-77); 26-week IV mdx mouse with surrogate AVI-4225
“Pivotal toxicology studies of eteplirsen were conducted in male monkeys (39-week study) and juvenile male rats (10-week study). A 26-week study was conducted with a mouse-specific surrogate (AVI-4225) in male transgenic mdx mice.”
DART package
Species: DART
Not conducted (patient population almost entirely male); male reproductive organs assessed in toxicity studies
“No developmental and reproductive toxicity studies were conducted with eteplirsen because the patient population is almost entirely male. Potential effects on male fertility were assessed by histopathological evaluation of male reproductive organs in toxicity studies.”
Reproductive & developmental
Not conducted (almost entirely male population); male reproductive organ histopathology in tox studies; juvenile rat study
“No developmental and reproductive toxicity studies were conducted with eteplirsen because the patient population is almost entirely male.”
PPND / ePPND: when
Not conducted: no female fertility, embryofetal or early postnatal development studies, as the DMD population is almost entirely male
“Assessments of the effects of eteplirsen on female fertility, embryofetal development, and early postnatal development were not conducted because the DMD patient population is almost entirely male.”
Carcinogenicity
Species: carcinogenicity
Male Tg.rasH2 mouse (26-week) and male rat (96-week)
“Administration of eteplirsen to male transgenic (Tg.rasH2) mice (0, 200, 500, or 960 mg/kg) weekly for 26 weeks (intravenous [IV] injection for 15 weeks, followed by subcutaneous injection for 11 weeks) and to male rats (0, 60, 180, or 600 mg/kg IV) weekly for 96 weeks resulted in no increase in neoplasms.”
Carcinogenicity model
26-week Tg.rasH2 mouse and 96-week rat; no increase in neoplasms
“Administration of eteplirsen to male transgenic (Tg.rasH2) mice (0, 200, 500, or 960 mg/kg) weekly for 26 weeks (intravenous [IV] injection for 15 weeks, followed by subcutaneous injection for 11 weeks) and to male rats (0, 60, 180, or 600 mg/kg IV) weekly for 96 weeks resulted in no increase in neoplasms.”
Carcinogenicity timing
26-week transgenic mouse and 2-year rat studies planned after approval; none conducted before the marketing application
“The sponsor plans to conduct a 26-week study in transgenic mice and a 2-year study in rats to assess the carcinogenicity of eteplirsen.”
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
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