Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)Canada: first-in-human study in healthy volunteers
Qalsody: what was done before first-in-human, and what came after?
tofersen · SOD1 (ASO)
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 Qalsody 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: Monkey 9-month IT NOAEL 12 mg Q2W (neurological signs at 35 mg); ~1.2-fold margin by CSF-volume scaling; mouse platelet decreases, no NOAEL (FDA integrated review, p. 180)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month (39-week) cynomolgus monkey (intrathecal, every other week) with recovery groups; recovery duration not stated
“In monkeys, IT administration of 0, 4, 12, and 35 mg tofersen in male and female cynomolgus monkeys every other week for 9 months resulted in histologic findings of neuronal vacuolation at all doses; however, vacuolation was not accompanied by neurodegeneration and was not present in recovery groups.”
Pivotal GLP studies
Monkey IT Q2W 13-week and 9-month; mouse SC 12- and 26-week; rat single-dose IT; full genetox and DART
“Nonclinical toxicity studies submitted to the NDA consisted of single dose (rat) and repeat dose (mouse and monkey) general toxicity studies, as well a complete battery of genetic toxicology and reproductive and developmental toxicology studies.”
DART package
Species: DART
Mouse (combined fertility/EFD and pre/postnatal) and rabbit (EFD)
“The reproductive and developmental toxicity of tofersen was investigated in a combined study on fertility and embryo-foetal development in mice, a study on embryo-foetal development in rabbits, and on prepostnatal development in mice.”
Reproductive & developmental
Mouse fertility (seminiferous tubule degeneration, NOAEL 10 mg/kg), mouse/rabbit EFD and mouse PPND negative; pharmacologically non-relevant species
“There were no effects on embryofetal development in CD1 mouse or NZW rabbit, or on pre- and postnatal development in CD1 mouse.”
PPND / ePPND: when
PPND in CD1 mouse completed before the marketing application; no effects on pre- and postnatal development
“There were no effects on embryofetal development in CD1 mouse or NZW rabbit, or on pre- and postnatal development in CD1 mouse.”
Carcinogenicity
Species: carcinogenicity
Not conducted pre-approval (severity of indication); to be assessed post-approval
“Due to the severity of the indication, the carcinogenic potential of tofersen is to be conducted post-approval.”
Carcinogenicity model
Not conducted (severity of indication); to be assessed post-approval
“Due to the severity of the indication, the carcinogenic potential of tofersen is to be conducted post-approval.”
Carcinogenicity timing
Not conducted before approval; carcinogenicity studies to be conducted after approval given the severity of the indication
“Due to the severity of the indication, the carcinogenic potential of tofersen is to be conducted post-approval.”
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
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Amvuttra
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Defitelio
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Exondys 51
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Hibsago
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Izervay
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Kynamro
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Leqvio
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Macugen
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Onpattro
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Qfitlia
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Redemplo
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Rivfloza
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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
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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