Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)Canada: first-in-human study in healthy volunteers
Oxlumo: what was done before first-in-human, and what came after?
lumasiran · HAO1 (siRNA)
Before first-in-human
First-in-human: where
UK: single ascending dose in healthy subjects (Study 001 Part A)
“Part A: SAD study (001A) in healthy subjects to evaluate safety, tolerability, PK, PD and ADA of lumasiran Country: UK”
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 Oxlumo 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: NOAELs = highest doses (200 mg/kg rat, 300 mg/kg monkey monthly); non-adverse liver, kidney, coagulation, injection site, lymph node findings (FDA integrated review, p. 56)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
36-week cynomolgus monkey (SC); recovery phase not stated
“Chronic administration of lumasiran was assessed in good laboratory practice (GLP) repeat-dose toxicology studies up to 25- and 36-weeks in rats and monkeys, respectively.”
Pivotal GLP studies
Rat 25-week SC monthly; monkey 36-week SC every 4 weeks (10 doses); plus 8-week weekly monkey study
“Dose and frequency of dosing: 30, 100, or 300 mg/kg lumasiran once every 4 weeks for a total of 10 doses Route of administration: SC”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“Lumasiran did not show any adverse effects on male and female fertility and pre- and post-natal development in rats. In embryo-foetal development studies in rats and rabbits, skeletal abnormalities were observed, but at high exposure multiples relative to human therapeutic exposures.”
Reproductive & developmental
Full DART: rat fertility, rat and rabbit EFD, rat PPND, plus juvenile rat study; no serious effects
“Reproductive toxicology studies did not reveal any serious fertility or teratogenic effects of lumasiran.”
PPND / ePPND: when
PPND study completed before the marketing application; NOAEL 50 mg/kg
“A pre- and postnatal development study had a NOAEL of 50 mg/kg with a safety margin of >2X.”
Carcinogenicity
Species: carcinogenicity
Tg-rasH2 mouse and Sprague Dawley rat
“Carcinogenicity studies were conducted in Tg-rasH2 mice and Sprague Dawley rats. Lumasiran was not carcinogenic in transgenic Tg-rasH2 mice following monthly subcutaneous administration of lumasiran for 26 weeks at doses of 150, 500, or 1500 mg/kg.”
Carcinogenicity model
26-week Tg-rasH2 mouse (up to 1500 mg/kg monthly) and rat study; not carcinogenic in mice
“Carcinogenicity studies were conducted in Tg-rasH2 mice and Sprague Dawley rats. Lumasiran was not carcinogenic in transgenic Tg-rasH2 mice following monthly subcutaneous administration of lumasiran for 26 weeks at doses of 150, 500, or 1500 mg/kg.”
Carcinogenicity timing
2-year rat and 6-month transgenic mouse studies underway at approval; postmarketing requirements
“Two-year rat and 6-month transgenic mouse carcinogenicity studies are underway. The available data do not raise concern for a risk of carcinogenicity that should delay approval given the apparent clinical benefit and unmet need. As such, these studies will be postmarketing requirements.”
Same question, other oligonucleotides
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Zanvastro
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Amondys 45
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Spinraza
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Tegsedi
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Viltepso
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Wainua
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Waylivra
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