Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)Canada: first-in-human study in healthy volunteers
Redemplo: what was done before first-in-human, and what came after?
plozasiran · APOC3 (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 Redemplo 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: Rat NOAEL 120 mg/kg Q4W (47x MRHD); monkey NOAEL 180 mg/kg (140x, top dose); liver, kidney, lymph node, injection-site changes (FDA integrated review, p. 247)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
37-week cynomolgus monkey (SC, monthly) with 4-week recovery (control and high dose)
“Monkey (cyno) 37w, 10 monthly doses +4w SC injection GLP SR-00804 Main: 7 M/F Recovery: 2 M/F (control and high dose)”
Pivotal GLP studies
24-week rat and 37-week monkey SC Q4W repeat-dose toxicity studies
“Repeat-dose general toxicology studies with plozasiran were conducted with SC administration (consistent with the clinical route) Q4W in rats”
DART package
Species: DART
Rat (FEED, EFD, PPND) and rabbit (EFD)
“Plozasiran was tested in a complete battery of nonclinical reproductive and developmental toxicity studies, including a fertility and early embryonic development (FEED) study in rats, embryo-fetal development (EFD) studies in rats and rabbits, and a pre/postnatal development (PPND) study in rats.”
Reproductive & developmental
Conducted in rat: fertility (NOAEL 50 mg/kg), EFD (NOAEL 60 mg/kg), PPND (pup survival reduced at 24 mg/kg and above); no rabbit
“The NOAEL for male and female fertility was 50 mg/kg (19-fold the human dose, based on BSA).”
PPND / ePPND: when
PPND in rat completed before the marketing application
“FEED and PPND were conducted in rats, EFD in rats and rabbits.”
Carcinogenicity
Species: carcinogenicity
6-month transgenic mouse and 2-year rat
“Carcinogenic potential of plozasiran was tested in a 6-month transgenic mouse and a 2-year rat carcinogenicity study, the latter of which was submitted in the second round of the procedure.”
Carcinogenicity model
26-week transgenic (Tg.rasH2) mouse completed; 2-year rat study to follow postmarketing
“The carcinogenic potential of plozasiran was assessed in the completed 26-week transgenic mouse carcinogenicity study. The Agency agreed that a 2-year rat carcinogenicity study should be conducted postmarketing considering the unmet medical need associated with the FCS clinical indication.”
Carcinogenicity timing
26-week rasH2 mouse completed; 2-year rat ongoing at approval, completion to be submitted postmarketing
“The 2-year rat carcinogenicity study is ongoing, and the Agency recommends that completion of this study should be submitted postmarketing (after approval) considering the unmet medical need associated with the FCS clinical indication.”
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
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