Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)Canada: first-in-human study in healthy volunteers
Givlaari: what was done before first-in-human, and what came after?
givosiran · ALAS1 (siRNA)
Before first-in-human
First-in-human: where
US, UK and Sweden: 6 clinical study centers (4 US, 1 UK, 1 Sweden)
“6 clinical study centers (4 in US, 1 in UK, 1 in Sweden)”
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 Givlaari 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: Liver primary target in rat and monkey (single-cell necrosis, enzyme increases); no adverse findings at 3.5x (rat) and 26.3x (monkey) exposure (EMA assessment report, p. 47)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week SC cynomolgus monkey with 13-week recovery
“In a 39-week monkey study, cynomolgus monkeys were subcutaneously administered vehicle or givosiran (10, 30, or 100 mg/kg) once weekly for 39 weeks followed by a 13-week recovery period.”
Pivotal GLP studies
Rat 26-week SC weekly (with male fertility arm), monkey 39-week SC weekly, both with 13-week recovery
“Dawley rats were subcutaneously administered vehicle or givosiran (3, 10, or 30 mg/kg) once weekly for 26 weeks followed by a 13-week recovery period.”
DART package
Species: DART
Rat and rabbit
“Maximal exposure was low in pregnant rats (maximally 1.7x human exposure based on AUC) and slightly higher in rabbits (maximally 5x human exposure).”
Reproductive & developmental
Full DART: rat fertility/EFD, rabbit EFD (postimplantation loss with maternal toxicity), rat PPND; no malformations
“Givosiran showed marked maternal toxicity in rabbits (including mean maternal body weight loss) and resulted in increased post-implantation loss as a result of increased early resorptions and a low incidence of skeletal variations.”
PPND / ePPND: when
PPND in rat completed and reviewed in the marketing application: dosing GD 7-19 and LD 6-18
“In a pre- and postnatal development study in rats, givosiran (0, 3, 10, or 30 mg/kg) was administered to pregnant rats approximately every 6 days on GD 7, 13, and 19 and lactation days (LD) 6, 12, and 18 .”
Carcinogenicity
Species: carcinogenicity
Tg-rasH2 mouse (26-week) and Sprague Dawley rat (2-year)
“There was no evidence of carcinogenicity in the 26-week conducted in f Tg-rasH2 mice. A longer, 2-year carcinogenicity study in Sprague Dawley rats (AS1-GLP18-007), currently ongoing, will be submitted upon its completion.”
Carcinogenicity model
Sprague Dawley rat, SC every 28 days up to 89 weeks: hepatocellular adenomas in males at 100 mg/kg/month
“In a carcinogenicity study in Sprague Dawley rats administered 25, 50, or 100 mg/kg givosiran by subcutaneous injection every 28 days for up to 89 weeks (males) or 85 weeks (females), givosiran doses in rats were 2, 3, and 6 times, respectively, the MRHD based on body surface area. A statistically significant increase in hepatocellular adenomas occurred in males at 100 mg/kg/month, the clinical significance of which is uncertain.”
Carcinogenicity timing
26-week Tg-rasH2 mouse completed (negative); 2-year Sprague Dawley rat ongoing at approval
“There was no evidence of carcinogenicity in the 26-week conducted in f Tg-rasH2 mice. A longer, 2-year carcinogenicity study in Sprague Dawley rats (AS1-GLP18-007), currently ongoing, will be submitted upon its completion.”
Same question, other oligonucleotides
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