Dawnzera
donidalorsen
Species
MonkeyMouse
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Mouse (CD-1) and cynomolgus monkey
“Mice and cynomolgus monkeys were considered suitable species for the pharmacology assessment because PKK is expressed in both species.”
Why that species
Donidalorsen inactive in mouse (no complementarity to mouse PKK transcript); monkey is pharmacologically relevant, mouse used with surrogate ASO
“Donidalorsen is not pharmacologically active in the mouse due to its lack of complementarity to the mouse PKK gene transcript.”
Surrogate molecule
Yes: mouse-specific surrogate ASO ISIS 482584 for pharmacology; ISIS 722059 mouse-active surrogate in 26-week mouse and repro studies
“ISIS 722059 (mouse-active surrogate) at 4 mg/kg/q2w was included in the 26-week mouse study.”
Study lengthopen answer page →
Longest pivotal study
39 weeks
“repeat dose studies in CD-1 mice and cynomolgus monkeys of up to 26- and 39-week duration, respectively”
Pivotal GLP studies
13- and 26-week SC studies in CD-1 mice; 13-week interim/39-week SC study in cynomolgus monkeys with 26-week recovery
“plasma TK profile of SC administration of donidalorsen was evaluated in a GLP-compliant 13-week interim/39-week repeat-dose toxicity study in Cynomolgus monkeys with a 26-week treatment-free recovery period”
Route in tox
Subcutaneous (intended clinical route)
“The subcutaneous (SC) route of administration was used, as this is the intended therapeutic route in humans.”
Skipped studiesopen answer page →
Genotoxicity
Conducted: in vitro Ames, CHL chromosomal aberration and in vivo mouse bone marrow micronucleus; no genotoxicity
“Donidalorsen was evaluated for genotoxicity potential both in vitro and in vivo.”
Carcinogenicity
Conducted: 27-week Tg.rasH2 mouse study; 2-year rat study ongoing at time of review
“its tumorigenic potential has been evaluated in a 27-week carcinogenicity study in Tg.rasH2 mice, and a 2-yr carcinogenicity study in Sprague Dawley (SD) rats, which is ongoing”
Reproductive & developmental
Conducted in mice only: combined fertility/EFD and PPND studies (with surrogate group); NOAEL top dose; no rabbit EFD
“Reproductive and developmental toxicity studies were conducted in one species only, namely CD-1 mice”
Safety pharmacology
Standalone monkey CV/respiratory/neurobehavioural study (up to 30 mg/kg) and hERG; no adverse effects
“An in vivo safety pharmacology study conducted in the monkey indicated that donidalorsen had no adverse effects on cardiovascular, respiratory or neurobehavioural parameters at a dose of up to 30 mg/kg.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
NOAEL / key findings
Monkey NOAEL 6 mg/kg/week (platelet reductions at higher doses; ~29-fold margin); mouse NOAEL top dose; liver and kidney target organs
“The NOAEL for donidalorsen was determined to be 6 mg/kg/week in monkeys, based on PLT reductions”
Risksopen answer page →
Immune & cytokine safety
No cytokine/chemokine or C3 effects; minimal transient complement Bb increase at 30 mg/kg/week; ADAs 12.5-62.5% in monkey without impact
“A potential test article-related minimal increase in mean complement Bb levels was observed at 4 hours post-dose on Day 1 in animals at 30 mg/kg/week.”
Biodistribution & persistence
Highest in liver and kidney (GalNAc-targeted); liver exposure >1000-fold plasma; little in brain
“the highest concentrations of radioactivity were observed in the liver and kidney, at their tmax observed at 24- and 168-h post dose in the liver and kidney, respectively.”
Modality-specific risk
Oligonucleotide class effects: liver/kidney accumulation, platelet reductions, proinflammatory effects in rodents
“The primary target organs for donidalorsen were the liver and kidney”