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.”
Species: general tox
CD-1 mouse and cynomolgus monkey
“repeat dose studies in CD-1 mice and cynomolgus monkeys of up to 26- and 39-week duration, respectively”
Species: DART
CD-1 mouse only (combined fertility/EFD and pre-/postnatal studies); no rabbit study
“Reproductive and developmental toxicity studies were conducted in one species only, namely CD-1 mice”
Species: carcinogenicity
Tg.rasH2 mouse (27-week, completed) and SD rat (2-year, ongoing)
“The carcinogenicity assessment for donidalorsen includes a completed 27-week study in Tg.rasH2 mice and a 2-year study in SD rats that is ongoing with the final report due in Q4 2025.”
Surrogate used in
Yes: mouse surrogate ISIS 722059 in mouse toxicity studies to assess on-target effects
“Donidalorsen does not align perfectly to the mouse PKK gene sequence, so the mouse toxicity studies also evaluated mouse surrogate ISIS 722059 to assess on-target effects.”
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.”
Genotox: Ames
Negative (bacterial reverse mutation)
“Donidalorsen was negative for genotoxicity (mutagenicity or clastogenicity) in the in vitro bacterial reverse mutation test (Ames assay), in vitro chromosome aberration assay in cultured Chinese Hamster Lung (CHL) cells, and bone marrow micronucleus assay in mice.”
Genotox: in vitro mammalian
Chromosome aberration in Chinese hamster lung cells: negative
“Donidalorsen was negative for genotoxicity (mutagenicity or clastogenicity) in the in vitro bacterial reverse mutation test (Ames assay), in vitro chromosome aberration assay in cultured Chinese Hamster Lung (CHL) cells, and bone marrow micronucleus assay in mice.”
Genotox: in vivo
Mouse bone marrow micronucleus: negative (up to 2000 mg/kg SC)
“In the in vivo mouse bone marrow micronucleus assay, two SC administrations of donidalorsen at doses up to 2000 mg/kg did not induce an increase in micronucleated polychromatic erythrocytes (MNPCE).”
Carcinogenicity model
27-week Tg.rasH2 mouse (completed); 2-year SD rat (ongoing)
“The carcinogenicity assessment for donidalorsen includes a completed 27-week study in Tg.rasH2 mice and a 2-year study in SD rats that is ongoing with the final report due in Q4 2025.”
Carcinogenicity timing
27-week Tg.rasH2 mouse completed; 2-year SD rat ongoing at approval, final report due Q4 2025
“The carcinogenicity assessment for donidalorsen includes a completed 27-week study in Tg.rasH2 mice and a 2-year study in SD rats that is ongoing with the final report due in Q4 2025.”
hERG / QT
No significant hERG inhibition; estimated IC50 >300 µM
“Donidalorsen did not statistically inhibit hERG current in HEK-293 cells stably transfected with hERG cDNA with an estimated IC50 greater than 300μM”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Dawnzera 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 NOAEL 6 mg/kg/week (platelet reductions at higher doses; ~29-fold margin); mouse NOAEL top dose; liver and kidney target organs (EMA assessment report, p. 31)
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”
Anti-drug antibodies: animals
ADAs in 12.5-62.5% of monkeys; no impact on PK, PD or safety
“Anti-drug antibodies (ADAs) ranged from 12.5- 62.5% and did not impact the PK, PD or safety profile of donidalorsen.”
Anti-drug antibodies: patients
Treatment-emergent ADAs in 20% (9/45) on 80 mg Q4W and 22% (5/23) on Q8W over 24 weeks
“In OASIS-HAE, with a treatment duration up to 24 weeks, the incidence rate of treatment‑emergent ADAs in adult and pediatric patients (≥12 years of age) with HAE was 20% (9 of 45 patients) in the DAWNZERA 80 mg every 4 weeks group and 22% (5 of 23 patients) in the DAWNZERA 80 mg every 8 weeks group.”
Label warnings
- Risk of Hypersensitivity Reactions, Including Anaphylaxis
Hypersensitivity & infusion reactions
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Canada: first-in-human study in healthy volunteers
“A phase 1 study, Protocol No. ISIS 721744-CS1, was previously conducted in Canada to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of ISIS 721744 in healthy volunteers.”
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 Dawnzera 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 NOAEL 6 mg/kg/week (platelet reductions at higher doses; ~29-fold margin); mouse NOAEL top dose; liver and kidney target organs (EMA assessment report, p. 31)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week SC cynomolgus monkey study (13-week interim) with 26-week treatment-free recovery
“The 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.”
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”
DART package
Species: DART
CD-1 mouse only (combined fertility/EFD and pre-/postnatal studies); no rabbit study
“Reproductive and developmental toxicity studies were conducted in one species only, namely CD-1 mice”
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”
PPND / ePPND: when
PPND in mouse completed and submitted with the marketing application
“This review evaluates the GLP-compliant reproductive and developmental toxicology studies with ISIS 721744 (i.e., combined fertility and developmental toxicity study in mice and PPND study in mice) to support the safety of ISIS 721744 for marketing approval.”
Carcinogenicity
Species: carcinogenicity
Tg.rasH2 mouse (27-week, completed) and SD rat (2-year, ongoing)
“The carcinogenicity assessment for donidalorsen includes a completed 27-week study in Tg.rasH2 mice and a 2-year study in SD rats that is ongoing with the final report due in Q4 2025.”
Carcinogenicity model
27-week Tg.rasH2 mouse (completed); 2-year SD rat (ongoing)
“The carcinogenicity assessment for donidalorsen includes a completed 27-week study in Tg.rasH2 mice and a 2-year study in SD rats that is ongoing with the final report due in Q4 2025.”
Carcinogenicity timing
27-week Tg.rasH2 mouse completed; 2-year SD rat ongoing at approval, final report due Q4 2025
“The carcinogenicity assessment for donidalorsen includes a completed 27-week study in Tg.rasH2 mice and a 2-year study in SD rats that is ongoing with the final report due in Q4 2025.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey NOAEL 6 mg/kg/wk: ~29x (monthly) and ~58x (Q8W) clinical exposure
“The NOAEL in this study was 6 mg/kg/wk and the exposure at this dose level provided an exposure-based safety margin to the proposed clinical regimen of ~29 fold (monthly) and ~58-fold (every-8- week).”
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”
Efficacy evidenceopen answer page →
Efficacy evidence
Mouse-specific surrogate ASO ISIS 482584 in five in vivo mouse vascular permeability studies
“Therefore, a mouse-specific surrogate ASO, ISIS 482584, was used in five in vivo studies to elucidate the role of PKK in vascular permeability.”
Why that model
Donidalorsen inactive in mouse: no complementarity to mouse PKK transcript
“Donidalorsen is not pharmacologically active in the mouse due to its lack of complementarity to the mouse PKK gene transcript.”
Reviewer's view of the efficacy data
EMA: surrogate studies confirm PKK role in kinin-kallikrein system and vascular permeability
“These results confirm the role of PKK in the kinin-kallikrein system and the important function of PKK in the regulation of vascular permeability.”
Flexibilityopen answer page →
Flexibility accepted
DARTAcceptedBeyond the letter
No rabbit embryo-fetal study with donidalorsen; DART in mice only, rabbit data leveraged from the unconjugated analogue ISIS 546254
Why: Neither donidalorsen nor unconjugated ISIS 546254 is pharmacologically active in rabbit; justification supported by literature · No relevant species
“The Applicant previously sought CHMP Scientific Advice on the necessity for studies in rabbits and it was agreed that studies may not be required on the basis that neither donidalorsen nor the unconjugated PS-only compound, ISIS 546254, were pharmacologically active in the rabbit.”
“This justification is well supported in the literature and is accepted by the CHMP.”
CarcinogenicityAccepted with a conditionBeyond the letter
Final 2-year rat carcinogenicity report deferred to a postmarketing requirement; only in-life summary at submission
Why: Agreed by the Division at the pre-NDA meeting
“At the pre-NDA meeting, the Division agreed that it would be acceptable to submit the report of the 6-month carcinogenicity study in Tg.rasH2 mice and a summary of the in-life data for the 2-year carcinogenicity study in rats at the time of the NDA submission and to submit the final report as a PMR (Refer to IND 142564 pre-NDA Meeting Preliminary Comments dated 04/10/2024).”
Safety marginCriticised but acceptedBeyond the letter
No plasma exposure data in the Tg.rasH2 carcinogenicity study; margin extrapolated from mouse PK data
Why: Weight of evidence · Weight of evidence
“While this may provide an explanation for the observations, there was an absence of plasma exposure data in this study to allow a direct derivation of safety to the clinical exposure.”
“Thus, based on the weight of evidence the carcinogenicity assessment to date is acceptable for the CHMP.”
Juvenile toxCriticised but acceptedBeyond the letter
No AUC data or exposure margins from the juvenile mouse study
Why: Additional data would not be useful; sufficient data for adolescents (≥12 years) · Other reason
“No AUC data was available for the juvenile mouse study. The lack of AUC data from the juvenile mouse study prevents a quantitative assessment of potential increased sensitivity in younger subjects.”
“It is agreed that additional study data would not provide further useful information for this procedure, and overall sufficient data are available for adolescents (≥12 years), thus this issue was not pursued from a nonclinical perspective.”
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