Source: European Medicines Agency (EU) Revision Year: 2026 Publisher: Otsuka Pharmaceutical Netherlands B.V., Herikerbergweg 292, 1101 CT Amsterdam, Netherlands
Pharmacotherapeutic group: Other haematological agents, drugs used in hereditary angioedema
ATC code: B06AC09
Donidalorsen is a 2'-O-methoxyethyl–modified antisense oligonucleotide (ASO) conjugated to a triantennary N-acetylgalactosamine (GalNAc3) moiety that causes ribonuclease H1 (RNase H1) mediated degradation of prekallikrein (PKK) mRNA through selective binding to PKK mRNA, which results in reduced production of PKK protein. PKK is a pro-enzyme for plasma kallikrein, which results in the release of bradykinin, a potent vasodilator causing inflammation and swelling in HAE.
In Trial 1, a 24-week multicenter, randomised, double blind, placebo-controlled trial in adult and paediatric patients (≥12 years) with HAE 1 or HAE 2 (see clinical efficacy and safety below), a decrease in plasma PKK concentrations was observed. The mean percentage change from baseline to 7 Week 24 in trough plasma PKK concentrations indicated reductions of 73% and 47% following treatment with donidalorsen 80 mg every 4 weeks and every 8 weeks, respectively, compared with 2% in the placebo group.
The efficacy of Dawnzera for the prevention of angioedema attacks in patients was studied in Trial 1.
Trial 1 included 90 (48 female and 42 male) adult and paediatric patients (≥ 12 years) with at least 2 investigator-confirmed attacks during the 8-week run in period, who received at least 1 dose of investigational medicinal product (IMP). Paediatric patients were 7 adolescents aged 12 years and older; furthermore, the trial included 2 elderly patients (≥65 years). 3 patients had a body weight of <50 kg at baseline, of which 2 were adolescents (see also section 5.2). Patients were randomised in a 2:1 ratio to 1 of 2 groups to receive study treatment either once every 4 weeks (q4wks group) or once every 8 weeks (q8wks group). Within each group, patients were randomised in a 3:1 ratio to receive Dawnzera 80 mg or a matching volume of placebo. The 2 placebo-treated groups were combined for analysis. Patients were required to discontinue other prophylactic HAE medicinal products prior to entering the trial; however, all patients were allowed to use rescue medicinal products for treatment of any breakthrough HAE attacks.
Overall, 93% of patients had HAE 1 and 7% had HAE 2. A history of laryngeal angioedema attacks was reported in 52% of patients, and 18% of patients were on prophylactic therapy prior to enrolment. The mean HAE attack rate during the prospective run-in period (baseline attack rate) was 3.33 (SD 2.086) attacks/4 weeks and an attack rate of >2 attacks/4 weeks was observed in 69% of patients overall.
Donidalorsen administered every 4 or 8 weeks produced statistically significant reductions in the HAE attack rate (number of investigator-confirmed HAE attacks per 4 weeks) compared to placebo. A sustained response to donidalorsen with mean decreases from baseline in the HAE attack rate was observed throughout the treatment period in the Dawnzera treatment groups.
Table 3. Results of primary and secondary efficacy endpoints (full analysis set):
| Endpoint statistics | Placebo (N=22) | Dawnzera 80 mg q4wks (N=45) | Dawnzera 80 mg q8wks (N=23) |
| HAE attack rate per 4 weeks from baseline to Week 24* | |||
| LS mean (95% CI) attack rate | 2.26 (1.66, 3.09) | 0.44 (0.27, 0.73) | 1.02 (0.65, 1.59) |
| % Reduction (95% CI) relative to placebo | -81 (-89, -65) | -55 (-74, -22) | |
| Wald chi-square p-value | <0.001‡ | 0.004‡ | |
| HAE attack rate per 4 weeks from Week 4 to Week 24 | |||
| LS mean (95% CI) attack rate starting from second dose (Week 4) | 2.25 (1.59, 3.18) | 0.30 (0.15, 0.58) | 0.90 (0.53, 1.52) |
| % Reduction (95% CI) relative to placebo starting from second dose (Week 4) | -87 (-94, -72) | -60 (-79, -25) | |
| Wald chi-square p-value | <0.001‡ | 0.004‡ | |
| Moderate or severe† HAE attack rate per 4 weeks from Week 4 to Week 24 | |||
| LS mean (95% CI) moderate or severe attack rate starting from second dose (Week 4) | 1.15 (0.72, 1.83) | 0.12 (0.04, 0.35) | 0.68 (0.37, 1.23) |
| % Reduction (95% CI) relative to placebo starting from second dose (Week 4) | -89 (-97, -66) | -41 (-72, 26) | |
| Wald chi-square p-value | <0.001‡ | NS | |
| HAE attacks per 4 weeks requiring acute therapy from Week 4 to Week 24 | |||
| LS mean (95% CI) HAE attacks requiring acute therapy starting from second dose (Week 4) | 1.80 (1.23, 2.62) | 0.15 (0.06, 0.39) | 0.59 (0.31, 1.15) |
| % Reduction (95% CI) relative to placebo starting from second dose (Week 4) | -92 (-97, -77) | -67 (-85, -29) | |
| Wald chi-square p-value | <0.001‡ | 0.004‡ | |
CI = confidence interval; HAE = hereditary angioedema; LS = least square; N = number of patients in the specific treatment group; NS = not statistically significant; q4wks = every 4 weeks; q8wks = every 8 weeks.
* Primary efficacy endpoint = comparison of the time normalised number of investigator-confirmed HAE attacks per 4 weeks from baseline to Week 24 between the Dawnzera 80 mg q4wks group and the placebo group.
† Moderate: mild to moderate limitation in activity, some assistance needed; severe: marked limitation in activity, assistance required.
‡ Statistically significant.
For 4 adolescent patients (aged 12 to 17 years) in the q4wks group, a 97.1% decrease (95% CI: -106.26%, -88.01%) from baseline (run-in period) in the time-normalized HAE attack rate (per 4 weeks) from Week 0 to Week 24 was observed.
Additional pre-defined trial secondary endpoints included the proportion of responders to IMP and percentage of patients who had well controlled angioedema activity. The proportion of patients with a ≥50%, ≥70%, ≥90%, and 100% (attack free) reduction from baseline in HAE attack rate from Week 4 to Week 24 in the Dawnzera treatment group was 93%, 82%, 62%, and 53%, respectively, in the 80 mg q4wks group, and 83%, 65%, 48%, and 35%, respectively, in the 80 mg q8wks group, compared to 27%, 18%, 9%, and 9%, respectively, in the placebo group.
The number of patients who had well controlled disease at Week 24 in the Dawnzera treatment group based on the Angioedema Control Test (AECT) score ≥10 at Week 24 was 41 (91%) in the 80 mg q4wks group and 17 (74%) in the 80 mg q8wks group, compared to 9 (41%) in the placebo group.
An improvement was observed for Dawnzera treatment groups compared to placebo in the Angioedema Quality of Life Questionnaire (AE-QoL) total score. A reduction of 6 points is considered a clinically meaningful improvement. For the total AE-QoL score at Week 24, the least square mean change from baseline in the Dawnzera treatment group was −24.8 and −19.9 for the 80 mg q4wks group (p<0.001) and 80 mg q8wks group, respectively, compared to −6.2 in the placebo group.
A total of 147 adult and paediatric patients (≥12 years) with HAE 1 or HAE 2 received at least 1 dose of Dawnzera in an open-label extension trial (Trial 2) of up to 3 years. Of these, 83 patients were previously treated with Dawnzera or placebo in Trial 1 and were included in the rollover group. Non-rollover patients (n=64) were to continue to take their prior HAE prophylactic treatment (berotralstat, C1 esterase inhibitors, or lanadelumab) during the run-in period as per the respective recommended treatment schedules based on the half-life of the individual medicinal products (see section 4.2).
After 52 weeks of Dawnzera treatment, patients showed a sustained 93% mean reduction in HAE attack rate compared to the baseline (0.22 vs. 3.42 attacks/4 weeks), with well-controlled disease by AECT increasing from 20.3% to 91.3% in the Q4W group and from 41.7% to 100.0% in the Q8W group, alongside improvements in AE-QoL scores at Week 24.
During the switch from lanadelumab, berotralstat, or C1-esterase inhibitor to Dawnzera, no increase in HAE attack rate was observed, with mean rates reduced by 66.1% (95% CI -79.69, -52.55) at Week 52, with overall disease control by AECT improving from 66.7% to 93.0% by Week 16, and AE-QoL scores showing meaningful reductions across all groups.
The phase 2 Trial 3 had an open-label arm for patients with HAE-nC1INH. It included 3 adult patients who received donidalorsen 80 mg every 4 weeks for up to 16 weeks. None of these patients had an established mutation in factor XII, plasminogen or angiopoietin-1 gene and only one had a positive family history.
For the 3 HAE-nC1-INH patients, there was an overall 76% reduction in HAE attack rate during the treatment period. The reduction in mean HAE attack rate was from 4.23 attacks/4 weeks during the run-in period to 1.52 attacks/4 weeks from baseline to Week 16. One patient was attack free from Week 1 to end of treatment. Quality of life improved concurrently.
A reduction in investigator-confirmed monthly angioedema attack rate was observed in all three enrolled patients with HAE with normal functional and antigenic C1-inhibitor levels following monthly administration of 80 mg donidalorsen.
Anti-drug antibodies (ADA) were commonly detected. ADA did not affect maximum plasma concentrations, but increased trough plasma concentrations. No evidence of ADA impact on pharmacodynamics, efficacy or safety was observed, however, the available data are limited to make definitive conclusions.
The European Medicines Agency has deferred the obligation to submit the results of trials with Dawnzera in one or more subsets of the paediatric population in the treatment of hereditary angioedema for the routine prevention of recurrent attacks of hereditary angioedema. See section 4.2.
The pharmacokinetic properties of donidalorsen were evaluated following subcutaneous administration of multiple doses every 4 weeks in healthy subjects and every 4 weeks or every 8 weeks in patients with HAE.
Donidalorsen exposure (area under the plasma concentration time curve [AUC]) increased in a dose dependent manner following subcutaneous doses ranging from 20 to 80 mg in healthy volunteers but was greater than dose proportional over the entire dose range.
Population estimates (geometric mean) of steady state maximum plasma concentration (Cmax,ss), trough plasma concentration (Ctrough,ss), and area under the plasma concentration time curve over the dosing interval (AUCτ,ss) are presented in Table 4. No accumulation of donidalorsen Cmax and AUC was observed in plasma after repeated dosing every 4 weeks.
Table 4. Summary of simulated pharmacokinetic parameters from population pharmacokinetic analysis following dosing of donidalorsen 80 mg q4wks or 80 mg q8wks in patients with HAE at steady state:
| Pharmacokinetic parameters (geometric mean) | Donidalorsen | |
| 80 mg q4wks | 80 mg q8wks | |
| Cmax,ss (ng/mL) | 417 | 416 |
| Ctrough,ss (ng/mL) | 0.755 | 0.255 |
| AUCτ,ss (ng·h/mL) | 5 240 | 5 210 |
AUCτ,ss = area under the plasma concentration time curve over the dosing interval at steady state; Cmax,ss = maximum plasma concentration at steady state; Ctrough,ss = trough plasma concentration at steady state; q4wks = every 4 weeks; q8wks = every 8 weeks.
Following subcutaneous administration, donidalorsen is absorbed with the time to maximum plasma concentration of approximately 2.5 hours post dose, based on population estimates.
Donidalorsen is expected to distribute primarily to the liver and kidney cortex after subcutaneous dosing. The population estimate of apparent volume of distribution for the central (Vc/F) and peripheral (Vp/F) compartment were 69.8 L and 1 840 L, respectively. Donidalorsen is highly bound to human plasma proteins (>98% bound) in vitro.
Donidalorsen is metabolised by endo- and exonucleases to short oligonucleotide fragments of varying sizes within the liver.
The population estimate of the terminal elimination half-life of donidalorsen in a typical patient with HAE is approximately 1 month.
The mean fraction of unchanged ASO eliminated in urine was less than 1% of the administered dose in healthy subjects within 24 hours. Linker related metabolites are minimally released to circulation and subsequently rapidly excreted to urine or faeces.
Population pharmacokinetics and pharmacodynamics analyses showed no clinically meaningful differences in the pharmacokinetics or pharmacodynamics of donidalorsen based on age (12 to 74 years), sex, mild renal impairment (eGFR ≥60 to <90 mL/min/1.73 m²), or mild hepatic impairment (total bilirubin ≤1 × ULN and AST >1 × ULN, or total bilirubin >1 to 1.5 × ULN and any AST). Regarding body weight, donidalorsen AUC predicted values for the 30‑40 kg body weight range were >17 500 ng·h/mL, >10 000 ng·h/mL for 40‑50 kg and around 10 000 ng·h/mL for 50‑60 kg. The corresponding values for patients with body weights >60 kg were <7 500 ng·h/mL.
Donidalorsen has not been studied in patients with moderate or severe renal impairment, end stage renal disease, or moderate or severe hepatic impairment.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction and development.
In a 6 month carcinogenicity study in transgenic (Tg.rasH2) mice, subcutaneous administration of donidalorsen (5, 10, 20, or 60 mg/kg) or a rodent specific surrogate (10 mg/kg) once every 2 weeks did not result in an increase in malignant tumors, indicating a lack of human carcinogenic risk.
Donidalorsen was negative for genotoxicity in in vitro (bacterial reverse mutation, chromosomal aberration in Chinese hamster lung cells) and in vivo (mouse bone marrow micronucleus) assays.
Subcutaneous administration of donidalorsen (0, 5, 10, or 20 mg/kg/week) or a rodent active inhibitor of PKK (5 mg/kg/week) to mice every other day throughout pregnancy and weekly throughout lactation produced no adverse effects on pre- and postnatal development.
In the mouse pre- and postnatal development study, the concentrations of donidalorsen in breast milk from lactating mice increased in a dose dependent manner at doses ≥10 mg/kg/week, but these concentrations of donidalorsen in breast milk were >3 000 fold lower than the observed tissue concentrations. Even though donidalorsen was detected in the maternal mouse milk, systemic exposure in pups was not expected due to the lack of oral absorption of donidalorsen.
In animal studies, administration of donidalorsen or a pharmacologically active rodent specific surrogate in a combined fertility and embryofetal development toxicity study in mice did not result in effects on male and female fertility or embryofetal development.
Subcutaneous administration of donidalorsen (0, 1, 4, or 10 mg/kg/week) or a rodent active inhibitor of prekallikrein (PKK) (4 mg/kg/week) to male and female mice weekly, prior to and during mating, and continuing every other day in females throughout the period of organogenesis, resulted in no adverse effects on fertility, pregnancy, or embryofetal development.
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