BACKGROUND: Hereditary angioedema is a rare disorder characterized by episodic, potentially life-threatening swelling caused by kallikrein-kinin dysregulation. Long-term prophylaxis can stabilize this system. Donidalorsen, an antisense oligonucleotide, specifically reduces prekallikrein expression. METHODS: In this phase 3, double-blind, randomized trial, we assigned patients with hereditary angioedema to receive donidalorsen (80 mg subcutaneously) or placebo once every 4 or 8 weeks. The primary end point was the time-normalized number of investigator-confirmed hereditary angioedema attacks per 4 weeks (attack rate) from week 1 to week 25. RESULTS: A total of 90 patients received donidalorsen every 4 weeks (45 patients), donidalorsen every 8 weeks (23 patients), or placebo (22 patients). The least-squares mean time-normalized attack rate was 0.44 (95% CI, 0.27 to 0.73) in the 4-week group, 1.02 (95% CI, 0.65 to 1.59) in the 8-week group, and 2.26 (95% CI, 1.66 to 3.09) in the placebo group. The mean attack rate from week 1 to week 25 was 81% lower (95% CI, 65 to 89) in the 4-week group than in the placebo group (P<0.001) and 55% lower (95% CI, 22 to 74) in the 8-week group than in the placebo group (P = 0.004); the median reduction in the attack rate from baseline was 90% in the 4-week group, 83% in the 8-week group, and 16% in the placebo group. The mean attack rate during weeks 5 to 25 was 87% lower (95% CI, 72 to 94) in the 4-week group than in the placebo group (P<0.001) and 60% lower (95% CI, 25 to 79) in the 8-week group than in the placebo group. Donidalorsen administered every 4 weeks resulted in an improvement in the least-squares mean total score for the change at week 25 on the Angioedema Quality-of-Life Questionnaire (scores range from 0 to 100, with a score of 100 indicating the worst possible quality of life) that was 18.6 points (95% CI, 9.5 to 27.7) better than that with placebo (P<0.001). The most common adverse events were erythema at the injection site, headache, and nasopharyngitis; 98% of adverse events were mild or moderate in severity. CONCLUSIONS: Donidalorsen treatment reduced the hereditary angioedema attack rate, a finding that supports potential prophylactic use for hereditary angioedema. (Funded by Ionis Pharmaceuticals; OASIS-HAE ClinicalTrials.gov number, NCT05139810.).
Donidalorsen at a dose of 80 mg administered subcutaneously every 4 or 8 weeks significantly reduced the hereditary angioedema attack rate
randomized placebo comparisons support both schedules, with less precise evidence from the smaller every-8-week group
a significant improvement of 24.8 points in the least-squares mean AE-QoL total score from baseline to week 25 was observed in the [donidalorsen] 4-week group
the placebo-adjusted improvement supports benefit, although a patient-reported outcome in a small trial remains susceptible to partial unblinding
The most common adverse events were erythema at the injection site, headache, and nasopharyngitis; 98% of adverse events were mild or moderate in severity.
systematic reporting supports observed event severity, but 90 participants followed for 25 weeks cannot establish uncommon or long-term harms
Derived from the full evaluation — not a separate score.
Strengths
The phase 3 study extends prior phase 2 evidence with placebo-controlled attack-rate comparisons for two dosing intervals and patient-reported quality-of-life outcomes.
↳ Introduction, final paragraph; Results, Efficacy; Table 2
The primary analysis adjusts for baseline attack rate, observed follow-up, and overdispersion. The hierarchical procedure withholds subsequent P values after the first nonsignificant test.
↳ Methods, Statistical Analysis; Table 2 footnotes
The Abstract reports the separate placebo comparisons and confines its conclusion to potential prophylactic use rather than superiority over active treatments or established long-term safety.
↳ Abstract, Results and Conclusions; Discussion, final paragraph
Limitations
Lack-of-efficacy withdrawals occurred in three placebo participants and one participant in each active arm. Time-normalised follow-up preserves observed data but does not itself establish that subsequent missing outcomes satisfy the MAR assumption.
↳ Results, Patients; Methods, Statistical Analysis
The trial uses placebo rather than an active prophylactic comparator, and the Discussion does not closely compare competing agents' efficacy or treatment burden. The proposed induction-to-maintenance switch also lacks direct testing.
↳ Methods, Trial Design and Oversight; Discussion
Only 90 patients were treated, including seven adolescents, with limited racial diversity and 25 weeks of controlled treatment. These boundaries constrain population transferability and detection of uncommon or longer-term harms.
↳ Table 1; Results, Adolescent Patients and Safety; Discussion, limitations
The randomized, double-blind design and Table 2 support substantial reductions in attacks versus placebo, particularly with every-4-week dosing. Baseline-adjusted count modelling and hierarchical testing strengthen the analysis, but efficacy-related withdrawals leave uncertainty under the stated missing-at-random assumption. The Abstract's conclusion is bounded appropriately, whereas the Discussion's switching proposal extends beyond the regimens directly tested. Limited comparison with established prophylactic agents and the small, demographically narrow population constrain treatment positioning rather than negate the observed efficacy.
Nabu’s assessment, alongside the field’s view.
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Strong4.0
Confidence highThe trial supplies phase 3 randomized confirmation of the phase 2 signal and adds an every-8-week regimen and patient-reported outcomes. Its advance remains confirmatory and does not establish relative benefit against existing prophylaxis.
Double blinding, investigator-confirmed attacks, baseline-adjusted count modelling, multiplicity control, and systematic harms reporting support the causal placebo comparisons. Differential efficacy-related withdrawal under an MAR assumption and unavailable sensitivity analyses retain uncertainty about missing-data handling.
The primary efficacy results and cautious conclusion are readily traceable to the reported comparisons. Discussion interpretations about dosing convergence and switching regimens extend beyond the tested treatment strategies.
The paper connects disease burden, guidelines, mechanism, and preceding donidalorsen trials. It provides limited comparison with individual established prophylactic therapies and does not establish the claimed direction of bias from baseline imbalance.
Lower confidence on Methodological Rigour, Positioning — domain match limited.
Caveats4 of 4 checks
One reported value does not reconcile, but the key claims do not rest on it.
Ethics approval, consent, trial registration, sponsor involvement, independent statistical analysis, and medical-writing support are disclosed. Unavailable supporting documents are assessability gaps, not demonstrated reporting misconduct.
Conflict of interest: declared · Ethics approval: declared · Preregistration: declared · Data availability: declared
22 of 22 checkable references verified
23 references in manuscript 1 have no canonical index record — counted, but not index-checkable 1 reference confirmed by manual review
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No retraction or expression of concern found in Crossref (includes Retraction Watch).
Sources: Crossref (incl. Retraction Watch) ✓
Where this paper’s evidence sits on the path from initial observation to real-world use.
Phase 3 randomized evidence on attacks, quality of life, and adverse events is relevant to treatment and regulatory decisions. Controlled follow-up of 25 weeks does not establish long-term durability or uncommon harms.
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