BACKGROUND: Hereditary angioedema is characterized by recurrent and unpredictable swellings that are disabling and potentially fatal. Selective inhibition of plasma prekallikrein production by antisense oligonucleotide treatment (donidalorsen) may reduce the frequency of attacks and the burden of disease. METHODS: In this phase 2 trial, we randomly assigned, in a 2:1 ratio, patients with hereditary angioedema with C1 inhibitor deficiency to receive four subcutaneous doses of either donidalorsen (80 mg) or placebo, with one dose administered every 4 weeks. The primary end point was the time-normalized number of investigator-confirmed angioedema attacks per month (attack rate) between week 1 (baseline) and week 17. Secondary end points included quality of life, as measured with the Angioedema Quality of Life Questionnaire (scores range from 0 to 100, with higher scores indicating worse quality of life), and safety. RESULTS: A total of 20 patients were enrolled, of whom 14 were randomly assigned to receive donidalorsen and 6 to receive placebo. The mean monthly rate of investigator-confirmed angioedema attacks was 0.23 (95% confidence interval [CI], 0.08 to 0.39) among patients receiving donidalorsen and 2.21 (95% CI, 0.58 to 3.85) among patients receiving placebo (mean difference, -90%; 95% CI, -96 to -76; P<0.001). The mean change from baseline to week 17 in the Angioedema Quality of Life Questionnaire score was -26.8 points in the donidalorsen group and -6.2 points in the placebo group (mean difference, -20.7 points; 95% CI, -32.7 to -8.7). The incidence of mild-to-moderate adverse events was 71% among patients receiving donidalorsen and 83% among those receiving placebo. CONCLUSIONS: Among patients with hereditary angioedema, donidalorsen treatment resulted in a significantly lower rate of angioedema attacks than placebo in this small, phase 2 trial. (Funded by Ionis Pharmaceuticals; ISIS 721744-CS2 ClinicalTrials.gov number, NCT04030598.).
The mean monthly rate of investigator-confirmed angioedema attacks was 0.23 among patients receiving donidalorsen and 2.21 among patients receiving placebo (mean difference, -90%; P<0.001)
randomized blinded comparison with a large effect, limited by 20 participants and six placebo recipients
The mean change from baseline to week 17 in the Angioedema Quality of Life Questionnaire score was -26.8 points in the donidalorsen group, as compared with -6.2 points in the placebo group
blinded patient-reported outcome showing a clinically meaningful difference in a small secondary analysis
The incidence of mild-to-moderate adverse events was higher among the patients receiving placebo than among those receiving donidalorsen (83% vs. 71%).
systematically collected observed events, with safety inference constrained by sample size and short exposure
No serious adverse events occurred in patients in either trial group.
accurate description of observed events during a four-dose trial too small for broad safety conclusions
During the period from week 5 to week 17, 12 of 13 patients (92%) receiving donidalorsen were attack-free, as compared with none of the 6 patients receiving placebo
exploratory endpoint based on 19 evaluable participants without primary-endpoint multiplicity protection
Derived from the full evaluation — not a separate score.
Strengths
The randomized comparison extends earlier phase 1 and compassionate-use work into the target patient population and reports a large reduction in investigator-confirmed attacks.
↳ Introduction, p. 1027; Abstract; Table 2
Treatment was assigned through an interactive response-technology system, patients and trial personnel were masked, and all randomized participants entered the primary efficacy analysis.
↳ Methods, Randomization and Procedures and Statistical Analysis, pp. 1028–29
The discussion reports quantitative results for lanadelumab, intravenous and subcutaneous C1 inhibitor, and berotralstat, while identifying monthly administration as the proposed practical distinction.
↳ Discussion, pp. 1032–33
Limitations
Only 20 participants were randomized, including six to placebo, limiting precision, baseline-balance assessment, and especially safety and secondary-endpoint inference.
↳ Abstract; Results, p. 1029; Table 1
The controlled trial included four doses through week 17, so long-term efficacy and safety remain dependent on the separately described extension study.
↳ Methods, p. 1028; Discussion, p. 1032
Nineteen of 20 participants were White, and the treated-group mean attack rate of 0.23 falls below its stated range minimum of 0.25.
↳ Results, pp. 1029–30; Discussion, p. 1033
The randomized, double-blind design and intention-to-treat Poisson analysis support the reported short-term difference in confirmed attack rates. The paper also uses calibrated wording, explicitly describing the study as a small phase 2 trial and warning that unadjusted confidence intervals should not support definitive secondary inferences. The quality score remains below the top band because only 20 participants received four controlled doses, limiting precision, safety assessment, and generalizability. Contextual engagement is substantive, although quantitative cross-trial comparisons are not developed into a robust comparative-effectiveness argument. The incompatible treated-group mean and range on p. 1030 warrants correction but does not negate the consistent abstract and Table 2 result.
Nabu’s assessment, alongside the field’s view.
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Strong3.9
Confidence mediumThe trial adds the first placebo-controlled efficacy evidence for donidalorsen after phase 1 and compassionate-use work, meaningfully advancing a novel prophylactic mechanism. Its contribution remains bounded by phase 2 status and the absence of definitive comparative evidence against established therapies.
“This phase 2, placebo-controlled trial involving 20 patients”
IRT randomization, masking, intention-to-treat analysis, a prespecified count model, and systematic harms monitoring support the within-trial comparison. Precision and robustness are limited by 20 participants, six placebo recipients, four controlled doses, and an isolated numerical reporting inconsistency.
“All the efficacy analyses were performed in the intention-to-treat population”
The manuscript follows a visible mechanism-to-design-to-results chain and repeatedly limits its conclusion to a small phase 2 trial. The incompatible treated-group mean and range modestly reduce numerical clarity.
“in this small, phase 2 trial”
The discussion quantitatively situates donidalorsen alongside lanadelumab, C1 inhibitor concentrate, and berotralstat and acknowledges demographic nonrepresentativeness. It does not fully integrate the short controlled exposure and small sample into conclusions about safety, durability, and clinical positioning.
“is thus a limitation of the trial”
Caveats4 of 4 checks
The primary result is consistent across the abstract and Table 2, but its accompanying treated-group range is incompatible with the reported mean. This appears to be a localized reporting error rather than evidence that the primary comparison is invalid.
The sponsor designed and funded the trial, supplied the intervention, analyzed the data, and contributed to the initial manuscript, creating a disclosed concentration of sponsor control. Ethics, consent, independent safety oversight, registration, and disclosure statements are reported.
Flags: 4 declared / 5 total
18 of 18 checkable references verified
18 references in manuscript 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.
A randomized controlled human trial with clinical endpoints advances the intervention beyond mechanistic or uncontrolled proof of concept. The phase 2 sample and four-dose controlled period leave confirmatory, comparative, and implementation work outstanding.
“receive four subcutaneous doses of either donidalorsen (80 mg) or placebo”
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Oral sebetralstat provided faster times to the beginning of symptom relief, reduction in attack severity, and complete attack resolution than placebo.
Well-supportedRiedl, Tachdjian, Lumry, et al. · 2024 · Clinical medicine
Donidalorsen at a dose of 80 mg administered subcutaneously every 4 or 8 weeks significantly reduced the hereditary angioedema attack rate
SupportedCohn, Gurugama, Magerl, et al. · 2024 · Clinical medicine
NTLA-2002 administered in a single dose of 25 mg or 50 mg reduced angioedema attacks and led to robust and sustained reduction in total plasma kallikrein levels in patients with hereditary angioedema.
Tentative