# Inhibition of Prekallikrein for Hereditary Angioedema

- **DOI:** [10.1056/nejmoa2109329](https://doi.org/10.1056/nejmoa2109329)
- **Rating:** Strong (3.9 out of 5)
- **Verdict:** Donidalorsen produces a strong placebo-controlled efficacy signal for hereditary angioedema, but the 20-patient phase 2 design limits clinical certainty.
- **Framework version:** v5.9
- **Pipeline version:** v0.4
- **Evaluation date:** 2026-09-18
- **Evaluation page:** https://www.nabu.science/paper/10.1056%2Fnejmoa2109329

## Key claims

1. 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)
   - Support: Supported
   - Type: Primary finding
   - Basis: randomized blinded comparison with a large effect, limited by 20 participants and six placebo recipients
   - Location: Abstract; Table 2
2. 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
   - Support: Supported
   - Type: Secondary
   - Basis: blinded patient-reported outcome showing a clinically meaningful difference in a small secondary analysis
   - Location: Abstract; Results, p. 1031
3. The incidence of mild-to-moderate adverse events was higher among the patients receiving placebo than among those receiving donidalorsen (83% vs. 71%).
   - Support: Supported
   - Type: Secondary
   - Basis: systematically collected observed events, with safety inference constrained by sample size and short exposure
   - Location: Safety End Points, p. 1031
4. No serious adverse events occurred in patients in either trial group.
   - Support: Supported
   - Type: Secondary
   - Basis: accurate description of observed events during a four-dose trial too small for broad safety conclusions
   - Location: Discussion, p. 1032
5. 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
   - Support: Tentative
   - Type: Secondary
   - Basis: exploratory endpoint based on 19 evaluable participants without primary-endpoint multiplicity protection
   - Location: Exploratory End Points, p. 1032

## Strengths

- **Controlled evidence for a novel mechanism** 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.
  - Dimension: contribution
  - Location: Introduction, p. 1027; Abstract; Table 2
- **Masked randomized design with ITT analysis** Treatment was assigned through an interactive response-technology system, patients and trial personnel were masked, and all randomized participants entered the primary efficacy analysis.
  - Dimension: methodological rigour
  - Location: Methods, Randomization and Procedures and Statistical Analysis, pp. 1028–29
- **Substantive comparison with existing prophylaxis** The discussion reports quantitative results for lanadelumab, intravenous and subcutaneous C1 inhibitor, and berotralstat, while identifying monthly administration as the proposed practical distinction.
  - Dimension: positioning
  - Location: Discussion, pp. 1032–33

## Limitations

- **Very small and unequal trial groups** Only 20 participants were randomized, including six to placebo, limiting precision, baseline-balance assessment, and especially safety and secondary-endpoint inference.
  - Dimension: methodological rigour
  - Location: Abstract; Results, p. 1029; Table 1
- **Short exposure limits durability evidence** The controlled trial included four doses through week 17, so long-term efficacy and safety remain dependent on the separately described extension study.
  - Dimension: application pathway
  - Location: Methods, p. 1028; Discussion, p. 1032
- **Demographically narrow and numerically inconsistent reporting** 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.
  - Dimension: reporting
  - Location: Results, pp. 1029–30; Discussion, p. 1033

## Reliability checks

Caveats (4 of 4 checks).

- **Internal coherence:** Noted. 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.
- **Research conduct:** Noted. 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.
- **Reference integrity:** Clean. 18 of 18 checkable references verified
  - 18 references in manuscript
  - 1 reference confirmed by manual review
  - References not verified automatically are resolved manually within 24 hours.

## Post-publication record

- **Status:** Clean
- **Summary:** No retraction or expression of concern found in Crossref (includes Retraction Watch).
- **Last checked:** 2026-10-17