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BACKGROUND: Hereditary angioedema (HAE) is a rare disease characterized by unpredictable, frequently severe swelling that negatively impacts patients' quality of life (QoL). In the phase III OASIS-HAE study (NCT05139810), donidalorsen reduced HAE attack rate, increased disease control, and improved QoL. Here, we report further analysis of donidalorsen's impact on QoL and other patient-reported outcomes (PROs).
METHODS: This double-blind, placebo-controlled study randomized patients with HAE to donidalorsen 80 mg or placebo once every 4 (Q4W) or 8 weeks (Q8W) over 24 weeks. PROs included Angioedema (AE)-QoL Questionnaire, Angioedema Control Test (AECT), Patient Global Impression of Severity (PGIS), and Work Productivity and Activity Impairment Questionnaire plus Classroom Impairment Questions (WPAI+CIQ).
RESULTS: Ninety patients received donidalorsen Q4W (n = 45), donidalorsen Q8W (n = 23), or placebo (n = 22). A larger percentage of the donidalorsen Q4W group (88%) achieved clinically meaningful improvement (≥ 6-point reduction) in AE-QoL total score vs. placebo (45%). Both donidalorsen groups reported larger least-squares mean (LSM) changes from baseline to week 24 vs. placebo in AE-QoL functioning (difference: Q4W, -24.5; Q8W, -16.1), fears/shame (Q4W, -23.9; Q8W, -20.1), and nutrition (Q4W, -15.7; Q8W, -10.7) domains. Donidalorsen improved AECT scores vs. placebo (difference: Q4W, 6.0; Q8W, 4.1). A greater proportion of the donidalorsen Q4W group reported decreased disease severity vs. the placebo group (PGIS; 82% vs. 44%). Donidalorsen Q4W showed benefits vs. placebo in the presenteeism, overall work/school impairment, and activity impairment domains of the WPAI+CIQ.
CONCLUSIONS: Donidalorsen significantly improved QoL and other PROs vs. placebo in patients with HAE.
Donidalorsen significantly improved QoL and other PROs vs. placebo in patients with HAE.
omnibus wording exceeds the exploratory, dosing-specific pattern of significant and nonsignificant results
A larger percentage of the donidalorsen Q4W group (88%) achieved clinically meaningful improvement (≥ 6-point reduction) in AE-QoL total score vs. placebo (45%).
large randomized Q4W responder difference from an exploratory, multiplicity-unadjusted analysis
Donidalorsen improved AECT scores vs. placebo (difference: Q4W, 6.0; Q8W, 4.1).
both randomized comparisons exceeded the MCID, though the analyses were post hoc and nominal
A greater proportion of the donidalorsen Q4W group reported decreased disease severity vs. the placebo group (PGIS; 82% vs. 44%).
randomized Q4W comparison supports the direction, with exploratory testing and a wide confidence interval
Donidalorsen Q4W showed benefits vs. placebo in the presenteeism, overall work/school impairment, and activity impairment domains of the WPAI+CIQ.
three specified Q4W domains favored treatment in post hoc or exploratory analyses
Derived from the full evaluation — not a separate score.
Strengths
The analysis spans AE-QoL, AECT, PGIS, and WPAI+CIQ, adding domain-level information about functioning, disease control, perceived severity, and work or school impairment.
↳ Methods, PRO Endpoints; Results, Quality of Life through Work and School Impairment
The methods distinguish secondary, prespecified exploratory, and post hoc outcomes and explicitly state that new p-values are nominal and not multiplicity-adjusted.
↳ Methods, PRO Endpoints and Statistical Analysis
The discussion connects the smaller Q8W allocation to fewer significant comparisons and identifies the implications of limited power, multiplicity, instrument specificity, and short follow-up.
↳ Discussion, limitations paragraph
Limitations
Only 90 treated patients were analysed, including 23 in the Q8W arm, and the study was not powered specifically for these PRO analyses. This limits precision, especially for Q8W comparisons.
↳ Results, Patient Population; Discussion, limitations paragraph
Numerous instrument, responder, and domain comparisons use nominal p-values without multiplicity correction, increasing uncertainty around individual significance findings.
↳ Methods, Statistical Analysis; Discussion, limitations paragraph
The conclusion states that donidalorsen significantly improved QoL and other PROs without retaining the dosing-specific heterogeneity and nonsignificant Q8W findings reported in the body.
↳ Abstract, Conclusions; Results, Quality of Life, Patient Impressions of Disease Severity, and Work and School Impairment
The paper meaningfully expands the parent trial's patient-reported evidence through domain-level QoL, disease-control, severity, and functioning analyses. Its randomized double-blind foundation and transparent labeling of exploratory and post hoc tests support the core Q4W findings, but small groups and nominal multiplicity-unadjusted analyses limit certainty. The Q8W arm is especially imprecise, and several Q8W responder, PGIS, and work or school outcomes were not statistically significant. The abstract conclusion therefore warranted a clarity deduction because it does not preserve this dosing-specific heterogeneity.
Nabu’s assessment, alongside the field’s view.
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Sound3.5
Confidence mediumThe analysis adds domain-level AE-QoL results and further AECT, PGIS, and WPAI+CIQ evidence beyond the parent trial. Its advance remains incremental because central total-score and disease-control findings had already been reported.
“Here, we report further analysis of the impact of donidalorsen on QoL, disease control, and other patient-reported outcomes.”
The double-blind randomized design, full analysis set, endpoint definitions, and statistical models are described, with exploratory status made explicit. Small uneven groups, nominal multiplicity-unadjusted testing, LOCF for some AECT analyses, and limited sensitivity analysis create meaningful uncertainty.
“All new analyses reported here are exploratory or post hoc, and resulting p-values are nominal and not corrected for multiplicity.”
The body separates Q4W and Q8W findings and reports significant and nonsignificant outcomes. The abstract conclusion nevertheless generalizes significant improvement across a PRO package in which several Q8W and domain-level comparisons were nonsignificant.
“Donidalorsen significantly improved QoL and other PROs vs. placebo in patients with HAE.”
The discussion relates the findings to recent HAE prophylaxis trials and explains how sample allocation, multiplicity, instrument specificity, and duration affect interpretation. Comparative engagement is substantive but brief and does not deeply examine cross-trial comparability.
“This disparity may have contributed to the fewer statistically significant differences in PROs between the donidalorsen Q8W and placebo groups.”
Caveats4 of 4 checks
Patient counts, effect estimates, and significance statements are consistent across the abstract, methods, and results, while null findings are also reported. The manuscript clearly distinguishes exploratory and post hoc analyses from previously reported endpoints.
Ethics approval, consent, prospective registration, and conflicts are declared. Sponsor employment and participation across design, analysis, interpretation, and manuscript preparation create a disclosed interpretive-independence concern rather than evidence of misconduct.
Flags: 3 declared / 5 total
28 of 29 checkable references verified
30 references in manuscript 1 are books, websites or datasets — counted, but not index-checkable
No retraction notice found in Retraction Watch.
Sources: Retraction Watch ✓
Where this paper’s evidence sits on the path from initial observation to real-world use.
Patient-reported evidence from a phase III placebo-controlled trial is close to clinical use as supportive information about treatment experience. Readiness remains limited by the 24-week duration and exploratory or post hoc status of the new analyses.
“The OLE will also provide the data required to determine the long-term durability.”
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