INTRODUCTION: Lanadelumab is approved for long-term prophylaxis of hereditary angioedema (HAE) attacks in patients aged ≥ 2 years in the USA and aged ≥ 12 years in Canada. The EMPOWER Study (NCT03845400) evaluated the real-world effectiveness and safety of lanadelumab in male and female patients with HAE due to C1 inhibitor deficiency type 1 or 2 from the USA and Canada. Here, we report final, up to 36-month, data.
METHODS: Patients aged ≥ 12 years were classified as newly treated with lanadelumab or established on lanadelumab (receiving < 4 and ≥ 4 lanadelumab doses at enrollment, respectively). The primary objective was effectiveness of lanadelumab as measured by HAE attack rate before and after lanadelumab initiation. Safety data were collected.
RESULTS: A total of 109 patients received ≥ 1 lanadelumab dose and had ≥ 1 post-baseline safety assessment. Patients were 40.9 (17.4) years of age (mean [standard deviation (SD)]), majority (72/109; 66.1%) female, 37/109 (33.9%) male, and over 90% white. Patients newly treated with and established on lanadelumab received lanadelumab for 737.7 (374.5) (mean [SD]) and 907.1 (469.3) days, respectively, during the study. In patients newly treated with lanadelumab, the mean (95% confidence interval) observed attack rate (attacks/month) decreased by 85% after lanadelumab initiation, from 1.42 (0.34-2.50) pre-lanadelumab to 0.20 (0.02-0.38) post-lanadelumab initiation (cumulative period). Patients established on lanadelumab had an observed attack rate of 0.20 (0.10-0.30) during 36 months' follow-up. Of 154 treatment-emergent adverse events (TEAEs), no injection site reactions were reported and 6 (in 2 patients) were considered related to lanadelumab; no lanadelumab-related TEAEs were serious.
CONCLUSION: Real-world data from EMPOWER showed marked HAE attack rate reduction up to 36 months after initiating lanadelumab in patients newly treated with lanadelumab and maintenance of low attack rates in patients established on lanadelumab. No new safety signals were identified.
TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT03845400. Graphical abstract available for this article.
In patients newly treated with lanadelumab, the mean observed attack rate decreased by 85% after lanadelumab initiation
uncontrolled before-after comparison with retrospective baseline ascertainment and prospective post-treatment diaries
Patients established on lanadelumab had an observed attack rate of 0.20 during 36 months' follow-up
direct descriptive estimate from the 91-patient established-treatment cohort
No new safety signals were identified.
descriptive safety surveillance without special monitoring for injection-site reactions
Derived from the full evaluation — not a separate score.
Strengths
The 109-patient full analysis set was drawn from 30 sites and followed for up to 36 months, extending the scale and duration of earlier real-world reports.
↳ Methods, Study Design and Population; Results, Patient Disposition; Discussion, paragraph 4
The paper reports pre-treatment, early-state, steady-state, and cumulative attack rates, alongside incidence-rate ratios and an age- and sex-adjusted sensitivity model.
↳ Methods, Statistical Analysis; Results, Figs. 3–4
The Discussion directly compares EMPOWER attack rates with HELP, HELP OLE, and smaller Canadian and French observational studies rather than merely listing prior work.
↳ Discussion, paragraphs 2–3
Limitations
Pre-enrollment attacks were reconstructed through physician eCRFs and recall or medical history, whereas study-period attacks were captured prospectively in patient diaries. This difference directly affects confidence in the reported 85% reduction.
↳ Methods, Study Assessments; Statistical Analysis; Fig. 1 footnote
The Discussion states that lanadelumab “effectively reduced” attacks despite the absence of a concurrent comparator and limited control of time-varying confounding or regression to the mean.
↳ Discussion, opening paragraph; Conclusion
The sponsor ended the study early based on consistency with phase 3 data, leaving incomplete follow-up for some participants and narrowing the basis for the long-term-persistence narrative.
↳ Results, Patient Disposition; Discussion, Limitations
The study contributes a larger and longer routine-practice cohort than the earlier observational reports discussed in the paper, but its main newly treated analysis includes only 18 patients. The self-controlled design and adjusted sensitivity model support a useful longitudinal description, while retrospective baseline ascertainment, prospective diary follow-up, censoring at treatment discontinuation, and the absence of a concurrent comparator constrain causal attribution. The Discussion engages substantively with HELP, HELP OLE, and smaller real-world studies, yet the concluding effectiveness language is stronger than the limitations warrant. Sponsor-initiated early termination further narrows confidence in claims about persistence through 36 months.
Nabu’s assessment, alongside the field’s view.
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Confidence mediumThe study extends trial and smaller observational evidence with a 109-patient, multicenter cohort and follow-up of up to 36 months. Its contribution remains confirmatory, particularly because the newly treated effectiveness subgroup contains only 18 patients.
EMPOWER provides long-term data on the effectiveness of lanadelumab prophylaxis, with a larger cohort and longer duration of lanadelumab exposure versus previous studies.
The self-controlled analysis, longitudinal follow-up, and age- and sex-adjusted sensitivity model provide a competent descriptive framework. Causal certainty is limited by retrospective-versus-prospective ascertainment, lack of a concurrent comparator, censoring at treatment discontinuation, and definitive effectiveness language.
LTP with lanadelumab effectively reduced attack rates
The progression from cohort definitions through attack-rate, dosing, and safety analyses is readily followable, with Figures 3–4 and Table 3 making the main results accessible. The abstract and Discussion do not consistently distinguish an observed before-after association from a treatment-attributable effect.
showed marked HAE attack rate reduction
The Discussion quantitatively compares EMPOWER with HELP, HELP OLE, and smaller Canadian and French observational studies. Material limitations are listed but not fully traced into the certainty of the effectiveness and long-term-persistence conclusions.
As with all observational studies, confounding is a threat to the validity of the findings
Caveats4 of 4 checks
The main effectiveness comparison has asymmetric outcome ascertainment across periods, and sponsor-initiated early termination truncated follow-up for some participants. These disclosed features affect confidence in the magnitude and long-term persistence of the findings without contradicting the reported numerical results.
The article declares ethics review, written informed consent, trial registration, and industry sponsorship. No supplied-text concern meets the threshold for a conduct notation.
Flags: 2 declared / 5 total
24 of 24 checkable references verified
28 references in manuscript 4 are books, websites or datasets — counted, but not index-checkable
References not verified automatically are resolved manually within 24 hours.
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.
Lanadelumab is already approved and deployed, and EMPOWER evaluates labeled dosing in routine practice across 30 North American sites. The evidence therefore sits at an advanced post-marketing translation stage.
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