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BACKGROUND: Symptoms of hereditary angioedema (HAE) often first occur during childhood, and HAE attacks in children can be severe and substantially affect health-related quality of life (HRQoL). However, there are no approved long-term prophylaxis treatments for children aged less than 6 years. OBJECTIVE: The SPRING Study (NCT04070326) evaluated the safety, pharmacokinetics, and efficacy of lanadelumab and HRQoL in patients aged 2 to less than 12 years. METHODS: Over 52 weeks of treatment, patients aged 2 to less than 6 years received lanadelumab 150 mg every 4 weeks (Q4W) and patients aged 6 to less than 12 years received 150 mg every 2 weeks (Q2W) but could switch to Q4W if they were attack-free for 26 weeks. RESULTS: We enrolled 21 patients (aged 2 to less than 6 years: n = 4; aged 6 to less than 12 years: n = 17), 20 of whom completed the study. There were no reported serious treatment-emergent adverse events or discontinuations resulting from such events. Treatment-emergent adverse events were reported for 17 patients (81.0%). The most common TEAE was injection site pain. Overall systemic exposure was comparable for both age groups. The mean (SD) attack rate during treatment decreased by 94.8% from baseline (1.84 [1.53] to 0.08 [0.17] attacks/mo), and 16 (76.2%) patients were attack-free. The attack rate reduction in both age groups was similar during the first 26-week fixed-dosing treatment. Seven patients switched from Q2W to Q4W and remained attack-free. A large, clinically meaningful increase in the Pediatric Quality of Life Inventory Generic Core Scale Total Score and a large increase in the Pediatric Quality of Life Inventory Generic Core Scale-Family Impact Module Total Score from baseline to end of study (better HRQoL) were observed. CONCLUSIONS: Findings support safety, efficacy, and improved HRQoL with lanadelumab 150 mg Q2W and Q4W regimens for the prevention of HAE attacks in patients aged 2 to less than 12 years.
The mean (SD) attack rate during treatment decreased by 94.8% from baseline (1.84 [1.53] to 0.08 [0.17] attacks/mo), and 16 (76.2%) patients were attack-free.
large, sustained within-patient reduction over 52 weeks, but without a concurrent control group
There were no reported serious treatment-emergent adverse events or discontinuations resulting from such events.
directly observed safety outcome in a 21-patient, 52-week safety set
A large, clinically meaningful increase in the Pediatric Quality of Life Inventory Generic Core Scale Total Score...was observed.
proxy-reported before–after improvement without a control condition and with very small age-specific denominators
Findings support safety, efficacy, and improved HRQoL with lanadelumab 150 mg Q2W and Q4W regimens for the prevention of HAE attacks in patients aged 2 to less than 12 years.
uncontrolled evidence with only four younger children and unequal age-specific exposure to the two regimens
Overall systemic exposure was comparable for both age groups.
model-based steady-state PK parameters reported for both age-defined dosing groups
Derived from the full evaluation — not a separate score.
Strengths
The Introduction identifies no approved long-term prophylaxis for children younger than 6, and SPRING includes patients aged 2 to less than 12 years. The Discussion links the resulting evidence to FDA approval from age 2.
↳ Introduction, p. 202; Discussion, p. 210
The study follows patients for 52 treatment weeks and reports attack timelines, safety events, PK parameters, PD, immunogenicity, and HRQoL. Twenty of 21 participants completed the study.
↳ Methods, pp. 203–204; Figures 1–3; Tables II–V
Age-specific dosing was evaluated in an operational multicenter trial, and the paper states that SPRING data supported FDA approval for prophylaxis in patients aged 2 years and older.
↳ Methods, p. 203; Discussion, p. 210
Limitations
The before–after reduction in attack rates was observed without randomization or placebo control. Regression to the mean, natural disease variation, and expectancy effects therefore cannot be separated from treatment effects.
↳ Methods, pp. 203–204; Discussion, p. 210
Only four participants were aged 2 to less than 6 years, despite this being the subgroup with the clearest unmet need. Conclusions about Q4W dosing in that age range consequently rest on a thin evidentiary base.
↳ Abstract; Table I, p. 205; Discussion, p. 210
The article states that lanadelumab demonstrated efficacy and was effective in preventing attacks, while its analysis is descriptive and explicitly non-placebo-controlled. This may encourage a causal reading beyond what SPRING alone identifies.
↳ Clinical implications box, p. 201; Statistical Analysis, p. 204; Discussion, p. 210
SPRING provides detailed prospective observations across safety, pharmacokinetics, attack outcomes, and proxy-reported quality of life, with 20 of 21 participants completing 52 weeks. Its contribution is strengthened by the documented treatment gap below age 6 and the reported FDA approval linked to the study. The principal quality constraint is the open-label, non-placebo-controlled before–after design, which limits causal interpretation despite the large observed attack-rate reduction. The very small under-6 cohort also narrows confidence in the age-specific dosing conclusions and broader transferability.
Nabu’s assessment, alongside the field’s view.
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Sound3.5
Confidence mediumThe study prospectively extends lanadelumab evidence to children aged 2 to less than 12 years and addresses the documented absence of approved prophylaxis below age 6. Its contribution is meaningful but incremental, and the most underserved subgroup contains only four participants.
“Based on the SPRING data...the US Food and Drug Administration approved lanadelumab”
The protocol specifies a baseline observation period, age-based dosing, investigator-confirmed attacks, PK/PD assessment, and 52 weeks of follow-up. The uncontrolled before–after design cannot separate treatment effects from regression to the mean, disease fluctuation, or expectancy effects, which are not traced beyond the general open-label limitation.
“this was an open-label study and not placebo-controlled”
The study sequence and numerical findings are readily traceable through the Methods, Tables II–V, and Discussion. Precision is reduced by management-facing language stating that lanadelumab demonstrated efficacy and was effective, which is stronger than the descriptive uncontrolled design supports.
“was effective in preventing HAE attacks”
The paper quantitatively situates pediatric outcomes against HELP and HELP-OLE and identifies the small sample, dose-switching limitations, and absence of placebo control. The limitations are engaged but their implications for expectancy-sensitive efficacy and HRQoL outcomes are not fully traced.
“The small sample size overall precluded statistical comparisons”
Caveats4 of 4 checks
The study population, completion count, attack outcomes, safety findings, and descriptive analysis are consistent across the abstract, Results, figures, and tables. No statistical impossibility or material methods–results mismatch was identified.
Ethics compliance, consent and assent, prospective registration, sponsor funding, conflicts of interest, and a conditional participant-data access process are disclosed. No text-grounded research-conduct concern was identified.
Flags: 4 declared / 5 total
8 of 8 checkable references verified
8 references in manuscript the reference list may be incompletely parsed; counts are indicative
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.
The age-specific regimens were tested in a multicenter 52-week study and subsequently informed FDA approval for patients aged 2 years and older. The evidence is operationally advanced, although comparative dosing conclusions remain limited.
“approved lanadelumab for prophylaxis to prevent attacks of HAE in patients aged 2 years and older”
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